WHO consolidated guidelines on tuberculosis · 2020. 6. 24. · WHO consolidated guidelines on...
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WHO consolidated guidelines ontuberculosis
Module 4: Treatment
Online annexes
Drug-resistant tuberculosis treatment
WHO consolidated guidelines on tuberculosis. Module 4: treatment - drug-resistant tuberculosis treatment. Online annexes
ISBN 978-92-4-000706-2 (electronic version)
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This publication forms part of the WHO guideline entitled WHO consolidated guidelines on tuberculosis. Module 4: treatment - drug-resistant tuberculosis treatment. It is being made publicly available for transparency purposes and information, in accordance with the WHO handbook for guideline development, 2nd edition (2014).
Design by Inis Communication.
WHO consolidated guidelines ontuberculosis
Drug-resistant tuberculosis treatment
Module 4: Treatment
Online annexes
Contents
Abbreviations and acronyms 3
Annex 1: Methods and expert panels 5
Annex 2: Declarations of interest 31
Annex 3: GRADE evidence summary tables 44
Annex 4: GRADE evidence-to-decision tables 64
Annex 5: Summaries of unpublished data 121
Annex 6: Statistical analysis plans 129
Abbreviations and acronyms 3
Abbreviations and acronyms
ACSM advocacy, communication and social mobilizationACTG AIDS Clinical Trials Group
ATS American Thoracic Society
CDC United States Centers for Disease Control and Prevention
DALY disability-adjusted life year
DoI declaration of interest
DR-TB drug-resistant tuberculosis
DSMB Data and Safety Monitoring Board
DST drug-susceptibility testing
EFPIA European Federation of Pharmaceutical Industries and Associations
ERG Evidence Review Group
EtD evidence-to-decision (framework)
EU European Union
FDC fixed-dose combination
FIND Foundation for Innovative New Diagnostics
FTE full-time equivalent
GDG Guideline Development Group
GRADE Grading of Recommendations Assessment, Development and Evaluation
GRC WHO Guideline Review Committee
GSK Glaxo SmithKline
HALT Hepatitis and Latent TB infection
HIV human immunodeficiency virus
Hr-TB isoniazid (H)-resistant tuberculosis
IDSA United States Infectious Diseases Society of America
IPD individual patient data
KNCV KNCV Tuberculosis Foundation
LAM lipoarabinomannan assay
LSHTM London School of Hygiene & Tropical Medicine
LTBI latent tuberculosis infectionMDR-TB multidrug-resistant tuberculosis
WHO consolidated guidelines on tuberculosis: Online annexes4
MDR/RR-TB multidrug- or rifampicin-resistant tuberculosisMSF Médecins Sans FrontièresNIAID United States National Institutes of Allergy and Infectious DiseaseNIH United States National Institutes of HealthOpti-Q Efficacy and safety of levofloxacin for the treatment of MDR-TB (study)PICO population, intervention, comparator and outcomesPMDT programmatic management of drug-resistant TBPK/PD pharmacokinetics/pharmacodynamicsTB-PRACTECAL Pragmatic clinical trial for more effective, concise and less toxic MDR-TB treatment
regimen(s)RCT randomized controlled trialRECRU Respiratory Epidemiology and Clinical Trials Unit (McGill University)RR-TB rifampicin-resistant TBSAE serious adverse eventSIAPS Systems for Improved Access to Pharmaceuticals and ServicesSTREAM Evaluation of a standardised treatment regimen of anti-tuberculosis drugs for
patients with MDR-TB (trial)TAG Treatment Action GroupTB tuberculosisTBTC Tuberculosis Trials ConsortiumUNION International Union Against Tuberculosis and Lung DiseaseUNITAID Global investment initiative for TB, HIV, malaria and Hepatitis CUSAID United States Agency for International DevelopmentWHO World Health OrganizationWHO/GTB World Health Organization Global TB ProgrammeXDR-TB extensively drug-resistant tuberculosis
Annex 1: Methods and expert panels 5
Annex 1: Methods and expert panels
A1 MethodsSince 2007, the guideline development process within the World Health Organization (WHO) has been overseen by the WHO Guidelines Review Committee (GRC), which follows internationally recognized standards such as the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach, to support to a structured and transparent methodology for policy-making. The policy recommendations presented here were developed following the standards and updated procedures described in the WHO handbook for guideline development.1
Initially, a WHO Guideline Steering Group was established to determine specific areas requiring up-to-date evidence, and to bring together experts to synthesize and independently review new evidence and develop recommendations (see Annex 2 and Annex 4). Also, an external review group was assembled to review the updated recommendations based on the input of the Guideline Development Group (GDG; see Annex 4). The GDG comprised researchers, epidemiologists, end-users (clinicians and national tuberculosis [TB] control programme officers), community representatives and experts in evidence synthesis. In compliance with the procedures and practices established by the GRC, declarations of interest (DOI) were managed according to the WHO Conflict of Interest Policy, including review of curricula vitae and critical evaluation of DOI. Additionally, contingent to the assessment of competing interests, the full list of members of the GDG and their biographies were published on the WHO website on 30 September 2019. This was followed by a public notice and comment period, during which WHO allowed members of the public to provide comments pertinent to any interests that might have gone unnoticed or unreported during earlier assessments.
During the face-to-face GDG meeting held in Geneva, Switzerland on 12–14 November 2019, the members of the GDG reached decisions through a process of discussion and consensus. Where consensus could not be reached through discussion, the GDG voted on decisions – these decisions were noted in GRADEpro and were made based on the vote of the majority.
A1.1 Preparation for evidence assessment The GRADE approach was used to rate the certainty in the estimate of effect (quality of evidence) as high, moderate, low or very low, and to determine the strength of the recommendations (as strong or conditional). A scoping proposal was submitted and approved by the WHO GRC in September 2019. Details about the preparatory work ahead of the update were released to the public through a public comment that focused on the following: the rationale for providing up-to-date guidance, including the scope of the updates; prioritization and formulation of key questions; and the list, affiliations and constituencies of potential members of the GDG undergoing conflict of interest assessments, as per the policies of the WHO Office of Compliance, Risk Management and Ethics policies.
1 WHO handbook for guideline development – 2nd edition Geneva, Switzerland World Health Organization; 2014 (https://apps.who.int/iris/handle/10665/145714, accessed 20 March 2020).
WHO consolidated guidelines on tuberculosis: Online annexes6
In preparation for the GDG meeting, four webinars were held with the group to finalize the scoping and PICO (patients, intervention, comparator and outcomes) questions, score outcomes of interest and discuss preliminary data analysis results. The PICO questions – inclusive of subpopulations, treatment regimen composition and duration, and outcomes – were agreed on by members of the GDG. The questions were framed to capture the effect of novel treatment regimens for specific populations and the value (in terms of effectiveness and safety) of adding, prolonging and combining specific anti-TB agents (see Box A1).
Î In MDR/RR-TB patients, does an all-oral treatment regimen lasting <12 months safely improve outcomes when compared with other regimens conforming to current WHO guidelines?
Î In XDR-TB patients or patients who are treatment intolerant or with non-responsive MDR-TB, does a treatment regimen lasting 6–9 months composed of bedaquiline, pretomanid and linezolid safely improve outcomes when compared with other regimens conforming to current WHO guidelines?
Î In MDR/RR-TB patients, does treatment with bedaquiline for more than six months safely improve outcomes when compared with treatment up to six months as part of regimens otherwise conforming to current WHO guidelines?
Î In MDR/RR-TB patients, does concurrent use of bedaquiline and delamanid safely improve outcomes when compared with other treatment regimen options otherwise conforming to current WHO guidelines?
MDR/RR-TB: multidrug-resistant or rifampicin-resistant tuberculosis; MDR-TB: multidrug-resistant tuberculosis; PICO: patients, intervention, comparator and outcomes; XDR-TB: extensively drug-resistant tuberculosis; WHO: World Health Organization.
Box A1. PICO questions
The PICO questions looked at the following eight distinct outcomes: successful completion of treatment; bacteriological cure by end of treatment; adherence to treatment (or treatment interruption by non-adherence); treatment failure or relapse; death during treatment; adverse reactions caused by anti-TB medicines; acquisition (amplification) of drug resistance; and sustained bacteriological cure at least 6 months after successful treatment.
Members of the GDG were invited to score the outcomes as “critical”, “important” or “not important” for making recommendations on the use of specific regimens under evaluation. The scores are shown in Table A1.
Annex 1: Methods and expert panels 7
Table A1. Scoring of outcomes considered relevant by the GDG for the evidence review
Outcomes (as outlined in scoping proposal) Rating
Survival (or death) 8.33
Relapse-free cure 8.22
Bacteriological cure by end of treatment 8.19
Successful completion of treatment (or lack of successful completion) 7.96
Treatment failure or relapse 7.93
Adherence to treatment (or treatment interruption due to non-adherence) 7.48
Acquisition (amplification) of drug resistance 7.33
Adverse events from anti-TB medicines 7.19
GDG: Guidelines Development Group; TB: tuberculosis.
Note: Relative importance was rated on an incremental scale, as follows: 1–3 points: not important for making recommendations; 4–6 points: important but not critical for making recommendations; and 7–9 points: critical for making recommendations on the evaluated interventions.
A1.2 Evidence gathering and analysis The evidence to inform the update and development of recommendations resulted from a cooperative effort between WHO, national TB programmes (NTPs) and partner organizations, and close collaboration a with not-for-profit product development partnership (TB Alliance). For this particular update, the following data sources were used:
• Programmatic data of multidrug- or rifampicin-resistant TB (MDR/RR-TB) patients from South Africa treated with all-oral bedaquiline-containing shorter regimens, provided by the National TB Control and Management Cluster of the Department of Health of the Republic of South Africa.
• Data from a single-arm study [Nix-TB] containing records on patients receiving a novel all-oral regimen consisting of bedaquiline, pretomanid and linezolid, provided by the TB Alliance.
• Data for patients with MDR/RR-TB and extensively drug-resistant TB (XDR-TB) from 17 epidemiologically diverse countries treated with bedaquiline or delamanid-containing regimens, from the observational study of the EndTB project provided by the EndTB Consortium (Partners in Health, Médecins Sans Frontières, Interactive Research & Development and Unitaid).
• Data from a cohort study that included records of women treated during pregnancy for MDR/RR-TB using bedaquiline-containing regimens, provided by the South African Medical Research Council.
• Data resulting from a public call for records on patients from India, Republic of Belarus and Uzbekistan, treated according to WHO-recommended regimens.
Only individual patient data (IPD) was used for purposes of this update. Comparator data was assembled as part of an IPD database containing records of more than 13 000 patients with MDR/RR-TB, from 53 individual datasets from 40 countries. Sample sizes varied according to the availability of IPD for each analysable outcome. Analysable sample sizes are presented in Annex 4.
The methods used to minimize bias and confounding, and to make the intervention and comparator groups as similar as possible were exact matching (HIV coinfection or antiretroviral therapy [ART] use, TB treatment history and total number of drugs the strain was resistant to) and propensity score-based matching (on age, sex, and baseline sputum acid-fast bacilli [AFB] smear result). This process was conducted with replacement using a caliper distance of 0.02 during the propensity score-based matching, to estimate the adjusted odds ratios (aORs) of outcomes and their 95% confidence intervals
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(CI). In addition, the distribution of the matched covariates within the intervention and comparator groups was further examined to assess the fidelity of the matching process.
The decision process that informs and leads to the making of any recommendations goes beyond the understanding of the magnitude of the desirable and undesirable effects resulting from the implementation of a particular intervention, and beyond the certainty of the evidence assessed. It also takes into account how people who are directly affected value a given intervention in terms of the main outcomes, resource implications, cost–effectiveness, impact on equity, feasibility and acceptability. For this update, the magnitude of the desirable and undesirable effects of the interventions was evaluated through the analysis methods already described. Other critical factors that could help to inform the judgements of the GDG for making an evidence-informed assessment were considered. The evidence reviews on cost–effectiveness, values, preferences and acceptability described below were commissioned to help inform the decision-making process and the conclusions drawn on the interventions under evaluation.
Evidence on cost–effectiveness
Costs could be affected, for example, through changes in duration of a regimen, use or replacement of newer agents, health care delivery costs, duration of follow-up visits and safety monitoring (and type of monitoring required; e.g. electrocardiography and audiometry). Therefore, a decision analytic model, together with estimates of the efficacy and safety differences between regimens, was used to help inform any considerations for the implementation of these recommendations. The model aimed to assess the cost of changes to recommended regimens for drug-resistant TB; estimate cost–effectiveness; and identify parameters and set specific characteristics that could influence cost or cost–effectiveness, focusing2 on the use of an all-oral bedaquiline-containing shorter regimen of 9–12 months’ duration, and on the use of bedaquiline for longer than 6 months and its concurrent use with delamanid. The modelling approach used projections from existing models, incorporated into certain individual parameter estimates (e.g. transmission models for secondary cases prevented by more effective treatment, and Markov cost–effectiveness models for total costs of MDR-TB cases). Costs were evaluated from a health system perspective (see Annex 4).
In addition, an economic evaluation was carried out to estimate the cost–effectiveness of a new regimen containing bedaquiline, pretomanid, and linezolid (BPaL), compared with the standard of care for patients who have XDR-TB, or have failed or are intolerant to their MDR-TB treatments, in three epidemiological settings at a given price. A Markov model was developed to follow a cohort of the intended population for the BPaL regimen. This provided the advantage of modelling both disease and treatment processes, where timing of events was important. Clinical data from the Nix-TB study were used to inform clinical efficacy of the intervention, and costing estimates were obtained through data available in the Global Health Costing Consortium database and from Value-TB (a multicounty TB costing study funded by the Bill & Melinda Gates Foundation).
Evidence on values and preferences
A qualitative study was undertaken to provide better understanding of the values and preferences for treatment, and perspectives on treatment acceptability, feasibility and equity. Although the goal was to gather evidence representing all individuals who would either use or be affected by the recommendations on each intervention – including policy-makers, health professionals, patients and other key stakeholders – this qualitative study was only able to capture data on patient representatives and MDR/RR-TB survivors. The methodology used to capture relevant data focused on in-depth interviews with stakeholders from high TB burden countries in Asia, Africa, Eastern Europe and South America. Fig. A1 provides an overview of the qualitative themes that reflect the values, preferences and perspectives regarding acceptability, feasibility and equity of the treatment of drug-resistant TB.
2 A separate evaluation of the BPaL regimen for the treatment of patients who have XDR-TB, or have failed or are intolerant to their MDR-TB treatments, was commissioned by the manufacturer and presented to the GDG.
Annex 1: Methods and expert panels 9
Fig. A1. Overview of the main qualitative themes
Values & Preferences
Equity
Acceptability
Feasibility
• Minimal life disruption• Full recovery• Independence• Informed choice
• Treatment access• Social and
economic burden
• Prompt effective treament
• Risk-priority balance• Community/
social ties
• Community-based treatment
• Rigorous monitoring• Individualized
treatment
A1.3 Certainty of evidence and strength of recommendationsIn assessing the quality of evidence, several factors can increase or decrease the quality of evidence. The highest quality rating is usually assigned to evidence gathered from randomized, controlled trials (RCTs), whereas evidence from observational studies, including programmatic data, is usually assigned a value of low or very low quality. The higher the quality of evidence, the more likely it is that a strong recommendation can be made (Table A2). The criteria used by the GDG to determine the quality of available evidence are summarized in Annex 4. The certainty in the estimates of effect (quality of evidence) was assessed and rated either down or up on the basis of risk of bias, inconsistency or heterogeneity, indirectness, imprecision and other considerations.
Table A2. Certainty of evidence and strength of recommendations
Certainty in the evidence Definition
High ( ) Further research is very unlikely to change our confidence in the estimate of effect.
Moderate ( ) Further research is likely to have an important impact on our confidence in the effect and may change the estimate.
Low ( ) Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low ( ) Any estimate of effect is very uncertain.
Through the GRADE system, the strength of a recommendation is classified as “strong” or “conditional”. The strength of a recommendation is determined by the balance between desirable and undesirable effects, values and preferences, resource use, equity considerations, acceptability and feasibility to implement the intervention. For strong recommendations, the GDG is confident that the desirable
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effects of adherence to the recommendation outweigh the undesirable effects. For conditional recommendations, the GDG considers that the desirable effects probably outweigh the undesirable effects. The strength of a recommendation has implications for the individuals affected by these guidelines (Table A3).
Table A3. Perspective taken, and description of strength and conditionality of recommendations
Perspective Strong recommendation Conditional recommendation
From patients Most individuals in this situation would want the recommended course of action and only a small proportion would not. Formal decision aids are not likely to be needed to help individuals make decisions consistent with their values and preferences.
The majority of individuals in this situation would want the suggested course of action, but many would not.
From clinicians Most individuals should receive the intervention. Adherence to this recommendation according to the guidelines could be used as a quality criterion or performance indicator.
Recognize that different choices will be appropriate for individual patients, and that patients must be helped to arrive at a management decision consistent with their values and preferences. Decision aids may be useful in helping individuals to make decisions consistent with their values and preferences.
From policy-makers
The recommendation can be adopted as policy in most situations.
Policy-making will require substantial debate and involvement of various stakeholders.
A1.4 Assessment of the quality of the evidenceThe WHO guideline development process uses specific criteria to assess the characteristics of a body of evidence, such as within-study bias (methodological quality), consistency, precision, and directness or applicability of the evidence. The evidence reviewed at the November 2019 GDG meeting was primarily programmatic data or data from cohort studies, although one dataset was from an RCT. These data were assessed as having low or very low certainty, based on an assessment of the criteria described above. The low or very low certainty of the evidence reinforced the need for additional high-quality evidence (from carefully executed research studies, including RCTs) to inform policy-making. To ensure proper assessment of the quality of the evidence, quality assurance procedures were performed by the Research Institute of the McGill University Health Centre, assisted by a GRADE methodologist.
Analysis of IPD data from studies or programmatic cohorts described in Section A1.1 was used to inform the development of specific recommendations. The IPD-based analyses help to reduce between-study heterogeneity; they also allow the examination of patient-level characteristics, harmonization of outcomes and exploration of variability in effectiveness. Although double-adjustment in propensity score matching analyses was carried out to remove the effects of confounding, there was still potential for bias in the effect estimates to have occurred through residual or unmeasured
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confounding. Residual confounding could also have arisen from unknown factors, associated with both the exposure and the outcome, for which data were not collected.
A1.5 Publication, implementation, evaluation and expiry These guidelines were prepared in accordance with the requirements of the GDG.3 They will be published on the WHO website and made freely available to download, as part of a comprehensive set of WHO consolidated guidelines on TB. They will also be communicated widely at international and regional conferences, and at meetings of programme managers in all regions. In 2020, WHO will also release an operational guide with more practical details, to support programmatic implementation of the revised recommendations. National programmes will be supported by WHO and technical and funding partners, to prepare a national plan for the programmatic management of drug-resistant TB. Implementers should create a conducive policy and programmatic environment – including national and local policies, and standard operating procedures – to facilitate implementation of the recommendations in these guidelines. This should include promoting universal health coverage and offering public financing for management of drug-resistant TB. Furthermore, dedicated resources should be allocated, including for staff development and service delivery in the community. It is important to train frontline health care staff and students in critical areas such as diagnosis, designing a regimen, patient support, monitoring response to treatment and management of adverse reactions. National programmes should ensure meaningful engagement with affected populations, their communities, the private sector, other relevant health programmes and ministries in both planning and implementing the recommendations. The uptake of these WHO recommendations will be monitored in the annual data collection of WHO Global TB Data Monitoring. WHO will update the guidelines 5 years after their publication, or earlier if new evidence becomes available that necessitates a revision.
3 WHO handbook for guideline development – 2nd edition Geneva, Switzerland World Health Organization; 2014 (https://apps.who.int/iris/handle/10665/145714, accessed 20 March 2020).
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A2 Expert panelsThis section lists the participants at GDG meetings for various updates of the drug-resistant TB treatment guidelines.
A2.1 WHO treatment guidelines for drug-resistant TB treatment guidelines, 2020 update
GDG members
1. Holger SCHÜNEMANN (Chair)GRADE methodologistCochrane Canada & McMaster UniversityHamilton, ONCanada
2. Rafael LANIADO-LABORIN (Co-Chair)Clinician; National TB programme; end-userNational TB ProgrammeTijuanaMexico
3. Susan ABDEL RAHMANChildren’s Mercy HospitalKansas City, MOUnited States of America
4. Erlina BURHANClinician; end-userDepartment of Respiratory and Pulmonology, Persahabatan HospitalJakartaIndonesia
5. Daniela CIRILLOLaboratory specialistSan Raffaele Supranational TB Reference LaboratoryMilanItaly
6. Charles DALEYPulmonologist; MDR-TB expertNational Jewish HealthDenver, COUnited States of America
7. Geraint (Gerry) Rhys DAVIESTrials expert; PharmacologistUniversity of LiverpoolLiverpoolUnited Kingdom of Great Britain and Northern Ireland
8. Fernanda DOCKHORN COSTA JOHANSENNational TB programme; end-user; ClinicianMinistry of Health MDR-TB referral centreBrasiliaBrazil
9. Kelly DOOLEYClinical pharmacologist; ResearcherJohns Hopkins University School of MedicineBaltimore, MDUnited States of America
10. Bernard FOURIEClinical trials expertUniversity of PretoriaPretoriaSouth Africa
11. Agnes GEBHARDTechnical agency; end-user; ClinicianKNCV Tuberculosis FoundationThe HagueNetherlands
12. Elmira GURBANOVArGLC; Clinician; end-userLung Clinic, University of TartuTartuEstonia
13. Muhammad Amir KHANCivil society representatitveAssociation for Social DevelopmentIslamabadPakistan
14. Yuhong LIUClinician; end-userNational Clinical Center on Tuberculosis, China CDC, Beijing Chest HospitalBeijingChina (People’s Republic of )
Annex 1: Methods and expert panels 13
15. Marian LOVEDAYSpecialist Scientist; maternal health medicineSouth African Medical Research CouncilCape TownSouth Africa
16. Barend (Ben) MARAISPaediatricianThe University of Sydney School of MedicineSydneyAustralia
17. Iqbal MASTERClinician; MDR-TB physician; end-userKing George V Hospital, Kwazulu NatalDurbanSouth Africa
18. Alberto MENDOZAClinician; end-userNational TB ProgrammeLimaPeru
19. Beatrice MUTAYOBAProgramme Manager; end-userNational TB and Leprosy ProgrammeDar Es SalaamUnited Republic of Tanzania
20. Payam NAHIDClinician; Clinical trials expertUniversity of California SF & American Thoracic Society ATSSan Francisco, CAUnited States of America
21. Mahshid NASEHIProgramme Manager; end-userNational TB and Leprosy Control ProgrammesTehranIran (Islamic Republic of )
22. Viet Nhung NGUYENNational TB programme; end-userNational TB Control Programme, Ministry of HealthHanoiViet Nam
23. Alberto PIUBELLOClinician; MDR-TB physician; end-userInternational Union Against Tuberculosis and Lung DiseaseNiameyNiger
24. Maria RODRIGUEZClinician; National TB programme; end-userMinistry of Health MDR-TB referral centreSanto DomingoDominican Republic
25. Rohit SARINTechnical agency end-userNational Institute of TB & Respiratory Diseases NITRDNew DelhiIndia
26. Ingrid SCHOEMANFormer MDR-TB patientTB PROOFPretoriaSouth Africa
27. Alena SKRAHINANational TB programme; MDR-TB physician; end-userRepublican Research and Practical Centre for Pulmonology and TuberculosisMinskBelarus
28. Carrie TUDORNursing specialist; Technical agency; end-userInternational Council of NursesDurbanSouth Africa
29. Debrah VAMBENational TB programme; end-userNational TB Control ProgramMbabaneEswatini
30. Andrew VERNONTrials expert; Technical agency end-userUS Centers for Disease Control and PreventionAtlanta, GAUnited States of America
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Evidence reviewers
31. Jonathon CAMPBELLEpidemiologist; health economist.McGill University’s Faculty of MedicineMontreal, QCCanada
32. Amrita DAFTARYBehavioural health scientistDahdaleh Institute for Global Health Research, York UniversityToronto, ONCanada
33. Gabriela GOMEZHonorary Associate ProfessorLondon School of Hygiene and Tropical MedicineLondonUnited Kingdom of Great Britain and Northern Ireland
34. Emily KENDALLInfectious diseases dynamics; mechanistic modelingJohns Hopkins Bloomberg School of Public HealthBaltimore, MDUnited States of America
35. Richard MENZIESLead - Evidence reviewerMcGill University’s Faculty of MedicineMontreal, QCCanada
36. Rada SAVICAssociate ProfessorDepartment of Bioengineering and Therapeutic Sciences, Division of Pulmonary and Critical Care Medicine, Schools of Pharmacy and Medicine, University of California San FranciscoSan Francisco, CAUnited States of America
37. Nick WINTERSResearch AssistantMcGill University’s Faculty of MedicineMontreal, QCCanada
Observers
38. Draurio BARREIRA CRAVO NETOTechnical manager, TBUnitaidGenevaSwitzerland
39. Dan EVERITTVice President and Senior Medical Officer, Principal Investigator Nix-TBTB AllianceNew York, NYUnited States of America
40. Abdul GHAFOORNational TB ProgrammeIslamabadPakistan
41. Christopher GILPINMigration Health DivisionInternational Organization for MigrationGenevaSwitzerland
42. Anisa HAJIZADEHMcMaster UniversityHamilton, ONCanada
43. Brian KAISERTechnical OfficerStop TB Partnership’s Global Drug FacilityGenevaSwitzerland
44. Blessina KUMARCEOGlobal Coalition of TB ActivistsNew DelhiIndia
45. Tamara LOTFIResearch AssociateFaculty of Medicine, American University of BeirutBeirutLebanon
46. YaDiul MUKADITechnical AdvisorUnited States Agency for International DevelopmentWashington, DCUnited States of America
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47. Norbert NDJEKADirector, Drug-Resistant TB, TB & HIVDepartment of HealthPretoriaSouth Africa
48. Eugene SUNHead of R&DTB AllianceNew York, NYUnited States of America
49. Kitty VAN WEEZENBEEKExecutive DirectorKNCV TB FoundationThe HagueNetherlands
50. Francis VARAINEProject Lead, EndTB ProjectMédecins Sans FrontièresParisFrance
51. Mohammed YASSINSenior Disease Advisor, TBThe Global Fund to Fight AIDS, Tuberculosis and MalariaGenevaSwitzerland
WHO Regional Offices
52. Askar YEDILBAYEVRegional TB adviser EUROWHO/EUROCopenhagenDenmark
53. Mohammed AKHTARRegional TB adviser EMROWHO/EMROCairoEgypt
54. Vineet BHATIArepresenting Regional TB adviser SEAROWHO/SEARONew DelhiIndia
WHO headquarters
55. Tereza KASAEVA, Director, GTB
56. John GROVE, Director, QNS
57. Medea GEGIA,Technical Officer, GTB/TSC
58. Lice GONZÁLEZ-ANGULO, Technical Officer, GTB/LDR
59. Malgorzata GRZEMSKA, Coordinator, GTB/TSC
60. Alexei KOROBITSYN,Technical Officer, GTB/LDR
61. Corinne MERLE, Scientist, IIR
62. Fuad MIRZAYEV, Medical Officer, GTB/LDR
63. Lorenzo MOJA, Technical Officer, IAU
64. Deusdedit MUBANGIZI, Coordinator, PQ
65. Linh Nhat NGUYEN, Technical Officer, GTB/TSC
66. Susan NORRIS, GRC Secretariat
67. Andreas REIS, Senior Ethics Officer, REK
68. Kerri VINEY, Scientist, GTB/LDR
69. Marco VITORIA, Medical Officer, TAC
70. Karin WEYER, Coordinator, GTB/LDR
71. Matteo ZIGNOL, Coordinator, THC/RTE
A2.2 WHO treatment guidelines for rifampicin- and multidrug-resistant tuberculosis, 2018 update
GDG members
1. Holger SCHÜNEMANN (Chair)Cochrane Canada & McMaster UniversityCanada(GRADE methodologist)
2. Susan ABDEL RAHMANChildren’s Mercy Hospital, KansasUnited States of America(Clinician; Pharmacologist (paediatrics))
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3. Sarabjit S CHADHAThe UNION / Regional Green Light CommitteeIndia(Technical agency end-user)
4. Daniela CIRILLOSan Raffaele Supranational TB Reference LaboratoryItaly(Laboratory specialist)
5. Geraint (Gerry) Rhys DAVIESUniversity of LiverpoolUnited Kingdom of Great Britain and Northern Ireland(Trials expert; Pharmacologist)
6. Fernanda DOCKHORN COSTA JOHANSENMinistry of Health (MDR-TB referral centre)Brazil(National TB programme end-user; Clinician)
7. Bernard FOURIEUniversity of PretoriaSouth Africa(Clinical trials expert)
8. Edwin HERRERA-FLORESHospital Nacional (MDR-TB referral centre), Arzobispo Loayza, LimaPeru(Clinician)
9. Ayuko HIRAIMédecins Sans FrontièresPapua New Guinea(Technical agency end-user; Clinician)
10. Alexander KAYBaylor Global TB Program, MbabaneEswatini(Paediatrician)
11. Rafael LANIADO-LABORINNational TB Programme / Regional Green Light CommitteeMexico(Clinician; National TB programme end-user)
12. Eden MARIANOSLB Group of TB ActivistsPhilippines(Past MDR-TB patient)
13. Lawrence MBUAGBAWMcMaster UniversityCanada(Epidemiologist; Biostatistician)
14. Payam NAHIDUniversity of California SF & American Thoracic Society (ATS)United States of America(Clinician; Clinical trials expert)
15. Austin Arinze OBIEFUNAAfro Global AllianceGhana(Civil society)
16. Cristina POPAMarius Nasta TB institute (MDR-TB referral centre), BucharestRomania(Clinician)
17. Wipa REECHAIPICHITKULUniversity of Khon Kaen (MDR-TB referral centre)Thailand(Clinician)
18. Maria RODRIGUEZMinistry of Health (MDR-TB referral centre)Dominican Republic(Clinician; National TB programme end-user)
19. Adman Skirry SHABANGUNational TB Control Programme, Ministry of HealthEswatini(National TB programme end-user)
20. Sabira TAHSEENNational Reference Laboratory, IslamabadPakistan(Laboratory specialist)
21. Carrie TUDORInternational Council of NursingUnited States of America(Nursing specialist; Technical agency end-user)
22. Zarir UDWADIAHinduja Hospital (MDR-TB referral centre), Breach Candy Hospital and Parsee General Hospitals, Mumbai,India(Clinician)
Annex 1: Methods and expert panels 17
23. Andrew VERNONUS-CDCUnited States of America(Trials expert; Technical agency end-user)
Evidence Reviewers (Observers)
24. Syed ABIDIMcGill University, MontréalCanada
25. Faiz A KHANMcGill University, MontréalCanada
26. Jonathon CAMPBELLMcGill University, MontréalCanada
27. Zhiyi LANMcGill University, MontréalCanada
28. Dick MENZIESMcGill University, MontréalCanada
Technical resource persons (observers)
29. Charles DALEYNational Jewish Health (MDR-TB referral centre), DenverUnited States of America(Clinician; Chair of the Global Drug-Resistant TB Initiative)
30. Kelly DOOLEYJohns Hopkins University, BaltimoreUnited States of America(Clinical trials expert; Clinician; Pharmacologist)
31. Gregory KEARNSArkansas Children’s Hospital Research InstituteUnited States of America(Pharmacologist (paediatrics))
32. Anneke HESSELING (remote participation)Stellenbosch University, Cape TownSouth Africa(Paediatrician; Clinical trials expert)
33. Gary MAARTENSUniversity of Cape TownSouth Africa(Clinician; TB/HIV specialist; Pharmacologist)
34. Norbert NDJEKADepartment of Health, PretoriaSouth Africa(National TB programme end-user; Clinician)
35. Michael L. RICHPartners in Health, BostonUnited States of America(Technical agency end-user; Clinician)
36. H Simon SCHAAF (remote participation)Stellenbosch University, Cape TownSouth Africa(Paediatrician; Clinical trials expert)
37. Valérie SCHWOEBELThe UNIONFrance(Technical agency end-user)
38. Shenjie TANGBeijing Chest Hospital (MDR-TB referral centre), BeijingChina(Clinician)
39. Ye TUNNational Expert DR-TB Committee & Thingungyun San Pya General Hospital (MDR-TB referral centre) / University of Medicine (2), YangonMyanmar(Clinician)
40. Kitty VAN WEEZENBEEKKNCV TB Foundation, The HagueNetherlands(Technical agency end-user)
41. Francis VARAINEMSF France, ParisFrance(Technical agency end-user)
42. Irina VASILYEVANational Medical Research Centre of TB and Infectious Disease, MoscowRussian Federation(National TB programme end-user; Clinician)
WHO consolidated guidelines on tuberculosis: Online annexes18
43. Kerri VINEYMeeting RapporteurSweden(WHO consultant)
Trial investigators (observers; joining via webinar)
44. Lawrence GEITEROtsukaUnited States of America
45. Chrispin KAMBILIJohnson & JohnsonUnited States of America
46. Carole MITNICKPartners in Health, BostonUnited States of America
47. Andrew NUNNMedical Research CouncilUnited Kingdom of Great Britain and Northern Ireland
Other observers
48. Draurio BARREIRA CRAVO NETOUNITAID, GenevaSwitzerland
49. Edward M COXUS Food and Drugs Administration, Washington DCUnited States of America
50. Jennifer FURINSentinel ProjectUnited States of America
51. Brian KAISERGlobal Drug Facility, Stop TB Partnership, GenevaSwitzerland
52. Lindsay McKennaTreatment Action GroupUnited States of America
53. YaDiul MUKADIUSAID, WashingtonUnited States of America
54. Eric PELFRENEEuropean Medicines Agency, LondonUnited Kingdom of Great Britain and Northern Ireland
55. Anna SCARDIGLIGlobal Fund to Fight AIDS, TB and Malaria, GenevaSwitzerland
WHO headquarters
Deputy Director General for ProgrammesSoumya SWAMINATHAN
Global TB Programme Tereza KASAEVA, DirectorNicola COCCODennis FALZONGiuliano GARGIONIMedea GEGIAChristopher GILPINLicé GONZALEZ-ANGULOMalgosia GRZEMSKAErnesto JARAMILLOAlexei KOROBITSYNFuad MIRZAYEV Kefas SAMSONKarin WEYERMatteo ZIGNOL
Guideline Review CommitteeSusan NORRIS
Tropical Disease ResearchPiero OLLIAROCorinne MERLE
HIV DepartmentSatvinder SINGH
Essential Medicines ProgrammeLorenzo MOJA
Research, Ethics and Knowledge ManagementAndreas Alois REIS
WHO Regional Offices
Ogtay GOZALOV (EUR)Vineet BHATIA (SEAR)
Annex 1: Methods and expert panels 19
A2.3 WHO treatment guidelines for isoniazid-resistant tuberculosis, 2018 update
GDG members
1. Farhana AMANULLAHConsultant PaediatricianDirector Paediatric TB ProgramThe Indus Hospital, Korangi Crossing,KarachiPAKISTAN
2. Tsira CHAKHAIA (via webinar)ACSM Advisor, Civil Society GeorgiaUSAID Georgia TB Prevention ProjectUniversity Research Co., LLCTbilisiGEORGIA
3. Daniela Maria CIRILLOHeadEmerging Bacterial Pathogens UnitFondazione Centro San RaffaeleMilanoITALY
4. Kelly DOOLEY (Co-chair)Associate Professor of MedicinePharmacology & Molecular ScienceDivisions of Clinical Pharmacology &Infectious DiseasesJohns Hopkins University Baltimore, MDUNITED STATES
5. Luis Gustavo DO VALLE BASTOSCapacity Building Team LeaderStop TB Partnership’s Global DrugFacility (GDF)SWITZERLAND
6. Philipp DU CROSResearch AdvisorMédecins Sans FrontièresLondonUNITED KINGDOM
7. Raquel DUARTETB consultantNational HIV/AIDS/TB ProgrammeMedical School, Porto UniversityInstitute of Public Health, Porto UniversityPortoPORTUGAL
8. Christopher KUABANDean, Faculty of Health SciencesUniversity of Bamenda, CameroonBamenda, North West RegionCAMEROON
9. Rafael LANIADO-LABORINHead, TB Clinic, HospitalGeneral de TijuanaInstituto Estatal de Salud de Baja CaliforniaTijuanaMEXICO
10. Gary MAARTENSFaculty of Health SciencesDivision of Clinical PharmacologyDepartment of MedicineUniversity of Cape TownCape Town SOUTH AFRICA
11. Andrei MARYANDYSHEVHead of Phthisiopulmonary DepartmentNorthern State Medical UniversityTroitsky 51, 163061 - ArkhangelskRUSSIAN FEDERATION
12. Ignacio MONEDERO-RECUEROMDR-TB and TB-HIV ConsultantInternational Union of TB and LungDisease (The Union)ParisFRANCE
13. Maria Imelda Josefa QUELAPIOSenior ConsultantKNCV TB FoundationThe HagueNETHERLANDS
14. Wipa REECHAIPITKULProfessorDepartment of MedicineFaculty of MedicineKhon Kaen UniversityKhon Kaen THAILAND
WHO consolidated guidelines on tuberculosis: Online annexes20
15. Michael RICHGlobal Health PhysicianPartners in HealthHarvard Medical SchoolBoston, MAUNITED STATES
16. Nancy SANTESSO (Co-chair)Assistant ProfessorDepartment of Health Research Methods,Evidence, and ImpactMcMaster UniversityHamiltonCANADA
17. Rada SAVIC Associate ProfessorDepartment of Bioengineering andTherapeutic SciencesDivision of Pulmonary and CriticalCare MedicineSchools of Pharmacy and MedicineUniversity of California San FranciscoSan Francisco, CAUNITED STATES
18. Welile SIKHONDZENational Tuberculosis Control Programme Advisor and Research CoordinatorMbabaneSWAZILAND
19. Armand VAN DEUNBacteriology ConsultantDepartment of Biomedical SciencesMycobacteriology UnitPrince Leopold Institute of TropicalMedicineAntwerpenBELGIUM
Observers
20. Giovanni Battista MIGLIORIDirector, WHO Collaborating Centre forTB and Lung DiseasesFondazione S. Maugeri, Care andResearch InstituteTradate ITALY
21. Ya Diul MUKADIMedical OfficerTuberculosis Division/InfectiousDisease OfficeGlobal Health BureauWashington, DC UNITED STATES
22. Payam NAHIDProfessor of MedicineDivision of Pulmonary and Critical CareMedicineUniversity of CaliforniaSan Francisco General HospitalSan Francisco CAUNITED STATES
23. Timothy RODWELLFoundation for Innovative NewDiagnostics (FIND)GenevaSWITZERLAND
24. Mohammed YASSINSenior AdvisorThe Global FundGenevaSWITZERLAND
Evidence Reviewers
25. Dick MENZIESDirector, Respiratory DivisionMUHC and McGill University,Room K1.24Montréal Chest InstituteMontréal, PQCANADA
26. Federica FREGONESEMcGill University Health CentreMontréal, Quebec,CANADA
WHO headquarters Secretariat
27. WEYER, Karin, Coordinator,HQ/HTM/GTB/LDR
28. FALZON, Dennis, Medical Officer,HQ/HTM/GTB/LDR
29. GAO Xu, Intern, HQ/HTM/GTB/RTE
30. van GEMERT, Wayne, TechnicalOfficer, HQ/HTM/GTB/LDR
Annex 1: Methods and expert panels 21
31. GILPIN, Christopher, Scientist,HQ/HTM/GTB/LDR
32. GONZÁLEZ-ANGULO, Lice Y., Technical Officer, HQ/HTM/GTB/RTE
33. JARAMILLO, Ernesto, MedicalOfficer, HQ/HTM/GTB/LDR
34. KOROBITSYN, Alexei, TechnicalOfficer, HQ/HTM/GTB/LDR
35. MIRYAZEV, Fuad, Medical Officer, HQ/HTM/GTB/LDR
36. OLLIARO, Piero, Unit Leader, Intervention Research, HQ/HTM/TDR/IIR
37. ZIGNOL, Matteo, Scientist, HQ/HTM/GTB/TM
A2.4 WHO guidelines for the treatment of drug-susceptible tuberculosis and patient care, 2017 update
GDG members
1. Si Thu AUNGDeputy Director (TB) and National TB Programme ManagerDepartment of Public Health Ministry of HealthNay Pyi Taw, Myanmar(Unable to attend the meeting)
2. Frank BONSUNational TB Programme Manager Ministry of HealthAccra, Ghana
3. Jeremiah Muhwa CHAKAYAClinicianNational TB Programme Manager KEMRI,Nairobi, Kenya
4. Lucy CHESIRETB ACTION Group Nairobi, Kenya
5. Daniela CIRILLOHead of Emerging Bacterial Pathogens Unit WHO Collaborating Centre and TB Supranational Reference LaboratorySan Raffaele Scientific Institute Milano, Italy
6. Poonam DHAVANMigration Health Programme Coordinator International Organization for Migration Geneva, Switzerland(Unable to attend the meeting)
7. Kelly DOOLEYAssociate Professor of Medicine, Pharmacology & Molecular Sciences Divisions of Clinical Pharmacology & Infectious Diseases
Center for Tuberculosis Research Faculty Leader, Janeway Firm of theOsler Residency ProgramJohns Hopkins University School of Medicine Baltimore, MD, United States of America
8. Kathy FIEKERTSenior TB ConsultantKNCV Tuberculosis FoundationThe Hague, Netherlands
9. Paula FUJIWARAScientific DirectorInternational Union Against Tuberculosis and Lung Disease (The Union) Paris, France
10. Mike FRICKTB/HIV Project Treatment Action Group New York, NY, United States of America
11. Andrei MARYANDYSHEVHead of Phthisiopulmonary Department Arkhangelsk, Russian Federation
12. Nguyen Viet NHUNGDirector of National Lung Hospital Vietnam National TB ProgrammeHanoi, Viet Nam
13. Ejaz QADEERMinistry of Health Islamabad, Pakistan
WHO consolidated guidelines on tuberculosis: Online annexes22
14. Abdul Hamid SALIMAdvisor to National TB Programme Bangladesh onGlobal Fund and MDR-TBTB Gate, Leprosy Hospital Compound, MohakhaliDhaka, Bangladesh
15. Simon SCHAAFPaediatricianPaediatrics and Child Health Faculty of Medicine and Health SciencesUniversity of Stellenbosch Stellenbosch, South Africa
16. Holger SCHÜNEMANN (Chair)MethodologistMcMaster UniversityHamilton, Canada
17. Pedro Guillermo SUAREZManagement Sciences for Health Arlington, VA, United States of America(Unable to attend the meeting)
18. Carrie TUDORTB Project Director International Council of NursesDurban, South Africa
19. Justin Wong Yun YAWHead, Disease Control Division Ministry of HealthJalan Menteri Besar Brunei
Evidence reviewers
20. Narges ALIPANAHPhysicianSanta Clara Valley Medical Center San Jose, CA, United States of America
21. Lelia CHAISSONEpidemiologistInfectious Disease Epidemiology Department of EpidemiologyJohns Hopkins Bloomberg School of Public Health Baltimore, MD, United States of America
22. Jennifer HOWoolcock Institute of Medical Research University of Sydney AustraliaJames JOHNSTONEvaluation Lead, TB Services British Columbia Centre for Disease Control VancouverBritish Columbia, Canada
23. Dick MENZIESRECRU/ Montreal Chest Institute MontrealQuebec, Canada
24. Payam NAHIDProfessorUniversity of California San FranciscoSan Francisco, CA, United States of America
Observers
25. Amy BLOOMSenior Technical Advisor Bureau of Global HealthUS Agency for International Development Washington, D.C., United States of America
26. Janet GINNARDUNITAIDGeneva, Switzerland
Members of the External Review Group (area of expertise shown in parentheses for non-WHO staff)
27. Mohammed AZIZ WHO Regional Office for the Eastern Mediterranean
28. Masoud DARA WHO Regional Office for Europe
29. Riitta DLODLO International Union Against Tuberculosis and Lung Disease (Technical agency/programme implementation)France
30. Celine GARFIN Ministry of Health (National programme/end-user)Philippines
31. Mirtha del GRANADO WHO Regional Office for the Americas
Annex 1: Methods and expert panels 23
32. Daniel KIBUGA WHO Regional Office for Africa
33. Hyder KHURSHID WHO Regional Office for South- East Asia
34. Vaira LEIMANE Riga East University Hospital,Centre of Tuberculosis and Lung Diseases(Clinician/end-user)Latvia
35. Nobuyuki NISHIKIORI WHO Regional Office for the Western Pacific
36. Lee REICHMAN Rutgers New Jersey Medical School(Clinician/end-user)United States of America
37. Rohit SARIN National Institute of TB & Respiratory Diseases, Ministry of Health(National programme/end-user)India
38. Dalene VON DELFT TB Proof (Patient representative)South Africa
39. Fraser WARES Royal Dutch Tuberculosis Foundation (KNCV)(Technical agency/programme implementation)The Netherlands
WHO headquarters Secretariat
40. Annabel BADDELEY, GTB/THC
41. Dennis FALZON, GTB/LDR
42. Giuliano GARGIONI, GTB/TSC
43. Nebiat GEBRESSELASSIE, GTB/RTE
44. Haileyesus GETAHUN, GTB/THC
45. Lice Y. GONZÁLEZ-ANGULO, GTB/RTE
46. Malgorzata GRZEMSKA, GTB/TSC
47. Elizabeth HARAUSZ (GTB/TSC Consultant)
48. Ernesto JARAMILLO, GTB/LDR
49. Avinash KANCHAR, GTB/THC
50. Soleil LABELLE, GTB/TSC
51. Christian LIENHARDT, GTB/RTE
52. Knut LÖNNROTH, GTB/PSI
53. Fuad MIRZAYEV, GTB/LDR
54. Linh NGUYEN, GTB/TSC
55. Marco VITORIA, HIV/TAC
56. Diana WEIL, GTB/PSI
57. Karin WEYER, GTB/LDR
58. Matteo ZIGNOL, GTB/TME
A2.5 WHO treatment guidelines for drug-resistant TB, 2016 update
GDG members
1. Farhana AMANULLAHAssociate DirectorPediatric TB ProgramIndus HospitalKarachiPakistan
2. Tsira CHAKHAIAACSM Advisor, Civil SocietyUniversity Research Co., LLCTbilisiGeorgia
3. Daniela Maria CIRILLOHeadEmerging Bacterial Pathogens UnitSan Raffaele del Monte Tabor Foundation (hSR)San Raffaele Scientific InstituteMilanoItaly
WHO consolidated guidelines on tuberculosis: Online annexes24
4. Charles L DALEY (Co-Chair)ChiefDivision of Mycobacterial and RespiratoryInfectionsNational Jewish HealthDenver, COUSA
5. Luis Gustavo DO VALLE BASTOSSenior Technical AdvisorCenter for Pharmaceutical ManagementManagement Sciences for HealthArlington, VAUSA
6. Kelly DOOLEYAssociate Professor of MedicinePharmacology & Molecular Science Divisions ofClinical Pharmacology & Infectious DiseasesJohns Hopkins University School of MedicineCenter for Tuberculosis ResearchBaltimore, MDUSA
7. Carlos A TORRES-DUQUEDirectorTuberculosis DepartmentLatin American Thoracic SocietyBogotáColombia
8. Michel GASANAManagerNational TB & Other RespiratoryCommunicable Diseases DivisionMinistry of HealthKigaliRwanda
9. Agnes GEBHARDSenior ConsultantTeam Leader of ACCESS TeamTechnical DivisionKNCV Tuberculosis FoundationThe HagueNetherlands
10. Armen HAYRAPETYANDirectorNational TB Control CentreMinistry of HealthAbovyan cityArmenia
11. Antonia KWIECIENSenior Technical AdvisorSystems for Improved Access toPharmaceuticals and Services Program (SIAPS)Management Sciences for Health (MSH)Arlington, VAUSA
12. José A CAMINERO LUNACoordinatorMDR-TB Unit, International Union AgainstTuberculosis & Lung Disease (UNION)General Hospital of Gran Canaria “Dr. Negrin”Las Palmas de Gran CanariaSpain
13. Sundari MASEMedical Team LeadField Services and Evaluation Branch Division of Tuberculosis Elimination National Center for HIV, Hepatitis, STD and TB PreventionCenters for Disease Control and PreventionAtlanta, GAUSA
14. Lindsay MCKENNATB/HIV Project OfficerTreatment Action GroupNew York, NYUSA
15. Nguyen Viet NhungDirectorNational Tuberculosis Control ProgrammeHanoiViet Nam
16. Maria RODRIGUEZCoordinatorMDR-TB National Technical UnitMinistry of HealthSanto DomingoDominican Republic
17. Holger SCHÜNEMANN (Chair)Chair and ProfessorDepartments of Clinical Epidemiology &Biostatistics and of MedicineMcMaster UniversityHamilton, ONCanada
Annex 1: Methods and expert panels 25
18. James SEDDONClinical LecturerDepartment of PaediatricsImperial CollegeLondonUnited Kingdom
19. Thomas SHINNICKAssociate DirectorGlobal Laboratory Activities MycobacteriologyLaboratory Branch, Division of TuberculosisElimination Centers for Disease Control andPreventionAtlanta, GAUSA
20. Alena SKRAHINAScientific DirectorRepublican Scientific & Practical Centre forPulmonology & TuberculosisBelarus Research Institute of Pulmonology and TuberculosisMinskBelarus
Observers (at the GDG meeting in Geneva in November 2015)
21. J Peter CEGIELSKITeam LeaderMDR TB International Programs and Research Branch, Division of Tuberculosis EliminationCenters for Disease Control & PreventionAtlanta, GAUSA
22. Janet Kristen GINNARDTechnical Officer Strategy & ResultsUNITAIDGenevaSwitzerland
23. Giovanni BATTISTA MIGLIORIDirectorWHO Collaborating Centre for Tuberculosisand Lung DiseasesFondazione Salvatore MaugeriTradate, VAItaly
24. Payam NAHIDProfessor of MedicineUniversity of California, San FranciscoSan Francisco General Hospital Division ofPulmonary and Critical Care MedicineSan Francisco, CAUSA
25. Nobuyuki NISHIKIORIRegional Adviser, TBWHO Western Pacific Regional OfficeManilaThe Philippines
26. Thomas W PIGGOTTResident PhysicianMcMaster UniversityHamilton ONCanada
27. Anna SCARDIGLIDisease Advisor, TuberculosisTechnical Advice and PartnershipThe Global Fund to Fight AIDS, Tuberculosisand MalariaGenevaSwitzerland
28. Barbara SEAWORTHProfessor of MedicineDirector Heartland National TB CenterUniversity of Texas Health Science Center, TylerSan Antonio, TXUSA
29. Mohammed YASSINTechnical Advisor, TuberculosisThe Global Fund to Fight AIDS, Tuberculosisand MalariaGenevaSwitzerland
30. Ya Diul MUKADISenior TB Technical AdvisorInfectious Disease Division, Global HealthBureauUS Agency for International Development(USAID)Washington, DCUSA
WHO consolidated guidelines on tuberculosis: Online annexes26
Resource persons
31. Philipp DU CROSTB AdvisorMédecins sans Frontières (MSF)LondonUnited Kingdom
32. Michael L RICHMedical OfficerPartners in HealthHarvard Medical SchoolBoston, MAUSA
33. Abdul Hamid SALIMAdvisor, NTP BangladeshTB Gate, Leprosy hospital CompoundMohakhaliDhakaBangladesh
34. Valérie SCHWOEBELMedical OfficerInternational Union Against Tuberculosis &Lung Disease (UNION)ParisFrance
35. Francis VARAINEInternational Medical CoordinatorMédecins sans Frontières (MSF)ParisFrance
36. Askar B. YEDILBAYEVMedical OfficerPartners in HealthBoston, MAUSA
External Review Group
37. Chen-Yuan CHIANGInternational Union Against Tuberculosis and Lung Disease (UNION)ParisFrance
38. Celine GARFINInfectious Diseases for Prevention and Control DivisionDisease Prevention and Control BureauDepartment of HealthManilaThe Philippines
39. Michael KIMERLINGKNCV Tuberculosis FoundationThe HagueNetherlands
40. Vaira LEIMANENational TB ProgrammeMinistry of HealthRigaLatvia
41. Guy MARKSInternational Union Against Tuberculosis and Lung Disease (UNION)ParisFrance
42. Gao MENGQIUBeijing Chest HospitalCapital Medical University, Beijing Tuberculosis and Thoracic Tumor Research InstituteBeijingChina
43. Norbert NDJEKADrug Resistant TB, TB & HIVDepartment of HealthPretoriaSouth Africa
44. Ejaz QADEERNational TB ProgrammeMinistry of HealthIslamabadPakistan
45. Lee REICHMANRutgers UniversityNew Jersey, NJUSA
46. Rohit SARINLRS Institute of TB and Respiratory DiseasesDelhiIndia
47. Irina VASILYEVACentral Tuberculosis Research Institute (CTRI)MoscowRussian Federation
48. Dalene VON DELFTTB ProofSouth Africa
Annex 1: Methods and expert panels 27
Evidence Reviewers
49. Mayara LISBOA SOARES DE BASTOSMcGill UniversityMontreal, QcCanada
50. Gregory J FOX*University of SydneySpit Junction, NSWAustralia
51. Rebecca HARRISLondon School of Hygiene and TropicalMedicineLondonUnited Kingdom
52. Anneke HESSELINGPaediatric TB Research ProgrammeDesmond Tutu TB Centre Department ofPaediatrics and Child HealthFaculty of Medicine and Health SciencesStellenbosch UniversityCape TownSouth Africa
53. Faiz KHANFaculty of Medicine, McGill UniversityMontreal Chest InstituteMcGill University Health CentreMontreal, QcCanada
54. Mishal KHANLondon School of Hygiene and TropicalMedicineLondonUnited Kingdom
55. Dick MENZIESMontreal Chest InstituteMcGill University Health CentreMontreal, QcCanada
WHO Guideline Steering Committee
56. Dennis FALZON, LDR/GTB
57. Nathan FORD, TAC/HIV
58. Giuliano GARGIONI, TSC/GTB
59. Haileyesus GETAHUN, THC/GTB
60. Malgorzata GRZEMSKA, TSC/GTB
61. Ernesto JARAMILLO, LDR/GTB
62. Avinash KANCHAR, THC/GTB
63. Soleil LABELLE, TSC/GTB
64. Christian LIENHARDT, PSI/GTB
65. Knut LÖNNROTH, PSI/GTB
66. Alberto MATTEELLI, THC/GTB
67. Fuad MIRZAYEV, LDR/GTB
68. Linh Nhat NGUYEN, LDR/GTB
69. Marco Antonio VITORIA, TAC/HIV
70. Fraser WARES, LDR/GTB
71. Diana WEIL, PSI/GTB
72. Karin WEYER, LDR/GTB
73. Matteo ZIGNOL, TME/GTB
WHO Consultant
74. Elizabeth HARAUSZ
A2.6 WHO guidelines for the programmatic management of drug-resistant tuberculosis, 2011 update
GDG members (area of expertise shown in parentheses)
1. Jaime BAYONASocios En Salud Sucursal(Programme management, public health)Peru
2. José A. CAMINEROUniversity General Hospital of Gran Canaria, Spain and The UNION(Clinical practice)Paris, France
* Affiliated with McGill University for the evidence reviews done for these guidelines
WHO consolidated guidelines on tuberculosis: Online annexes28
3. Charles L. DALEYNational Jewish Health, (clinical practice)United States of America
4. Agnes GEBHARDKNCVTuberculosis Foundation(Programme management)Netherlands
5. Myriam HENKENS, Médecins Sans Frontières(Programme management)France
6. Timothy H. HOLTZHIV/STD Research Program, United States Centers for Disease Control and Prevention–CDC, Asia Regional Office(Epidemiology, surveillance, programme evaluation)Thailand
7. Joël KERAVECManagement Sciences for Health(Drug management)Brazil
8. Salmaan KESHAVJEEHarvard Medical School(Programme management, public health)United States of America
9. Aamir J. KHANIndus Hospital TB Program(Epidemiology, programme management) Pakistan
10. Vaira LEIMANEState Infectology CenterClinic of Tuberculosis and Lung Diseases(Programme management, clinical practice)Latvia
11. Andrei MARYANDYSHEVNorthern State Medical UniversityArchangelsk(Clinical practice)Russian Federation
12. Carole D. MITNICKHarvard Medical School(Epidemiology, programme support)United States of America
13. Gloria NWAGBONIWEAlliance for Hope, (Civil society)Nigeria
14. Domingo PALMEROPulmonology DivisionHospital Muñiz,(Clinical practice)Argentina
15. Ma. Imelda QUELAPIOTropical Disease Foundation, (Programme management)Philippines
16. Michael L. RICHPartners In Health(Clinical practice)United States of America
17. Sarah ROYCEPATH(Surveillance, public health)United States of America
18. Sabine RÜSCH-GERDESNational Reference Centre for Mycobacteria, (Laboratory specialist)Germany
19. Archil SALAKAIAManagement Sciences for Health, (Programme management)United States of America
20. Rohit SARINLRS Institute of TB and Allied Diseases, (Clinical practice)India
21. Holger SCHÜNEMANNMcMaster University(Chairman of the Guideline Development Group; epidemiology, guideline methodology)Canada
22. Elena SKACHKOVAFederal Centre of TB Monitoring, (Surveillance)Russian Federation
23. Francis VARAINEMédecins Sans Frontières(Clinical and programme management)France
Annex 1: Methods and expert panels 29
WHO headquarters, Geneva, Switzerland
TB Department
24. Léopold BLANC
25. Dennis FALZON
26. Christopher FITZPATRICK
27. Katherine FLOYD
28. Haileyesus GETAHUN
29. Malgorzata GRZEMSKA
30. Christian GUNNEBERG
31. Ernesto JARAMILLO
32. Christian LIENHARDT
33. Fuad MIRZAYEV
34. Paul NUNN
35. Mario C. RAVIGLIONE
36. Delphine SCULIER
37. Fraser WARES
38. Karin WEYER
39. Matteo ZIGNOL
HIV Department
40. Chris DUNCOMBE
41. Marco Antonio DE AVILA VITORIA
External Review Group (area of expertise shown in parentheses for non-WHO staff)
42. Samiha BAGHDADIWHO Regional Office for the Eastern MediterraneanEgypt
43. Mercedes BECERRAHarvard Medical School(Academia)United States of America
44. Vineet BHATIAWHO Regional Office for South-East AsiaIndia
45. Masoud DARAWHO Regional Office for EuropeDenmark
46. Mirtha DEL GRANADOWHO Regional Office for the AmericasUnited States of America
47. Reuben GRANICHWHO HIV DepartmentSwitzerland
48. Lindiwe MVUSIDepartment of Health(Programme management)South Africa
49. Nani NAIRWHO Regional Office for South- East AsiaIndia
50. Norbert NDJEKADepartment of Health(Programme management, clinical practice)South Africa
51. Wilfred A.C. NKHOMAWHO Regional Office for Africa, Zimbabwe
52. Katsunori OSUGAWHO Regional Office for the Western PacificPhilippines
53. Hendrik Simon SCHAAFDepartment of Paediatrics and Child Health, Stellenbosch University and Tygerberg Children’s Hospital(Clinical practice, paediatric MDR-TB, surveillance)South Africa
54. Catharina VAN WEEZENBEEKWHO Regional Office for the Western Pacific, Philippines
55. Irina VASILYEVACentral TB Research Institute of RAMS(Research, clinical practice)Russian Federation
56. Wang Xie XIUTianjin Centers for Disease Control and Prevention(Surveillance)China
57. Richard ZALESKISWHO Regional Office for EuropeDenmark
WHO consolidated guidelines on tuberculosis: Online annexes30
Evidence review teams
58. Chunling LUHarvard Medical SchoolUnited States of America
59. Carole D. MITNICKHarvard Medical School United States of America
60. Richard A. WHITEHarvard Medical SchoolUnited States of America
61. Gail KENNEDYUniversity of California (San Francisco)United States of America
62. George RUTHERFORDUniversity of California (San Francisco)United States of America
63. Karen STEINGARTUniversity of California (San Francisco)United States of America
64. Matthew ARENTZUniversity of WashingtonUnited States of America
65. David HORNEUniversity of WashingtonUnited States of America
66. Patricia PAVLINACUniversity of WashingtonUnited States of America
67. Judd L. WALSONUniversity of WashingtonUnited States of America
68. Melissa BAUERMcGill UniversityCanada
69. Richard (Dick) MENZIESMcGill UniversityCanada
70. Olivia OXLADEMcGill UniversityCanada
71. Patricia WHYTEGriffith University Queensland(Guideline development)Australia
Annex 2: Declarations of interest 31
Annex 2: Declarations of interest
A2.1 WHO treatment guidelines for multidrug- and rifampicin-resistant tuberculosis, 2020In conformity with WHO guidelines for declaration of interests for WHO experts issued by the WHO Office for Compliance and Risk Management and Ethics, members of the Guideline Development Group, External Review Group and evidence reviewers were requested to submit completed WHO Declaration of Interest forms (DOIs) and declare in writing any competing interest (whether academic, financial or other) which could be deemed as conflicting with their role in the development of this guideline. In order to ensure the neutrality and independence of experts, an assessment of the DOI forms, curricula vitae, research interests and activities was conducted by the WHO Guideline Steering Committee. For cases in which potential conflicts were identified, the WHO Office for Compliance and Risk Management and Ethics was consulted for further clarification and advice as to how to manage competing interests. If any declared interests were judged significant, individuals were not included as members of the Guideline Development Group.
As per WHO rules, the objectives of the guideline development process and the composition of the GDG, including member biographies, were made public ahead of the meeting (https://www.who.int/tb/areas-of-work/drug-resistant-tb/treatment/drug-resistant-tb-gdg/en/). This public notice was conducted to allow the public to provide comments pertinent to any competing interests that may have gone unnoticed or not reported during earlier assessments.
Guideline Development Group The following Guideline Development Group members declared no conflicts of interest: Holger Schünemann (Chair); Rafael Laniado-Laborin (Co-Chair); Erlina Burhan; Fernanda Dockhorn Costa Johansen; Bernard Fourie; Elmira Gurbanova; Muhammad Amir Khan; Marian Loveday; Mahshid Nasehi; Ben Marais; Beatrice Mutayoba; Maria Rodríguez; Debrah Vambe; and Nguyen Viet Nhung. One member of the Guideline Development Group submitted additional information, which required no further action as this did not result in any conflict.
• Ingrid Schoeman: As an XDR-TB survivor, she went through the side-effects of being on treatment for 2 years. She works at TB Proof, and advocacy organisation which is often invited to attend key stakeholder meetings where they share the experiences of DR-TB survivors and advocated for high-quality TB care. She has been employed by TB Proof since 2017. She is certain that better evidence-based guidelines for treating DR-TB would benefit her colleagues, friends and local communities.
Six members of the Guideline Development Group declared interests that were judged non-significant and were believed not to affect the independence and impartiality of the experts during the guideline development process. Therefore, no restrictions to their participation applied:
• Charles Daley: Participation in the Data Monitoring Committee (DMC) for delamanid. A total of 5000 USD by Otsuka Pharmaceutical for services rendered in 2016 as the Chairman of the Committee. Participation in the DMC for pediatric trials of delamanid (Role Member). A total of 4000 USD by Otsuka Pharmaceutical for current services as a member of the Committee.
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• Gerry Davies: Participation in the PreDiCT-TB consortium, a public-private partnership funded by the European Union Innovative Medicines Initiative and the European Federation of Pharmaceutical Industries and Associations (EFPIA). Role as academic coordinator (2012–2017) led to engagement with industrial partners in pre-competitive areas of research into TB drug development. All of these activities were fully supported by public funding from the European Union. No financial support was received from EFPIA. Current collaborator on pharmacokinetic sub-studies deriving from the STREAM Stage 1 trial. Funding support will be provided through research institution [University of Liverpool] to support analysis of pharmacokinetic samples and data later in late 2019/early 2020. This works focuses on evaluating clofazimine and fluoroquinolones. Academic co-supervisor of PhD candidate who is currently involved in the TB-PRACTECAL trial (chief investigator) at the London School of Hygiene and Tropical Medicine. Funding support will be provided through research institution [University of Liverpool] from Médecins Sans Frontières to support analysis of pharmacokinetic samples in early 2020. This work will involve bedaquiline, pretomanid, clofazimine, linezolid and moxifloxacin.
• Yuhong Liu: China’s New Drug Introduction and Protection Program (NDIP) was supported by the Bill & Melinda Gates Foundation (BMGF) and Janssen Pharmaceutica. Bedaquiline was provided by Janssen Pharmaceutica through the global donation project (4000 patients) . BMGF and Janssen Pharmaceutica also project support to doctors’ training, project activity implementation, quality control, etc. A total of 500 000 USD were provided for project implementation by BMGF including training, data collection, project supervision, between 2016–2020. Financial interests (resulting from funding source) that could directly affect, or could appear to affect, the professional judgment of the expert were not identified.
• Iqbal Master: Non-monetary support provided by Janssen Pharmaceutica to attend the 2016 International Lung conference in Liverpool. Only flights and accommodation were sponsored. No direct or indirect payments were made. As a manger in the MDR unit, I provide a link for the implementation of research studies, including STREAM 1 and the Nix-TB trial from 2013 onwards. I received no monetary support or remuneration for involvement in these studies. My involvement was purely from an altruistic wish to facilitate research in order to improve treatment regimens and outcomes in MDR patients in general. As a Government official, working in at a public health hospital, participation in the roll-out of bedaquiline and delamanid through a Clinical access programme, launched by the National TB programme. Member of the Provincial and National MDR-TB Advisory Committee of South Africa which makes recommendations and advises Government sites on clinical management.
• Payam Nahid: Federal CDC contract to support clinical trial units in San Francisco and Hanoi, Vietnam United States Centers for Disease Control and Prevention University of California, San Francisco Federal contract to support clinical trial units in San Francisco and Hanoi, Vietnam. Participation as a member of the DSMB for an MDR-TB clinical trial, TB-PRACTECAL. All DSMB related materials are obviously kept confidential. Discussions are underway with Médecins Sans Frontières (MSF) for future potential participation of Vietnam clinical trial units in Hanoi and HCMC in EndTB MDR -TB clinical trials. No contracts or agreements have been offered, signed or formalized. If agreements are formalized, enrolments into the EndTB trials would be anticipated to begin in 2020.
• Carrie Tudor: Grant from Eli Lilly Foundation – Lilly MDR-TB Partnership for TB Project managed by the International Council of Nurses. Award of approximately USD 1 000 000 from 2013–2019.
The below-mentioned members of the Guideline Development Group declared interests which were judged to be significant and which required further discussion and assessment by the WHO Office for Compliance and Risk Management and Ethics to outline a management plan:
• Susan Abdel-Rahman: (Significant) Research Support from the Thrasher Foundation for an amount of 197 000 USD. Funding ended on 30 October 2017. The Thrasher Research Fund provides grants for paediatric medical research. The Fund is currently supporting over 150 projects, including but not limited to research on childhood blindness, nutritional deficiencies, brain injuries, diabetes, asthma, cancer, genetic diseases and a number of infections including HIV, malaria, TB, schistosomiasis, cytomegalovirus and otitis media. Employment & Consultancies: WHO Agreement
Annex 2: Declarations of interest 33
for performance of work to conduct a summary review of preclinical and EBA data on pretomanid use. Financial interests (resulting from research support) that could directly affect, or could appear to affect, the professional judgment of the expert were not identified. Financial interest resulting from WHO Agreement for performance of work may be perceived to compromise the expert’s objectivity or independent professional judgment in the discharge of GDG duties and responsibilities led to partial exclusion from decision-making and voting limited to BPaL regimen.
• Daniela Cirillo: Research grant to measure minimum inhibitory concentrations (MIC) for bedaquiline. Work sponsored through the Ospedale San Raffaele by Janssen Therapeutics. The amount granted was 50 000 USD in 2018. Research grant to study MIC distributions for new TB drugs. Work sponsored through the Ospedale San Raffaele by the TB Alliance. The amount granted was 30 000 USD in 2018. Payment for MIC work for new TB drugs was done through Ospedale San Raffaele and not direct to the individual. Although these interests are tangentially related to the subject of the current guideline development meeting (i.e. diagnostics), a significant conflict of interest was identified for participation in the decision-making process and voting related to funding from the TB Alliance, leading to partial exclusion from decision-making and voting limited to BPaL regimen.
• Kelly Dooley: Participation as PI of the “Assessing Pretomanid for TB (APT)” trial, assessing pretomanid for treatment of drug-sensitive TB. Support and funding is from the U.S. FDA. Drug donation from TB Alliance (pretomanid) and Pfizer (rifabutin). No salary support. Participation as investigator on trials sponsored by the NIH, FDA, the U.S. CDC or UNITAID, assessing: Use of rifapentine for TB infection in pregnant women, young children, patients with HIV co-infection; use of rifapentine for treatment shortening in patients with pulmonary TB (rifapentine donated by Sanofi); use of high-dose rifampin and levofloxacin for pediatric TB meningitis (NIH funded); use of high-dose isoniazid for MDR-TB (NIH funded, ACTG A5312); delamanid for MDR-TB in children with HIV infection (NIH funded, IMPAACT 2005; drug donation by Otsuka); bedaquiline for children with MDR-TB and HIV infection (NIH Funded, IMPAACT 1108); meropenem/amox/clav for drug-sensitive- and MDR-TB (FDA funded). No salary support. Protocol Co-Chair ACTG study A5343 assessing use of delamanid and bedaquiline among patients with MDR-TB. Drug donation by Otsuka, Janssen and ViiV Healthcare. Support and funding for this trial are provided by the U.S. NIH, Division of AIDS (DAIDS); no salary support. Involvement in the DELamanId BEdaquiline for ResistAnt TubErculosis study (A53439) led to partial exclusion limited to discussions and voting processes related to the combined use of bedaquiline and delamanid.
• Agnes Gebhard: Research grant provided to KNCV by the TB Alliance to conduct a situational analysis in 3 countries (Indonesia, Kyrgyzstan, Nigeria) to understand the current infrastructure, resources, and practices for management of all forms of TB, and potential hurdles for integrating regimens (BPaL, BPaMZ, separately and together as a comprehensive solution to TB treatment). Research grant provided by the TB Alliance (305 000 USD – Between 2018 and 2019) to develop a country roadmap for introduction of new regimens. Four countries were chosen as examples (Kazakhstan, Kyrgyzstan, Uzbekistan and Indonesia). These roadmaps are flexible for use with any new (DR) TB regimen. Public support for the approval of Pretomanid in combination with bedaquiline and linezolid submitted to the U.S. FDA Antimicrobial Drugs Advisory Committee in response to a request for comments. The letter is in the public domain (https://www.regulations.gov/docketBrowser?rpp=25&so=DESC&sb=commentDueDate&po=0&dct=PS&D=FDA-2019-N-1317). Financial interest (Institutional) resulting from research grants provided by the TB Alliance led to partial exclusion from decision-making and voting limited to BPaL regimen.
• Alberto Piubello: Involvement in the Union-sponsored study “Treatment Regimen of Anti-tuberculosis Drugs for Patients With Multi-Drug-Resistant TB (STREAM), Stage 2” led to partial exclusion from decision-making and voting limited to the all-oral bedaquiline-containing shorter regimen.
• Alena Skrahina: Principal Investigator in the Pragmatic Clinical Trial for a More Effective Concise and Less Toxic MDR-TB Treatment Regimen(s) (TB-PRACTECAL) led to partial led to partial exclusion from decision-making and voting limited to BPaL regimen.
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• Andrew Vernon: Work in the Division of TB Elimination at CDC which involved collaboration with NIH and Sanofi on the conduct of a multinational phase 3 trial of TB treatment using daily rifapentine. Sanofi provided medications for the trial, and has supported costs of PK testing. Total contribution to CDC Foundation was ~$3million (from 2007–17). No payment was received through these funds. Moreover, these funds were only a small proportion of overall trial costs, the vast majority of which were borne by CDC as the trial sponsor. In his capacity as a TB researcher and clinician at CDC, Andrew participated in meetings, both internal and external, concerned with the development of guidelines for the treatment of active TB and of LTBI in the United States. Role of the U.S. CDC as temporary voting members within the U.S. FDA’s Antimicrobial Drugs Advisory Committee Meeting. The latter interest led to partial exclusion from decision-making and voting limited to BPaL regimen.
External Review GroupThe following External Review Group members declared no conflicts of interest: Heather ALEXANDER, Sarabjit Singh CHADHA, Lisa CHEN, Edwin H HERRERA-FLORES, Anna Marie Celina GARFIN, Mathilde JACHYM, Giovanni Battista MIGLIORI, Thato MOSIDI, Welile SIKHONDZE, Bhabana SHRESTHA, Ivan SOLOVIC, Carlos TORRES, Zarir UDWADIA.
The following ERG member declared interests that were judged not to be in conflict with the objectives of the guidelines:
• Amanullah FARHANA: Declared that she has been employed and undertaken consultancy work for WHO and that she has had research activities funded by WHO and the Global Fund.
• Guy MARKS: Is the President of The Union (IUATLD), which undertakes projects and work in the field of MDR-TB. He is an investigator on the VQUIN trial, an investigated-initiated, publicly funded study on preventive therapy for contacts of patients with MDR-TB.
• Andrei MARYANDYSHEV: Declared research undertaken on MDR/RR-TB. The new TB drugs were investigated in the clinical trials in the hospital where Dr Maryandyshev works, i.e. Arkhangelsk clinical antituberculosis dispensary, Russian Federation where he was a main investigator. He participated in the clinical trials of new TB drugs: TMC207-TiDP13-C209 and TMC207TBC3001 phase II-III from 1.02.2012 to 3.10.2016; “An international, multicenter, prospective, randomized, double-blind, controlled study evaluating the efficacy and tolerability of a chemotherapy regimen including SQ 109 in pulmonary tuberculosis patients with multiple drug-resistant M. tuberculosis (phase IIc-III) from 19.08.2014 to 13.07.2016; PBTZ169-A15-C2b-1 “An international multicenter, double-blind, placebo-controlled, randomized trial to evaluate the efficacy, safety, and pharmacokinetics of PBTZ169 when used in combination therapy for patients with respiratory tuberculosis with bacterial excretion and drug resistance, phase IIb-III” from 13.12.2016 to 29.05.2017; Compassionate use of Delamanid (OPC-6768) for patients MDR TB, 6.12.2016 his hospital has received Delamanid for 5 patients from Otsuka company.
• Lawrence MBUAGBAW: Undertook a biostatistical consultation to support FDA reporting requirements for the use of bedaquiline, for Janssen Pharmaceuticals for which he received payment.
• Anuj K BHATNAGAR: Is the Co-Principal investigator for the STREAM 2 trial (Medical Research Council Clinical Trials Unit, London), for the Rajan Babu Institute of Pulmonary Medicine and Tuberculosis (RBIPMT) site, Delhi in India. The trial was initiated in this site in March 2019. The monetary aspects of the trial are being looked after by Vital Strategies as an affiliate of IUATLD for refurbishment of the ward, equipment, hiring of staff, upgrading laboratory facilities, access to all laboratory tests and patient support including monetary compensation. No money has been transferred to the institute for this trial. In addition, the National Institute for Research in Tuberculosis, Chennai (NIRT), an organization of the Indian Council of Medical Research (ICMR), Ministry of Health and Family Welfare, Government of India has initiated a Phase 3 trial – called BEAT TB, to study the efficacy and tolerability of a combination of newer drugs for shortening the treatment for pre-XDR and XDR-TB in 5 sites of India. At the RBIPMT site, of which Dr Bhatnagar is the Principal Investigator for this trial, they have just completed a site initiation visit and recruitment of personnel.
Annex 2: Declarations of interest 35
The first instalment of the grant for the initiation of this trial by NIRT Chennai has been given for recruitment of staff, equipment, laboratory reagents and patient and DOT provider support.
Evidence reviewers:The following experts who conducted the evidence for to inform the revision of the recommendations declared the below interests, which require no action beyond reporting for transparency purposes.
• Amrita Daftary: Columbia University Consultancy (2016–2021) – This is an ongoing consultancy to provide qualitative expertise to the design and evaluation of an adherence intervention in people with XDRTB-HIV in KwaZulu Natal, South Africa. Commissioned qualitative research for current GDG meeting. IC-IMPACTS funded grant (2015 – 2018) – study has been completed at McGill University; this was an intervention to engage pharmacy providers in Patna, India, to screen and refer TB symptomatic persons for a chest x-ray and doctor for timely TB detection. BMGF funded grant (2017–2020) – This study is held at McGill University where she was based until June 2019; this is an observational study using standardized patients to assess quality of clinical care for TB diagnosis in Cape Town and Durban, South Africa. NIH funded grant (2018 – 2020) – study is based at CAPRISA and Columbia University; this is an intervention to reduce XDRTB-HIV stigma in coinfected patients in KwaZulu Natal, South Africa.
• David Dowdy: Research grant Bill and Melinda Gates Foundation Grant to Institution (not owned by me) approx $300,000 current year interest, approximately $50,000. Travel to meetings Bill and Melinda Gates Foundation Travel paid for me to attend, approx. $10,000.
• Gabriela Gomez: Consultant providing modelling results for an investment case on a universal drug regimen for TB. Direct funding granted through BMGF for an amount of USD 40000. Funding concluded in 2018. Managed research grant to LSHTM for an economic evaluation of TB-PRACTECAL. Funding provided through MSF to research unit. Approximately £ 150 000. Her involvement stopped August 2019, although the project continues. In addition, a second grant from TB Alliance was granted to conduct an economic evaluation of the BPaL regimen. Approximately £ 60 000. Since 12 August 2019, she has been employed by Sanofi Pasteur. She is the lead for Europe in Vaccine Epidemiology and Modelling. There is no TB vaccine in the commercial pipeline of Sanofi Pasteur to her knowledge currently. She was not representing Sanofi Pasteur at this meeting, but only presenting work done as part of her previous position as Associate Professor at LSHTM.
• Richard Menzies: Commissioned WHO evidence reviews (2016-current) to identify, assess and synthesize the evidence for the development of guidelines for treatment of MDR-TB.
• Rada Savic: She received research funding from NIH, UNITAID and BMGF. Research funding to her institution (UCSF) where she is a principal investigator. She serves on Scientific Advisory Committee for TB Alliance, but receives no income for that role. She is a member of Core Science Group for NIH clinical trial network (ACTG) and for CDC clinical trial consortia (TBTC).
A2.2 WHO treatment guidelines for multidrug- and rifampicin-resistant tuberculosis, 2018Guideline Development Group The scope of the guidelines update and the composition of the Guidelines Development Group (GDG), including the biographies of the members, were made public for comment ahead of the meeting, in line with WHO requirements (https://www.who.int/tb/areas-of-work/drug-resistant-tb/treatment/gdg-meeting-mdr-rr-tb-treatment-2018-update/en/). All GDG members completed the WHO Declaration of interest (DoI) form and agreed to the confidentiality undertaking. The WHO Guideline Steering Committee reviewed the completed forms.
The following GDG members declared no interests conflicting with the objectives of the guidelines: Eden ABADIANO MARIANO, Sarabjit S CHADHA, Fernanda DOCKHORN COSTA JOHANSEN, Edwin
WHO consolidated guidelines on tuberculosis: Online annexes36
HERRERA-FLORES, Ayuko HIRAI, Alexander KAY, Rafael LANIADO-LABORIN, Lawrence MBUAGBAW, Austin Arinze OBIEFUNA, Cristina POPA, Wipa REECHAIPICHITKUL, Maria RODRIGUEZ, Holger SCHÜNEMANN, Adman Skirry SHABANGU and Sabira TAHSEEN.
The following GDG members declared interests that were judged not to be in conflict with the objectives of the guidelines:
Susan ABDEL-RAHMAN declared that a research grant (US$ 196 356) was received by her institution from the Thrasher Foundation in September 2017 for her role as Principal Investigator to study whether second-line TB medicines can be accurately quantified from dried blood spots (funding ongoing). Daniela CIRILLO declared that a grant (US$ 26 000) was provided to her research unit by the Foundation for Innovative New Diagnostics (FIND) to evaluate new TB diagnostics (funding ongoing). In 2014, she received funding from Janssen (US$ 10 000) and Otsuka (US$ 25 000) for work on drug-susceptibility testing (DST) of new drugs. In 2014, Janssen Italy funded her participation in an expert working group on the use of bedaquiline in Italy (US$ 1000). Geraint (Gerry) Rhys DAVIES declared that he was until November 2017 the academic coordinator of the PreDiCT-TB consortium, a public–private partnership funded by the European Union Innovative Medicines Initiative and the European Federation of Pharmaceutical Industries and Associations (EFPIA). Although this role involved engagement with industrial partners (GSK, Sanofi, Janssen) in pre-competitive areas of research into TB drug development, these activities were fully supported by public funding from the European Union (EU) and neither he nor his research institution have received any funding from EFPIA or from the individual industrial partners. He has been asked and intends to provide advice to the STREAM study team on possible PK studies, which may be carried out in future using existing or further prospectively collected samples (no payment or research support has been offered for this activity). In 2017, he was paid fees by WHO for expert consultancies (US$ 5000). He is a member of a steering group convened by Critical Path to TB Regimens to advise on development of the lipoarabinomannan (LAM) biomarker developed by Otsuka in the context of adaptive clinical trials (receives no payment for this activity). Bernard FOURIE declares receiving US$ 16 000 per year (ongoing) to act as a non-executive director and member of the Board of the National Bioproducts Institute in South Africa, which is exclusively involved in the production and marketing of blood- and plasma-derived products. Payam NAHID declares an ongoing Federal US Centers for Disease Control and Prevention (CDC) contract to the University of California San Francisco to support clinical trial units in San Francisco and Viet Nam (total amount not specified). Carrie TUDOR declares that her employer receives funding from the Eli Lilly Foundation (~US$ 1000 000 for 2013–2017; ongoing at US$ 243 000 in 2018) to run the International Council of Nurses’ TB/MDR-TB project. The project focuses on building the capacity of nurses and allied professionals on TB and DR-TB care through training and currently operates in China, Eswatini, Ethiopia, Lesotho, Malawi, the Russian Federation, Uganda and Zambia. She also received US$ 20 000 from the KwaZulu Natal Research Institute for TB & HIV (South Africa) and Fogarty/NIH (US) for her dissertation and postdoctoral research on TB until 2014. Zarir UDWADIA declares that he has supported about 40 patients to access bedaquiline and three patients to access delamanid through the compassionate use programmes of Janssen and Otsuka, respectively. He declares that he did not charge fees to the patients involved and there were no financial transactions with the manufacturers. Andrew VERNON declares that he heads a clinical research group at US CDC (Tuberculosis Trials Consortium [TBTC]) doing TB trials. TBTC often collaborates with pharmaceutical companies, which may provide modest support, e.g. drug supplies, funding for PK sub-studies. Sanofi Aventis awarded ~US$ 2.8 million in six unrestricted grants to CDC Foundation in 2007–2015 to facilitate or support TBTC work on rifapentine (e.g. PK studies, staff contracts, travel for invited speakers, preparation of data to support regulatory filings). These funds have not otherwise benefited the research group. TBTC has studies under way with rifapentine (TBTC Study 31) and levofloxacin (Opti-Q, TBTC Study 32). He declares that his branch has supported studies of drug-susceptible TB that have included moxifloxacin (TBTC Study 27, Study 28 and Study 31). His branch has also supported enrolment at two of the three sites involved in the Opti-Q Study. This study evaluates different doses of levofloxacin in the treatment of DR-TB and has no comparator arm. There is no involvement with drug procurement. The principal investigator and management of the study, including data handling, analysis and drug
Annex 2: Declarations of interest 37
procurement, are at Boston University. The Opti-Q outcomes are not yet known and the final analysis has yet to start. The majority of the study was funded by the US NIH (National Institutes of Allergy and Infectious Diseases [NIAID]).
The following GDG member declared an interest that was judged to conflict with the objectives of the guidelines (funding for new medicines for use in MDR-TB regimens). He therefore withdrew from the GDG panel and participated as a technical resource. Gary MAARTENS declared that his laboratory will receive US$ 2 184 608 from the US NIH (NIAID) to undertake drug assays for a trial on the safety, tolerability and PK of bedaquiline and delamanid, alone and in combination, among patients on MDR-TB treatment (AIDS Clinical Trials Group study A5343). He will receive no salary support.
External Review Group (ERG)The following ERG members declared no interest conflicting with the objectives of the guidelines: Essam ELMOGHAZI, Mildred FERNANDO-PANCHO, Anna Marie Celina GARFIN, Barend (Ben) MARAIS, Andrei MARYANDYSHEV, Alberto MATTEELLI, Giovanni Battista MIGLIORI, Nguyen Viet NHUNG, Rohit SARIN, Welile SIKHONDZE, Ivan SOLOVIC, Pedro SUAREZ and Carlos TORRES.
The following ERG member declared interests that were judged not to be in conflict with the objectives of the guidelines:
Thato MOSIDI declares that she represents people affected by and living with TB on the Global Fund Country Coordinating Mechanism in South Africa. She is also an active member of TB Proof, a not-for-profit organization that advocates for patient access to TB medicines.
The following evidence reviewers were from McGill University, Montréal, Canada – Syed ABIDI, Jonathon CAMPBELL, Zhiyi LAN and Dick MENZIES. They declared no interest conflicting with the objectives of the guidelines.
The following evidence reviewer declared interests that were judged not to be in conflict with the objectives of the guidelines: Faiz Ahmad KHAN declared payment by WHO to collect data and carry out a meta-analysis on the shorter MDR-TB regimens for the 2016 guidelines (CAD$ 4080) and travel fees to present these findings at a GDG meeting in 2015. He also declares undertaking an update of the same analysis in 2016–2018 for the ATS guidelines for which he receives no remuneration.
A2.3 WHO treatment guidelines for isoniazid-resistant tuberculosis, 2018In conformity with the WHO guidelines for declarations of interest1 for WHO experts issued by the WHO Compliance, Risk Management and Ethics Office, members of the Guideline Development Group (GDG), Evidence Review Group (ERG) and evidence reviewers were requested to submit completed WHO Declaration of Interest forms (DoIs) and declare in writing any competing interest (whether academic, financial or other) that could be deemed as conflicting with their role in the development of this guideline. In order to ensure the neutrality and independence of experts, an assessment of the DoI forms, curricula vitae, research interests and activities was conducted by the WHO Guideline Steering Committee. For cases in which potential conflicts were identified, the WHO Compliance, Risk Management and Ethics Office was consulted for further clarification and advice as to how to manage competing interests. If any declared interests were judged significant, individuals were not included in the GDG.
ERG members were also requested to declare interests and these were also assessed for potential conflict. As per WHO rules, the objectives of the guideline development process and the composition of the GDG, including member biographies, were made public 4 weeks ahead of the meeting (https://www.who.int/tb/areas-of-work/drug-resistant-tb/treatment/gdg-meeting-izoniazid-resistant-tb/en/).
WHO consolidated guidelines on tuberculosis: Online annexes38
This public notice was conducted to allow the public to provide comments pertinent to any competing interests that may have gone unnoticed or not reported during earlier assessments.
Guideline Development GroupThe following GDG members declared no interests: Daniela CIRILLO, Kelly DOOLEY (Co-Chair), Gustavo DO VALLE BASTOS, Raquel DUARTE, Christopher KUABAN, Rafael LANIADO-LABORIN, Gary MAARTENS, Andrei MARYANDYSHEV, Ignacio MONEDERO-RECUERO, Maria Imelda Josefa QUELAPIO, Wipa REECHAIPICHITKUL, Nancy SANTESSO (Co-Chair), Welile SIKHONDZE and Armand VAN DEUN.
Five GDG members declared interests that were judged non-significant and not affecting the neutrality of the guideline development process. Therefore, no restrictions to their participation applied:
Farhana AMANULLAH: (1b) paediatric expert for WHO TB monitoring mission in Indonesia (value US$ 600/day, 14–27 January 2017); (2a) paediatric TB expert for Harvard Medical School Global Health Delivery grant (20% full-time equivalent [FTE]; June 2016–June 2018); (2b) paediatric TB expert for Global Fund grant (20% FTE; June 2016–December 2017).
Tsira CHAKHAIA: (1b) Research coordinator for TB Alliance NC-006 clinical trial (2016); community engagement project coordinator for TB Alliance (current); research coordinator for NiX-TB (from May 2017).
Philipp DU CROS: (2a) Member of the protocol writing committee and steering committee of the TB-PRACTECAL Clinical Trial, which has received a grant of €6.8 million from the Dutch Postcode Lottery to Médecins Sans Frontières, Operational Centre Amsterdam (currently active).
Michael RICH: (1a) employed by Partners in Health to work on clinical care guidelines and in the programmatic management of DR-TB; (1a) WHO consultancies on treatment of drug-resistant TB to national TB programmes; (2a) conduct research and develop regimens for drug-resistant tuberculosis (DR-TB) as a recipient of the UNITAID’s Expand new drug markets for TB [EndTB] grant (all active during the development of the present recommendations).
Rada SAVIC: (1b) Member of the panel of the WHO Meeting on Target Regimen Profiles (value US$ 2500); grant reviewer for European and Developing Countries Clinical Trials Partnership (value US$ 1000); (2a) principal investigator or co-principal investigator of research grants by United States National Institutes of Health (NIH) and Gates Foundation on improving TB treatment options (all currently active).
External Review GroupThe following ERG members declared no interests related to the objectives of this meeting: Essam ELMOGHAZI, James JOHNSTON, Enos MASINI, Rohit SARIN, Kitty VAN WEEZENBEEK, Irina VASILYEVA and Piret VIIKLEPP.
The below-mentioned ERG members declared interests that were judged not to be significant to the topic of the guideline. Some of the ERG members were involved in clinical trials not related to the treatment of Hr-TB and therefore no restrictions applied to their participation as expert reviewers.
Charles L. DALEY: (1b) Chair and member of data monitoring committees for delamanid studies (US$ 45 000 provided by Otsuka Pharmaceutical over 8 years; ongoing); Chair of data monitoring committee for clofazimine studies (US$ 2500 provided by Novartis; finished in 2016).
Ingrid OXLEY: (5b) at the Union Conference 2015 in Cape Town, TB Proof campaigns advocated for treatment of latent TB infection (LTBI) among health care workers. She is a health care worker and has had two episodes of TB. Many members of TB Proof who are health care workers may have benefited
Annex 2: Declarations of interest 39
from the WHO guidelines for the treatment of LTBI or received funding for LTBI treatment. This was not the focus of the current guideline.
Simon SCHAAF: (2a) research support to employer for pharmacokinetics work on second-line TB medicines in children from the NIH and Otsuka Pharmaceutical (approximately ZAR 5 million/year). NIH grant ceased in 2015; Otsuka Pharmaceutical grant is still active.
Helen STAGG: (1b) grant to employer for consultancy work on MDR-TB clinical pathways in eastern Europe (Otsuka Pharmaceutical: £59 925; 2013–2015); (2a) grant to employer for Hepatitis and Latent TB Infection (HALT) study (Department of Health of the United Kingdom; National Institute for Health Research, United Kingdom; £86 000 for HALT study (2014); £315 265 for fellowship, salary, research costs; 2015–2017); (2b) non-monetary support for HALT study (Sanofi provides free rifapentine to the research study participants; 2014–2017); (6d) received International Trainee Scholarship Award (US$ 1000 value) at the American Thoracic Society (ATS) conference 2016 where she presented the results of a review she conducted (1).
Carlos A. TORRES-DUQUE: (5a) & (5b) as member of the National Advisory Committee for Tuberculosis (Ministry of Health of Colombia) participates in the updates of national TB treatment guidelines. His expert opinion is based upon evidence and local/international experience and does not generate any profits for him.
Evidence reviewersThe independent experts who undertook the systematic reviews of evidence for this revision declared no interests related to the topic of the policy guideline objectives.
This information is included in the Declaration of interest section in the WHO treatment guidelines for isoniazid-resistant tuberculosis, pages ix–xi, available at: https://apps.who.int/iris/bitstream/handle/10665/260494/9789241550079-eng.pdf
A2.4 WHO guidelines for the treatment of drug-susceptible tuberculosis and patient care, 2017 updateThe scope for the update of the Guidelines for treatment of drug-susceptible tuberculosis and patient care and the composition of the Guideline Development Group (GDG), as well as the External Review Group, were established in line with WHO’s policy on conflict of interest. All contributors completed a WHO Declaration of Interest form. All stated declarations of interest were evaluated by three members of the steering group for the existence of any possible financial or intellectual conflict of interest. In some cases there was possible conflict of interest justifying the exclusion from membership of the GDG, and the Director of the WHO Global TB Programme, the WHO Guideline Review Committee and the WHO Legal Office were consulted on this and a decision was made. Diversity and broad representation in the GDG were sought in an effort to address and overcome any potential intellectual conflicts of interest. The GDG was composed of representatives of technical partners and academia, a GRADE methodologist, national TB programme managers from different WHO regions, representatives of civil society organizations, experts from WHO collaborating centres, professional organizations and a representative from the International Organization for Migration (see web Annex 1). The biographies of the GDG members were made public ahead of the meeting, and the WHO Guidelines Steering Committee, which was formed in preparation for the update of the guidelines, reviewed the completed forms at the beginning of the meeting with everyone present.
WHO consolidated guidelines on tuberculosis: Online annexes40
Guideline Development GroupThe following members declared no interests: Si Thu AUNG; Frank BONSU; Jeremiah CHAKAYA; Lucy CHESIRE; Daniela CIRILLO; Poonam DHAVAN; Kathy FIEKERT; Andrei MARYANDYSHEV; Nguyen Viet NHUNG; Ejaz QADEER; Abdul Hamid SALIM; Holger SCHÜNEMANN; Pedro SUAREZ; Justin Wong Yun YAW.
The following GDG members declared interests that were judged not to be in conflict with the policy of WHO, or the objectives of the meeting:
Kelly DOOLEY declared that she did not receive any salary support from drug companies for her work in the following roles and activities: Co-chair of the AIDS Clinical Trials Group (ACTG) study assessing bedaquiline and delamanid for MDR-TB; principal investigator, assessing pretomanid for tuberculosis trial, assessing pretomanid (PA-824, investigational drug) for treatment of drug-sensitive TB; investigator on trials assessing rifapentine for pregnant women with latent TB infection, rifapentine for treatment shortening in patients with pulmonary TB, high-dose rifampicin and levofloxacin for paediatric TB meningitis, high-dose isoniazid for MDR-TB, and delamanid for MDR-TB in children with and without HIV. Mike FRICK declared that his organization received non-commercial support (1) to track investment made in TB research and development; (2) to host a symposium at the UNION meeting; (3) advocate for increased funding for TB research and development, research and access to evidence-based interventions; and (4) management of community research advisors group. Simon SCHAAF declared receiving grants for pharmacokinetic drug studies in children of second-line drugs and for studying preventive therapy in MDR-TB. Carrie TUDOR declared that her organization receives funding from Eli Lilly Foundation for activities related to TB and MDR-TB projects.
External Review GroupThe following External Review Group members declared no interest related to the objectives of this meeting: Riitta DLODLO, Celine GARFIN, Lee REICHMAN, Vaira LEIMANE, Rohit SARIN, Dalene VON DELFT and Fraser WARES. The following WHO staff from the regional offices reviewed the final draft of the guideline document: Masoud DARA (Europe), Mirtha DEL GRANADO (Americas), Daniel KIBUGA (Africa), Hyder KHURSHID (South-East Asia), Mohamed AZIZ (Eastern Mediterranean), and Nobuyuki NISHIKIORI (Western Pacific).
Evidence ReviewersThe researchers who undertook the systematic reviews of evidence for this revision were the following:
Narges ALIPANAH, Cecily MILLER, Payam NAHID (team leader for PICO 1, 2 & 7–10), University of California, San Francisco, United States of America; and Lelia CHAISSON, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States of America.
Richard MENZIES, McGill University, Montreal, Canada (team leader for PICO 3, 4 & 6); and James JOHNSTON, University of British Columbia, Vancouver, Canada.
Gregory FOX (team leader for PICO 11) and Jennifer HO, University of Sydney, Sydney, Australia.
The evidence reviewers did not participate in the formulation of the policy recommendations.
The following reviewers declared no interest related to the objectives of and their attendance at the meeting: Narges ALIPANAH, Jennifer HO and James JOHNSTON. The following reviewer declared interests that were judged not to be in conflict with the policy of WHO, or the objectives of the meeting: Payam NAHID declared that his research unit received support from the United States Centers for Disease Control and Prevention through a federal contract to support clinical trial units in San Francisco, USA, and in Hanoi, Viet Nam.
Annex 2: Declarations of interest 41
This information is included in the Declaration and management of conflict of interest section in the Guidelines for treatment of drug-susceptible tuberculosis and patient care, 2017 update, pages 6–7, available at: https://apps.who.int/iris/bitstream/handle/10665/255052/9789241550000-eng.pdf
A2.5 WHO treatment guidelines for drug-resistant tuberculosis, 2016 updateGuideline Development GroupThe scope of the guidelines update, and the composition of the GDG, including their biographies, were made public for comment ahead of the meeting in line with WHO’s conflict of interest policy. All GDG members completed the WHO Declaration of Interest forms. The WHO Guideline Steering Committee, in preparation for the update of the guidelines and the GDG meeting, reviewed the completed forms. The following GDG members declared no conflicting interests: Luis Gustavo do
Valle BASTOS, José A CAMINERO, Tsira CHAKHAIA, Michel GASANA, Armen HAYRAPETYAN, Antonia KWIECIEN, Sundari MASE, Nguyen Viet NHUNG, Maria RODRIGUEZ, Holger SCHÜNEMANN, James SEDDON and Alena SKRAHINA.
The following GDG members declared interests that were judged not to be in conflict with the objectives of the meeting: Farhana AMANULLAH declared having received funding for consultancies (US$ 500/ day) and travel from WHO; and grants from the Global Fund and TB-REACH to cover her salary (10% full-time equivalent).
Daniela CIRILLO declared having received funding from FIND to conduct evaluation of drug-susceptibility testing (DST) for new drugs (US$ 16 000), and from Otsuka to evaluate DST for delamanid (US$ 25 000). She also declared being the head of a supranational TB reference laboratory in Italy involved in country capacity-building in DST technologies for second-line drugs and new diagnostics for drug-resistant TB; and being a member of the Italian national committee for the use of bedaquiline. Charles L. DALEY declared having received funding from Otsuka to serve as chair of the data monitoring committee for trials of delamanid (US$ 47 000 over 7 years–current). Kelly DOOLEY declared having received funding to provide expert advice on a trial design for TB/HI (US$ 2000/year paid to the university/ employer); she also declared the following activities and roles: co-chair AIDS Clinical Trials Group (ACTG) study assessing bedaquiline and delamanid; principal investigator for adjuvant paclitaxel and trastuzumab (APT) trial assessing pretomanid (PA-824); and investigator in trials assessing high-dose isoniazid for MDR-TB, rifapentine for pregnant women and children with latent TB infection (LTBI), high- dose rifampicin and levofloxacin for paediatric TB meningitis, as well as bedaquiline and delamanid for children with MDR-TB and HIV infection.
Agnes GEBHARD declared that she works for the KNCV TB Foundation, which has two projects funded by the Eli Lilly and Company Foundation: (i) engaging the private sector in diagnosis and treatment of TB and MDR-TB with quality-assured second-line TB drugs, and (ii) the roll-out of QuanTB (a drug forecasting tool) in countries not supported by the Systems for Improved Access to Pharmaceuticals and Services (SIAPS) implemented by Management Sciences for Health. In addition, she declared that the KNCV TB Foundation has a collaborative project with Cepheid in two countries (Nigeria, Viet Nam), with KCNV providing services for the installation and initial training on the use of GeneXpert machines. Carlos TORRES-DUQUE declared having received honoraria from Janssen Pharmaceuticals for presentations on TB prevention and WHO policy on bedaquiline at a Latin American Meeting on MDR-TB held in 2014 (US$ 2000). Tom SHINNICK declared being an employee of the United States Centers for Disease Control and Prevention (CDC). CDC supports his travel and research related to his work on laboratory services needed for TB control. He declared having often represented CDC’s position on laboratory services needed for TB diagnosis, treatment and control. As part of his official duties for CDC, he served on the Data and Safety Monitoring Board (DSMB) organized by Otsuka
WHO consolidated guidelines on tuberculosis: Online annexes42
for the clinical trial of delamanid. He did not receive any remuneration for serving on the DSMB nor for travel expenses (CDC paid for all travel expenses related to serving on the DSMB). The DSMB has completed its work for the trial.
The following GDG members declared interests that were judged to be in conflict with some of the objectives of the meeting and were thus recused from some of the discussions: Lindsay MCKENNA declared non-commercial support to Treatment Action Group (TAG), her employer, from Stop TB Partnership; Bill & Melinda Gates Foundation; the US Department of Veteran Affairs (on behalf of CDC); Janssen Therapeutics for Hepatitis C and HIV projects and the Global Alliance for TB Drug Development (a public–private entity developing new drugs and regimens for TB treatment). She was thus recused from participating in the 9 November 2015 meeting session on Patients, Intervention, Comparator and Outcomes (PICO) question 1 on MDR-TB regimen composition for adults and children. José A CAMINERO stated in his biosketch that he is a staff consultant of the International Union Against Tuberculosis and Lung Disease (UNION), an agency directly involved in the implementation and evaluation of programmes using shorter MDR-TB regimens. He was therefore recused from the 10 November 2015 meeting session on PICO question 3 on shorter regimens for MDR-TB.
External Review GroupThe following ERG members declared no interest related to the objectives of this meeting: Chen-Yuan CHIANG, Celine GARFIN, Michael KIMERLING, Vaira LEIMANE, Gao MENGQIU, Norbert NDJEKA, Ejaz QADEER, Lee REICHMAN, Rohit SARIN and Irina VASILYEVA.
The following two ERG members declared interests which were judged not to be in conflict with the objectives of the guidelines. Guy MARKS declared research support from AERAS (US$ 450 000) related to the evaluation of latent TB infection and the rate of recurrence of TB after initial treatment in Viet Nam. He also declared being the Vice-President (and a board member) of the UNION and Editor-in-Chief of the International Journal of Tuberculosis and Lung Disease (for which he receives an honorarium). Dalene VON DELFT declared having received support from TAG, USAID, UNITAID, Janssen Pharmaceuticals, Critical Path to TB Drug Regimens (CPTR) and AERAS to cover travel costs and accommodation to give presentations/speeches on drug-resistant TB. She declared that in 2011 she received bedaquiline as part of her MDR-TB treatment through a compassionate use access programme.
Evidence ReviewersThe following reviewers declared interests that were judged not to be in conflict with the objectives of the meeting:
Gregory J FOX declared having received research and non-monetary support from the UNION (sponsored by Otsuka) valued at about US$ 5000 to attend the 2015 International UNION Conference and to receive the Young Innovator Award (he declares no work for Otsuka or any relationship of this award with any commercial or research activities with Otsuka).
Katherine FIELDING declared that her employer (LSHTM) was a recipient of an award from Médecins Sans Frontières (MSF) (£26 890) for the period February–December 2015 to provide statistical support for the TB-PRACTECAL study on which she is a co-investigator. The study is a Phase II–III randomized controlled trial (RCT) to evaluate the efficacy and safety of shorter MDR-TB regimens for adults.
Rebecca HARRIS declared she is consulting for a clinical research organization (Cromsource) working for Glaxo SmithKline (GSK) vaccines (~£90 000 in 2013); and on GSK vaccines not related to TB (~£10 000 since 2013) for Manpower Solutions.
David MOORE declared receiving research support from the Wellcome Trust Research Training Fellowship Programme to supervise a PhD student to study MDR-TB in Peru (£207 056 in 2014).
Annex 2: Declarations of interest 43
Anneke HESSELING declared that her employer (Stellenbosch University) is a recipient of an award from Otsuka Pharmaceutical (~US$ 70 000 to date) for her work on the Phase III delamanid clinical trials in children.
This information is included in the Declaration of interest section in the WHO treatment guidelines for drug-resistant tuberculosis, 2016 update, pages 2–5, available at: https://www.who.int/tb/areas-of-work/drug-resistant-tb/Annexes_8-10.pdf
A2.6 WHO guidelines for the programmatic management of drug-resistant tuberculosis, 2011 updateFunding for the meetings and reviews involved in the updating of the guidelines came entirely from the United States Agency for International Development (USAID). The experts on the Guideline Development Group (GDG) and the institutions where they work contributed time for the various discussions and other activities involved in the update process.
The Declaration of interest forms were completed by all non-WHO members of the GDG and the External Review Group, as well as the members of the academic centres who were involved in the reviews. Four members of the GDG declared interests that were judged to represent a potential conflict and were excused from the sessions of the meeting on 25–27 October 2010 during which recommendations relating to the drug regimens were discussed. Jaime BAYONA was a consultant for the development of clinical trial design for studies of an anti-tuberculosis drug manufactured by Otsuka Pharmaceutical Co. Ltd (OPC-67683). Charles L. DALEY was chairperson of drug-safety monitoring for two trials conducted by Otsuka Pharmaceutical Co. Ltd. Carole D. MITNICK served as a member of the Scientific Advisory Board of Otsuka Pharmaceutical Co. Ltd and had an advisory role on drug OPC-67683. Ma. Imelda QUELAPIO received support (monetary and non-monetary) for research from Otsuka Pharmaceutical Co. Ltd.
The following members of the academic centres, who performed the reviews of evidence from which the recommendations contained in these guidelines are derived, presented their findings at the meeting: Matthew ARENTZ, Melissa BAUER, Richard MENZIES, Carole D. MITNICK, Olivia OXLADE, Patricia PAVLINAC and Judd L. WALSON. They did not participate in the formulation of recommendations related to the respective reviews of evidence that they performed.
This information is included in the Funding and declarations of interest section in the Guidelines for the programmatic management of drug-resistant tuberculosis, 2011 update, page 2, available at: https://apps.who.int/iris/bitstream/handle/10665/44597/9789241501583_eng.pdf
WHO consolidated guidelines on tuberculosis: Online annexes44
Anne
x 3:
GRA
DE
evid
ence
sum
mar
y ta
bles
A3.
1 W
HO
trea
tmen
t gui
delin
es fo
r mul
tidru
g- a
nd ri
fam
pici
n-re
sist
ant
tube
rcul
osis
, 202
0 up
date
Aut
hor(
s):
Rese
arch
Inst
itute
of t
he M
cGill
Univ
ersit
y H
ealth
Cen
tre
Que
stio
n:
Shou
ld a
n al
l-ora
l sho
rter
reg
imen
of 9
–12
mon
ths’
dura
tion
inclu
ding
bed
aqui
line
vs a
sho
rter
reg
imen
rec
omm
ende
d by
WH
O (w
ith
inje
ctab
le) b
e us
ed fo
r MD
R/RR
-TB
patie
nts
to s
afel
y im
prov
e ou
tcom
es?
Sett
ing:
In
tern
atio
nal
Dat
e:
April
202
0
Cert
aint
y as
sess
men
t№
of p
atie
nts
Effe
ct
Cert
aint
yIm
port
ance
№ o
f st
udie
sSt
udy
desi
gnRi
sk o
f bi
asIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Oth
er
cons
ider
atio
ns
All-
oral
be
daqu
iline
-co
ntai
ning
sh
orte
r reg
imen
of
9–1
2 m
onth
s du
ratio
n
Shor
ter r
egim
en
reco
mm
ende
d by
WH
O
(with
inje
ctab
le)
Rela
tive
(95%
CI)
Abs
olut
e (9
5% C
I)
Succ
ess
vs. F
ailu
re/R
ecur
renc
e (f
ollo
w u
p: m
ean
18 m
onth
s)1
obse
rvat
iona
l st
udie
sse
rious
ano
t ser
ious
not s
erio
usno
t ser
ious
none
631/
653
(96.
6%)
573/
621
(92.
3%)
OR
2.1
(1.1
to
4.0)
3 m
ore
per 1
00
(from
1
mor
e to
6
mor
e)b,
c
VE
RY
LOW
CRIT
ICAL
Succ
ess
vs. D
eath
(fol
low
up:
mea
n 18
mon
ths)
1ob
serv
atio
nal
stud
ies
serio
usa
not s
erio
usno
t ser
ious
not s
erio
usno
ne63
1/79
1 (7
9.8%
)57
3/79
2 (7
2.3%
)O
R 1.
6 (1
.2 to
2.
1)
8 m
ore
per 1
00
(from
3
mor
e to
13
mor
e)b,
c
VE
RY
LOW
CRIT
ICAL
Succ
ess
vs. F
ailu
re/R
ecur
renc
e/D
eath
(fol
low
up:
mea
n 18
mon
ths)
1ob
serv
atio
nal
stud
ies
serio
usa
not s
erio
usno
t ser
ious
not s
erio
usno
ne63
1/81
3 (7
7.6%
)57
3/84
0 (6
8.2%
)O
R 1.
7 (1
.3 to
2.
2)
10 m
ore
per 1
00
(from
5
mor
e to
15
mor
e)b,
c
VE
RY
LOW
CRIT
ICAL
Annex 3: GRADE evidence summary tables 45
Cert
aint
y as
sess
men
t№
of p
atie
nts
Effe
ct
Cert
aint
yIm
port
ance
№ o
f st
udie
sSt
udy
desi
gnRi
sk o
f bi
asIn
cons
iste
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Indi
rect
ness
Impr
ecis
ion
Oth
er
cons
ider
atio
ns
All-
oral
be
daqu
iline
-co
ntai
ning
sh
orte
r reg
imen
of
9–1
2 m
onth
s du
ratio
n
Shor
ter r
egim
en
reco
mm
ende
d by
WH
O
(with
inje
ctab
le)
Rela
tive
(95%
CI)
Abs
olut
e (9
5% C
I)
Succ
ess
vs. A
ll U
nfav
orab
le (f
ollo
w u
p: m
ean
18 m
onth
s)1
obse
rvat
iona
l st
udie
sse
rious
ano
t ser
ious
not s
erio
usno
t ser
ious
none
631/
891
(70.
8%)
573/
987
(58.
1%)
OR
1.9
(1.6
to
2.4)
14 m
ore
per 1
00
(from
9
mor
e to
19
mor
e)b,
c
VE
RY
LOW
CRIT
ICAL
Lost
vs.
All
Oth
er O
utco
mes
(fol
low
up:
mea
n 18
mon
ths)
1ob
serv
atio
nal
stud
ies
serio
usa
not s
erio
usno
t ser
ious
not s
erio
usno
ne88
/891
(9.9
%)
171/
987
(17.
3%)
OR
0.5
(0.4
to
0.7)
7 fe
wer
pe
r 100
(fr
om
11 fe
wer
to
4 fe
wer
)b,c
VE
RY
LOW
CRIT
ICAL
AFB
Sm
ear P
ositi
ve: S
ucce
ss v
s. F
ailu
re/R
ecur
renc
e (f
ollo
w u
p: m
ean
18 m
onth
s)1
obse
rvat
iona
l st
udie
sse
rious
ano
t ser
ious
not s
erio
usno
t ser
ious
none
267/
274
(97.
4%)
197/
221
(89.
1%)
OR
4.4
(1.6
to
11.9
)
8 m
ore
per 1
00
(from
3
mor
e to
13
mor
e)b
VE
RY
LOW
CRIT
ICAL
AFB
Sm
ear P
ositi
ve: S
ucce
ss v
s. D
eath
(fol
low
up:
mea
n 18
mon
ths)
1ob
serv
atio
nal
stud
ies
serio
usa
not s
erio
usno
t ser
ious
not s
erio
usno
ne26
7/34
1 (7
8.3%
)19
7/26
9 (7
3.2%
)O
R 1.
3 (0
.8 to
2.
1)
5 m
ore
per 1
00
(from
3
few
er to
12
mor
e)b
VE
RY
LOW
CRIT
ICAL
AFB
Sm
ear P
ositi
ve: S
ucce
ss v
s. F
ailu
re/R
ecur
renc
e/D
eath
(fol
low
up:
mea
n 18
mon
ths)
1ob
serv
atio
nal
stud
ies
serio
usa
not s
erio
usno
t ser
ious
not s
erio
usno
ne26
7/34
8 (7
6.7%
)19
7/29
3 (6
7.2%
)O
R 1.
7 (1
.1 to
2.
6)
10 m
ore
per 1
00
(from
2
mor
e to
17
mor
e)b
VE
RY
LOW
CRIT
ICAL
AFB
Sm
ear P
ositi
ve: S
ucce
ss v
s. A
ll U
nfav
orab
le (f
ollo
w u
p: m
ean
18 m
onth
s)1
obse
rvat
iona
l st
udie
sse
rious
ano
t ser
ious
not s
erio
usno
t ser
ious
none
267/
378
(70.
6%)
197/
345
(57.
1%)
OR
2.3
(1.6
to
3.3)
16 m
ore
per 1
00
(from
9
mor
e to
24
mor
e)b
VE
RY
LOW
CRIT
ICAL
WHO consolidated guidelines on tuberculosis: Online annexes46
Cert
aint
y as
sess
men
t№
of p
atie
nts
Effe
ct
Cert
aint
yIm
port
ance
№ o
f st
udie
sSt
udy
desi
gnRi
sk o
f bi
asIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Oth
er
cons
ider
atio
ns
All-
oral
be
daqu
iline
-co
ntai
ning
sh
orte
r reg
imen
of
9–1
2 m
onth
s du
ratio
n
Shor
ter r
egim
en
reco
mm
ende
d by
WH
O
(with
inje
ctab
le)
Rela
tive
(95%
CI)
Abs
olut
e (9
5% C
I)
AFB
Sm
ear P
ositi
ve: L
ost v
s. A
ll O
ther
Out
com
es (f
ollo
w u
p: m
ean
18 m
onth
s)1
obse
rvat
iona
l st
udie
sse
rious
ano
t ser
ious
not s
erio
usno
t ser
ious
none
33/3
78 (8
.7%
)63
/345
(18.
3%)
OR
0.4
(0.2
to
0.6)
11 fe
wer
pe
r 100
(fr
om
16 fe
wer
to
5 fe
wer
)b
VE
RY
LOW
CRIT
ICAL
HIV
-Pos
itive
on
ART
: Suc
cess
vs.
Fai
lure
/Rec
urre
nce
(fol
low
up:
mea
n 18
mon
ths)
1ob
serv
atio
nal
stud
ies
serio
usa
not s
erio
usno
t ser
ious
not s
erio
usno
ne42
9/44
6 (9
6.2%
)34
6/36
8 (9
4.0%
)O
R 1.
4 (0
.7 to
2.
9)
2 m
ore
per 1
00
(from
2
few
er to
5
mor
e)b
VE
RY
LOW
CRIT
ICAL
HIV
-Pos
itive
on
ART
: Suc
cess
vs.
Dea
th (f
ollo
w u
p: m
ean
18 m
onth
s)1
obse
rvat
iona
l st
udie
sse
rious
ano
t ser
ious
not s
erio
usno
t ser
ious
none
429/
541
(79.
3%)
346/
492
(70.
3%)
OR
1.6
(1.2
to
2.3)
8 m
ore
per 1
00
(from
3
mor
e to
14
mor
e)b
VE
RY
LOW
CRIT
ICAL
HIV
-Pos
itive
on
ART
: Suc
cess
vs.
Fai
lure
/Rec
urre
nce/
Dea
th (f
ollo
w u
p: m
ean
18 m
onth
s)1
obse
rvat
iona
l st
udie
sse
rious
ano
t ser
ious
not s
erio
usno
t ser
ious
none
429/
558
(76.
9%)
346/
514
(67.
3%)
OR
1.6
(1.2
to
2.2)
9 m
ore
per 1
00
(from
3
mor
e to
15
mor
e)b
VE
RY
LOW
CRIT
ICAL
HIV
-Pos
itive
on
ART
: Suc
cess
vs.
All
Oth
er U
nfav
orab
le (f
ollo
w u
p: m
ean
18 m
onth
s)1
obse
rvat
iona
l st
udie
sse
rious
ano
t ser
ious
not s
erio
usno
t ser
ious
none
429/
613
(70.
0%)
346/
599
(57.
8%)
OR
1.9
(1.4
to
2.4)
14 m
ore
per 1
00
(from
8
mor
e to
19
mor
e)b
VE
RY
LOW
CRIT
ICAL
HIV
-Pos
itive
on
ART
: Los
t vs.
All
Oth
er O
utco
mes
(fol
low
up:
mea
n 18
mon
ths)
1ob
serv
atio
nal
stud
ies
serio
usa
not s
erio
usno
t ser
ious
not s
erio
usno
ne63
/613
(10.
3%)
97/5
99 (1
6.2%
)O
R 0.
6 (0
.4 to
0.
8)
6 fe
wer
pe
r 100
(fr
om
10 fe
wer
to
2 fe
wer
)b
VE
RY
LOW
CRIT
ICAL
Annex 3: GRADE evidence summary tables 47
Cert
aint
y as
sess
men
t№
of p
atie
nts
Effe
ct
Cert
aint
yIm
port
ance
№ o
f st
udie
sSt
udy
desi
gnRi
sk o
f bi
asIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Oth
er
cons
ider
atio
ns
All-
oral
be
daqu
iline
-co
ntai
ning
sh
orte
r reg
imen
of
9–1
2 m
onth
s du
ratio
n
Shor
ter r
egim
en
reco
mm
ende
d by
WH
O
(with
inje
ctab
le)
Rela
tive
(95%
CI)
Abs
olut
e (9
5% C
I)
HIV
Neg
ativ
e: S
ucce
ss v
s. F
ailu
re/R
ecur
renc
e (f
ollo
w u
p: m
ean
18 m
onth
s)1
obse
rvat
iona
l st
udie
sse
rious
ano
t ser
ious
not s
erio
usno
t ser
ious
none
195/
199
(98.
0%)
205/
228
(89.
9%)
OR
6.5
(1.4
to
29.5
)
7 m
ore
per 1
00
(from
2
mor
e to
12
mor
e)b
VE
RY
LOW
CRIT
ICAL
HIV
Neg
ativ
e: S
ucce
ss v
s. D
eath
(fol
low
up:
mea
n 18
mon
ths)
1ob
serv
atio
nal
stud
ies
serio
usa
not s
erio
usno
t ser
ious
not s
erio
usno
ne19
5/23
4 (8
3.3%
)20
5/25
4 (8
0.7%
)O
R 1.
9 (1
.1 to
3.
5)
10 m
ore
per 1
00
(from
1
mor
e to
18
mor
e)b
VE
RY
LOW
CRIT
ICAL
HIV
Neg
ativ
e: S
ucce
ss v
s. F
ailu
re/R
ecur
renc
e/D
eath
(fol
low
up:
mea
n 18
mon
ths)
1ob
serv
atio
nal
stud
ies
serio
usa
not s
erio
usno
t ser
ious
not s
erio
usno
ne19
5/23
8 (8
1.9%
)20
5/27
7 (7
4.0%
)O
R 2.
1 (1
.3 to
3.
6)
13 m
ore
per 1
00
(from
4
mor
e to
21
mor
e)b
VE
RY
LOW
CRIT
ICAL
HIV
Neg
ativ
e: S
ucce
ss v
s. A
ll O
ther
Out
com
es (f
ollo
w u
p: m
ean
18 m
onth
s)1
obse
rvat
iona
l st
udie
sse
rious
ano
t ser
ious
not s
erio
usno
t ser
ious
none
195/
255
(76.
5%)
205/
327
(62.
7%)
OR
2.7
(1.7
to
4.3)
20 m
ore
per 1
00
(from
11
mor
e to
29
mor
e)b
VE
RY
LOW
CRIT
ICAL
HIV
Neg
ativ
e: L
ost v
s. A
ll O
ther
Out
com
es (f
ollo
w u
p: m
ean
18 m
onth
s)1
obse
rvat
iona
l st
udie
sse
rious
ano
t ser
ious
not s
erio
usno
t ser
ious
none
18/2
55 (7
.1%
)61
/327
(18.
7%)
OR
0.3
(0.2
to
0.7)
10 fe
wer
pe
r 100
(fr
om
17 fe
wer
to
4 fe
wer
)b
VE
RY
LOW
CRIT
ICAL
AFB:
acid
-fas
t bac
illi; a
OR:
adj
uste
d od
ds ra
tio; A
RT: a
ntire
trovi
ral t
hera
py; C
I: co
nfid
ence
inte
rval
; HIV
: hum
an im
mun
odef
icien
cy v
irus;
MD
R/RR
-TB:
mul
tidru
g- o
r rifa
mpi
cin-r
esist
ant T
B; O
R: o
dds
ratio
; WH
O:
Wor
ld H
ealth
Org
aniz
atio
n.
Expl
anat
ions
a. F
or s
ome
patie
nts,
info
rmat
ion
was
miss
ing
on A
FB s
mea
r res
ult a
nd c
ultu
re re
sult
in th
e an
alys
is. P
atie
nts
with
unk
now
n ag
e, s
ex, o
r HIV
sta
tus
wer
e ex
clude
d fro
m a
ll an
alys
es.
b. O
utco
mes
and
cos
ts a
re s
imul
ated
usin
g a
mod
el th
at d
raw
s pa
ram
eter
est
imat
es fr
om m
ultip
le s
ourc
es, i
nclu
ding
the
aORs
for s
ucce
ss v
ersu
s de
ath/
failu
re d
escr
ibed
abo
ve.
c. T
he a
bsol
ute
effe
ct is
cal
cula
ted
afte
r mat
chin
g in
terv
entio
n an
d co
mpa
rato
r pop
ulat
ions
, and
per
form
ing
bino
mia
l reg
ress
ion
with
an
iden
tity
link.
WHO consolidated guidelines on tuberculosis: Online annexes48
Aut
hor(
s):
Rese
arch
Inst
itute
of t
he M
cGill
Univ
ersit
y H
ealth
Cen
tre
Que
stio
n:
Shou
ld a
n al
l-ora
l sho
rter
regi
men
of 9
–12
mon
ths’
dura
tion
inclu
ding
bed
aqui
line
vs lo
nger
regi
men
s with
out n
ew T
B dr
ugs
be u
sed
for
MD
R/RR
-TB
patie
nts
to s
afel
y im
prov
e ou
tcom
es?
Sett
ing:
In
tern
atio
nal
Dat
e:
April
202
0
Cert
aint
y as
sess
men
t№
of p
atie
nts
Effe
ct
Cert
aint
yIm
port
ance
№ o
f st
udie
sSt
udy
desi
gnRi
sk o
f bi
asIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Oth
er
cons
ider
atio
ns
All-
oral
be
daqu
iline
-co
ntai
ning
sh
orte
r reg
imen
of
9–1
2 m
onth
s du
ratio
n
Long
er
regi
men
s w
ithou
t new
TB
drug
s
Rela
tive
(95%
CI)
Abs
olut
e (9
5% C
I)
Succ
ess
vs. F
ailu
re/R
ecur
renc
e (f
ollo
w u
p: m
ean
18 m
onth
s)1
obse
rvat
iona
l st
udie
sse
rious
ano
t ser
ious
not s
erio
usno
t ser
ious
none
631/
653
(96.
6%)
679/
771
(88.
1%)
OR
3.7
(2.2
to
6.3)
8 m
ore
per 1
00
(from
5
mor
e to
11
mor
e)b,
c
VE
RY L
OW
CRIT
ICAL
Succ
ess
vs. D
eath
(fol
low
up:
mea
n 18
mon
ths)
1ob
serv
atio
nal
stud
ies
serio
usa
not s
erio
usno
t ser
ious
not s
erio
usno
ne63
1/79
1 (7
9.8%
)67
9/10
44 (6
5.0%
)O
R 2.
3 (1
.8 to
3.
0)
15 m
ore
per 1
00
(from
10
mor
e to
19
mor
e)b,
c
VE
RY L
OW
CRIT
ICAL
Succ
ess
vs. F
ailu
re/R
ecur
renc
e/D
eath
(fol
low
up:
mea
n 18
mon
ths)
1ob
serv
atio
nal
stud
ies
serio
usa
not s
erio
usno
t ser
ious
not s
erio
usno
ne63
1/81
3 (7
7.6%
)67
9/11
36 (5
9.8%
)O
R 2.
6 (2
.0 to
3.
3)
18 m
ore
per 1
00
(from
14
mor
e to
23
mor
e)b,
c
VE
RY L
OW
CRIT
ICAL
Succ
ess
vs. A
ll U
nfav
orab
le (f
ollo
w u
p: m
ean
18 m
onth
s)1
obse
rvat
iona
l st
udie
sse
rious
ano
t ser
ious
not s
erio
usno
t ser
ious
none
631/
891
(70.
8%)
679/
1437
(47.
3%)
OR
2.8
(2.3
to
3.5)
23 m
ore
per 1
00
(from
18
mor
e to
27
mor
e)b,
c
VE
RY L
OW
CRIT
ICAL
Annex 3: GRADE evidence summary tables 49
Cert
aint
y as
sess
men
t№
of p
atie
nts
Effe
ct
Cert
aint
yIm
port
ance
№ o
f st
udie
sSt
udy
desi
gnRi
sk o
f bi
asIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Oth
er
cons
ider
atio
ns
All-
oral
be
daqu
iline
-co
ntai
ning
sh
orte
r reg
imen
of
9–1
2 m
onth
s du
ratio
n
Long
er
regi
men
s w
ithou
t new
TB
drug
s
Rela
tive
(95%
CI)
Abs
olut
e (9
5% C
I)
Lost
vs.
All
Oth
er O
utco
mes
(fol
low
up:
mea
n 18
mon
ths)
1ob
serv
atio
nal
stud
ies
serio
usa
not s
erio
usno
t ser
ious
not s
erio
usno
ne88
/891
(9.9
%)
368/
1437
(25.
6%)
OR
0.4
(0.3
to
0.5)
14 fe
wer
pe
r 100
(fr
om
17 fe
wer
to
10 fe
wer
)b,c
VE
RY L
OW
CRIT
ICAL
AFB
Sm
ear P
ositi
ve: S
ucce
ss v
s. F
ailu
re/R
ecur
renc
e (f
ollo
w u
p: m
ean
18 m
onth
s)1
obse
rvat
iona
l st
udie
sse
rious
ano
t ser
ious
not s
erio
usno
t ser
ious
none
267/
274
(97.
4%)
248/
288
(86.
1%)
OR
8.9
(3.4
to
23.7
)
12 m
ore
per 1
00
(from
7
mor
e to
17
mor
e)b
VE
RY L
OW
CRIT
ICAL
AFB
Sm
ear P
ositi
ve: S
ucce
ss v
s. D
eath
(fol
low
up:
mea
n 18
mon
ths)
1ob
serv
atio
nal
stud
ies
serio
usa
not s
erio
usno
t ser
ious
not s
erio
usno
ne26
7/34
1 (7
8.3%
)24
8/37
8 (6
5.6%
)O
R 2.
1 (1
.5 to
3.
1)
13 m
ore
per 1
00
(from
6
mor
e to
20
mor
e)b
VE
RY L
OW
CRIT
ICAL
AFB
Sm
ear P
ositi
ve: S
ucce
ss v
s. F
ailu
re/R
ecur
renc
e/D
eath
(fol
low
up:
mea
n 18
mon
ths)
1ob
serv
atio
nal
stud
ies
serio
usa
not s
erio
usno
t ser
ious
not s
erio
usno
ne26
7/34
8 (7
6.7%
)24
8/41
8 (5
9.3%
)O
R 3.
0 (2
.1 to
4.
4)
19 m
ore
per 1
00
(from
12
mor
e to
26
mor
e)b
VE
RY L
OW
CRIT
ICAL
AFB
Sm
ear P
ositi
ve: S
ucce
ss v
s. A
ll U
nfav
orab
le (f
ollo
w u
p: m
ean
18 m
onth
s)1
obse
rvat
iona
l st
udie
sse
rious
ano
t ser
ious
not s
erio
usno
t ser
ious
none
267/
378
(70.
6%)
248/
529
(46.
9%)
OR
2.9
(2.1
to
4.0)
24 m
ore
per 1
00
(from
17
mor
e to
31 m
ore)
b
VE
RY L
OW
CRIT
ICAL
AFB
Sm
ear P
ositi
ve: L
ost v
s. A
ll O
ther
Out
com
es (f
ollo
w u
p: m
ean
18 m
onth
s)1
obse
rvat
iona
l st
udie
sse
rious
ano
t ser
ious
not s
erio
usno
t ser
ious
none
33/3
78 (8
.7%
)13
1/52
9 (2
4.8%
)O
R 0.
3 (0
.2 to
0.
6)
15 fe
wer
pe
r 100
(fr
om
20 fe
wer
to
9 fe
wer
)b
VE
RY L
OW
CRIT
ICAL
WHO consolidated guidelines on tuberculosis: Online annexes50
Cert
aint
y as
sess
men
t№
of p
atie
nts
Effe
ct
Cert
aint
yIm
port
ance
№ o
f st
udie
sSt
udy
desi
gnRi
sk o
f bi
asIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Oth
er
cons
ider
atio
ns
All-
oral
be
daqu
iline
-co
ntai
ning
sh
orte
r reg
imen
of
9–1
2 m
onth
s du
ratio
n
Long
er
regi
men
s w
ithou
t new
TB
drug
s
Rela
tive
(95%
CI)
Abs
olut
e (9
5% C
I)
HIV
-Pos
itive
on
ART
: Suc
cess
vs.
Fai
lure
/Rec
urre
nce
(fol
low
up:
mea
n 18
mon
ths)
1ob
serv
atio
nal
stud
ies
serio
usa
not s
erio
usno
t ser
ious
not s
erio
usno
ne42
9/44
6 (9
6.2%
)43
2/49
1 (8
8.0%
)O
R 4.
5 (2
.4 to
8.
4)
8 m
ore
per 1
00
(from
4
mor
e to
11
mor
e)b
VE
RY L
OW
CRIT
ICAL
HIV
-Pos
itive
on
ART
: Suc
cess
vs.
Dea
th (f
ollo
w u
p: m
ean
18 m
onth
s)1
obse
rvat
iona
l st
udie
sse
rious
ano
t ser
ious
not s
erio
usno
t ser
ious
none
429/
541
(79.
3%)
432/
689
(62.
7%)
OR
2.7
(2.0
to
3.7)
18 m
ore
per 1
00
(from
12
mor
e to
23 m
ore)
b
VE
RY L
OW
CRIT
ICAL
HIV
-Pos
itive
on
ART
: Suc
cess
vs.
Fai
lure
/Rec
urre
nce/
Dea
th (f
ollo
w u
p: m
ean
18 m
onth
s)1
obse
rvat
iona
l st
udie
sse
rious
ano
t ser
ious
not s
erio
usno
t ser
ious
none
429/
558
(76.
9%)
432/
748
(57.
8%)
OR
2.9
(2.2
to
3.9)
21 m
ore
per 1
00
(from
15
mor
e to
26 m
ore)
b
VE
RY L
OW
CRIT
ICAL
HIV
-Pos
itive
on
ART
: Suc
cess
vs.
All
Unf
avor
able
(fol
low
up:
mea
n 18
mon
ths)
1ob
serv
atio
nal
stud
ies
serio
usa
not s
erio
usno
t ser
ious
not s
erio
usno
ne42
9/61
3 (7
0.0%
)43
2/91
9 (4
7.0%
)O
R 2.
7 (2
.1 to
3.
5)
23 m
ore
per 1
00
(from
17
mor
e to
28 m
ore)
b
VE
RY L
OW
CRIT
ICAL
HIV
-Pos
itive
on
ART
: Los
t vs.
All
Oth
er O
utco
mes
(fol
low
up:
mea
n 18
mon
ths)
1ob
serv
atio
nal
stud
ies
serio
usa
not s
erio
usno
t ser
ious
not s
erio
usno
ne63
/613
(10.
3%)
214/
919
(23.
3%)
OR
0.4
(0.3
to
0.6)
11 fe
wer
pe
r 100
(fr
om
15 fe
wer
to
7 fe
wer
)b
VE
RY L
OW
CRIT
ICAL
HIV
Neg
ativ
e: S
ucce
ss v
s. F
ailu
re/R
ecur
renc
e (f
ollo
w u
p: m
ean
18 m
onth
s)1
obse
rvat
iona
l st
udie
sse
rious
ano
t ser
ious
not s
erio
usno
t ser
ious
none
195/
199
(98.
0%)
227/
258
(88.
0%)
OR
6.7
(2.2
to
20.8
)
12 m
ore
per 1
00
(from
6
mor
e to
18
mor
e)b
VE
RY L
OW
CRIT
ICAL
Annex 3: GRADE evidence summary tables 51
Cert
aint
y as
sess
men
t№
of p
atie
nts
Effe
ct
Cert
aint
yIm
port
ance
№ o
f st
udie
sSt
udy
desi
gnRi
sk o
f bi
asIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Oth
er
cons
ider
atio
ns
All-
oral
be
daqu
iline
-co
ntai
ning
sh
orte
r reg
imen
of
9–1
2 m
onth
s du
ratio
n
Long
er
regi
men
s w
ithou
t new
TB
drug
s
Rela
tive
(95%
CI)
Abs
olut
e (9
5% C
I)
HIV
Neg
ativ
e: S
ucce
ss v
s. D
eath
(fol
low
up:
mea
n 18
mon
ths)
1ob
serv
atio
nal
stud
ies
serio
usa
not s
erio
usno
t ser
ious
not s
erio
usno
ne19
5/23
4 (8
3.3%
)22
7/30
2 (7
5.2%
)O
R 2.
1 (1
.2 to
3.
8)
13 m
ore
per 1
00
(from
5
mor
e to
21
mor
e)b
VE
RY L
OW
CRIT
ICAL
HIV
Neg
ativ
e: S
ucce
ss v
s. F
ailu
re/R
ecur
renc
e/D
eath
(fol
low
up:
mea
n 18
mon
ths)
1ob
serv
atio
nal
stud
ies
serio
usa
not s
erio
usno
t ser
ious
not s
erio
usno
ne19
5/23
8 (8
1.9%
)22
7/33
3 (6
8.2%
)O
R 2.
5 (1
.6 to
3.
8)
17 m
ore
per 1
00
(from
9
mor
e to
26
mor
e)b
VE
RY L
OW
CRIT
ICAL
HIV
Neg
ativ
e: S
ucce
ss v
s. A
ll O
ther
Out
com
es (f
ollo
w u
p: m
ean
18 m
onth
s)1
obse
rvat
iona
l st
udie
sse
rious
ano
t ser
ious
not s
erio
usno
t ser
ious
none
195/
255
(76.
5%)
227/
440
(51.
6%)
OR
3.5
(2.4
to
5.2)
28 m
ore
per 1
00
(from
20
mor
e to
37
mor
e)b
VE
RY L
OW
CRIT
ICAL
HIV
Neg
ativ
e: L
ost v
s. A
ll O
ther
Out
com
es (f
ollo
w u
p: m
ean
18 m
onth
s)1
obse
rvat
iona
l st
udie
sse
rious
ano
t ser
ious
not s
erio
usno
t ser
ious
none
18/2
55 (7
.1%
)13
0/44
0 (2
9.5%
)O
R 0.
2 (0
.1 to
0.
4)
21 fe
wer
pe
r 100
(fr
om
28 fe
wer
to
14 fe
wer
)b
VE
RY L
OW
CRIT
ICAL
AFB:
acid
-fas
t bac
illi; a
OR:
adj
uste
d od
ds ra
tio; A
RT: a
ntire
trovi
ral t
hera
py; C
I: co
nfid
ence
inte
rval
; HIV
: hum
an im
mun
odef
icien
cy v
irus;
MD
R/RR
-TB:
mul
tidru
g- o
r rifa
mpi
cin-r
esist
ant T
B: O
R: o
dds
ratio
; WH
O:
Wor
ld H
ealth
Org
aniz
atio
n.
Expl
anat
ions
a. F
or s
ome
patie
nts,
info
rmat
ion
was
miss
ing
on A
FB s
mea
r res
ult a
nd c
ultu
re re
sult
in th
e an
alys
is. P
atie
nts
with
unk
now
n ag
e, s
ex, o
r HIV
sta
tus
wer
e ex
clude
d fro
m a
ll an
alys
es.
b. O
utco
mes
and
cos
ts a
re s
imul
ated
usin
g a
mod
el th
at d
raw
s pa
ram
eter
est
imat
es fr
om m
ultip
le s
ourc
es, i
nclu
ding
the
aORs
for s
ucce
ss v
ersu
s de
ath/
failu
re d
escr
ibed
abo
ve.
c. T
he a
bsol
ute
effe
ct is
cal
cula
ted
afte
r mat
chin
g in
terv
entio
n an
d co
mpa
rato
r pop
ulat
ions
, and
per
form
ing
bino
mia
l reg
ress
ion
with
an
iden
tity
link.
WHO consolidated guidelines on tuberculosis: Online annexes52
Aut
hor(
s):
Rese
arch
Inst
itute
of t
he M
cGill
Univ
ersit
y H
ealth
Cen
treQ
uest
ion:
Sh
ould
an
all-o
ral s
hort
er re
gim
en o
f 9–1
2 m
onth
s’ du
ratio
n in
cludi
ng b
edaq
uilin
e vs
long
er re
gim
ens c
onta
inin
g be
daqu
iline
be u
sed
in
MD
R/RR
-TB
patie
nts
to s
afel
y im
prov
e ou
tcom
es?
Sett
ing:
In
tern
atio
nal
Dat
e:
April
202
0
Cert
aint
y as
sess
men
t№
of p
atie
nts
Effe
ct
Cert
aint
yIm
port
ance
№ o
f st
udie
sSt
udy
desi
gnRi
sk o
f bi
asIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Oth
er
cons
ider
atio
ns
All-
oral
be
daqu
iline
-co
ntai
ning
sh
orte
r reg
imen
of
9–1
2 m
onth
s du
ratio
n
Long
er
regi
men
s co
ntai
ning
be
daqu
iline
Rela
tive
(95%
CI)
Abs
olut
e (9
5% C
I)
Succ
ess
vs. F
ailu
re/R
ecur
renc
e (f
ollo
w u
p: m
ean
18 m
onth
s)1
obse
rvat
iona
l st
udie
sse
rious
ano
t ser
ious
not s
erio
usno
t ser
ious
none
631/
653
(96.
6%)
268/
292
(91.
8%)
OR
3.9
(1.7
to
9.1)
5 m
ore
per 1
00
(from
1
mor
e to
9
mor
e)b,
c
VE
RY
LOW
CRIT
ICAL
Succ
ess
vs. D
eath
(fol
low
up:
mea
n 18
mon
ths)
1ob
serv
atio
nal
stud
ies
serio
usa
not s
erio
usno
t ser
ious
not s
erio
usno
ne63
1/79
1 (7
9.8%
)26
8/33
8 (7
9.3%
)O
R 1.
0 (0
.6 to
1.
5)
4 fe
wer
pe
r 100
(fr
om
10 fe
wer
to
3 m
ore)
b,c
VE
RY
LOW
CRIT
ICAL
Succ
ess
vs. F
ailu
re/R
ecur
renc
e/D
eath
(fol
low
up:
mea
n 18
mon
ths)
1ob
serv
atio
nal
stud
ies
serio
usa
not s
erio
usno
t ser
ious
not s
erio
usno
ne63
1/81
3 (7
7.6%
)26
8/36
2 (7
4.0%
) O
R 1.
4 (0
.9 to
2.
0)
2 m
ore
per 1
00
(from
4
few
er to
9
mor
e)b,
c
VE
RY
LOW
CRIT
ICAL
Succ
ess
vs. A
ll U
nfav
orab
le (f
ollo
w u
p: m
ean
18 m
onth
s)1
obse
rvat
iona
l st
udie
sse
rious
ano
t ser
ious
not s
erio
usno
t ser
ious
none
631/
891
(70.
8%)
268/
440
(60.
9%)
OR
1.6
(1.2
to
2.2)
7 m
ore
per 1
00
(from
1
mor
e to
14
mor
e)b,
c
VE
RY
LOW
CRIT
ICAL
Annex 3: GRADE evidence summary tables 53
Cert
aint
y as
sess
men
t№
of p
atie
nts
Effe
ct
Cert
aint
yIm
port
ance
№ o
f st
udie
sSt
udy
desi
gnRi
sk o
f bi
asIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Oth
er
cons
ider
atio
ns
All-
oral
be
daqu
iline
-co
ntai
ning
sh
orte
r reg
imen
of
9–1
2 m
onth
s du
ratio
n
Long
er
regi
men
s co
ntai
ning
be
daqu
iline
Rela
tive
(95%
CI)
Abs
olut
e (9
5% C
I)
Lost
vs.
All
Oth
er O
utco
mes
(fol
low
up:
mea
n 18
mon
ths)
1ob
serv
atio
nal
stud
ies
serio
usa
not s
erio
usno
t ser
ious
not s
erio
usno
ne88
/891
(9.9
%)
88/4
40 (2
0.0%
) O
R 0.
5 (0
.4 to
0.
8)
8 fe
wer
pe
r 100
(fr
om
13 fe
wer
to
3 fe
wer
)b,c
VE
RY
LOW
CRIT
ICAL
AFB
Sm
ear P
ositi
ve: S
ucce
ss v
s. F
ailu
re/R
ecur
renc
e (f
ollo
w u
p: m
ean
18 m
onth
s)1
obse
rvat
iona
l st
udie
sse
rious
ano
t ser
ious
not s
erio
usno
t ser
ious
none
267/
274
(97.
4%)
133/
148
(89.
9%)
OR
4.1
(1.4
to
12.2
)
6 m
ore
per 1
00
(from
1
few
er to
12
mor
e)b
VE
RY
LOW
CRIT
ICAL
AFB
Sm
ear P
ositi
ve: S
ucce
ss v
s. D
eath
(fol
low
up:
mea
n 18
mon
ths)
1ob
serv
atio
nal
stud
ies
serio
usa
not s
erio
usno
t ser
ious
not s
erio
usno
ne26
7/34
1 (7
8.3%
)13
3/17
1 (7
7.8%
)O
R 0.
8 (0
.5 to
1.
4)
4 fe
wer
pe
r 100
(fr
om
13 fe
wer
to
5 m
ore)
b
VE
RY
LOW
CRIT
ICAL
AFB
Sm
ear P
ositi
ve: S
ucce
ss v
s. F
ailu
re/R
ecur
renc
e/D
eath
(fol
low
up:
mea
n 18
mon
ths)
1ob
serv
atio
nal
stud
ies
serio
usa
not s
erio
usno
t ser
ious
not s
erio
usno
ne26
7/34
8 (7
6.7%
)13
3/18
6 (7
1.5%
)O
R 1.
5 (0
.9 to
2.
5)
4 m
ore
per 1
00
(from
5
few
er to
13
mor
e)b
VE
RY
LOW
CRIT
ICAL
AFB
Sm
ear P
ositi
ve: S
ucce
ss v
s. A
ll U
nfav
orab
le (f
ollo
w u
p: m
ean
18 m
onth
s)1
obse
rvat
iona
l st
udie
sse
rious
ano
t ser
ious
not s
erio
usno
t ser
ious
none
267/
378
(70.
6%)
133/
223
(59.
6%)
OR
2.0
(1.3
to
3.1)
12 m
ore
per 1
00
(from
3
mor
e to
21
mor
e)b
VE
RY
LOW
CRIT
ICAL
AFB
Sm
ear P
ositi
ve: L
ost v
s. A
ll O
ther
Out
com
es (f
ollo
w u
p: m
ean
18 m
onth
s)1
obse
rvat
iona
l st
udie
sse
rious
ano
t ser
ious
not s
erio
usno
t ser
ious
none
33/3
78 (8
.7%
)41
/223
(18.
4%)
OR
0.3
(0.2
to
0.6)
11 fe
wer
pe
r 100
(fr
om
17 fe
wer
to
5 fe
wer
)b
VE
RY
LOW
CRIT
ICAL
WHO consolidated guidelines on tuberculosis: Online annexes54
Cert
aint
y as
sess
men
t№
of p
atie
nts
Effe
ct
Cert
aint
yIm
port
ance
№ o
f st
udie
sSt
udy
desi
gnRi
sk o
f bi
asIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Oth
er
cons
ider
atio
ns
All-
oral
be
daqu
iline
-co
ntai
ning
sh
orte
r reg
imen
of
9–1
2 m
onth
s du
ratio
n
Long
er
regi
men
s co
ntai
ning
be
daqu
iline
Rela
tive
(95%
CI)
Abs
olut
e (9
5% C
I)
HIV
-Pos
itive
on
ART
: Suc
cess
vs.
Fai
lure
/Rec
urre
nce
(fol
low
up:
mea
n 18
mon
ths)
1ob
serv
atio
nal
stud
ies
serio
usa
not s
erio
usno
t ser
ious
not s
erio
usno
ne42
9/44
6 (9
6.2%
)19
1/20
5 (9
3.2%
)O
R 2.
8 (1
.0 to
8.
2)
4 m
ore
per 1
00
(from
0
few
er to
8
mor
e)b
VE
RY
LOW
CRIT
ICAL
HIV
-Pos
itive
on
ART
: Suc
cess
vs.
Dea
th (f
ollo
w u
p: m
ean
18 m
onth
s)1
obse
rvat
iona
l st
udie
sse
rious
ano
t ser
ious
not s
erio
usno
t ser
ious
none
429/
541
(79.
3%)
191/
244
(78.
3%)
OR
1.0
(0.6
to
1.6)
1 fe
wer
pe
r 100
(fr
om
9 fe
wer
to
6 m
ore)
b
VE
RY
LOW
CRIT
ICAL
HIV
-Pos
itive
on
ART
: Suc
cess
vs.
Fai
lure
/Rec
urre
nce/
Dea
th (f
ollo
w u
p: m
ean
18 m
onth
s)1
obse
rvat
iona
l st
udie
sse
rious
ano
t ser
ious
not s
erio
usno
t ser
ious
none
429/
558
(76.
9%)
191/
258
(74.
0%)
OR
1.2
(0.8
to
1.9)
1 m
ore
per 1
00
(from
6
few
er to
9
mor
e)b
VE
RY
LOW
CRIT
ICAL
HIV
-Pos
itive
on
ART
: Suc
cess
vs.
All
Unf
avor
able
(fol
low
up:
mea
n 18
mon
ths)
1ob
serv
atio
nal
stud
ies
serio
usa
not s
erio
usno
t ser
ious
not s
erio
usno
ne42
9/61
3 (7
0.0%
)19
1/31
1 (6
1.4%
)O
R 2.
1 (1
.4 to
3.
1)
12 m
ore
per 1
00
(from
5
mor
e to
20
mor
e)b
VE
RY
LOW
CRIT
ICAL
HIV
-Pos
itive
on
ART
: Los
t vs.
All
Oth
er O
utco
mes
(fol
low
up:
mea
n 18
mon
ths)
1ob
serv
atio
nal
stud
ies
serio
usa
not s
erio
usno
t ser
ious
not s
erio
usno
ne63
/613
(10.
3%)
62/3
11 (1
9.9%
)O
R 0.
3 (0
.2 to
0.
6)
12 fe
wer
pe
r 100
(fr
om
18 fe
wer
to
7 fe
wer
)b
VE
RY
LOW
CRIT
ICAL
HIV
Neg
ativ
e: S
ucce
ss v
s. F
ailu
re/R
ecur
renc
e (f
ollo
w u
p: m
ean
18 m
onth
s)1
obse
rvat
iona
l st
udie
sse
rious
ano
t ser
ious
not s
erio
usno
t ser
ious
none
195/
199
(98.
0%)
73/8
2 (8
9.0%
)O
R 3.
5 (0
.8 to
15
.4)
8 m
ore
per 1
00
(from
1
few
er to
16
mor
e)b
VE
RY
LOW
CRIT
ICAL
Annex 3: GRADE evidence summary tables 55
Cert
aint
y as
sess
men
t№
of p
atie
nts
Effe
ct
Cert
aint
yIm
port
ance
№ o
f st
udie
sSt
udy
desi
gnRi
sk o
f bi
asIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Oth
er
cons
ider
atio
ns
All-
oral
be
daqu
iline
-co
ntai
ning
sh
orte
r reg
imen
of
9–1
2 m
onth
s du
ratio
n
Long
er
regi
men
s co
ntai
ning
be
daqu
iline
Rela
tive
(95%
CI)
Abs
olut
e (9
5% C
I)
HIV
Neg
ativ
e: S
ucce
ss v
s. D
eath
(fol
low
up:
mea
n 18
mon
ths)
1ob
serv
atio
nal
stud
ies
serio
usa
not s
erio
usno
t ser
ious
not s
erio
usno
ne19
5/23
4 (8
3.3%
)73
/87
(83.
9%)
OR
1.3
(0.5
to
3.3)
1 m
ore
per 1
00
(from
11
fewe
r to
13 m
ore)
b
VE
RY
LOW
CRIT
ICAL
HIV
Neg
ativ
e: S
ucce
ss v
s. F
ailu
re/R
ecur
renc
e/D
eath
(fol
low
up:
mea
n 18
mon
ths)
1ob
serv
atio
nal
stud
ies
serio
usa
not s
erio
usno
t ser
ious
not s
erio
usno
ne19
5/23
8 (8
1.9%
)73
/96
(76.
0%)
OR
1.7
(0.8
to
3.7)
6 m
ore
per 1
00
(from
7
few
er to
18
mor
e)b
VE
RY
LOW
CRIT
ICAL
HIV
Neg
ativ
e: S
ucce
ss v
s. A
ll U
nfav
orab
le (f
ollo
w u
p: m
ean
18 m
onth
s)1
obse
rvat
iona
l st
udie
sse
rious
ano
t ser
ious
not s
erio
usno
t ser
ious
none
195/
255
(76.
5%)
73/1
17 (6
2.4%
)O
R 1.
8 (0
.9 to
3.
4)
11 m
ore
per 1
00
(from
1
few
er to
24
mor
e)b
VE
RY
LOW
CRIT
ICAL
HIV
Neg
ativ
e: L
ost v
s. A
ll O
ther
Out
com
es (f
ollo
w u
p: m
ean
18 m
onth
s)1
obse
rvat
iona
l st
udie
sse
rious
ano
t ser
ious
not s
erio
usno
t ser
ious
none
18/2
55 (7
.1%
)22
/117
(18.
8%)
OR
0.4
(0.2
to
0.9)
11 fe
wer
pe
r 100
(fr
om
20 fe
wer
to
2 fe
wer
)b
VE
RY
LOW
CRIT
ICAL
AFB:
acid
-fas
t bac
illi; a
OR:
adj
uste
d od
ds ra
tio; A
RT: a
ntire
trovi
ral t
hera
py; C
I: co
nfid
ence
inte
rval
; HIV
: hum
an im
mun
odef
icien
cy v
irus;
MD
R/RR
-TB:
mul
tidru
g- o
r rifa
mpi
cin-r
esist
ant T
B; O
R: o
dds
ratio
.
Expl
anat
ions
a. F
or s
ome
patie
nts,
info
rmat
ion
was
miss
ing
on A
FB s
mea
r res
ult a
nd c
ultu
re re
sult
in th
e an
alys
is. P
atie
nts
with
unk
now
n ag
e, s
ex, o
r HIV
sta
tus
wer
e ex
clude
d fro
m a
ll an
alys
es.
b. O
utco
mes
and
cos
ts a
re s
imul
ated
usin
g a
mod
el th
at d
raw
s pa
ram
eter
est
imat
es fr
om m
ultip
le s
ourc
es, i
nclu
ding
the
aORs
for s
ucce
ss v
ersu
s de
ath
or fa
ilure
des
crib
ed a
bove
.
c. T
he a
bsol
ute
effe
ct is
cal
cula
ted
afte
r mat
chin
g in
terv
entio
n an
d co
mpa
rato
r pop
ulat
ions
, and
per
form
ing
bino
mia
l reg
ress
ion
with
an
iden
tity
link.
WHO consolidated guidelines on tuberculosis: Online annexes56
Aut
hor(
s):
Rese
arch
Inst
itute
of t
he M
cGill
Univ
ersit
y H
ealth
Cen
tre
Que
stio
n:
Shou
ld a
n al
l-ora
l sho
rter
regi
men
of 9
–12
mon
ths d
urat
ion
inclu
ding
bed
aqui
line
vs lo
nger
regi
men
s con
tain
ing
beda
quilin
e an
d lin
ezol
id
be u
sed
in M
DR/
RR-T
B pa
tient
s to
saf
ely
impr
ove
outc
omes
?Se
ttin
g:
Inte
rnat
iona
lD
ate:
Ap
ril 2
020
Cert
aint
y as
sess
men
t№
of p
atie
nts
Effe
ct
Cert
aint
yIm
port
ance
№ o
f st
udie
sSt
udy
desi
gnRi
sk o
f bi
asIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Oth
er
cons
ider
atio
ns
All-
oral
be
daqu
iline
-co
ntai
ning
sho
rter
re
gim
en o
f 9–1
2 m
onth
s du
ratio
n
Long
er
regi
men
s co
ntai
ning
be
daqu
iline
an
d lin
ezol
id
Rela
tive
(95%
CI)
Abs
olut
e (9
5% C
I)
Succ
ess
vs. F
ailu
re/R
ecur
renc
e (f
ollo
w u
p: m
ean
18 m
onth
s)1
obse
rvat
iona
l st
udie
sse
rious
ano
t ser
ious
not s
erio
usno
t ser
ious
none
631/
653
(96.
6%)
103/
110
(93.
6%)
OR
1.8
(0.5
to
6.3)
3 m
ore
per 1
00
(from
3
few
er to
9
mor
e)b,
c
VE
RY
LOW
CRIT
ICAL
Succ
ess
vs. D
eath
(fol
low
up:
mea
n 18
mon
ths)
1ob
serv
atio
nal
stud
ies
serio
usa
not s
erio
usno
t ser
ious
not s
erio
usno
ne63
1/79
1 (7
9.8%
)10
3/11
8 (8
7.3%
)O
R 1.
1 (0
.5 to
2.
6)
1 fe
wer
pe
r 100
(fr
om
10 fe
wer
to
8 m
ore)
b,c
VE
RY
LOW
CRIT
ICAL
Succ
ess
vs. F
ailu
re/R
ecur
renc
e/D
eath
(fol
low
up:
mea
n 18
mon
ths)
1ob
serv
atio
nal
stud
ies
serio
usa
not s
erio
usno
t ser
ious
not s
erio
usno
ne63
1/81
3 (7
7.6%
)10
3/12
5 (8
2.4%
)O
R 0.
9 (0
.5 to
1.
8)
5 fe
wer
pe
r 100
(fr
om
15 fe
wer
to
5 m
ore)
b,c
VE
RY
LOW
CRIT
ICAL
Succ
ess
vs. A
ll U
nfav
orab
le (f
ollo
w u
p: m
ean
18 m
onth
s)1
obse
rvat
iona
l st
udie
sse
rious
ano
t ser
ious
not s
erio
usno
t ser
ious
none
631/
891
(70.
8%)
103/
157
(65.
6%)
OR
2.1
(1.2
to
3.7)
13 m
ore
per 1
00
(from
3
mor
e to
23
mor
e)b,
c
VE
RY
LOW
CRIT
ICAL
Lost
vs.
All
Oth
er O
utco
mes
(fol
low
up:
mea
n 18
mon
ths)
1ob
serv
atio
nal
stud
ies
serio
usa
not s
erio
usno
t ser
ious
not s
erio
usno
ne88
/891
(9.9
%)
36/1
57 (2
2.9%
)O
R 0.
4 (0
.1 to
0.
6)
15 fe
wer
pe
r 100
(fr
om
23 fe
wer
to
7 fe
wer
)b,c
VE
RY
LOW
CRIT
ICAL
Annex 3: GRADE evidence summary tables 57
Cert
aint
y as
sess
men
t№
of p
atie
nts
Effe
ct
Cert
aint
yIm
port
ance
№ o
f st
udie
sSt
udy
desi
gnRi
sk o
f bi
asIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Oth
er
cons
ider
atio
ns
All-
oral
be
daqu
iline
-co
ntai
ning
sho
rter
re
gim
en o
f 9–1
2 m
onth
s du
ratio
n
Long
er
regi
men
s co
ntai
ning
be
daqu
iline
an
d lin
ezol
id
Rela
tive
(95%
CI)
Abs
olut
e (9
5% C
I)
HIV
-Pos
itive
on
ART
: Suc
cess
vs.
Fai
lure
/Rec
urre
nce
(fol
low
up:
mea
n 18
mon
ths)
1ob
serv
atio
nal
stud
ies
serio
usa
not s
erio
usno
t ser
ious
not s
erio
usno
ne42
9/44
6 (9
6.2%
)80
/85
(94.
1%)
OR
2.6
(0.5
to
13.8
)
4 m
ore
per 1
00
(from
2
few
er to
10
mor
e)b
VE
RY
LOW
CRIT
ICAL
HIV
-Pos
itive
on
ART
: Suc
cess
vs.
Dea
th (f
ollo
w u
p: m
ean
18 m
onth
s)1
obse
rvat
iona
l st
udie
sse
rious
ano
t ser
ious
not s
erio
usno
t ser
ious
none
429/
541
(79.
3%)
80/9
1 (8
7.9%
)O
R 0.
6 (0
.2 to
1.
4)
9 fe
wer
pe
r 100
(fr
om
20 fe
wer
to
2 m
ore)
b
VE
RY
LOW
CRIT
ICAL
HIV
-Pos
itive
on
ART
: Suc
cess
vs.
Fai
lure
/Rec
urre
nce/
Dea
th (f
ollo
w u
p: m
ean
18 m
onth
s)1
obse
rvat
iona
l st
udie
sse
rious
ano
t ser
ious
not s
erio
usno
t ser
ious
none
429/
558
(76.
9%)
80/9
6 (8
3.3%
)O
R 1.
0 (0
.4 to
2.
3)
3 fe
wer
pe
r 100
(fr
om
14 fe
wer
to
8 m
ore)
b
VE
RY
LOW
HIV
-Pos
itive
on
ART
: Suc
cess
vs.
All
Unf
avor
able
(fol
low
up:
mea
n 18
mon
ths)
1ob
serv
atio
nal
stud
ies
serio
usa
not s
erio
usno
t ser
ious
not s
erio
usno
ne42
9/61
3 (7
0.0%
)80
/119
(67.
2%)
OR
1.8
(0.9
to
3.6)
11 m
ore
per 1
00
(from
0
few
er to
23
mor
e)b
VE
RY
LOW
CRIT
ICAL
HIV
-Pos
itive
on
ART
: Los
t vs.
All
Oth
er O
utco
mes
(fol
low
up:
mea
n 18
mon
ths)
1ob
serv
atio
nal
stud
ies
serio
usa
not s
erio
usno
t ser
ious
not s
erio
usst
rong
as
socia
tion
63/6
13 (1
0.3%
)26
/119
(21.
8%)
OR
0.3
(0.1
to
0.7)
15 fe
wer
pe
r 100
(fr
om
24 fe
wer
to
6 fe
wer
)b
VE
RY
LOW
CRIT
ICAL
aOR:
adj
uste
d od
ds ra
tio; A
RT: a
ntire
trovi
ral t
hera
py; C
I: co
nfid
ence
inte
rval
; HIV
: hum
an im
mun
odef
icien
cy v
irus;
MD
R/RR
-TB:
mul
tidru
g- o
r rifa
mpi
cin-r
esist
ant T
B; O
R: o
dds
ratio
.
Expl
anat
ions
a. F
or s
ome
patie
nts,
info
rmat
ion
was
miss
ing
on A
FB s
mea
r res
ult a
nd c
ultu
re re
sult
in th
e an
alys
is. P
atie
nts
with
unk
now
n ag
e, s
ex, o
r HIV
sta
tus
wer
e ex
clude
d fro
m a
ll an
alys
es.
b. O
utco
mes
and
cos
ts a
re s
imul
ated
usin
g a
mod
el th
at d
raw
s pa
ram
eter
est
imat
es fr
om m
ultip
le s
ourc
es, i
nclu
ding
the
aORs
for s
ucce
ss v
ersu
s de
ath
or fa
ilure
des
crib
ed a
bove
.
c. T
he a
bsol
ute
effe
ct is
cal
cula
ted
afte
r mat
chin
g in
terv
entio
n an
d co
mpa
rato
r pop
ulat
ions
, and
per
form
ing
bino
mia
l reg
ress
ion
with
an
iden
tity
link.
WHO consolidated guidelines on tuberculosis: Online annexes58
Aut
hor(
s):
TB A
llianc
e Q
uest
ion:
Sh
ould
trea
tmen
t reg
imen
last
ing
6–9
mon
ths c
ompo
sed
of b
edaq
uilin
e, p
reto
man
id a
nd lin
ezol
id v
s. lo
nger
regi
men
s con
tain
ing
beda
quilin
e an
d lin
ezol
id in
add
ition
to o
ther
ant
i-TB
drug
s be
used
for X
DR-
TB p
atie
nts o
r pat
ient
s who
are
trea
tmen
t int
oler
ant o
r with
non
-res
pons
ive
MD
R-TB
?Se
ttin
g:
Five
site
s in
Sou
th A
frica
Bi
blio
grap
hy:
Conr
adie
F, D
iaco
n AH
, Ngu
bane
N e
t al.
Trea
tmen
t of h
ighl
y dr
ug-r
esist
ant p
ulm
onar
y tu
berc
ulos
is, N
ew E
ngla
nd Jo
urna
l of M
edici
ne.
2020
; 382
(10)
: 893
–902
.
Cert
aint
y as
sess
men
t№
of p
atie
nts
Effe
ct
Cert
aint
yIm
port
ance
№ o
f st
udie
sSt
udy
desi
gnRi
sk o
f bi
asIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Oth
er
cons
ider
atio
ns
trea
tmen
t re
gim
en la
stin
g 6–
9 m
onth
s co
mpo
sed
of
beda
quili
ne,
pret
oman
id a
nd
linez
olid
long
er re
gim
ens
cont
aini
ng
beda
quili
ne
and
linez
olid
in
add
ition
to
othe
r ant
i-TB
dr
ugs
Rela
tive
(95%
CI)
Abs
olut
e (9
5% C
I)
Succ
ess
vs. F
ailu
re/R
ecur
renc
e (f
ollo
w u
p: m
ean
24 m
onth
s)1a
obse
rvat
iona
l st
udie
s ve
ry
serio
usb
serio
usc
serio
usd
very
ser
ious
eno
ne
96/9
9 (9
7.0%
) 37
5/40
9 (9
1.7%
) O
R 3.
3 (0
.8 to
13
.7)
6 m
ore
per 1
00
(from
2
few
er to
14
mor
e)f,g
VE
RY
LOW
CRIT
ICAL
Succ
ess
vs. D
eath
(fol
low
up:
mea
n 24
mon
ths)
1aob
serv
atio
nal
stud
ies
very
se
rious
bse
rious
cse
rious
dve
ry s
erio
use
none
96
/103
(93.
2%)
375/
408
(91.
9%)
OR
1.0
(0.1
to
8.2)
1 m
ore
per 1
00
(from
7
few
er to
8
mor
e)f,g
VE
RY
LOW
CRIT
ICAL
Succ
ess
vs. F
ailu
re/R
ecur
renc
e/D
eath
(fol
low
up:
mea
n 24
mon
ths)
1aob
serv
atio
nal
stud
ies
very
se
rious
bse
rious
cse
rious
dve
ry s
erio
use
none
96
/106
(90.
6%)
375/
442
(84.
8%)
OR
1.8
(0.7
to
4.4)
6 m
ore
per 1
00
(from
4
few
er to
16
mor
e)f,g
VE
RY
LOW
CRIT
ICAL
Succ
ess
vs. A
ll U
nfav
orab
le (f
ollo
w u
p: m
ean
24 m
onth
s)1a
obse
rvat
iona
l st
udie
s ve
ry
serio
usb
serio
usc
serio
usd
very
ser
ious
eno
ne
96/1
08 (8
8.9%
) 37
5/45
6 (8
2.2%
) O
R 1.
2 (0
.5 to
3.
1)
2 m
ore
per 1
00
(from
7
few
er to
12
mor
e)f,g
VE
RY
LOW
CRIT
ICAL
Annex 3: GRADE evidence summary tables 59
Cert
aint
y as
sess
men
t№
of p
atie
nts
Effe
ct
Cert
aint
yIm
port
ance
№ o
f st
udie
sSt
udy
desi
gnRi
sk o
f bi
asIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Oth
er
cons
ider
atio
ns
trea
tmen
t re
gim
en la
stin
g 6–
9 m
onth
s co
mpo
sed
of
beda
quili
ne,
pret
oman
id a
nd
linez
olid
long
er re
gim
ens
cont
aini
ng
beda
quili
ne
and
linez
olid
in
add
ition
to
othe
r ant
i-TB
dr
ugs
Rela
tive
(95%
CI)
Abs
olut
e (9
5% C
I)
Adv
erse
eve
nts
1 h
obse
rvat
iona
l st
udie
s ve
ry
serio
us i
not s
erio
us
serio
us
very
ser
ious
jno
ne
BPaL
reg
imen
: 1
(0.9
%)
patie
nt d
ied,
27
(25%
) pa
tient
s ex
perie
nced
ot
her
serio
us
adve
rse
even
ts
incl
udin
g ho
spita
lizat
ions
and
life
thr
eate
ning
eve
nts,
and
53 (
49%
) pa
tient
s ex
perie
nced
at l
east
one
Gra
de 3
–4 a
dver
se e
vent
s. D
rug
disc
ontin
uatio
n fo
r ad
vers
e ev
ents
: rel
ated
to a
ll th
ree
drug
s in
1 p
atie
nt, a
nd re
late
d to
line
zolid
(ini
tial d
ose
1200
m
g/da
y) d
iscon
tinue
d in
ano
ther
35
(32%
) pat
ient
s. O
nly
20
(18%
) pat
ient
s com
plet
ed a
full c
ours
e of
120
0 m
g/da
y. In
the
IPD
stud
ies (
90%
rece
ived
600
mg/
day
or le
ss),
the
pool
ed ra
te
of L
ZD p
erm
anen
t disc
ontin
uatio
n w
as 1
7.9%
, and
in th
e En
dTB
stud
y (a
ll pat
ient
s rec
eive
d 60
0mg/
day
or le
ss),
the
rate
of L
ZD
disc
ontin
uatio
n w
as 1
3.1%
. In
EndT
B: 9
per
sons
out
of 1
094
(0.8
%) d
ied
of a
pos
sibly/
prob
ably
drug
rela
ted
AE, i
nclu
ding
tw
o pe
rson
s with
sudd
en c
ardi
ac d
eath
and
QT
prol
onga
tion.
VE
RY
LOW
CRIT
ICAL
AE: a
dver
se e
vent
; BPa
L: b
edaq
uilin
e, p
reto
man
id a
nd li
nezo
lid; C
I: co
nfid
ence
inte
rval
; IPD
: ind
ivid
ual p
atie
nt d
ata;
LZD
: lin
ezol
id; M
DR/
RR-T
B: m
ultid
rug-
or r
ifam
picin
-res
istan
t TB;
OR:
odd
s ra
tio.
Expl
anat
ions
a. O
ne c
ohor
t stu
dy c
ompa
red
with
IPD
met
a-an
alys
is of
55
stud
ies.
b. T
his
was
a s
mal
l and
one
-arm
ed u
nblin
ded
coho
rt s
tudy
with
sub
stan
tial s
elec
tion
into
the
coh
ort;
follo
w-u
p da
ta t
o 24
mon
ths
wer
e no
t av
aila
ble
for
all p
atie
nts,
so e
nd-p
oint
s of
clin
ical f
ailu
re m
ay b
e un
dere
stim
ated
.
c. T
here
wer
e m
ajor
diff
eren
ces
betw
een
the
inte
rven
tion
and
com
para
tor g
roup
s (in
sel
ectio
n, c
hara
cter
istics
and
inte
nsity
of c
are)
, all
of w
hich
cou
ld h
ave
affe
cted
the
com
paris
on.
d. T
his
was
a s
mal
l, w
ell-r
esou
rced
, one
-arm
ed, u
nblin
ded
coho
rt s
tudy
that
was
com
pare
d w
ith c
ohor
ts a
nd ro
utin
ely
colle
cted
pro
gram
mat
ic da
ta in
the
IPD.
All
com
paris
ons
betw
een
the
inte
rven
tion
and
the
com
para
tor w
ere
indi
rect
.
e. T
his w
as a
smal
l stu
dy (1
08 p
atie
nts i
n to
tal in
mod
ified
inte
ntio
n-to
-tre
at a
nalys
is). I
t was
diff
icult
to p
erfo
rm a
dequ
ate
mat
chin
g in
the
anal
ysis,
so so
me
seco
ndar
y an
alys
es w
ere
even
mor
e lim
ited
by sm
all n
umbe
rs.
f. O
utco
mes
and
cos
ts w
ere
simul
ated
usin
g a
mod
el th
at d
raw
s pa
ram
eter
est
imat
es fr
om m
ultip
le s
ourc
es, i
nclu
ding
the
adju
sted
odd
s ra
tios
for s
ucce
ss v
ersu
s de
ath
or fa
ilure
des
crib
ed a
bove
.
g. T
he a
bsol
ute
effe
ct is
cal
cula
ted
afte
r mat
chin
g in
terv
entio
n an
d co
mpa
rato
r pop
ulat
ions
, and
per
form
ing
bino
mia
l reg
ress
ion
with
an
iden
tity
link.
h. O
ne c
ohor
t stu
dy (c
ompa
red
with
IPD
met
a-an
alys
is of
30
stud
ies
cont
aini
ng a
dver
se e
vent
info
rmat
ion
and
the
EndT
B ob
serv
atio
nal s
tudy
)
i. W
ithin
the
IPD,
adv
erse
eve
nt d
ata
are
only
con
siste
ntly
repo
rted
for i
ndiv
idua
ls w
ho p
erm
anen
tly s
topp
ed th
e dr
ug o
f int
eres
t; al
so, c
erta
in d
rugs
may
be
mor
e clo
sely
mon
itore
d fo
r tox
icitie
s (e
.g. b
edaq
uilin
e an
d lin
ezol
id).
j. Th
is w
as a
sm
all s
tudy
(109
pat
ient
s in
the
safe
ty a
naly
sis) c
ompa
red
with
30
diffe
rent
stu
dies
in th
e IP
D, w
hich
may
var
y in
the
inte
nsity
and
com
plet
enes
s of
adv
erse
eve
nt re
port
ing.
WHO consolidated guidelines on tuberculosis: Online annexes60
Aut
hor(
s):
Rese
arch
Inst
itute
of t
he M
cGill
Univ
ersit
y H
ealth
Cen
tre
Que
stio
n:
Shou
ld b
edaq
uilin
e fo
r mor
e th
an s
ix m
onth
s vs
. bed
aqui
line
for u
p to
six
mon
ths
be u
sed
in M
DR/
RR-T
B pa
tient
s as
par
t of t
he lo
nger
tre
atm
ent r
egim
ens?
Sett
ing:
In
tern
atio
nal
Bibl
iogr
aphy
: Un
publ
ished
dat
a fro
m th
e in
divi
dual
pat
ient
dat
aset
, 201
9 (h
eld
by M
cGill
Univ
ersit
y)
Cert
aint
y as
sess
men
t№
of p
atie
nts
Effe
ct
Cert
aint
yIm
port
ance
№ o
f st
udie
sSt
udy
desi
gnRi
sk o
f bi
asIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Oth
er
cons
ider
atio
ns
beda
quili
ne fo
r m
ore
than
six
m
onth
s
beda
quili
ne
for u
p to
six
m
onth
s
Rela
tive
(95%
CI)
Abs
olut
e (9
5% C
I)
Succ
ess
vs. F
ailu
re (f
ollo
w u
p: m
ean
21 m
onth
s)1
obse
rvat
iona
l st
udie
s ve
ry
serio
usa
not s
erio
us
not s
erio
us
serio
usb
none
18
8/21
2 (8
8.7%
) 23
5/25
5 (9
2.2%
) O
R 1.
4 (0
.7 to
2.
7)
5 m
ore
per 1
00
(from
1
few
er to
11
mor
e)c,
d
VE
RY
LOW
CRIT
ICAL
Succ
ess
vs. D
eath
(fol
low
up:
mea
n 21
mon
ths)
1 ob
serv
atio
nal
stud
ies
very
se
rious
ano
t ser
ious
no
t ser
ious
se
rious
bno
ne
188/
200
(94.
0%)
235/
242
(97.
1%)
OR
0.8
(0.2
to
2.4)
4 fe
wer
pe
r 100
(fr
om
8 fe
wer
to
1 m
ore)
c,d
VE
RY
LOW
CRIT
ICAL
Succ
ess
vs. F
ailu
re/D
eath
(fol
low
up:
mea
n 21
mon
ths)
1 ob
serv
atio
nal
stud
ies
very
se
rious
ano
t ser
ious
no
t ser
ious
se
rious
bno
ne
188/
224
(83.
9%)
235/
262
(89.
7%)
OR
1.0
(0.5
to
1.7)
1 m
ore
per 1
00
(from
6
few
er to
7
mor
e)c,
d
VE
RY
LOW
CRIT
ICAL
Succ
ess
vs. A
ll U
nfav
orab
le (f
ollo
w u
p: m
ean
21 m
onth
s)1
obse
rvat
iona
l st
udie
s ve
ry
serio
usa
not s
erio
us
not s
erio
us
serio
usb
none
18
8/24
2 (7
7.7%
) 23
5/27
3 (8
6.1%
) O
R 0.
8 (0
.5 to
1.
2)
1 fe
wer
pe
r 100
(fr
om
8 fe
wer
to
6 m
ore)
c,d
VE
RY
LOW
CRIT
ICAL
CI: c
onfid
ence
inte
rval
; MD
R/RR
-TB:
mul
tidru
g- o
r rifa
mpi
cin-r
esist
ant t
uber
culo
sis; O
R: o
dds
ratio
.
Expl
anat
ions
a. D
ata
from
a si
ngle
coh
ort s
tudy
with
exc
elle
nt q
ualit
y of
info
rmat
ion,
but
reas
ons f
or b
edaq
uilin
e ex
tens
ion
varie
d by
pro
vider
and
site
, with
man
y de
cisio
ns in
divid
ualiz
ed. S
ome
sites
rare
ly ga
ve b
edaq
uilin
e fo
r mor
e th
an 6
mon
ths a
nd o
ther
s rar
ely
gave
bed
aqui
line
for l
ess t
han
or e
qual
to 6
mon
ths.
In m
ost s
ites,
how
ever
, dur
atio
n ap
pear
ed to
be
base
d at
leas
t par
tly o
n po
or re
spon
se to
ther
apy,
crea
ting
subs
tant
ial s
elec
tion
bias
.
b. S
tudy
invo
lved
rela
tivel
y sm
all n
umbe
rs w
ith b
edaq
uilin
e ex
tens
ion,
with
lim
ited
even
ts.
c. O
utco
mes
and
cos
ts a
re s
imul
ated
usin
g a
mod
el th
at d
raw
s pa
ram
eter
est
imat
es fr
om m
ultip
le s
ourc
es, i
nclu
ding
the
adju
sted
odd
s ra
tios
for s
ucce
ss v
ersu
s de
ath/
failu
re d
escr
ibed
abo
ve.
d. T
he a
bsol
ute
effe
ct is
cal
cula
ted
afte
r mat
chin
g in
terv
entio
n an
d co
mpa
rato
r pop
ulat
ions
, and
per
form
ing
bino
mia
l reg
ress
ion
with
an
iden
tity
link.
Annex 3: GRADE evidence summary tables 61
Aut
hor(
s):
Rese
arch
Inst
itute
of t
he M
cGill
Univ
ersit
y H
ealth
Cen
tre a
nd P
rofe
ssor
Kel
ly D
oole
y, Jo
hns
Hop
kins
Univ
ersit
yQ
uest
ion:
Sh
ould
con
curre
nt u
se o
f bed
aqui
line
and
dela
man
id v
s. no
con
curre
nt u
se o
f bed
aqui
line
and
dela
man
id b
e us
ed in
MD
R/RR
-TB
patie
nts
as p
art o
f the
long
er tr
eatm
ent r
egim
ens?
Sett
ing:
In
tern
atio
nal (
for t
he d
atas
et fr
om M
cGill
Univ
ersit
y) a
nd S
outh
Afri
ca a
nd P
eru
for t
he d
atas
et fr
om Jo
hns
Hop
kins
Univ
ersit
y Bi
blio
grap
hy:
Unpu
blish
ed d
ata
from
the
indi
vidua
l pat
ient
dat
aset
, 201
9 (h
eld
by M
cGill
Unive
rsity
) and
unp
ublis
hed
data
from
the
DEL
aman
Id B
Edaq
uilin
e fo
r Res
istAn
t Tub
Ercu
losis
(DEL
IBER
ATE)
tria
l, Jo
hns
Hop
kins
Univ
ersit
y
Cert
aint
y as
sess
men
t№
of p
atie
nts
Effe
ct
Cert
aint
yIm
port
ance
№ o
f st
udie
sSt
udy
desi
gnRi
sk o
f bi
asIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Oth
er
cons
ider
atio
ns
conc
urre
nt u
se
of b
edaq
uilin
e an
d de
lam
anid
no c
oncu
rren
t us
e of
be
daqu
iline
and
de
lam
anid
Rela
tive
(95%
CI)
Abs
olut
e (9
5% C
I)
Succ
ess
vs. F
ailu
re (f
ollo
w u
p: m
ean
17.5
mon
ths)
4 ob
serv
atio
nal
stud
ies
very
se
rious
ase
rious
bno
t ser
ious
se
rious
cno
ne
52/5
8 (8
9.7%
) 28
5/30
6 (9
3.1%
) O
R 1.
6 (0
.5 to
5.
4)
6 m
ore
per 1
00
(from
6
few
er to
18
mor
e)d,
e
VE
RY
LOW
CRIT
ICAL
Succ
ess
vs. D
eath
(fol
low
up:
mea
n 17
.5 m
onth
s)4
obse
rvat
iona
l st
udie
s ve
ry
serio
usa
serio
usb
not s
erio
us
serio
usc
none
52
/69
(75.
4%)
285/
333
(85.
6%)
OR
0.8
(0.3
to
2.1)
1 fe
wer
pe
r 100
(fr
om
15 fe
wer
to
12 m
ore)
d,e
VE
RY
LOW
CRIT
ICAL
Succ
ess
vs. F
ailu
re/D
eath
(fol
low
up:
mea
n 17
.5 m
onth
s)4
obse
rvat
iona
l st
udie
s ve
ry
serio
usa
serio
usb
not s
erio
us
serio
usc
none
52
/75
(69.
3%)
285/
354
(80.
5%)
OR
1.2
(0.6
to
2.5)
5 m
ore
per 1
00
(from
10
few
er to
20
mor
e)d,
e
VE
RY
LOW
CRIT
ICAL
Succ
ess
vs. A
ll U
nfav
orab
le (f
ollo
w u
p: m
ean
17.5
mon
ths)
4 ob
serv
atio
nal
stud
ies
very
se
rious
ase
rious
bno
t ser
ious
se
rious
cno
ne
52/8
4 (6
1.9%
) 28
5/40
1 (7
1.1%
) O
R 0.
6 (0
.3 to
1.
1)
11 fe
wer
pe
r 100
(fr
om
25 fe
wer
to
2 m
ore)
d,e
VE
RY
LOW
CRIT
ICAL
WHO consolidated guidelines on tuberculosis: Online annexes62
Cert
aint
y as
sess
men
t№
of p
atie
nts
Effe
ct
Cert
aint
yIm
port
ance
№ o
f st
udie
sSt
udy
desi
gnRi
sk o
f bi
asIn
cons
iste
ncy
Indi
rect
ness
Impr
ecis
ion
Oth
er
cons
ider
atio
ns
conc
urre
nt u
se
of b
edaq
uilin
e an
d de
lam
anid
no c
oncu
rren
t us
e of
be
daqu
iline
and
de
lam
anid
Rela
tive
(95%
CI)
Abs
olut
e (9
5% C
I)
Sudd
en c
ardi
ac d
eath
(fol
low
up:
mea
n 24
wee
ks; a
sses
sed
with
: QTc
F pr
olon
gatio
n m
easu
red
in m
illis
econ
ds c
hang
e fr
om b
asel
ine)
1 ra
ndom
ised
trial
s no
t se
rious
no
t ser
ious
se
rious
se
rious
fno
ne
The
prim
ary
aim
of t
he D
ELIB
ERAT
E tri
al w
as to
com
pare
the
mea
n ch
ange
from
bas
elin
e (a
vera
ged
over
wee
ks 8
–24)
in
QTc
F w
hen
beda
quilin
e an
d de
lam
anid
are
co-
adm
inist
ered
to
the
mea
n ch
ange
obs
erve
d w
hen
each
dru
g is
adm
inist
ered
al
one.
At w
eek
24, in
28
patie
nts w
ho re
ceive
d be
daqu
iline
as
part
of t
heir
MD
R -T
B tre
atm
ent r
egim
en th
e m
ean
incr
ease
in
QTc
F w
as 1
1.9
ms
(95%
CI 7
.4–1
6.4
ms)
. For
28
patie
nts
who
rece
ived
del
aman
id a
s pa
rt o
f the
ir M
DR-
TB tr
eatm
ent
regi
men
the
mea
n in
crea
se in
QTc
F w
as 8
.6 m
s (9
5% C
I 4.0
–13
.2 m
s). W
hen
28 p
atie
nts
rece
ived
con
curre
nt b
edaq
uilin
e an
d de
lam
anid
as
part
of t
heir
MD
R-TB
trea
tmen
t reg
imen
th
e m
ean
incr
ease
in Q
TcF
was
20.
7 m
s (95
% C
I 16.
1–25
.4 m
s).
The
addi
tive
effe
ct o
f add
ing
dela
man
id t
o a
regi
men
tha
t al
read
y co
ntai
ned
beda
quilin
e w
as d
eter
min
ed to
be
a m
ean
of 8
.8 m
s (9
5% C
I 2.3
–15.
3 m
s), w
here
as th
e ad
ditiv
e ef
fect
of
add
ing
beda
quilin
e to
a r
egim
en t
hat
alre
ady
cont
aine
d de
lam
anid
was
a m
ean
of 1
2.1
ms (
95%
CI 5
.6–1
8.6
ms).
The
re
wer
e no
Gra
de 3
or G
rade
4 Q
T ad
vers
e ev
ents
reco
rded
in
all t
hree
pat
ient
gro
ups,
inclu
ding
am
ong
thos
e w
ho re
ceive
d be
daqu
iline
and
dela
man
id c
oncu
rrent
ly.
LOW
CR
ITIC
AL
CI: c
onfid
ence
inte
rval
; MD
R-TB
: mul
tidru
g-re
sista
nt tu
berc
ulos
is; M
DR/
RR-T
B: m
ultid
rug-
or r
ifam
picin
-res
istan
t tub
ercu
losis
; OR:
odd
s ra
tio.
Expl
anat
ions
a.Fo
r th
e tw
o co
hort
stu
dies
with
the
inte
rven
tion,
the
smal
l num
ber
of p
atie
nts
repr
esen
ts le
ss th
an 3
% o
f all
patie
nts
in o
ne c
ohor
t stu
dy w
ith e
xcel
lent
qua
lity
of in
form
atio
n; h
ence
, the
re is
a p
ossib
ility
ofsu
bsta
ntia
l sel
ectio
n bi
as. T
he s
econ
d co
hort
also
had
sm
all n
umbe
rs, b
ut th
e pa
tient
s re
pres
ent a
lmos
t hal
f of a
ll co
hort
mem
bers
; hen
ce, t
here
is le
ss p
ossib
ility
of s
elec
tion
bias
.
b.Pa
tient
s fo
r the
inte
rven
tion
wer
e tre
ated
in tw
o ve
ry d
iffer
ent c
ohor
t stu
dies
, with
diff
eren
t cen
tres
or p
rovi
ders
and
pro
toco
ls. P
atie
nts
for t
he c
ompa
rato
r wer
e tre
ated
in fo
ur v
ery
diffe
rent
coh
ort s
tudi
es.
c.Th
ere
are
serio
us c
once
rns
abou
t thi
s st
udy,
give
n th
at s
mal
l num
bers
rece
ived
bed
aqui
line
and
dela
man
id c
onco
mita
ntly
(n=8
4).
d.O
utco
mes
and
cos
ts a
re s
imul
ated
usin
g a
mod
el th
at d
raw
s pa
ram
eter
est
imat
es fr
om m
ultip
le s
ourc
es, i
nclu
ding
the
adju
sted
odd
s ra
tios
for s
ucce
ss v
ersu
s de
ath/
failu
re d
escr
ibed
abo
ve.
e.Th
e ab
solu
te e
ffect
is c
alcu
late
d af
ter m
atch
ing
inte
rven
tion
and
com
para
tor p
opul
atio
ns, a
nd p
erfo
rmin
g bi
nom
ial r
egre
ssio
n w
ith a
n id
entit
y lin
k.
f. Im
prec
ision
is se
cond
ary
to th
e sm
all n
umbe
r of i
ndiv
idua
ls en
rolle
d. T
ypica
lly, f
or c
ontin
uous
out
com
es, a
sam
ple
size
of 4
00 m
akes
it p
ossib
le to
dra
w c
onclu
sions
with
con
fiden
ce, a
lthou
gh th
is is
a ge
nera
l rul
e.
Annex 3: GRADE evidence summary tables 63
A3.2 WHO treatment guidelines for isoniazid-resistant tuberculosis, 2018Refer to Annex 5: GRADE evidence summary tables in the WHO treatment guidelines for isoniazid-resistant tuberculosis (https://www.who.int/tb/publications/2018/WHO_treatment_guidelines_ isoniazid_resistant_TB_Online_GRADE_tables_Annexes.pdf, accessed 2 March 2019).
A3.3 WHO treatment guidelines for multidrug- and rifampicin-resistant tuberculosis, 2018 updateRefer to Annex 8: GRADE evidence summary tables in the WHO treatment guidelines for multidrug-and rifampicin-resistant tuberculosis, 2018 update (https://www.who.int/tb/areas-of-work/drug-resistant-tb/ Annexes_8–10.pdf, accessed 2 March 2019).
A3.4 Guidelines for the programmatic management of drug-resistant tuberculosis, 2011 updateRefer to Annex 2: GRADE glossary and summary of evidence tables (questions 6 and 7) in the Guidelines for the programmatic management of drug-resistant tuberculosis, 2011 update (https://apps.who.int/ iris/bitstream/handle/10665/70677/WHO_HTM_TB_2011.6b_eng.pdf, accessed 2 March 2019).
A3.5 WHO treatment guidelines for drug-resistant tuberculosis, 2016 updateRefer to Annex 4: GRADE tables (question 4) in the WHO treatment guidelines for drug-resistant tuberculosis, 2016 update (https://apps.who.int/iris/bitstream/handle/10665/250125/ 9789241549639-webannexes-eng.pdf, accessed 2 March 2019).
A3.6 Guidelines for treatment of drug-susceptible tuberculosis and patient care, 2017 updateRefer to Annex 3: GRADE evidence profiles (questions 10 and 11) in the Guidelines for treatment of drug-susceptible tuberculosis and patient care, 2017 update (https://www.who.int/tb/publications/2017/ dstb_guidance_2017/en/, accessed 2 March 2019).
WHO consolidated guidelines on tuberculosis: Online annexes64
Anne
x 4:
GRA
DE
evid
ence
-to-
deci
sion
tabl
es
A4.
1 W
HO
trea
tmen
t gui
delin
es fo
r mul
tidru
g- o
r rifa
mpi
cin-
resi
stan
t tu
berc
ulos
is, 2
020
upda
teSh
ould
an
all-
oral
sho
rter
regi
men
of 9
–12
mon
ths’
dur
atio
n in
clud
ing
beda
quili
ne v
s a
shor
ter r
egim
en re
com
men
ded
by W
HO
(with
inje
ctab
le) b
e us
ed fo
r MD
R/RR
-TB
patie
nts
to s
afel
y im
prov
e ou
tcom
es?
POPU
LATI
ON
:M
DR-
/RR-
TB p
atie
nts
to s
afel
y im
prov
e ou
tcom
esIN
TERV
ENTI
ON
:Al
l-ora
l bed
aqui
line-
cont
aini
ng s
hort
er re
gim
en o
f 9–1
2 m
onth
s du
ratio
n (B
DQ
-LFX
/MFX
-ETO
-E-Z
-Hh -C
FZ)
COM
PARI
SON
:Sh
orte
r reg
imen
reco
mm
ende
d by
WH
O (w
ith a
n in
ject
able
age
nt)
MAI
N O
UTCO
MES
:Su
cces
s vs
. Fai
lure
/Rec
urre
nce;
Suc
cess
vs.
Dea
th; S
ucce
ss v
s. Fa
ilure
/Rec
urre
nce/
Dea
th; S
ucce
ss v
s. Al
l Unf
avou
rabl
e; L
ost v
s. Al
l Oth
er O
utco
mes
; AFB
Sm
ear
Posit
ive:
Suc
cess
vs.
Failu
re/R
ecur
renc
e; A
FB S
mea
r Pos
itive
: Suc
cess
vs.
Dea
th; A
FB S
mea
r Pos
itive
: Suc
cess
vs.
Failu
re/R
ecur
renc
e/D
eath
; AFB
Sm
ear P
ositi
ve:
Succ
ess
vs. A
ll Un
favo
urab
le; A
FB S
mea
r Pos
itive
: Los
t vs.
All O
ther
Out
com
es; H
IV-P
ositi
ve o
n AR
T: S
ucce
ss v
s. Fa
ilure
/Rec
urre
nce;
HIV
-Pos
itive
on
ART:
Suc
cess
vs
. Dea
th; H
IV-P
ositi
ve o
n AR
T: S
ucce
ss v
s. Fa
ilure
/Rec
urre
nce/
Dea
th; H
IV-P
ositi
ve o
n AR
T: S
ucce
ss v
s. Al
l Oth
er U
nfav
oura
ble;
HIV
-Pos
itive
on
ART:
Los
t vs.
All O
ther
Out
com
es; H
IV N
egat
ive:
Suc
cess
vs.
Failu
re/R
ecur
renc
e; H
IV N
egat
ive:
Suc
cess
vs.
Dea
th; H
IV N
egat
ive:
Suc
cess
vs.
Failu
re/R
ecur
renc
e/D
eath
; HIV
N
egat
ive:
Suc
cess
vs.
All O
ther
Out
com
es; H
IV N
egat
ive:
Los
t vs.
All O
ther
Out
com
es.
SETT
ING
:So
uth
Afric
a.
PERS
PECT
IVE:
Publ
ic he
alth
and
hea
lth s
yste
ms
pers
pect
ive
BACK
GRO
UND
:M
ultid
rug-
resis
tant
(MD
R-) a
nd ri
fam
picin
-res
istan
t tub
ercu
losis
(MD
R-/R
R-TB
) is
emer
ging
as
a m
ajor
pro
blem
due
to p
oor m
anag
emen
t of d
rug-
sens
itive
as
wel
l as
dru
g-re
sista
nt T
B. M
DR-
/RR-
TB is
trea
tabl
e, b
ut h
as re
quire
d th
e us
e of
long
er tr
eatm
ent r
egim
ens
whi
ch c
onta
in p
oten
tially
toxic
dru
gs. T
he in
tere
st in
redu
cing
the
dura
tion
of tr
eatm
ent f
or M
DR-
TB m
otiv
ated
a n
umbe
r of i
nitia
tives
in re
cent
yea
rs to
trea
t pat
ient
s w
ith s
hort
er re
gim
ens
unde
r pro
gram
mat
ic as
wel
l as
trial
co
nditi
ons.
In 2
016,
on
the
basis
of d
ata
from
obs
erva
tiona
l stu
dies
of t
he s
hort
er re
gim
ens
in d
iffer
ent A
sian
and
Afric
an c
ount
ries,
WH
O s
tart
ed to
reco
mm
end
a st
anda
rdiz
ed s
hort
er M
DR-
TB re
gim
en, c
onta
inin
g an
inje
ctab
le a
gent
, bas
ed o
n th
e on
es u
nder
stu
dy fo
r elig
ible
pat
ient
s. In
201
8, fu
rthe
r mod
ifica
tions
w
ere
mad
e to
the
earli
er re
com
men
ded
shor
ter r
egim
en, r
epla
cing
kana
myc
in b
y am
ikacin
(bas
ed o
n ev
iden
ce fr
om th
e co
mpa
rativ
e ef
fect
iven
ess
of th
ese
two
inje
ctab
le a
gent
s).
Evid
ence
of p
erm
anen
t effe
cts
attri
bute
d to
the
toxic
ity o
f inj
ecta
ble
agen
ts, h
ave
prom
pted
furt
her a
dvan
ces
in th
e de
velo
pmen
t of n
ew tr
eatm
ents
suc
h as
sh
orte
r inj
ecta
ble-
spar
ing
regi
men
s. In
par
ticul
ar, o
bser
vatio
nal d
ata
on a
n al
l-ora
l bed
aqui
line-
cont
aini
ng s
hort
er re
gim
en o
f 9–1
2 m
onth
s du
ratio
n be
cam
e av
aila
ble.
Thi
s is
of p
artic
ular
impo
rtan
ce g
iven
that
the
regi
men
may
offe
r pat
ient
s th
e lik
elih
ood
of b
ette
r tol
erat
ing
treat
men
t with
out s
igni
fican
t tox
icity.
CON
FLIC
T O
F IN
TERE
STS:
Albe
rto
Piub
ello
.
Annex 4: GRADE evidence-to-decision tables 65
Ass
essm
ent
Prob
lem
Is th
e pr
oble
m a
prio
rity?
JUD
GEM
ENT
RESE
ARC
H E
VID
ENCE
AD
DIT
ION
AL
CON
SID
ERAT
ION
S○
No
○ P
roba
bly
no
○ P
roba
bly
yes
● Ye
s ○
Var
ies
○ D
on’t
know
Tube
rcul
osis
(TB)
rem
ains
a th
reat
to g
loba
l pub
lic h
ealth
and
is th
e to
pmos
t inf
ectio
us c
ause
of
dea
th in
the
wor
ld. I
n 20
18, a
n es
timat
ed 1
0 m
illion
peo
ple
deve
lope
d TB
and
1.4
milli
on
died
from
the
dise
ase.
Abo
ut 5
00 0
00 n
ew c
ases
of m
ultid
rug-
or r
ifam
picin
-res
istan
t TB
(MD
R/RR
-TB)
wer
e es
timat
ed to
em
erge
in 2
018.
Alth
ough
all
of th
ese
wou
ld h
ave
been
el
igib
le fo
r a s
econ
d-lin
e TB
trea
tmen
t reg
imen
, onl
y 15
6 07
1 en
rolm
ents
on
treat
men
t wer
e re
port
ed b
y co
untri
es in
201
8 –
abou
t 30%
of t
he e
stim
ated
cas
eloa
d. D
espi
te th
is, s
igni
fican
t im
prov
emen
ts in
the
avai
labi
lity
of e
nhan
ced
diag
nost
ics a
nd m
ore
effe
ctiv
e m
edici
nes
have
oc
curre
d in
rece
nt y
ears
and
hav
e le
d to
ear
lier d
etec
tion
and
high
er s
ucce
ss ra
tes
amon
g pa
tient
s w
ith M
DR/
RR-T
B in
a n
umbe
r of n
atio
nal p
rogr
amm
es. H
owev
er, t
hese
suc
cess
es h
ave
not b
een
repr
oduc
ed in
the
rest
of t
he w
orld
, and
the
over
all t
reat
men
t suc
cess
rate
wor
ldw
ide
reac
hed
only
56%
for p
atie
nts
with
MD
R/RR
-TB
who
sta
rted
on
treat
men
t in
2016
, and
onl
y 39
% fo
r pat
ient
s w
ith e
xten
sivel
y dr
ug-r
esist
ant T
B (X
DR-
TB).
WHO consolidated guidelines on tuberculosis: Online annexes66
Des
irab
le E
ffec
tsH
ow s
ubst
antia
l are
the
desi
rabl
e an
ticip
ated
eff
ects
?
JUD
GEM
ENT
RESE
ARC
H E
VID
ENCE
AD
DIT
ION
AL
CON
SID
ERAT
ION
S○
Triv
ial
○ S
mal
l ○
Mod
erat
e ●
Larg
e ○
Var
ies
○ D
on’t
know
Out
com
esEf
fect
Rela
tive
Abs
olut
eSu
cces
s vs
. Fai
lure
/Rec
urre
nce
(follo
w u
p: m
ean
18 m
onth
s)O
R 2.
1 (1
.1 to
4.0
)3
mor
e pe
r 100
(1
mor
e to
6 m
ore)
Su
cces
s vs
. Dea
th (f
ollo
w u
p: m
ean
18 m
onth
s)O
R 1.
6 (1
.2 to
2.1
)8
mor
e pe
r 100
(3
mor
e to
13
mor
e)
Succ
ess
vs. F
ailu
re/R
ecur
renc
e/D
eath
(fol
low
up:
m
ean
18 m
onth
s)O
R 1.
7 (1
.3 to
2.2
)10
mor
e pe
r 100
(5
mor
e to
15
mor
e)
Succ
ess
vs. A
ll Un
favo
rabl
e (fo
llow
up:
mea
n 18
mon
ths)
OR
1.9
(1.6
to 2
.4)
14 m
ore
per 1
00
(9 m
ore
to 1
9 m
ore)
Lost
vs.
All O
ther
Out
com
es (f
ollo
w u
p: m
ean
18 m
onth
s)O
R 0.
5 (0
.4 to
0.7
)7
few
er p
er 1
00
(11
few
er to
4 fe
wer
)AF
B Sm
ear P
ositi
ve: S
ucce
ss v
s. Fa
ilure
/Rec
urre
nce
(follo
w u
p: m
ean
18 m
onth
s)O
R 4.
4 (1
.6 to
11.
9)8
mor
e pe
r 100
(3
mor
e to
13
mor
e)AF
B Sm
ear P
ositi
ve: S
ucce
ss v
s. D
eath
(fol
low
up:
m
ean
18 m
onth
s)O
R 1.
3 (0
.8 to
2.1
)5
mor
e pe
r 100
(3
few
er to
12
mor
e)AF
B Sm
ear P
ositi
ve: S
ucce
ss v
s. Fa
ilure
/Rec
urre
nce/
Dea
th (f
ollo
w u
p: m
ean
18 m
onth
s)O
R 1.
7 (1
.1 to
2.6
)10
mor
e pe
r 100
(2
mor
e to
17
mor
e)AF
B Sm
ear P
ositi
ve: S
ucce
ss v
s. Al
l Unf
avor
able
(fo
llow
up:
mea
n 18
mon
ths)
OR
2.3
(1.6
to 3
.3)
16 m
ore
per 1
00
(9 m
ore
to 2
4 m
ore)
AFB
Smea
r Pos
itive
: Los
t vs.
All O
ther
Out
com
es
(follo
w u
p: m
ean
18 m
onth
s)O
R 0.
4 (0
.2 to
0.6
)11
few
er p
er 1
00
(16
few
er to
5 fe
wer
)H
IV-P
ositi
ve o
n AR
T: S
ucce
ss v
s. Fa
ilure
/Rec
urre
nce
(follo
w u
p: m
ean
18 m
onth
s)O
R 1.
4 (0
.7 to
2.9
)2
mor
e pe
r 100
(2
few
er to
5 m
ore)
HIV
-Pos
itive
on
ART:
Suc
cess
vs.
Dea
th (f
ollo
w u
p:
mea
n 18
mon
ths)
OR
1.6
(1.2
to 2
.3)
8 m
ore
per 1
00
(3 m
ore
to 1
4 m
ore)
HIV
-Pos
itive
on
ART:
Suc
cess
vs.
Failu
re/R
ecur
renc
e/D
eath
(fol
low
up:
mea
n 18
mon
ths)
OR
1.6
(1.2
to 2
.2)
9 m
ore
per 1
00
(3 m
ore
to 1
5 m
ore)
HIV
-Pos
itive
on
ART:
Suc
cess
vs.
All O
ther
Un
favo
rabl
e (fo
llow
up:
mea
n 18
mon
ths)
OR
1.9
(1.4
to 2
.4)
14 m
ore
per 1
00
(8 m
ore
to 1
9 m
ore)
HIV
-Pos
itive
on
ART:
Los
t vs.
All O
ther
Out
com
es
(follo
w u
p: m
ean
18 m
onth
s)O
R 0.
6 (0
.4 to
0.8
)6
few
er p
er 1
00
(10
few
er to
2 fe
wer
)
Resu
lts fr
om th
e da
ta a
sses
smen
t com
miss
ione
d to
info
rm
thes
e re
com
men
datio
ns s
how
that
favo
urab
le o
utco
mes
w
ere
signi
fican
tly b
ette
r for
the
all-o
ral s
hort
er b
edaq
uilin
e-co
ntai
ning
sho
rter
regi
men
than
for a
sho
rter
regi
men
re
com
men
ded
by W
HO
(with
inje
ctab
le).
Annex 4: GRADE evidence-to-decision tables 67
Und
esir
able
Eff
ects
How
sub
stan
tial a
re th
e un
desi
rabl
e an
ticip
ated
eff
ects
?
JUD
GEM
ENT
RESE
ARC
H E
VID
ENCE
AD
DIT
ION
AL
CON
SID
ERAT
ION
S○
Lar
ge
○ M
oder
ate
○ S
mal
l ○
Triv
ial
○ V
arie
s ●
Don
’t kn
ow
The
Gui
delin
e D
evel
opm
ent G
roup
(GD
G) d
iscus
sed
earli
er re
sults
of t
he in
divi
dual
-pat
ient
da
ta (I
PD) m
eta-
anal
ysis
cond
ucte
d to
ass
ess
the
over
all b
alan
ce b
etw
een
bene
fits
and
harm
s of
indi
vidu
al a
gent
s. In
the
anal
ysis,
199
5 pa
tient
s re
ceiv
ed k
anam
ycin
and
268
(13.
4%)
expe
rienc
ed a
n ad
vers
e ev
ent c
ausin
g pe
rman
ent d
rug
disc
ontin
uatio
n; 4
106
patie
nts
rece
ived
am
ikacin
, of w
hom
235
(5.7
%) e
xper
ienc
ed a
n ad
vers
e ev
ent c
ausin
g pe
rman
ent
drug
disc
ontin
uatio
n; a
dditi
onal
ly, 1
932
rece
ived
cap
reom
ycin
and
161
(8.3
%) e
xper
ienc
ed
an a
dver
se e
vent
cau
sing
perm
anen
t dru
g di
scon
tinua
tion.
In c
ontra
st, 4
64 p
atie
nts
rece
ived
bed
aqui
line,
of w
hom
9 (1
.9%
) exp
erie
nced
an
adve
rse
even
t cau
sing
perm
anen
t dr
ug d
iscon
tinua
tion.
Thou
gh n
o m
ajor
sig
nals
of ri
sk w
ere
obse
rved
with
the
use
of th
e al
l-ora
l bed
aqui
line-
base
d sh
orte
r reg
imen
, the
GD
G
ackn
owle
dged
that
som
e un
cert
aint
ies
rem
aine
d gi
ven
the
lack
of s
yste
mat
ic co
llect
ion
of d
ata,
and
lack
of c
larit
y as
to
any
chan
ges
in th
e re
gim
en th
at c
ould
hav
e be
en in
form
ed
by th
e pr
esen
ce o
f adv
erse
eve
nts.
How
ever
, the
GD
G
reco
gniz
ed th
at th
e an
alys
is w
as n
ot c
ompl
etel
y ag
nost
ic ab
out s
afet
y, in
par
ticul
ar th
e ba
lanc
e be
twee
n de
sirab
le v
ersu
s un
desir
able
effe
cts,
and
the
grou
p w
as s
omew
hat r
eass
ured
th
at e
arlie
r sig
nals
attri
bute
d to
the
use
of b
edaq
uilin
e w
ere
not
obse
rved
, pre
sent
ing
no a
dditi
onal
saf
ety
conc
erns
. The
gro
up
re-e
mph
asiz
ed th
at a
lthou
gh 1
.9%
of p
atie
nts
usin
g be
daqu
iline
expe
rienc
e an
adv
erse
eve
nt th
at le
ads
to th
e di
scon
tinua
tion
of th
e dr
ug, t
his
cons
eque
nce
is no
t to
be c
onsid
ered
as“
trivi
al”,
and
that
for n
ow, s
afet
y da
ta a
re n
eede
d to
bet
ter u
nder
stan
d [s
afet
y] a
spec
ts o
f the
all-
oral
bed
aqui
line-
cont
aini
ng s
hort
er
regi
men
. saf
ety
data
are
nee
ded
to b
ette
r und
erst
and
[saf
ety]
as
pect
s of
the
all-o
ral b
edaq
uilin
e-co
ntai
ning
sho
rter
regi
men
.
Cert
aint
y of
evi
denc
eW
hat i
s th
e ov
eral
l cer
tain
ty o
f the
evi
denc
e of
eff
ects
?
JUD
GEM
ENT
RESE
ARC
H E
VID
ENCE
AD
DIT
ION
AL
CON
SID
ERAT
ION
S●
Very
low
○
Low
○
Mod
erat
e ○
Hig
h ○
No
inclu
ded
stud
ies
The
GD
G p
oint
ed o
ut th
at, o
n th
e ba
sis o
f the
evi
denc
e as
sess
ed –
nam
ely,
obse
rvat
iona
l dat
a an
d po
tent
ial r
esid
ual
conf
ound
ing
– th
e ov
eral
l cer
tain
ty re
gard
ing
the
estim
ates
of
effe
ct b
ased
was
judg
ed to
be
very
low,
with
the
effe
cts
for a
ll ou
tcom
es a
lso ra
ted
as “v
ery
low
”. Al
thou
gh d
oubl
e-ad
just
men
t in
prop
ensit
y sc
ore
mat
chin
g an
alys
es w
as c
arrie
d ou
t to
rem
ove
the
effe
cts
of c
onfo
undi
ng, m
embe
rs o
f the
GD
G
furt
her d
iscus
sed
that
alth
ough
thes
e ef
fort
s co
mpe
nsat
ed
for s
ome
pote
ntia
l con
foun
ders
, res
idua
l bia
s is
likel
y to
be
pres
ent.
The
grou
p ac
know
ledg
ed th
at a
lthou
gh th
e us
e of
pr
ogra
mm
atic
data
hol
ds g
reat
pro
mise
bec
ause
they
bet
ter
refle
ct re
al p
ract
ice, s
ome
cons
ider
atio
ns in
term
s of
the
exte
nt
to w
hich
thes
e fin
ding
s co
uld
be a
pplie
d to
oth
er s
ettin
gs a
re
to b
e co
ntem
plat
ed. F
or in
stan
ce, s
pecif
ic cli
nica
l cha
ract
erist
ics
of th
e po
pula
tion
(e.g
. HIV
pre
vale
nce
and
drug
-res
istan
ce
patte
rns)
as
wel
l as
qual
ity o
f hea
lth c
are
serv
ices,
mod
els
of
care
, and
trea
tmen
t adh
eren
ce s
trate
gies
.
WHO consolidated guidelines on tuberculosis: Online annexes68
Valu
esIs
ther
e im
port
ant u
ncer
tain
ty a
bout
or v
aria
bilit
y in
how
muc
h pe
ople
val
ue th
e m
ain
outc
omes
?
JUD
GEM
ENT
RESE
ARC
H E
VID
ENCE
AD
DIT
ION
AL
CON
SID
ERAT
ION
S○
Impo
rtan
t un
cert
aint
y or
va
riabi
lity
○ P
ossib
ly im
port
ant
unce
rtai
nty
or
varia
bilit
y ○
Pro
babl
y no
im
port
ant u
ncer
tain
ty
or v
aria
bilit
y ●
No
impo
rtan
t un
cert
aint
y or
va
riabi
lity
A qu
alita
tive
stud
y un
dert
aken
to h
ighl
ight
the
pers
pect
ives
of k
ey s
take
hold
ers,
mai
nly,
patie
nt
and
civil
socie
ty re
pres
enta
tives
(n =
16)
look
ed a
t gen
eral
pre
fere
nces
and
val
ues
rega
rdin
g di
ffere
nt a
spec
ts o
f tre
atm
ent r
egim
ens
for d
rug-
resis
tant
TB,
suc
h as
dur
atio
n, p
ill bu
rden
, use
of
inje
ctab
le a
gent
s an
d po
tent
ial f
or e
xper
ienc
ing
adve
rse
even
ts.
Part
icipa
nts
had
the
oppo
rtun
ity to
disc
uss
impo
rtan
t adv
erse
effe
cts,
inclu
ding
per
man
ent
sens
orin
eura
l hea
ring
loss
, nep
hrot
oxici
ty, e
lect
roly
te a
bnor
mal
ities
, inj
ectio
n pa
in a
nd lo
cal
inje
ctio
n-sit
e co
mpl
icatio
ns. F
rom
a p
atie
nt p
ersp
ectiv
e, a
dver
se e
vent
s su
ch a
s op
tic n
eurit
is,
hear
ing
impa
irmen
t, m
enta
l sta
tus
chan
ges
due
to u
rem
ia, a
nd e
lect
roly
te a
bnor
mal
ities
are
la
te e
ffect
s am
ong
othe
rs a
ssoc
iate
d w
ith th
e us
e of
spe
cific
seco
nd-li
ne a
gent
s, in
cludi
ng
inje
ctab
le a
gent
s, an
d w
ere
deem
ed u
nacc
epta
ble.
.
Pref
eren
ces
abou
t tre
atm
ent a
ppea
red
to b
e ro
oted
in c
ore
valu
es, i
nclu
ding
min
imal
disr
uptio
n to
nor
mal
life
. Rel
ativ
ely
few
pat
ient
s se
emed
to p
refe
r a s
hort
regi
men
that
was
tied
to
mor
e se
rious
sid
e-ef
fect
s, bu
t onl
y if
the
side-
effe
cts
wer
e ra
re
or re
vers
ible
. In
addi
tion,
in te
rms
of th
e du
ratio
n of
trea
tmen
t, pr
efer
ence
s se
emed
to b
e gu
ided
firs
t by
side-
effe
cts
and
seco
nd b
y ef
ficac
y of
trea
tmen
t reg
imen
s.
Bala
nce
of e
ffec
tsD
oes
the
bala
nce
betw
een
desi
rabl
e an
d un
desi
rabl
e ef
fect
s fa
vor t
he in
terv
entio
n or
the
com
paris
on?
JUD
GEM
ENT
RESE
ARC
H E
VID
ENCE
AD
DIT
ION
AL
CON
SID
ERAT
ION
S○
Fav
ors
the
com
paris
on
○ P
roba
bly
favo
rs th
e co
mpa
rison
○
Doe
s no
t fav
or
eith
er th
e in
terv
entio
n or
the
com
paris
on
○ P
roba
bly
favo
rs th
e in
terv
entio
n ●
Favo
rs th
e in
terv
entio
n ○
Var
ies
○ D
on’t
know
The
GD
G c
onsid
ered
whe
ther
the
bala
nce
betw
een
desir
able
an
d un
desir
able
effe
cts
favo
ured
the
inte
rven
tion.
Dat
a as
sess
men
t sho
wed
that
the
over
all r
ate
of a
dver
se e
vent
s at
tribu
ted
to b
edaq
uilin
e as
com
pare
d w
ith in
ject
able
age
nts
was
two
times
less
. At t
he s
ame
time,
the
GD
G n
oted
a 5
0%
redu
ctio
n in
dea
th, a
ttrib
utin
g th
is ef
fect
to th
e ad
ditio
n of
be
daqu
iline.
How
ever
, the
gro
up e
mph
asiz
ed th
e po
tent
ial
harm
s if
this
beda
quilin
e-co
ntai
ning
regi
men
wer
e to
be
impl
emen
ted
with
out e
nsur
ing
prop
er d
rug-
susc
eptib
ility
test
ing
(DST
), an
d th
e po
tent
ial f
or a
mpl
ifica
tion
of re
sista
nce
patte
rns.
Whe
n de
cidin
g on
whe
ther
or n
ot th
e ba
lanc
e of
ef
fect
s fa
vour
ed th
e in
terv
entio
n or
the
com
para
tor,
the
grou
p pr
ocee
ded
to v
ote.
Tota
l vot
ing
mem
bers
pre
sent
: 29
expe
rts
(plu
s 1
conf
lict o
f int
eres
t). V
otin
g pr
ocee
ded
as fo
llow
s: Pr
obab
ly, 1
3; fa
vour
s th
e in
terv
entio
n, 1
4; v
arie
s, 1;
abs
tent
ion,
1;
plu
s on
e vo
ting
mem
ber w
ho a
bsta
ined
due
to c
onfli
ct
of in
tere
st.
Annex 4: GRADE evidence-to-decision tables 69
Reso
urce
s re
quir
edH
ow la
rge
are
the
reso
urce
requ
irem
ents
(cos
ts)?
JUD
GEM
ENT
RESE
ARC
H E
VID
ENCE
AD
DIT
ION
AL
CON
SID
ERAT
ION
S○
Lar
ge c
osts
○
Mod
erat
e co
sts
○ N
eglig
ible
cos
ts
and
savi
ngs
● M
oder
ate
savi
ngs
○ L
arge
sav
ings
○
Var
ies
○ D
on’t
know
Com
pare
d w
ith th
e in
ject
able
-con
tain
ing
shor
ter r
egim
en, t
he 9
–12-
mon
th a
ll-or
al re
gim
en is
pr
ojec
ted
to b
e bo
th c
ost-
savi
ng a
nd m
ore
effe
ctiv
e th
an th
e in
ject
able
-con
tain
ing
shor
ter
regi
men
und
er n
early
all
mod
elle
d co
nditi
ons.
The
proj
ecte
d co
st s
avin
gs a
vera
ge U
S$ 1
000
(201
9) in
Sou
th A
frica
and
dep
end
prim
arily
on
the
exte
nt to
whi
ch h
ighe
r dru
g co
sts
are
outw
eigh
ed b
y th
e re
duce
d co
sts
of d
eliv
erin
g in
ject
able
age
nts,
and
treat
ing
recu
rrent
and
se
cond
ary
case
s (a
bout
US$
200
0 pe
r pat
ient
is s
aved
in s
ettin
gs w
ith tw
o-tim
es-h
ighe
r hea
lth
care
cos
ts, v
ersu
s <U
S$ 1
00 s
aved
in s
ettin
gs w
ith h
igh
drug
cos
ts b
ut lo
w h
ealth
car
e co
sts)
.
An im
port
ant i
ssue
ack
now
ledg
ed b
y th
e G
DG
was
that
al
thou
gh th
e al
l-ora
l bed
aqui
line-
cont
aini
ng re
gim
en s
eem
ed
to b
e bo
th c
ost-s
avin
g an
d m
ore
effe
ctiv
e as
com
pare
d w
ith th
e sh
orte
r reg
imen
reco
mm
ende
d by
WH
O (w
ith a
n in
ject
able
), co
sts
are
not e
xpec
ted
to a
utom
atica
lly e
limin
ated
or
decr
ease
d. S
ever
al o
ther
key
fact
ors
mus
t also
be
cons
ider
ed,
inclu
ding
the
exist
ing
stoc
k of
sec
ond-
line
med
icatio
ns w
hile
tra
nsiti
onin
g fro
m a
n in
ject
able
-bas
ed re
gim
en to
an
all-o
ral
one,
dia
gnos
tic c
apac
ity to
iden
tify
elig
ible
indi
vidu
als
into
cu
rrent
ly re
com
men
ded
regi
men
s (b
ased
on
drug
-sus
cept
ibilit
y pa
ttern
s, et
c.),
and
capa
city
to c
ondu
ct re
gula
r act
ive
TB d
rug
safe
ty m
onito
ring
and
man
agem
ent.
How
ever
, the
re w
ere
no d
ata
for d
eter
min
ing
the
exac
t res
ourc
es th
at w
ould
be
cons
umed
with
the
impl
emen
tatio
n of
this
all-o
ral b
edaq
uilin
e-co
ntai
ning
regi
men
.Th
e G
DG
did
agr
ee th
at, o
vera
ll, sa
ving
s ca
n be
con
sider
ed
in te
rms
of fu
ture
retre
atm
ents
pre
vent
ed, a
s w
ell a
s re
duce
d ho
spita
lizat
ion
rate
s re
sulti
ng fr
om le
ss a
dver
se re
actio
ns.
Cert
aint
y of
evi
denc
e of
req
uire
d re
sour
ces
Wha
t is
the
cert
aint
y of
the
evid
ence
of r
esou
rce
requ
irem
ents
(cos
ts)?
JUD
GEM
ENT
RESE
ARC
H E
VID
ENCE
AD
DIT
ION
AL
CON
SID
ERAT
ION
S○
Ver
y lo
w
○ L
ow
● M
oder
ate
○ H
igh
○ N
o in
clude
d st
udie
s
The
cost
sav
ings
rela
tive
to a
sho
rt in
ject
able
-con
tain
ing
regi
men
are
also
robu
st, e
xcep
t at
ext
rem
es w
ith d
rug
cost
s, he
alth
car
e co
sts
or th
e co
st o
f bed
aqui
line
and
othe
r co
mpa
nion
dru
gs.
Thou
gh th
e un
cert
aint
y ar
ound
the
estim
ates
of e
ffect
was
ac
know
ledg
ed, t
he G
DG
agr
eed
that
ther
e se
emed
to b
e m
oder
ate
cost
sav
ings
, bec
ause
of r
educ
ed h
ospi
taliz
atio
n ra
tes
resu
lting
from
few
er a
dver
se re
actio
ns, l
ess
mon
itorin
g/vi
sits
(for
inje
ctab
le u
se),
and
few
er tr
eatm
ent i
nter
rupt
ions
bec
ause
of
bette
r adh
eren
ce.
WHO consolidated guidelines on tuberculosis: Online annexes70
Cost
eff
ecti
vene
ssD
oes
the
cost
-eff
ectiv
enes
s of
the
inte
rven
tion
favo
r the
inte
rven
tion
or th
e co
mpa
rison
?
JUD
GEM
ENT
RESE
ARC
H E
VID
ENCE
AD
DIT
ION
AL
CON
SID
ERAT
ION
S○
Fav
ors
the
com
paris
on
○ P
roba
bly
favo
rs th
e co
mpa
rison
○
Doe
s no
t fav
or
eith
er th
e in
terv
entio
n or
the
com
paris
on
● Pr
obab
ly fa
vors
the
inte
rven
tion
○ F
avor
s th
e in
terv
entio
n ○
Var
ies
○ N
o in
clude
d st
udie
s
A co
st–e
ffect
iven
ess
mod
el w
as d
evel
oped
, inc
orpo
ratin
g es
timat
ed h
ealth
sys
tem
cos
ts w
ith
drug
pro
cure
men
t, he
alth
car
e de
liver
y, ad
vers
e ev
ents
, ret
reat
men
ts, s
econ
dary
cas
es, a
nd
mor
bidi
ty a
nd m
orta
lity
asso
ciate
d w
ith T
B m
orta
lity
and
recu
rrenc
e, tr
eatm
ent d
urat
ion,
dru
g to
xicity
and
TB
trans
miss
ion.
Cos
ts a
nd c
ost–
effe
ctiv
enes
s w
ere
eval
uate
d in
Sou
th A
frica
, w
ith s
ensit
ivity
ana
lyse
s re
pres
entin
g a
rang
e of
dru
g an
d he
alth
car
e co
sts,
high
and
low
H
IV c
o-pr
eval
ence
, 95%
CIs
for e
stim
ates
of r
elat
ive
effic
acy
deriv
ed fr
om s
tatis
tical
ana
lysis
of
pat
ient
coh
ort d
ata,
and
unc
erta
inty
in th
e va
lues
of p
aram
eter
s re
pres
entin
g th
e na
tura
l hi
stor
y of
TB.
Com
pare
d w
ith th
e in
ject
able
-con
tain
ing
shor
ter r
egim
en, t
he 9
–12-
mon
th a
ll-or
al re
gim
en
is pr
ojec
ted
to b
e bo
th c
ost s
avin
g an
d m
ore
effe
ctiv
e th
an th
e in
ject
able
-con
tain
ing
shor
ter r
egim
en u
nder
nea
rly a
ll m
odel
led
cond
ition
s. Th
e pr
ojec
ted
cost
sav
ings
ave
rage
US
$ 10
00 (2
019)
in S
outh
Afri
ca a
nd d
epen
d pr
imar
ily o
n th
e ex
tent
to w
hich
hig
her d
rug
cost
s ar
e ou
twei
ghed
by
redu
ced
cost
s of
del
iver
ing
inje
ctab
le a
gent
s, an
d tre
atin
g re
curre
nt a
nd
seco
ndar
y ca
ses
(abo
ut U
S$ 2
000
save
d pe
r pat
ient
is s
aved
in s
ettin
gs w
ith tw
o-tim
es-h
ighe
r he
alth
car
e co
sts,
vers
us <
US$
100
save
d in
set
tings
with
hig
h dr
ug c
osts
but
low
hea
lth c
are
cost
s). I
n a
scen
ario
whe
re th
e al
l-ora
l reg
imen
was
no
long
er c
ost-s
avin
g be
caus
e be
daqu
iline
price
s w
ere
four
fold
hig
her t
han
curre
nt p
ricin
g in
Sou
th A
frica
or v
ia th
e G
DF,
the
incr
emen
tal
cost
–effe
ctiv
enes
s ra
tio o
f the
all-
oral
regi
men
was
US$
400
per
disa
bilit
y ad
just
ed li
fe-y
ear
aver
ted
(rang
e: U
S$ 1
00–U
S$ 9
00 a
cros
s 95
% C
I for
rela
tive
regi
men
effi
cacy
).
Equi
tyW
hat w
ould
be
the
impa
ct o
n he
alth
equ
ity?
JUD
GEM
ENT
RESE
ARC
H E
VID
ENCE
AD
DIT
ION
AL
CON
SID
ERAT
ION
S○
Red
uced
○
Pro
babl
y re
duce
d ○
Pro
babl
y no
impa
ct
○ P
roba
bly
incr
ease
d ●
Incr
ease
d ○
Var
ies
○ D
on’t
know
A qu
alita
tive
stud
y un
dert
aken
to h
ighl
ight
the
pers
pect
ives
of k
ey s
take
hold
ers,
mai
nly,
patie
nt
and
civil
socie
ty re
pres
enta
tives
(n=1
6) lo
oked
at g
ener
al p
refe
renc
es a
nd v
alue
s re
gard
ing
diffe
rent
asp
ects
of t
reat
men
t reg
imen
s fo
r dru
g-re
sista
nt T
B tre
atm
ent,
such
as
dura
tion,
pill
burd
en, u
se o
f inj
ecta
ble
agen
ts a
nd p
oten
tial f
or e
xper
ienc
ing
adve
rse
even
ts.
Part
icipa
nts
cons
ider
ed a
nyth
ing
less
than
uni
vers
al a
nd im
med
iate
acc
ess
to n
ew tr
eatm
ents
to
be u
neth
ical,
but w
hen
prom
pted
to c
onsid
er th
is pr
efer
ence
aga
inst
a li
mite
d su
pply
of d
rugs
, a
few
wou
ld p
riorit
ize
the
youn
gest
and
sick
est,
as w
ell a
s th
ose
who
are
adh
eren
t and
cou
ld
be m
onito
red
for a
dver
se e
vent
s. Pa
tient
s w
ho fa
ce s
ocio
econ
omic
chal
leng
es to
adh
eren
ce,
or w
ho li
ve in
rem
ote,
rura
l or p
oore
r com
mun
ities
that
lack
tech
nica
l skil
l or e
quip
men
t for
tre
atm
ent m
onito
ring,
cou
ld th
en b
e di
spro
port
iona
tely
and
unj
ustly
pla
ced
at a
disa
dvan
tage
The
GD
G a
gree
d th
at in
ject
able
-spa
ring
regi
men
s w
ould
be
eas
ier t
o de
cent
raliz
e an
d, th
eref
ore,
in re
mot
e an
d un
ders
ervi
ced
setti
ngs
and
disa
dvan
tage
d po
pula
tions
, w
ould
hel
p to
alle
viat
e he
alth
ineq
uitie
s, w
ithou
t ant
icipa
ting
diffe
renc
es in
out
com
es in
spe
cific
popu
latio
ns. F
urth
er, t
he
grou
p al
so n
oted
that
bec
ause
aud
iom
etry
wou
ld n
ot b
e re
quire
d, it
mig
ht b
e ea
sier t
o m
onito
r ind
ivid
uals
in s
pite
of
incr
ease
d re
quire
men
ts fo
r ele
ctro
card
iogr
aphy
, whi
ch is
a
prer
equi
site
for t
he u
se o
f bed
aqui
line-
cont
aini
ng re
gim
ens.
How
ever
, the
gro
up s
tress
ed th
at th
e us
e of
ele
ctro
card
iogr
aphy
sh
ould
not
be
a di
ffere
ntia
ting
elem
ent b
etw
een
thes
e tw
o re
gim
ens,
beca
use
patie
nts
rece
ivin
g in
ject
able
age
nts
such
as
am
ikacin
sho
uld
also
hav
e re
gula
r car
diac
mon
itorin
g. T
he
grou
p ac
know
ledg
ed th
at it
is p
ossib
le th
at, i
n so
me
setti
ngsk
no
t all
patie
nts
will
be a
ble
to u
nder
go e
lect
roca
rdio
grap
hic
mon
itorin
g; h
owev
er, i
t was
also
not
ed th
at th
e in
crea
sing
acce
ss to
ele
ctro
card
iogr
aphy
at p
erip
hery
leve
ls m
ight
im
prov
e eq
uity.
Annex 4: GRADE evidence-to-decision tables 71
Cost
eff
ecti
vene
ssD
oes
the
cost
-eff
ectiv
enes
s of
the
inte
rven
tion
favo
r the
inte
rven
tion
or th
e co
mpa
rison
?
JUD
GEM
ENT
RESE
ARC
H E
VID
ENCE
AD
DIT
ION
AL
CON
SID
ERAT
ION
S○
Fav
ors
the
com
paris
on
○ P
roba
bly
favo
rs th
e co
mpa
rison
○
Doe
s no
t fav
or
eith
er th
e in
terv
entio
n or
the
com
paris
on
● Pr
obab
ly fa
vors
the
inte
rven
tion
○ F
avor
s th
e in
terv
entio
n ○
Var
ies
○ N
o in
clude
d st
udie
s
A co
st–e
ffect
iven
ess
mod
el w
as d
evel
oped
, inc
orpo
ratin
g es
timat
ed h
ealth
sys
tem
cos
ts w
ith
drug
pro
cure
men
t, he
alth
car
e de
liver
y, ad
vers
e ev
ents
, ret
reat
men
ts, s
econ
dary
cas
es, a
nd
mor
bidi
ty a
nd m
orta
lity
asso
ciate
d w
ith T
B m
orta
lity
and
recu
rrenc
e, tr
eatm
ent d
urat
ion,
dru
g to
xicity
and
TB
trans
miss
ion.
Cos
ts a
nd c
ost–
effe
ctiv
enes
s w
ere
eval
uate
d in
Sou
th A
frica
, w
ith s
ensit
ivity
ana
lyse
s re
pres
entin
g a
rang
e of
dru
g an
d he
alth
car
e co
sts,
high
and
low
H
IV c
o-pr
eval
ence
, 95%
CIs
for e
stim
ates
of r
elat
ive
effic
acy
deriv
ed fr
om s
tatis
tical
ana
lysis
of
pat
ient
coh
ort d
ata,
and
unc
erta
inty
in th
e va
lues
of p
aram
eter
s re
pres
entin
g th
e na
tura
l hi
stor
y of
TB.
Com
pare
d w
ith th
e in
ject
able
-con
tain
ing
shor
ter r
egim
en, t
he 9
–12-
mon
th a
ll-or
al re
gim
en
is pr
ojec
ted
to b
e bo
th c
ost s
avin
g an
d m
ore
effe
ctiv
e th
an th
e in
ject
able
-con
tain
ing
shor
ter r
egim
en u
nder
nea
rly a
ll m
odel
led
cond
ition
s. Th
e pr
ojec
ted
cost
sav
ings
ave
rage
US
$ 10
00 (2
019)
in S
outh
Afri
ca a
nd d
epen
d pr
imar
ily o
n th
e ex
tent
to w
hich
hig
her d
rug
cost
s ar
e ou
twei
ghed
by
redu
ced
cost
s of
del
iver
ing
inje
ctab
le a
gent
s, an
d tre
atin
g re
curre
nt a
nd
seco
ndar
y ca
ses
(abo
ut U
S$ 2
000
save
d pe
r pat
ient
is s
aved
in s
ettin
gs w
ith tw
o-tim
es-h
ighe
r he
alth
car
e co
sts,
vers
us <
US$
100
save
d in
set
tings
with
hig
h dr
ug c
osts
but
low
hea
lth c
are
cost
s). I
n a
scen
ario
whe
re th
e al
l-ora
l reg
imen
was
no
long
er c
ost-s
avin
g be
caus
e be
daqu
iline
price
s w
ere
four
fold
hig
her t
han
curre
nt p
ricin
g in
Sou
th A
frica
or v
ia th
e G
DF,
the
incr
emen
tal
cost
–effe
ctiv
enes
s ra
tio o
f the
all-
oral
regi
men
was
US$
400
per
disa
bilit
y ad
just
ed li
fe-y
ear
aver
ted
(rang
e: U
S$ 1
00–U
S$ 9
00 a
cros
s 95
% C
I for
rela
tive
regi
men
effi
cacy
).
Equi
tyW
hat w
ould
be
the
impa
ct o
n he
alth
equ
ity?
JUD
GEM
ENT
RESE
ARC
H E
VID
ENCE
AD
DIT
ION
AL
CON
SID
ERAT
ION
S○
Red
uced
○
Pro
babl
y re
duce
d ○
Pro
babl
y no
impa
ct
○ P
roba
bly
incr
ease
d ●
Incr
ease
d ○
Var
ies
○ D
on’t
know
A qu
alita
tive
stud
y un
dert
aken
to h
ighl
ight
the
pers
pect
ives
of k
ey s
take
hold
ers,
mai
nly,
patie
nt
and
civil
socie
ty re
pres
enta
tives
(n=1
6) lo
oked
at g
ener
al p
refe
renc
es a
nd v
alue
s re
gard
ing
diffe
rent
asp
ects
of t
reat
men
t reg
imen
s fo
r dru
g-re
sista
nt T
B tre
atm
ent,
such
as
dura
tion,
pill
burd
en, u
se o
f inj
ecta
ble
agen
ts a
nd p
oten
tial f
or e
xper
ienc
ing
adve
rse
even
ts.
Part
icipa
nts
cons
ider
ed a
nyth
ing
less
than
uni
vers
al a
nd im
med
iate
acc
ess
to n
ew tr
eatm
ents
to
be u
neth
ical,
but w
hen
prom
pted
to c
onsid
er th
is pr
efer
ence
aga
inst
a li
mite
d su
pply
of d
rugs
, a
few
wou
ld p
riorit
ize
the
youn
gest
and
sick
est,
as w
ell a
s th
ose
who
are
adh
eren
t and
cou
ld
be m
onito
red
for a
dver
se e
vent
s. Pa
tient
s w
ho fa
ce s
ocio
econ
omic
chal
leng
es to
adh
eren
ce,
or w
ho li
ve in
rem
ote,
rura
l or p
oore
r com
mun
ities
that
lack
tech
nica
l skil
l or e
quip
men
t for
tre
atm
ent m
onito
ring,
cou
ld th
en b
e di
spro
port
iona
tely
and
unj
ustly
pla
ced
at a
disa
dvan
tage
The
GD
G a
gree
d th
at in
ject
able
-spa
ring
regi
men
s w
ould
be
eas
ier t
o de
cent
raliz
e an
d, th
eref
ore,
in re
mot
e an
d un
ders
ervi
ced
setti
ngs
and
disa
dvan
tage
d po
pula
tions
, w
ould
hel
p to
alle
viat
e he
alth
ineq
uitie
s, w
ithou
t ant
icipa
ting
diffe
renc
es in
out
com
es in
spe
cific
popu
latio
ns. F
urth
er, t
he
grou
p al
so n
oted
that
bec
ause
aud
iom
etry
wou
ld n
ot b
e re
quire
d, it
mig
ht b
e ea
sier t
o m
onito
r ind
ivid
uals
in s
pite
of
incr
ease
d re
quire
men
ts fo
r ele
ctro
card
iogr
aphy
, whi
ch is
a
prer
equi
site
for t
he u
se o
f bed
aqui
line-
cont
aini
ng re
gim
ens.
How
ever
, the
gro
up s
tress
ed th
at th
e us
e of
ele
ctro
card
iogr
aphy
sh
ould
not
be
a di
ffere
ntia
ting
elem
ent b
etw
een
thes
e tw
o re
gim
ens,
beca
use
patie
nts
rece
ivin
g in
ject
able
age
nts
such
as
am
ikacin
sho
uld
also
hav
e re
gula
r car
diac
mon
itorin
g. T
he
grou
p ac
know
ledg
ed th
at it
is p
ossib
le th
at, i
n so
me
setti
ngsk
no
t all
patie
nts
will
be a
ble
to u
nder
go e
lect
roca
rdio
grap
hic
mon
itorin
g; h
owev
er, i
t was
also
not
ed th
at th
e in
crea
sing
acce
ss to
ele
ctro
card
iogr
aphy
at p
erip
hery
leve
ls m
ight
im
prov
e eq
uity.
Acc
epta
bilit
yIs
the
inte
rven
tion
acce
ptab
le to
key
sta
keho
lder
s?
JUD
GEM
ENT
RESE
ARC
H E
VID
ENCE
AD
DIT
ION
AL
CON
SID
ERAT
ION
S○
No
○ P
roba
bly
no
○ P
roba
bly
yes
● Ye
s ○
Var
ies
○ D
on’t
know
A qu
alita
tive
stud
y un
dert
aken
to h
ighl
ight
the
pers
pect
ives
of k
ey s
take
hold
ers,
mai
nly
patie
nt a
nd c
ivil
socie
ty re
pres
enta
tives
(n =
16)
, loo
ked
at g
ener
al p
refe
renc
es a
nd v
alue
s re
gard
ing
diffe
rent
asp
ects
of t
reat
men
t reg
imen
s fo
r dru
g-re
sista
nt T
B, s
uch
as d
urat
ion,
pill
burd
en, u
se o
f inj
ecta
ble
agen
ts a
nd p
oten
tial f
or e
xper
ienc
ing
adve
rse
even
ts. T
he re
sults
of
this
qual
itativ
e an
alys
is su
gges
ted
that
mos
t pat
ient
s w
ould
prio
ritiz
e a
regi
men
with
few
er
and
less
-sev
ere
side-
effe
cts
abov
e al
l else
, bec
ause
it w
ould
allo
w th
em to
con
tinue
rout
ine
activ
ities
. Of n
ote,
sur
vivo
rs o
f dru
g-re
sista
nt T
B re
mar
ked
that
they
wou
ld a
ccep
t a lo
nger
tre
atm
ent t
hat p
rom
ised
few
er s
ever
e ad
vers
e ef
fect
s ov
er a
sho
rter
regi
men
tied
to m
ore
seve
re s
ide-
effe
cts,
even
if tr
eatm
ent w
as e
xper
imen
tal o
r effi
cacy
was
unc
lear
. Thi
s co
ntra
sted
w
ith c
ompa
rativ
ely
few
par
ticip
ants
who
prio
ritiz
ed ra
pid
retu
rn to
nor
mal
life
and
wou
ld ra
ther
as
sum
e th
e ris
k of
mor
e se
rious
sid
e-ef
fect
s w
ithin
a s
hort
er re
gim
en, e
ven
if tre
atm
ent w
as
expe
rimen
tal a
nd e
ffica
cy u
ncle
ar.
The
GD
G n
oted
that
pat
ient
s re
cogn
ize
that
thei
r exp
erie
nces
an
d pe
rcep
tions
are
hig
hly
pers
on-
and
cont
ext-d
epen
dent
, th
ough
pre
fere
nce
for t
his
[sho
rter
] reg
imen
see
med
to b
e co
nditi
onal
upo
n ad
vers
e ev
ents
bei
ng ra
re o
r rev
ersib
le.
Nev
erth
eles
s, ov
eral
l, a
shor
t, in
ject
ion-
free
regi
men
with
few
to
no p
hysic
al a
nd m
enta
l hea
lth s
ide-
effe
cts
and
a lo
w p
ill bu
rden
ap
pear
ed to
be
the
mos
t acc
epta
ble.
WHO consolidated guidelines on tuberculosis: Online annexes72
Feas
ibili
tyIs
the
inte
rven
tion
feas
ible
to im
plem
ent?
JUD
GEM
ENT
RESE
ARC
H E
VID
ENCE
AD
DIT
ION
AL
CON
SID
ERAT
ION
S○
No
○ P
roba
bly
no
○ P
roba
bly
yes
○ Y
es
● Va
ries
○ D
on’t
know
A qu
alita
tive
stud
y un
dert
aken
to h
ighl
ight
the
pers
pect
ives
of k
ey s
take
hold
ers,
mai
nly
patie
nts
and
civil
socie
ty re
pres
enta
tives
(n =
16)
look
ed a
t gen
eral
pre
fere
nces
and
val
ues
rega
rdin
g di
ffere
nt a
spec
ts o
f tre
atm
ent r
egim
ens
for d
rug-
resis
tant
TB,
suc
h as
dur
atio
n, p
ill bu
rden
, use
of
inje
ctab
le a
gent
s an
d po
tent
ial f
or e
xper
ienc
ing
adve
rse
even
ts.
This
stud
y re
veal
ed th
at a
s th
e re
gim
en, i
n pa
rticu
lar t
he e
xpan
sion
of b
edaq
uilin
e ac
cess
to
all p
atie
nts,
is he
ld b
ack
in s
ome
setti
ngs
as a
resu
lt of
rest
rictiv
e el
igib
ility
(i.e.
prio
ritiz
atio
n of
spe
cific
grou
ps) c
riter
ia, l
ack
of fu
ndin
g, o
r lac
k of
ade
quat
e in
frast
ruct
ure
in p
lace
(e.g
. di
agno
stics
), th
e op
erat
iona
lizat
ion
and
imm
edia
te ro
llout
of t
he a
ll-or
al b
edaq
uilin
e-co
ntai
ning
re
gim
en m
ay b
e ha
mpe
red.
One
impo
rtan
t req
uire
men
t hig
hlig
hted
by
the
GD
G w
as th
at
of e
nsur
ing
the
care
ful s
elec
tion
of p
atie
nts
who
are
to b
enef
it fro
m th
is re
gim
en, c
ondu
ctin
g ra
pid
and
accu
rate
DST
, and
the
mon
itorin
g of
bed
aqui
line
resis
tanc
e. T
he im
plem
enta
tion
of th
e re
gim
en m
ay b
e lim
ited
by th
e ne
ed fo
r im
prov
ed la
bora
tory
in
frast
ruct
ure.
Alth
ough
cou
ntrie
s ar
e im
plem
entin
g ra
pid
mol
ecul
ar te
sts
to id
entif
y rif
ampi
cin re
sista
nce,
labo
rato
ry
capa
city
need
s to
be
effe
ctiv
ely
esta
blish
ed to
con
duct
ge
noty
pic
and
phen
otyp
ic te
stin
g fo
r oth
er im
port
ant a
gent
s in
the
regi
men
. Also
, alth
ough
the
prev
alen
ce o
f ide
ntifi
ed
mut
atio
ns c
onfe
rrin
g lo
w-le
vel d
rug
resis
tanc
e is
very
low,
co
untri
es a
re to
stre
ngth
en la
bora
tory
cap
acity
and
to m
onito
r th
e ac
quisi
tion
of re
sista
nce
to b
edaq
uilin
e th
ough
thei
r nat
iona
l re
fere
nce
labo
rato
ries
or T
B su
pran
atio
nal r
efer
ence
site
s. Th
is is
espe
cially
impo
rtan
t giv
en th
e pi
pelin
e of
new
ant
i-TB
regi
men
s th
at a
re re
lyin
g on
bed
aqui
line
as a
bac
kbon
e.Th
e re
mov
al o
f inj
ecta
ble
agen
ts, a
s di
scus
sed
by th
e G
DG
, al
so p
oint
ed to
war
ds th
e co
nven
ienc
e (fo
r hea
lth c
are
wor
kers
) of
not
hav
ing
to d
eliv
er d
aily
inje
ctio
ns, a
nd m
ore
so, f
or
patie
nts
not h
avin
g to
end
ure
the
pain
and
oth
er s
igni
fican
t ad
vers
e ev
ents
.Th
e im
plem
enta
tion
of th
e re
gim
en is
per
ceiv
ed to
go
beyo
nd
secu
ring
of fu
ndin
g, b
ut it
furt
her r
equi
res
mak
ing
long
-te
rm, s
usta
inab
le s
yste
ms
chan
ge to
ens
ure
rapi
d tra
nsiti
on,
cons
ider
ing
the
regi
stra
tion
of b
edaq
uilin
e an
d ot
her n
ew
agen
ts, u
nint
erru
pted
sup
ply
of q
ualit
y-as
sure
d dr
ugs
and
activ
e TB
dru
g sa
fety
mon
itorin
g an
d m
anag
emen
t sys
tem
in
coor
dina
tion
with
exis
ting
phar
mac
ovig
ilanc
e st
ruct
ures
at t
he
coun
try
leve
l.Al
so, t
he im
plem
enta
tion
of th
is re
gim
en (a
nd a
ny o
ther
nov
el
regi
men
) will
requ
ire d
ecisi
on-m
akin
g to
war
ds m
ultis
ecto
ral
polic
ies,
tailo
ring
patie
nt c
entre
d pr
ogra
mm
es w
hich
also
co
nsid
er a
spec
ts s
uch
as m
enta
l hea
lth a
nd m
anag
emen
t of
othe
r com
orbi
ditie
s, fa
cilita
ting
coun
sellin
g an
d su
ppor
t dur
ing
treat
men
t, an
d af
ter c
ompl
etio
n, fa
cilita
ting
full
reco
very
.
Annex 4: GRADE evidence-to-decision tables 73
Sum
mar
y of
judg
emen
ts
JUD
GEM
ENT
PRO
BLEM
Ye
sVa
ries
Don
’t kn
owD
ESIR
ABLE
EFF
ECTS
Triv
ial
Smal
lM
oder
ate
Larg
eVa
ries
Don
’t kn
owUN
DES
IRAB
LE E
FFEC
TSLa
rge
Mod
erat
eSm
all
Triv
ial
Varie
sD
on’t
know
CERT
AIN
TY O
F EV
IDEN
CEVe
ry lo
wLo
wM
oder
ate
Hig
hN
o in
clude
d st
udie
sVA
LUES
Impo
rtan
t un
cert
aint
y or
va
riabi
lity
Poss
ibly
impo
rtan
t un
cert
aint
y or
va
riabi
lity
Prob
ably
no
impo
rtan
t un
cert
aint
y or
va
riabi
lity
No
impo
rtan
t un
cert
aint
y or
va
riabi
lity
BALA
NCE
OF
EFFE
CTS
Favo
rs th
e co
mpa
rison
Prob
ably
favo
rs th
e co
mpa
rison
Doe
s no
t fav
or
eith
er th
e in
terv
entio
n or
the
com
paris
on
Prob
ably
favo
rs th
e in
terv
entio
nFa
vors
the
inte
rven
tion
Varie
sD
on’t
know
RESO
URCE
S RE
QUI
RED
Larg
e co
sts
Mod
erat
e co
sts
Neg
ligib
le c
osts
and
sa
ving
sM
oder
ate
savi
ngs
Larg
e sa
ving
sVa
ries
Don
’t kn
ow
CERT
AIN
TY O
F EV
IDEN
CE
OF
REQ
UIRE
D R
ESO
URCE
SVe
ry lo
wLo
wM
oder
ate
Hig
hN
o in
clude
d st
udie
s
COST
EFF
ECTI
VEN
ESS
Favo
rs th
e co
mpa
rison
Prob
ably
favo
rs th
e co
mpa
rison
Doe
s no
t fav
or
eith
er th
e in
terv
entio
n or
the
com
paris
on
Prob
ably
favo
rs
the
inte
rven
tion
Favo
rs th
e in
terv
entio
nVa
ries
No
inclu
ded
stud
ies
EQUI
TYRe
duce
dPr
obab
ly re
duce
dPr
obab
ly n
o im
pact
Prob
ably
incr
ease
dIn
crea
sed
Varie
sD
on’t
know
ACCE
PTAB
ILIT
YN
oPr
obab
ly n
oPr
obab
ly y
esYe
sVa
ries
Don
’t kn
owFE
ASIB
ILIT
YN
oPr
obab
ly n
oPr
obab
ly y
esYe
sVa
ries
Don
’t kn
ow
Type
of r
ecom
men
datio
nSt
rong
reco
mm
enda
tion
agai
nst
the
inte
rven
tion
○
Cond
ition
al re
com
men
datio
n ag
ains
t the
inte
rven
tion
○
Cond
ition
al re
com
men
datio
n fo
r eith
er th
e in
terv
entio
n or
the
com
paris
on○
Cond
ition
al re
com
men
datio
n fo
r the
inte
rven
tion
●
Stro
ng re
com
men
datio
n fo
r the
in
terv
entio
n○
WHO consolidated guidelines on tuberculosis: Online annexes74
Conc
lusi
ons
Reco
mm
enda
tion
A sh
orte
r, al
l-ora
l, be
daqu
iline-
cont
aini
ng re
gim
en o
f 9–1
2 m
onth
s’ du
ratio
n is
reco
mm
ende
d in
elig
ible
pat
ient
s w
ith c
onfir
med
MD
R/RR
-TB
who
hav
e no
t bee
n ex
pose
d to
trea
tmen
t w
ith s
econ
d-lin
e TB
med
icine
s us
ed in
this
regi
men
for m
ore
than
1 m
onth
and
in w
hom
resis
tanc
e to
fluo
roqu
inol
ones
has
bee
n ex
clude
d.
(Con
ditio
nal r
ecom
men
datio
n, v
ery
low
cer
tain
ty in
the
evid
ence
)
Just
ifica
tion
Ove
rall,
the
GD
G n
oted
that
the
cert
aint
y of
the
evid
ence
on
the
effic
acy
of th
e al
l-ora
l sho
rter
regi
men
was
ver
y lo
w, a
ttrib
utab
le n
amel
y to
con
cern
s of
ser
ious
risk
of b
ias,
desp
ite
effo
rts
to b
alan
ce b
asel
ine
cova
riate
s. H
owev
er, t
he g
roup
reco
gniz
ed th
at th
e cu
rrent
evi
denc
e as
sess
men
t of t
he a
ll-or
al, b
edaq
uilin
e-co
ntai
ning
sho
rter
regi
men
sho
wed
a b
ette
r ra
tio o
f suc
cess
ver
sus
unfa
vour
able
out
com
es a
nd a
sig
nific
ant r
educ
tion
in lo
ss to
follo
w-u
p. W
hen
decid
ing
on th
e st
reng
th o
f the
reco
mm
enda
tion,
the
GD
G re
ache
d a
unan
imou
s de
cisio
n on
the
cond
ition
ality
of t
he re
com
men
datio
n, m
ainl
y at
tribu
ted
to th
e ve
ry lo
w c
erta
inty
in th
e ev
iden
ce a
nd re
quire
men
ts to
bui
ld la
bora
tory
cap
acity
and
ens
ure
DST
.O
ther
gro
unds
for t
he s
treng
th a
nd d
irect
ion
of th
is re
com
men
datio
n ar
e as
follo
ws:
• Th
e an
alys
is co
nduc
ted
to in
form
the
deve
lopm
ent o
f thi
s re
com
men
datio
n w
as b
ased
on
obse
rvat
iona
l pro
gram
mat
ic da
ta fr
om S
outh
Afri
ca w
here
the
stan
dard
ized
sho
rter
, all-
oral
, be
daqu
iline-
cont
aini
ng re
gim
en (B
DQ
-LFX
/MFX
-ETO
-E-Z
-Hh -C
FZ) w
as u
sed
for p
atie
nts
with
MD
R/RR
-TB.
• Th
ough
no
maj
or s
igna
ls of
risk
wer
e ob
serv
ed w
ith th
e us
e of
the
all-o
ral b
edaq
uilin
e-ba
sed
shor
ter r
egim
en, t
here
also
rem
aine
d so
me
unce
rtai
ntie
s, gi
ven
the
lack
of s
yste
mat
ic co
llect
ion
of d
ata,
and
giv
en th
e la
ck o
f cla
rity
as to
any
cha
nges
in th
e re
gim
en th
at c
ould
hav
e be
en in
form
ed b
y th
e pr
esen
ce o
f adv
erse
eve
nts.
• Co
st–e
ffect
iven
ess
mod
ellin
g of
the
all-o
ral,
shor
ter,
beda
quilin
e-co
ntai
ning
regi
men
sho
wed
robu
st c
ost s
avin
gs re
lativ
e to
eith
er a
long
er o
ral r
egim
en o
r a s
hort
inje
ctab
le-
cont
aini
ng re
gim
en.
–Th
e G
DG
judg
ed th
at m
any
elig
ible
pat
ient
s w
ould
pre
fer t
he a
ll-or
al, b
edaq
uilin
e-co
ntai
ning
regi
men
of 9
–12
mon
ths’
dura
tion.
Thi
s is
supp
orte
d by
lim
ited
obse
rvat
ions
invo
lvin
g 16
sur
vivo
rs o
f dru
g-re
sista
nt T
B. In
add
ition
, thi
s re
gim
en m
ay h
elp
prom
ote
heal
th e
quity
or m
itiga
te th
e w
orse
ning
of h
ealth
ineq
uitie
s. Al
thou
gh th
e pa
nel r
ecog
nize
d th
at
impl
emen
tatio
n an
d sc
ale-
up o
f thi
s re
gim
en m
ay b
e slo
w d
ue p
rere
quisi
tes
on la
bora
tory
cap
acity
and
mon
itorin
g.Su
bgro
up c
onsi
dera
tions
The
anal
ysis
atte
mpt
ed to
des
crib
e th
e ba
lanc
e of
effe
cts
and
cons
ider
atio
ns fo
r var
ious
sub
grou
ps o
r spe
cial p
opul
atio
ns. H
owev
er, t
he e
vide
nce
revi
ewed
sup
port
ed th
e us
e of
this
on
the
follo
win
g, w
ith s
pecif
ic ca
veat
s:•
Peop
le li
ving
with
HIV
infe
ctio
n: T
he d
ata
eval
uate
d co
rresp
onde
d to
a s
ettin
g w
ith a
hig
h pr
eval
ence
of H
IV, a
nd o
f par
ticul
ar s
igni
fican
ce, m
ost P
LHIV
(>95
%) w
ho s
tart
ed th
e al
l-or
al b
edaq
uilin
e-co
ntai
ning
regi
men
wer
e re
ceiv
ing
antir
etro
vira
l the
rapy
(ART
). In
vie
w o
f the
trea
tmen
t out
com
es d
escr
ibed
in th
e an
alys
is, th
ere
wer
e no
gro
unds
to b
elie
ve th
at th
e re
gim
en w
ould
per
form
any
diff
eren
tly in
PLH
IV. I
t is
nece
ssar
y to
con
sider
sig
nific
ant c
linica
l int
erac
tions
that
may
incr
ease
bed
aqui
line
expo
sure
or t
hat o
f oth
er a
gent
s w
ith p
oten
tial
for c
ardi
otox
icity
whe
n th
ese
are
co-a
dmin
ister
ed w
ith a
ntire
trovi
rals.
• Ch
ildre
n: A
lthou
gh n
o di
rect
out
com
e es
timat
ions
cou
ld b
e dr
awn
for t
his
popu
latio
n, e
xtra
pola
tion
was
dee
med
reas
onab
le. H
owev
er, b
ecau
se b
edaq
uilin
e is
curre
ntly
reco
mm
ende
d fo
r chi
ldre
n an
d ad
oles
cent
s ag
ed 6
–17
year
s, th
e G
DG
con
clude
d th
at th
e al
l-ora
l bed
aqui
line-
cont
aini
ng re
gim
en m
ay b
e us
ed in
elig
ible
chi
ldre
n w
ithin
this
age
grou
p, ta
king
into
ac
coun
t spe
cifica
tions
for r
egim
en c
ompa
nion
dru
gs –
in p
artic
ular
, bed
aqui
line.
• Pr
egna
nt a
nd la
ctat
ing
wom
en: M
ore
evid
ence
is n
eede
d to
bet
ter i
nfor
m th
e us
e of
the
all-o
ral,
beda
quilin
e-co
ntai
ning
sho
rter
regi
men
(BD
Q-L
FX/M
FX-E
TO-E
-Z-H
h -CFZ
). O
ne
of th
e ag
ents
in th
is al
l-ora
l sho
rter
regi
men
, eth
iona
mid
e, is
usu
ally
con
train
dica
ted
in p
regn
ancy
, and
with
hold
ing
this
agen
t or r
epla
cing
it w
ith a
noth
er o
ne c
ould
ser
ious
ly
com
prom
ise th
e ef
fect
iven
ess
of th
e re
gim
en. I
n th
e ca
se o
f pre
gnan
t and
lact
atin
g w
omen
, it i
s th
eref
ore
reco
mm
ende
d th
at a
n in
divi
dual
ized
, all-
oral
long
er re
gim
en (w
ith in
clusio
n of
bed
aqui
line)
is u
sed
in th
is po
pula
tion
(see
Rec
omm
enda
tions
on
the
use
of lo
nger
regi
men
s fo
r MD
R/RR
-TB)
. –Ex
trapu
lmon
ary
dise
ase:
In v
iew
of t
he u
nava
ilabi
lity
of e
vide
nce
on s
urro
gate
s fo
r sev
erity
or e
xten
t of d
iseas
e, c
linica
l jud
gem
ent i
s ad
vise
d to
dec
ide
on th
e us
e of
this
regi
men
in
patie
nts
with
ext
ensiv
e TB
dise
ase
or s
ever
e fo
rms
of e
xtra
pulm
onar
y TB
.
Annex 4: GRADE evidence-to-decision tables 75
Impl
emen
tatio
n co
nsid
erat
ions
The
inte
rest
in re
ducin
g th
e du
ratio
n of
trea
tmen
t for
MD
R/RR
-TB
has
mot
ivat
ed a
num
ber o
f stu
dies
in re
cent
yea
rs to
trea
t pat
ient
s w
ith s
hort
er re
gim
ens
unde
r pro
gram
mat
ic as
wel
l as
tria
l con
ditio
ns. F
ollo
win
g ex
perie
nces
in v
ario
us s
ettin
gs, [
elig
ible
] pat
ient
s no
w h
ave
an o
ptio
n to
be
treat
ed w
ith a
sho
rter
, inj
ecta
ble-
spar
ing
regi
men
of 9
–12
mon
ths’
dura
tion.
To
ensu
re th
at th
e re
gim
en a
chie
ves
its d
esira
ble
effe
cts,
prev
ent t
he a
cqui
sitio
n (o
r am
plifi
catio
n) o
f add
ition
al d
rug
resis
tanc
e, w
hile
regi
men
com
pone
nts
are
prot
ecte
d, c
ount
ries
are
to
cons
ider
the
follo
win
g:•
Patie
nt s
elec
tion
and
decis
ions
to s
tart
the
all-o
ral s
hort
er re
gim
en: P
atie
nts
with
con
firm
ed M
DR/
RR-T
B an
d w
ith re
sista
nce
to fl
uoro
quin
olon
es ru
led
out a
re e
xpec
ted
to b
enef
it th
e m
ost f
rom
this
regi
men
. Pro
per p
atie
nt s
elec
tion
wou
ld n
ot o
nly
lead
to im
prov
ed tr
eatm
ent o
utco
mes
but
will
also
con
tribu
te to
pro
tect
ing
agai
nst t
he d
evel
opm
ent o
f bed
aqui
line
resis
tanc
e. In
this
resp
ect,
the
regi
men
is to
onl
y be
impl
emen
ted
in s
ettin
gs w
here
rout
ine
DST
for r
ifam
picin
and
fluo
roqu
inol
ones
can
be
guar
ante
ed.
It is
very
impo
rtan
t tha
t the
impl
emen
tatio
n of
thes
e re
com
men
datio
ns is
acc
ompa
nied
by
cont
inue
d ef
fort
s to
incr
ease
acc
ess
to D
ST fo
r all
med
icine
s fo
r whi
ch re
liabl
e m
etho
ds
exist
, as
wel
l as
for t
he d
evel
opm
ent a
nd ro
llout
of D
ST m
etho
ds fo
r new
er m
edici
nes.
In th
e ab
senc
e of
a d
rug-
susc
eptib
ility
test
, ass
ays
spec
ific
for b
edaq
uilin
e re
sista
nce
shou
ld b
e m
onito
red
thro
ugh
asse
ssm
ent o
f MIC
s of
bed
aqui
line.
• Re
sista
nce
to o
ther
ant
i-TB
drug
s sh
ould
be
mon
itore
d in
acc
orda
nce
to W
HO
reco
mm
enda
tions
.•
Use
of li
nezo
lid: T
he e
vide
nce
mad
e av
aila
ble
to in
form
this
reco
mm
enda
tion
focu
sed
on th
e as
sess
men
t of a
regi
men
com
pose
d of
bed
aqui
line,
levo
floxa
cin/m
oxifl
oxac
in,
ethi
onam
ide,
eth
ambu
tol,
pyra
zina
mid
e, h
igh-
dose
ison
iazi
d, c
lofa
zim
ine
and
pyra
zina
mid
e. H
owev
er, s
econ
dary
ana
lyse
s (o
nly
in lo
nger
regi
men
s co
ntai
ning
bed
aqui
line
and
beda
quilin
e pl
us li
nezo
lid) s
how
ed fa
vour
able
out
com
es w
hen
treat
men
t reg
imen
s in
clude
d bo
th li
nezo
lid a
nd b
edaq
uilin
e. T
he b
asis
for t
he a
dditi
on o
f lin
ezol
id w
as to
pro
tect
the
regi
men
– in
par
ticul
ar, b
edaq
uilin
e –
whi
le a
wai
ting
susc
eptib
ility
resu
lts o
n ad
ditio
nal r
esist
ance
to fl
uoro
quin
olon
es a
nd o
ther
dru
gs. T
he G
DG
dec
ided
that
, unt
il ne
w e
vide
nce
is av
aila
ble
on s
hort
er re
gim
ens
that
inclu
de b
oth
of th
ese
agen
ts, t
he a
ll-or
al b
edaq
uilin
e-co
ntai
ning
sho
rter
regi
men
adv
ised
here
in s
houl
d no
t inc
lude
line
zolid
. How
ever
, the
gro
up
enco
urag
ed c
ount
ries
to c
onsid
er th
e us
e of
a m
odifie
d al
l-ora
l bed
aqui
line-
and
linez
olid
-con
tain
ing
regi
men
onl
y un
der o
pera
tiona
l res
earc
h un
til n
ew e
viden
ce b
ecom
es a
vaila
ble.
• Pa
tient
-cen
tred
appr
oach
: Effo
rts
are
requ
ired
to p
rovi
de p
atie
nt s
uppo
rt to
ena
ble
full
adhe
renc
e to
trea
tmen
t.M
onito
ring
and
eval
uatio
n•
The
impl
emen
tatio
n of
this
regi
men
requ
ires
the
use
of ro
utin
e D
ST n
ot o
nly
for p
atie
nt s
elec
tion
but a
lso to
mon
itor t
he a
cqui
sitio
n of
resis
tanc
e.•
Alth
ough
the
data
ass
esse
d di
d no
t une
arth
any
maj
or s
igna
ls of
risk
, act
ive
TB d
rug
safe
ty m
onito
ring
and
man
agem
ent s
yste
ms
mus
t be
func
tiona
l in
orde
r to
cond
uct r
igor
ous
activ
e m
onito
ring
of a
dver
se e
vent
s an
d to
det
ect,
man
age,
and
repo
rt s
uspe
cted
or c
onfir
med
dru
g to
xiciti
es in
a ti
mel
y m
anne
r.
Rese
arch
prio
ritie
sM
embe
rs o
f the
GD
G d
iscus
sed
the
rese
arch
gap
s to
info
rm th
e de
velo
pmen
t of p
ublic
hea
lth re
com
men
datio
ns fo
r the
man
agem
ent a
nd c
are
of o
f pat
ient
s w
ith M
DR/
RR-T
B, a
nd
high
light
ed th
e fo
llow
ing
prio
ritie
s:•
stud
ies
asse
ssin
g co
mpa
rison
s of
all-
oral
sho
rter
regi
men
s w
hich
inclu
de b
oth
beda
quilin
e an
d lin
ezol
id, i
n ad
ditio
n to
oth
er c
ompa
nion
dru
gs;
• st
udie
s as
sess
ing
com
paris
ons
of a
ll-or
al s
hort
er re
gim
ens
amon
g di
ffere
nt s
ubgr
oups
and
spe
cial p
opul
atio
ns, i
nclu
ding
pre
gnan
t and
lact
atin
g w
omen
;•
rand
omiz
ed, c
ontro
lled
trial
s or
ope
ratio
nal r
esea
rch
of th
e ef
fect
iven
ess
and
safe
ty o
f all-
oral
sho
rter
regi
men
s, in
crea
sing
the
cert
aint
y in
the
evid
ence
;•
stud
ies
expl
orin
g m
echa
nism
s of
acq
uisit
ion
of re
sista
nce
to b
edaq
uilin
e an
d ge
netic
mar
kers
to id
entif
y re
sista
nce;
and
• ef
fort
s to
det
erm
ine
best
way
s to
sta
ndar
dize
dat
a co
llect
ion
so th
at c
ount
ries
can
cont
ribut
e to
dev
elop
men
t of g
loba
l rec
omm
enda
tions
.
ART:
ant
iretro
vira
l the
rapy
; DST
: dru
g-su
scep
tibilit
y te
stin
g; G
DF:
Glo
bal D
rug
Facil
ity; G
DG
: Gui
delin
e D
evel
opm
ent
Gro
up; M
DR/
RR-T
B: m
ultid
rug-
resis
tant
or
rifam
picin
-res
istan
t tu
berc
ulos
is; M
IC: m
inim
um
inhi
bito
ry c
once
ntra
tion;
WH
O: W
orld
Hea
lth O
rgan
izat
ion.
WHO consolidated guidelines on tuberculosis: Online annexes76
Shou
ld a
n al
l-or
al s
hort
er re
gim
en o
f 9–1
2 m
onth
s’ d
urat
ion
incl
udin
g be
daqu
iline
vs
long
er re
gim
ens
cont
aini
ng b
edaq
uilin
e be
use
d fo
r MD
R/RR
-TB
patie
nts
to s
afel
y im
prov
e ou
tcom
es?
POPU
LATI
ON
:M
DR-
/RR-
TB p
atie
nts
to s
afel
y im
prov
e ou
tcom
esIN
TERV
ENTI
ON
:Al
l-ora
l bed
aqui
line-
cont
aini
ng s
hort
er re
gim
en o
f 9–1
2 m
onth
s du
ratio
n (B
DQ
-LFX
/MFX
-ETO
-E-Z
-Hh -C
FZ)
COM
PARI
SON
:Lo
nger
bed
aqui
line-
cont
aini
ng re
gim
en
MAI
N O
UTCO
MES
:Su
cces
s vs
. Fai
lure
/Rec
urre
nce;
Suc
cess
vs.
Dea
th; S
ucce
ss v
s. Fa
ilure
/Rec
urre
nce/
Dea
th; S
ucce
ss v
s. Al
l Unf
avou
rabl
e; L
ost v
s. Al
l Oth
er O
utco
mes
; AF
B Sm
ear P
ositi
ve: S
ucce
ss v
s. Fa
ilure
/Rec
urre
nce;
AFB
Sm
ear P
ositi
ve: S
ucce
ss v
s. D
eath
; AFB
Sm
ear P
ositi
ve: S
ucce
ss v
s. Fa
ilure
/Rec
urre
nce/
Dea
th; A
FB S
mea
r Pos
itive
: Suc
cess
vs.
All U
nfav
oura
ble;
AFB
Sm
ear P
ositi
ve: L
ost v
s. Al
l Oth
er O
utco
mes
; HIV
-Pos
itive
on
ART:
Suc
cess
vs.
Failu
re/R
ecur
renc
e; H
IV-P
ositi
ve o
n AR
T: S
ucce
ss v
s. D
eath
; HIV
-Pos
itive
on
ART:
Suc
cess
vs.
Failu
re/R
ecur
renc
e/D
eath
; HIV
-Pos
itive
on
ART:
Su
cces
s vs
. All
Oth
er U
nfav
oura
ble;
HIV
-Pos
itive
on
ART:
Los
t vs.
All O
ther
Out
com
es; H
IV N
egat
ive:
Suc
cess
vs.
Failu
re/R
ecur
renc
e; H
IV N
egat
ive:
Su
cces
s vs
. Dea
th; H
IV N
egat
ive:
Suc
cess
vs.
Failu
re/R
ecur
renc
e/D
eath
; HIV
Neg
ativ
e: S
ucce
ss v
s. Al
l Oth
er O
utco
mes
; HIV
Neg
ativ
e: L
ost v
s. Al
l O
ther
Out
com
es.
SETT
ING
:So
uth
Afric
a.
PERS
PECT
IVE:
Publ
ic he
alth
and
hea
lth s
yste
ms
pers
pect
ive
BACK
GRO
UND
:M
ultid
rug-
resis
tant
(MD
R-) a
nd ri
fam
picin
-res
istan
t tub
ercu
losis
(MD
R-/R
R-TB
) is
emer
ging
as
a m
ajor
pro
blem
due
to p
oor m
anag
emen
t of d
rug-
sens
itive
as
wel
l as
drug
-res
istan
ce T
B. M
DR-
/RR-
TB is
trea
tabl
e, b
ut h
as re
quire
d th
e us
e of
long
er tr
eatm
ent r
egim
ens
whi
ch c
onta
in p
oten
tially
to
xic d
rugs
. The
inte
rest
in re
ducin
g th
e du
ratio
n of
trea
tmen
t for
MD
R-TB
mot
ivat
ed a
num
ber o
f ini
tiativ
es in
rece
nt y
ears
to tr
eat p
atie
nts
with
sh
orte
r reg
imen
s un
der p
rogr
amm
atic
as w
ell a
s tri
al c
ondi
tions
. In
2016
, on
the
basis
of d
ata
from
obs
erva
tiona
l stu
dies
of t
he s
hort
er re
gim
ens
in
diffe
rent
Asia
n an
d Af
rican
cou
ntrie
s, W
HO
sta
rted
to re
com
men
d a
stan
dard
ised
shor
ter M
DR-
TB re
gim
en, c
onta
inin
g an
inje
ctab
le a
gent
, bas
ed
on th
e on
es u
nder
stu
dy fo
r elig
ible
pat
ient
s. In
201
8, fu
rthe
r mod
ifica
tions
wer
e m
ade
to th
e ea
rlier
reco
mm
ende
d sh
orte
r reg
imen
, rep
lacin
g ka
nam
ycin
by
amika
cin (b
ased
on
evid
ence
from
the
com
para
tive
effe
ctiv
enes
s of
thes
e tw
o in
ject
able
age
nts)
. Ev
iden
ce o
f per
man
ent e
ffect
s at
tribu
ted
to th
e to
xicity
of i
njec
tabl
e ag
ents
, hav
e pr
ompt
ed fu
rthe
r adv
ance
s in
the
deve
lopm
ent o
f new
trea
tmen
ts
such
as
shor
ter i
njec
tabl
e-sp
arin
g re
gim
ens.
In p
artic
ular
, obs
erva
tiona
l dat
a on
an
all-o
ral b
edaq
uilin
e-co
ntai
ning
sho
rter
regi
men
of 9
–12
mon
ths
dura
tion
beca
me
avai
labl
e. T
his
is of
par
ticul
ar im
port
ance
giv
en th
at th
e re
gim
en m
ay o
ffer p
atie
nts
the
likel
ihoo
d of
bet
ter t
oler
atin
g tre
atm
ent
with
out s
igni
fican
t tox
icity.
CON
FLIC
T O
F IN
TERE
STS:
Albe
rto
Piub
ello
.
Annex 4: GRADE evidence-to-decision tables 77
Ass
essm
ent
Prob
lem
Is th
e pr
oble
m a
prio
rity?
JUD
GEM
ENT
RESE
ARC
H E
VID
ENCE
AD
DIT
ION
AL
CON
SID
ERAT
ION
S○
No
○ P
roba
bly
no
○ P
roba
bly
yes
● Ye
s ○
Var
ies
○ D
on’t
know
TB re
mai
ns a
thre
at to
glo
bal p
ublic
hea
lth a
nd is
the
top
infe
ctio
us c
ause
of d
eath
in th
e w
orld
. In
201
8, a
n es
timat
ed 1
0 m
illion
peo
ple
deve
lope
d TB
and
1.4
milli
on d
ied
from
the
dise
ase.
Ab
out 5
00 0
00 n
ew c
ases
of m
ultid
rug-
or r
ifam
picin
-res
istan
t TB
(MD
R/RR
-TB)
wer
e es
timat
ed
to e
mer
ge in
201
8. A
lthou
gh a
ll of
thes
e w
ould
hav
e be
en e
ligib
le fo
r a s
econ
d-lin
e TB
trea
tmen
t re
gim
en, o
nly
156
071
enro
lmen
ts in
trea
tmen
t wer
e re
port
ed b
y co
untri
es in
201
8 –
abou
t 30%
of
the
estim
ated
cas
eloa
d. D
espi
te th
is, s
igni
fican
t im
prov
emen
ts in
the
avai
labi
lity
of e
nhan
ced
diag
nost
ics a
nd m
ore
effe
ctiv
e m
edici
nes
have
occ
urre
d in
rece
nt y
ears
, and
hav
e le
d to
ear
lier
dete
ctio
n an
d hi
gher
suc
cess
rate
s am
ong
patie
nts
with
MD
R/RR
-TB
in a
num
ber o
f nat
iona
l pr
ogra
mm
es. H
owev
er, t
hese
suc
cess
es h
ave
not b
een
repr
oduc
ed in
the
rest
of t
he w
orld
, and
th
e ov
eral
l tre
atm
ent s
ucce
ss ra
te w
orld
wid
e re
ache
d on
ly 5
6% fo
r pat
ient
s w
ith M
DR/
RR-T
B w
ho
star
ted
treat
men
t in
2016
, and
onl
y 39
% fo
r pat
ient
s w
ith e
xten
sivel
y dr
ug-r
esist
ant T
B (X
DR-
TB).
WHO consolidated guidelines on tuberculosis: Online annexes78
Des
irab
le E
ffec
tsH
ow s
ubst
antia
l are
the
desi
rabl
e an
ticip
ated
eff
ects
?
JUD
GEM
ENT
RESE
ARC
H E
VID
ENCE
AD
DIT
ION
AL
CON
SID
ERAT
ION
S○
Triv
ial
● Sm
all
○ M
oder
ate
○ L
arge
○
Var
ies
○ D
on’t
know
The
anal
ysis
also
sug
gest
ed th
at w
hen
the
all-o
ral s
hort
er re
gim
en w
as c
ompa
red
with
an
inje
ctab
le-f
ree
long
er4 re
gim
en c
onta
inin
g be
daqu
iline,
ther
e se
emed
to b
e no
mar
ked
diffe
renc
es
in th
e ou
tcom
es o
bser
ved
earli
er; h
owev
er, r
elat
ivel
y m
odes
t ben
efici
al e
ffect
s w
ere
note
d in
the
dire
ctio
n of
the
inte
rven
tion;
in p
artic
ular
, suc
cess
vs
failu
re/r
ecur
renc
e (a
OR
3.9,
95%
CI 1
.7–9
.1),
succ
ess
vs a
ll un
favo
urab
le o
utco
mes
(aO
R 1.
6, 9
5% C
I 1.2
–2.2
) and
loss
to fo
llow
up
(aO
R 0.
5,
95%
CI 0
.4–0
.8),
all f
avou
ring
the
use
of th
e al
l-ora
l sho
rter
regi
men
.
Out
com
en/
N(B
dq s
hort
)
n/N
(Lon
g,
new
dru
gs)
Num
ber
of Pairs
aOR
(95%
CI)
aRD
(9
5% C
I)
Succ
ess
vs.
Failu
re/R
ecur
renc
e63
1/65
326
8/29
228
53.
9 (1
.7, 9
.1)
5 (1
, 9)
Succ
ess
vs. D
eath
631/
791
268/
338
328
1.0
(0.6
, 1.5
)-4
(-10
, 3)
Succ
ess
vs. F
ailu
re/
Recu
rrenc
e/ D
eath
*63
1/81
326
8/36
235
21.
4 (0
.9, 2
.0)
2 (-
4, 9
)Su
cces
s vs
. All
Unfa
vora
ble
631/
891
268/
440
427
1.6
(1.2
, 2.2
)7
(1, 1
4)
Lost
vs.
All O
ther
O
utco
mes
88/8
9188
/440
427
0.5
(0.4
, 0.8
)-8
(-13
, -3)
The
GD
G ju
dged
the
desir
able
ant
icipa
ted
effe
cts
to
be s
mal
l. Th
e gr
oup
argu
ed th
at w
hen
a dr
ug s
uch
as
beda
quilin
e is
inclu
ded
in a
regi
men
– a
s se
en in
the
anal
ysis
– th
e ou
tcom
es in
the
inte
rven
tion
and
com
paris
on
grou
ps a
re n
ot to
o di
stan
t. In
act
ualit
y, th
e da
ta e
valu
ated
se
emed
to in
dica
te th
at th
e al
l-ora
l bed
aqui
line-
cont
aini
ng
shor
ter r
egim
en o
f 9–1
2 m
onth
s’ du
ratio
n w
as ju
st a
s go
od a
s al
l-ora
l lon
ger r
egim
ens
cont
aini
ng b
edaq
uilin
e.
The
mai
n ad
vant
ages
of t
he a
ll-or
al s
hort
er re
gim
en a
s ob
serv
ed in
the
anal
ysis
was
mos
tly in
term
s of
dec
reas
ed
rate
s of
loss
to fo
llow
-up.
Und
esir
able
Eff
ects
How
sub
stan
tial a
re th
e un
desi
rabl
e an
ticip
ated
eff
ects
?
JUD
GEM
ENT
RESE
ARC
H E
VID
ENCE
AD
DIT
ION
AL
CON
SID
ERAT
ION
S○
Lar
ge
○ M
oder
ate
○ S
mal
l ○
Triv
ial
● Va
ries
○ D
on’t
know
In
pas
t yea
rs, t
he in
crea
sed
use
of b
edaq
uilin
e ha
s re
assu
red
the
TB c
omm
unity
of t
he p
oten
tial f
or a
dver
se
even
ts a
ssoc
iate
d w
ith th
is ag
ent.
The
GD
G a
ntici
pate
d th
at th
e un
desir
able
ant
icipa
ted
effe
cts
on th
e us
e of
regi
men
s m
ay n
ot b
e so
diff
eren
t be
twee
n an
all-
oral
sho
rter
and
an
all-o
ral l
onge
r reg
imen
w
hen
both
con
tain
bed
aqui
line.
How
ever
, the
se e
ffect
s m
ay v
ary,
depe
ndin
g on
, for
exa
mpl
e, th
e se
lect
ion
or
allo
catio
n of
pat
ient
s in
to re
gim
ens
cont
aini
ng b
edaq
uilin
e,
seve
rity
of d
iseas
e, d
rug-
resis
tanc
e pa
ttern
s, qu
ality
of c
are
and
mon
itorin
g.
4 Re
com
men
datio
ns re
leas
ed b
y W
HO
in D
ecem
ber 2
018
emph
asiz
ed th
at fu
lly o
ral [
long
er] r
egim
ens
shou
ld b
e pr
iorit
ized
and
bec
ome
the
pref
erre
d op
tion
for m
ost p
atie
nts,
and
that
inje
ctab
le a
gent
s w
ere
no lo
nger
am
ong
the
prio
rity
med
icine
s to
con
sider
whe
n de
signi
ng lo
nger
MD
R-TB
regi
men
s.
Annex 4: GRADE evidence-to-decision tables 79
Cert
aint
y of
evi
denc
eW
hat i
s th
e ov
eral
l cer
tain
ty o
f the
evi
denc
e of
eff
ects
?
JUD
GEM
ENT
RESE
ARC
H E
VID
ENCE
AD
DIT
ION
AL
CON
SID
ERAT
ION
S●
Very
low
○
Low
○
Mod
erat
e ○
Hig
h ○
No
inclu
ded
stud
ies
Th
e G
DG
poi
nted
out
that
on
the
basis
of t
he e
vide
nce
asse
ssed
– n
amel
y, ob
serv
atio
nal d
ata
and
pote
ntia
l re
sidua
l con
foun
ding
–th
e ov
eral
l cer
tain
ty in
the
estim
ates
of
effe
ct w
as ju
dged
to b
e ve
ry lo
w, w
ith th
e ef
fect
s fo
r al
l out
com
es a
lso ra
ted
as “v
ery
low
”. Al
thou
gh d
oubl
e ad
just
men
t in
prop
ensit
y sc
ore
mat
chin
g an
alys
es w
as
carr
ied
out t
o re
mov
e th
e ef
fect
s of
con
foun
ding
, mem
bers
of
the
GD
G fu
rthe
r not
ed th
at a
lthou
gh th
ese
effo
rts
com
pens
ated
for s
ome
pote
ntia
l con
foun
ders
, res
idua
l bi
as is
like
ly to
be
pres
ent.
The
grou
p ac
know
ledg
ed
that
alth
ough
the
use
of p
rogr
amm
atic
data
hol
ds g
reat
pr
omise
bec
ause
they
bet
ter r
efle
ct re
al p
ract
ice, s
ome
cons
ider
atio
ns in
term
s of
the
exte
nt to
whi
ch th
ese
findi
ngs
coul
d be
app
lied
to o
ther
set
tings
are
to b
e co
ntem
plat
ed. F
or in
stan
ce, s
pecif
ic cli
nica
l cha
ract
erist
ics
of th
e po
pula
tion
(e.g
. HIV
pre
vale
nce
and
drug
-re
sista
nce
patte
rns)
may
hav
e an
effe
ct, a
s m
ay q
ualit
y of
hea
lth c
are
serv
ices,
mod
els
of c
are,
and
trea
tmen
t ad
here
nce
stra
tegi
es.
Valu
esIs
ther
e im
port
ant u
ncer
tain
ty a
bout
or v
aria
bilit
y in
how
muc
h pe
ople
val
ue th
e m
ain
outc
omes
?
JUD
GEM
ENT
RESE
ARC
H E
VID
ENCE
AD
DIT
ION
AL
CON
SID
ERAT
ION
S○
Impo
rtan
t un
cert
aint
y or
va
riabi
lity
○ P
ossib
ly im
port
ant
unce
rtai
nty
or
varia
bilit
y ○
Pro
babl
y no
im
port
ant u
ncer
tain
ty
or v
aria
bilit
y ●
No
impo
rtan
t un
cert
aint
y or
va
riabi
lity
A qu
alita
tive
stud
y un
dert
aken
to h
ighl
ight
the
pers
pect
ives
of k
ey s
take
hold
ers,
mai
nly
patie
nt a
nd
civil
socie
ty re
pres
enta
tives
(n=1
6) lo
oked
at g
ener
al p
refe
renc
es a
nd v
alue
s re
gard
ing
diffe
rent
as
pect
s of
dru
g-re
sista
nt T
B tre
atm
ent r
egim
ens,
such
as
dura
tion,
pill
burd
en, u
se o
f inj
ecta
ble
agen
ts a
nd p
oten
tial f
or e
xper
ienc
ing
adve
rse
even
ts.
Part
icipa
nts
had
the
oppo
rtun
ity to
disc
uss
impo
rtan
t adv
erse
effe
cts
inclu
ding
per
man
ent
sens
orin
eura
l hea
ring
loss
, nep
hrot
oxici
ty, e
lect
roly
te a
bnor
mal
ities
, inj
ectio
n pa
in a
nd lo
cal
inje
ctio
n-sit
e co
mpl
icatio
ns. F
rom
a p
atie
nt p
ersp
ectiv
e, a
dver
se e
vent
s (e
.g. o
ptic
neur
itis,
hear
ing
impa
irmen
t and
men
tal s
tatu
s ch
ange
s du
e to
ure
mia
or e
lect
roly
te a
bnor
mal
ities
) ass
ocia
ted
with
th
e us
e of
spe
cific
seco
nd-li
ne a
gent
s, in
cludi
ng in
ject
able
age
nts,
wer
e de
emed
una
ccep
tabl
e.
Pref
eren
ces
rega
rdin
g tre
atm
ent a
ppea
red
to b
e ro
oted
in
cor
e va
lues
, inc
ludi
ng m
inim
al d
isrup
tion
to n
orm
al li
fe.
Rela
tivel
y fe
w p
atie
nts
seem
ed to
pre
fer a
sho
rt re
gim
en
that
is ti
ed to
mor
e se
rious
sid
e-ef
fect
s, an
d th
en o
nly
if th
e sid
e-ef
fect
s w
ere
rare
or r
ever
sible
. In
addi
tion,
in
term
s of
trea
tmen
t dur
atio
n, p
refe
renc
es s
eem
ed to
be
guid
ed fi
rst b
y sid
e-ef
fect
s an
d se
cond
by
effic
acy
of
treat
men
t reg
imen
s.
WHO consolidated guidelines on tuberculosis: Online annexes80
Bala
nce
of e
ffec
tsD
oes
the
bala
nce
betw
een
desi
rabl
e an
d un
desi
rabl
e ef
fect
s fa
vor t
he in
terv
entio
n or
the
com
paris
on?
JUD
GEM
ENT
RESE
ARC
H E
VID
ENCE
AD
DIT
ION
AL
CON
SID
ERAT
ION
S○
Fav
ors
the
com
paris
on
○ P
roba
bly
favo
rs th
e co
mpa
rison
○
Doe
s no
t fav
or
eith
er th
e in
terv
entio
n or
the
com
paris
on
● Pr
obab
ly fa
vors
the
inte
rven
tion
○ F
avor
s th
e in
terv
entio
n ○
Var
ies
○ D
on’t
know
Reso
urce
s re
quir
edH
ow la
rge
are
the
reso
urce
requ
irem
ents
(cos
ts)?
JUD
GEM
ENT
RESE
ARC
H E
VID
ENCE
AD
DIT
ION
AL
CON
SID
ERAT
ION
S○
Lar
ge c
osts
○
Mod
erat
e co
sts
○ N
eglig
ible
cos
ts
and
savi
ngs
● M
oder
ate
savi
ngs
○ L
arge
sav
ings
○
Var
ies
○ D
on’t
know
The
proj
ecte
d co
st s
avin
g is
near
ly U
S$ 3
000
(201
9 US
$) in
Sou
th A
frica
, and
var
ies
acro
ss s
ettin
gs,
larg
ely
in p
ropo
rtio
n to
hea
lth c
are
and
drug
cos
ts (w
ith s
avin
gs o
f >US
$ 20
00 e
ven
in a
low
-in
com
e se
tting
and
afte
r red
uctio
n in
dru
g co
sts
to h
alf o
f cur
rent
Glo
bal D
rug
Facil
ity [G
DF]
pric
es).
Smal
ler i
f lin
ezol
id is
not
inclu
ded.
Cert
aint
y of
evi
denc
e of
req
uire
d re
sour
ces
Wha
t is
the
cert
aint
y of
the
evid
ence
of r
esou
rce
requ
irem
ents
(cos
ts)?
JUD
GEM
ENT
RESE
ARC
H E
VID
ENCE
AD
DIT
ION
AL
CON
SID
ERAT
ION
S○
Ver
y lo
w
○ L
ow
○ M
oder
ate
○ H
igh
● N
o in
clude
d st
udie
s
Annex 4: GRADE evidence-to-decision tables 81
Cost
eff
ecti
vene
ssD
oes
the
cost
-eff
ectiv
enes
s of
the
inte
rven
tion
favo
r the
inte
rven
tion
or th
e co
mpa
rison
?
JUD
GEM
ENT
RESE
ARC
H E
VID
ENCE
AD
DIT
ION
AL
CON
SID
ERAT
ION
S○
Fav
ors
the
com
paris
on
○ P
roba
bly
favo
rs th
e co
mpa
rison
○
Doe
s no
t fav
or
eith
er th
e in
terv
entio
n or
the
com
paris
on
● Pr
obab
ly fa
vors
the
inte
rven
tion
○ F
avor
s th
e in
terv
entio
n ○
Var
ies
○ N
o in
clude
d st
udie
s
A co
st–e
ffect
iven
ess
mod
el w
as d
evel
oped
, inc
orpo
ratin
g es
timat
ed h
ealth
sys
tem
cos
ts w
ith d
rug
proc
urem
ent,
heal
th c
are
deliv
ery,
adve
rse
even
ts, r
etre
atm
ents
, sec
onda
ry c
ases
, and
mor
bidi
ty
and
mor
talit
y as
socia
ted
with
TB
mor
talit
y an
d re
curre
nce,
trea
tmen
t dur
atio
n, d
rug
toxic
ity, a
nd
TB tr
ansm
issio
n. C
osts
and
cos
t–ef
fect
iven
ess
wer
e ev
alua
ted
in S
outh
Afri
ca, w
ith s
ensit
ivity
an
alys
es re
pres
entin
g a
rang
e of
dru
g an
d he
alth
car
e co
sts,
high
and
low
HIV
co-
prev
alen
ce,
95%
con
fiden
ce in
terv
als
(Cis)
for e
stim
ates
of r
elat
ive
effic
acy
deriv
ed fr
om s
tatis
tical
ana
lysis
of
patie
nt c
ohor
t dat
a, a
nd u
ncer
tain
ty in
the
valu
es o
f par
amet
ers
repr
esen
ting
TB n
atur
al h
istor
y. Co
mpa
red
an 1
8–20
-mon
th a
ll-or
al re
gim
en (m
odel
led
as c
onta
inin
g W
HO
gro
up A
dru
gs
inclu
ding
bed
aqui
line
and
linez
olid
), a
9–12
-mon
th a
ll-or
al, b
edaq
uilin
e-co
ntai
ning
regi
men
is
proj
ecte
d to
be
both
cos
t sav
ing
and
effe
ctiv
e un
der a
ll m
odel
led
scen
ario
s. Be
caus
e th
e sh
orte
r or
al re
gim
en d
omin
ated
ove
r the
long
er re
gim
en in
all
scen
ario
s m
odel
led,
cos
t–ef
fect
iven
ess
was
no
t cal
cula
ted.
Equi
tyW
hat w
ould
be
the
impa
ct o
n he
alth
equ
ity?
JUD
GEM
ENT
RESE
ARC
H E
VID
ENCE
AD
DIT
ION
AL
CON
SID
ERAT
ION
S○
Red
uced
○
Pro
babl
y re
duce
d ○
Pro
babl
y no
impa
ct
○ P
roba
bly
incr
ease
d ●
Incr
ease
d ○
Var
ies
○ D
on’t
know
A qu
alita
tive
stud
y un
dert
aken
to h
ighl
ight
the
pers
pect
ives
of k
ey s
take
hold
ers,
mai
nly
patie
nts
and
civil
socie
ty re
pres
enta
tives
(n =
16)
, loo
ked
at g
ener
al p
refe
renc
es a
nd v
alue
s re
gard
ing
diffe
rent
asp
ects
of t
reat
men
t reg
imen
s fo
r dru
g-re
sista
nt T
B, s
uch
as d
urat
ion,
pill
burd
en, u
se o
f in
ject
able
age
nts,
and
pote
ntia
l for
exp
erie
ncin
g ad
vers
e ev
ents
.Pa
rtici
pant
s co
nsid
ered
any
thin
g le
ss th
an u
nive
rsal
and
imm
edia
te a
cces
s to
new
trea
tmen
ts to
be
une
thica
l, bu
t whe
n pr
ompt
ed to
con
sider
this
pref
eren
ce a
gain
st a
lim
ited
supp
ly o
f dru
gs, a
fe
w w
ould
prio
ritiz
e th
e yo
unge
st a
nd s
ickes
t, as
wel
l as
thos
e w
ho w
ere
adhe
rent
and
cou
ld b
e m
onito
red
for a
dver
se e
vent
s. Pa
tient
s w
ho fa
ce s
ocio
econ
omic
chal
leng
es to
adh
eren
ce o
r who
liv
e in
rem
ote,
rura
l or p
oore
r com
mun
ities
that
lack
tech
nica
l skil
l or e
quip
men
t for
trea
tmen
t m
onito
ring,
cou
ld th
en b
e di
spro
port
iona
tely
and
unj
ustly
pla
ced
at a
disa
dvan
tage
.
The
GD
G a
gree
d th
at in
ject
able
-spa
ring
regi
men
s w
ould
be
eas
ier t
o de
cent
raliz
e an
d th
eref
ore
to u
se in
rem
ote
and
unde
rser
vice
d se
tting
s an
d di
sadv
anta
ged
popu
latio
ns,
help
ing
to a
llevi
ate
heal
th in
equi
ties,
with
out a
ntici
patin
g di
ffere
nces
in o
utco
mes
in s
pecif
ic po
pula
tions
. The
gr
oup
also
not
ed th
at b
ecau
se a
udio
met
ry w
ould
not
be
requ
ired,
it m
ight
be
easie
r to
mon
itor i
ndiv
idua
ls, in
spi
te
of in
crea
sed
requ
irem
ents
for e
lect
roca
rdio
grap
hy, w
hich
is
a pr
ereq
uisit
e fo
r the
use
of b
edaq
uilin
e-co
ntai
ning
re
gim
ens.
How
ever
, the
gro
up s
tress
ed th
at th
e us
e of
el
ectro
card
iogr
aphy
sho
uld
not b
e a
diffe
rent
iatin
g el
emen
t be
twee
n th
ese
two
regi
men
s, be
caus
e pa
tient
s re
ceiv
ing
inje
ctab
le a
gent
s su
ch a
s am
ikacin
sho
uld
also
hav
e re
gula
r car
diac
mon
itorin
g. T
he g
roup
ack
now
ledg
ed th
at
it is
poss
ible
that
in s
ome
setti
ngs
not a
ll pa
tient
s w
ould
be
abl
e to
und
ergo
ele
ctro
card
iogr
aphi
c m
onito
ring;
ho
wev
er, t
he g
roup
also
not
ed th
at th
e in
crea
sing
acce
ss to
ele
ctro
card
iogr
aphy
at p
erip
hera
l lev
els
mig
ht
impr
ove
equi
ty.
WHO consolidated guidelines on tuberculosis: Online annexes82
Acc
epta
bilit
yIs
the
inte
rven
tion
acce
ptab
le to
key
sta
keho
lder
s?
JUD
GEM
ENT
RESE
ARC
H E
VID
ENCE
AD
DIT
ION
AL
CON
SID
ERAT
ION
S○
No
○ P
roba
bly
no
○ P
roba
bly
yes
● Ye
s ○
Var
ies
○ D
on’t
know
A qu
alita
tive
stud
y un
dert
aken
to h
ighl
ight
the
pers
pect
ives
of k
ey s
take
hold
ers,
mai
nly
patie
nts
and
civil
socie
ty re
pres
enta
tives
(n =
16)
, loo
ked
at g
ener
al p
refe
renc
es a
nd v
alue
s re
gard
ing
diffe
rent
asp
ects
of t
reat
men
t reg
imen
s fo
r dru
g-re
sista
nt T
B, s
uch
as d
urat
ion,
pill
burd
en, u
se
of in
ject
able
age
nts,
and
pote
ntia
l for
exp
erie
ncin
g ad
vers
e ev
ents
. The
resu
lts o
f thi
s qu
alita
tive
anal
ysis
sugg
este
d th
at m
ost p
atie
nts
wou
ld p
riorit
ize
a re
gim
en w
ith fe
wer
and
less
sev
ere
side-
effe
cts
abov
e al
l else
, bec
ause
it w
ould
allo
w th
em to
con
tinue
rout
ine
activ
ities
. Of n
ote,
sur
vivo
rs
of d
rug-
resis
tant
TB
rem
arke
d th
at th
ey w
ould
acc
ept a
long
er tr
eatm
ent t
hat p
rom
ised
less
se
vere
adv
erse
eff
ects
ove
r a s
hort
er re
gim
en ti
ed to
mor
e se
vere
sid
e-ef
fect
s, ev
en if
trea
tmen
t w
as e
xper
imen
tal o
r effi
cacy
unc
lear
. Thi
s co
ntra
sted
with
the
com
para
tivel
y fe
w p
artic
ipan
ts w
ho
prio
ritiz
ed ra
pid
retu
rn to
nor
mal
life
and
wou
ld ra
ther
ass
ume
the
risk
of m
ore
serio
us s
ide-
effe
cts
with
in a
sho
rter
regi
men
, eve
n if
treat
men
t was
exp
erim
enta
l and
effi
cacy
unc
lear
.
The
GD
G n
oted
that
pat
ient
s re
cogn
ize
that
thei
r ex
perie
nces
and
per
cept
ions
are
hig
hly
pers
on-
and
cont
ext-d
epen
dent
, tho
ugh
pref
eren
ce fo
r thi
s [s
hort
er]
regi
men
see
med
to b
e co
nditi
onal
upo
n ad
vers
e ev
ents
be
ing
rare
or r
ever
sible
. N
ever
thel
ess,
over
all,
a sh
ort,
inje
ctio
n-fre
e re
gim
en w
ith
few
to n
o ph
ysica
l and
men
tal h
ealth
sid
e-ef
fect
s an
d a
low
pi
ll bu
rden
app
eare
d to
be
the
mos
t acc
epta
ble.
Annex 4: GRADE evidence-to-decision tables 83
Feas
ibili
tyIs
the
inte
rven
tion
feas
ible
to im
plem
ent?
JUD
GEM
ENT
RESE
ARC
H E
VID
ENCE
AD
DIT
ION
AL
CON
SID
ERAT
ION
S○
No
○ P
roba
bly
no
○ P
roba
bly
yes
● Ye
s ○
Var
ies
○ D
on’t
know
A qu
alita
tive
stud
y un
dert
aken
to h
ighl
ight
the
pers
pect
ives
of k
ey s
take
hold
ers,
mai
nly
patie
nts
and
civil
socie
ty re
pres
enta
tives
(n=1
6) lo
oked
at g
ener
al p
refe
renc
es a
nd v
alue
s re
gard
ing
diffe
rent
as
pect
s of
dru
g-re
sista
nt T
B tre
atm
ent r
egim
ens,
such
as
dura
tion,
pill
burd
en, u
se o
f inj
ecta
ble
agen
ts a
nd p
oten
tial f
or e
xper
ienc
ing
adve
rse
even
ts.
This
stud
y re
veal
ed th
at a
s th
e re
gim
en, i
n pa
rticu
lar t
he e
xpan
sion
of b
edaq
uilin
e ac
cess
to a
ll pa
tient
s is
held
bac
k is
som
e se
tting
s as
a re
sult
of re
stric
tive
elig
ibilit
y (i.
e. p
riorit
izat
ion
of s
pecif
ic gr
oups
) crit
eria
, lac
k of
fund
ing
or la
ck o
f ade
quat
e in
frast
ruct
ure
in p
lace
(e.g
. dia
gnos
tics)
; th
eref
ore,
the
oper
atio
naliz
atio
n an
d im
med
iate
roll-
out o
f the
all-
oral
bed
aqui
line-
cont
aini
ng
regi
men
may
be
ham
pere
d.
One
impo
rtan
t req
uire
men
t hig
hlig
hted
by
the
GD
G w
as
that
of e
nsur
ing
the
care
ful s
elec
tion
of p
atie
nts
who
ar
e to
ben
efit
from
this
regi
men
, con
duct
ing
rapi
d an
d ac
cura
te D
ST, a
nd m
onito
ring
beda
quilin
e re
sista
nce.
The
im
plem
enta
tion
of th
e re
gim
en m
ay b
e lim
ited
by th
e ne
ed fo
r im
prov
ed la
bora
tory
infra
stru
ctur
e. A
lthou
gh
coun
tries
are
impl
emen
ting
rapi
d m
olec
ular
test
s to
id
entif
y rif
ampi
cin re
sista
nce,
labo
rato
ry c
apac
ity n
eeds
to
be
effe
ctiv
ely
esta
blish
ed to
con
duct
gen
otyp
ic an
d ph
enot
ypic
test
ing
for o
ther
impo
rtan
t age
nts
in th
e re
gim
en. A
lso, a
lthou
gh th
e pr
eval
ence
of i
dent
ified
m
utat
ions
con
ferr
ing
low
-leve
l dru
g re
sista
nce
is ve
ry lo
w,
coun
tries
are
to s
treng
then
labo
rato
ry c
apac
ity a
nd to
m
onito
r the
acq
uisit
ion
of re
sista
nce
to b
edaq
uilin
e th
ough
th
eir n
atio
nal r
efer
ence
labo
rato
ries
or T
B su
pran
atio
nal
refe
renc
e ne
twor
k sit
es. T
his
is es
pecia
lly im
port
ant g
iven
th
e pi
pelin
e of
new
ant
i-TB
regi
men
s th
at a
re re
lyin
g on
be
daqu
iline
as a
bac
kbon
e.Th
e re
mov
al o
f inj
ecta
ble
agen
ts, a
s di
scus
sed
by th
e G
DG
, also
poi
nted
tow
ards
the
conv
enie
nce
(for h
ealth
ca
re w
orke
rs) o
f not
hav
ing
to d
eliv
er d
aily
inje
ctio
ns, a
nd
mor
e so
, for
pat
ient
s no
t hav
ing
to e
ndur
e pa
in a
nd o
ther
sig
nific
ant a
dver
se e
vent
s.Th
e im
plem
enta
tion
of th
e re
gim
en is
per
ceiv
ed to
go
beyo
nd s
ecur
ing
of fu
ndin
g, b
ut it
furt
her r
equi
res
mak
ing
long
-ter
m, s
usta
inab
le s
yste
ms
chan
ges
to e
nsur
e ra
pid
trans
ition
, con
sider
ing
the
regi
stra
tion
of b
edaq
uilin
e an
d ot
her n
ew a
gent
s, un
inte
rrup
ted
supp
ly o
f qua
lity-
assu
red
drug
s, an
d ac
tive
TB d
rug
safe
ty m
onito
ring
and
man
agem
ent s
yste
m in
coo
rdin
atio
n w
ith e
xistin
g ph
arm
acov
igila
nce
stru
ctur
es a
t the
cou
ntry
leve
l.Al
so, t
he im
plem
enta
tion
of th
is re
gim
en (a
nd a
ny o
ther
no
vel r
egim
en) w
ill re
quire
dec
ision
-mak
ing
tow
ards
m
ultis
ecto
ral p
olici
es, t
ailo
ring
patie
nt-c
entre
d pr
ogra
mm
es
that
also
con
sider
asp
ects
suc
h as
men
tal h
ealth
and
m
anag
emen
t of o
ther
com
orbi
ditie
s, fa
cilita
ting
coun
sellin
g an
d su
ppor
t dur
ing
treat
men
t, an
d af
ter c
ompl
etio
n,
facil
itatin
g fu
ll re
cove
ry.
WHO consolidated guidelines on tuberculosis: Online annexes84
Sum
mar
y of
judg
emen
ts
JUD
GEM
ENT
PRO
BLEM
No
Prob
ably
no
Prob
ably
yes
Yes
Varie
sD
on’t
know
DES
IRAB
LE E
FFEC
TSTr
ivia
lSm
all
Mod
erat
eLa
rge
Varie
sD
on’t
know
UND
ESIR
ABLE
EFF
ECTS
Larg
eM
oder
ate
Smal
lTr
ivia
lVa
ries
Don
’t kn
owCE
RTAI
NTY
OF
EVID
ENCE
Very
low
Low
Mod
erat
eH
igh
No
inclu
ded
stud
ies
VALU
ESIm
port
ant
unce
rtai
nty
or
varia
bilit
y
Poss
ibly
impo
rtan
t un
cert
aint
y or
va
riabi
lity
Prob
ably
no
impo
rtan
t un
cert
aint
y or
va
riabi
lity
No
impo
rtan
t un
cert
aint
y or
va
riabi
lity
BALA
NCE
OF
EFFE
CTS
Favo
rs th
e co
mpa
rison
Prob
ably
favo
rs th
e co
mpa
rison
Doe
s not
favo
r eith
er
the
inte
rven
tion
or
the
com
paris
on
Prob
ably
favo
rs
the
inte
rven
tion
Favo
rs th
e in
terv
entio
nVa
ries
Don
’t kn
ow
RESO
URCE
S RE
QUI
RED
Larg
e co
sts
Mod
erat
e co
sts
Neg
ligib
le c
osts
and
sa
ving
sM
oder
ate
savi
ngs
Larg
e sa
ving
sVa
ries
Don
’t kn
ow
CERT
AIN
TY O
F EV
IDEN
CE
OF
REQ
UIRE
D R
ESO
URCE
SVe
ry lo
wLo
wM
oder
ate
Hig
hN
o in
clude
d st
udie
s
COST
EFF
ECTI
VEN
ESS
Favo
rs th
e co
mpa
rison
Prob
ably
favo
rs th
e co
mpa
rison
Doe
s not
favo
r eith
er
the
inte
rven
tion
or
the
com
paris
on
Prob
ably
favo
rs
the
inte
rven
tion
Favo
rs th
e in
terv
entio
nVa
ries
No
inclu
ded
stud
ies
EQUI
TYRe
duce
dPr
obab
ly re
duce
dPr
obab
ly n
o im
pact
Prob
ably
incr
ease
dIn
crea
sed
Varie
sD
on’t
know
ACCE
PTAB
ILIT
YN
oPr
obab
ly n
oPr
obab
ly y
esYe
sVa
ries
Don
’t kn
owFE
ASIB
ILIT
YN
oPr
obab
ly n
oPr
obab
ly y
esYe
sVa
ries
Don
’t kn
ow
Type
of r
ecom
men
datio
nSt
rong
reco
mm
enda
tion
agai
nst
the
inte
rven
tion
○
Cond
ition
al re
com
men
datio
n ag
ains
t the
inte
rven
tion
○
Cond
ition
al re
com
men
datio
n fo
r eith
er th
e in
terv
entio
n or
the
com
paris
on○
Cond
ition
al re
com
men
datio
n fo
r the
inte
rven
tion
●
Stro
ng re
com
men
datio
n fo
r the
in
terv
entio
n○
Annex 4: GRADE evidence-to-decision tables 85
Conc
lusi
ons
Reco
mm
enda
tion
A sh
orte
r, al
l-ora
l, be
daqu
iline-
cont
aini
ng re
gim
en o
f 9–1
2 m
onth
s du
ratio
n is
reco
mm
ende
d in
elig
ible
pat
ient
s w
ith c
onfir
med
MD
R/RR
-TB
who
hav
e no
t bee
n ex
pose
d to
trea
tmen
t w
ith s
econ
d-lin
e TB
med
icine
s us
ed in
this
regi
men
for m
ore
than
one
mon
th a
nd in
who
m re
sista
nce
to fl
uoro
quin
olon
es h
as b
een
exclu
ded.
(Con
ditio
nal r
ecom
men
datio
n, v
ery
low
cer
tain
ty in
the
evid
ence
)Ju
stifi
catio
nO
vera
ll, th
e G
DG
not
ed th
at th
e ce
rtai
nty
of th
e ev
iden
ce re
gard
ing
the
effic
acy
of th
e al
l-ora
l sho
rter
regi
men
was
“ver
y lo
w”,
attri
buta
ble
to c
once
rns
of s
erio
us ri
sk o
f bia
s, de
spite
ef
fort
s to
bal
ance
bas
elin
e co
varia
tes.
How
ever
, the
gro
up re
cogn
ized
that
the
curre
nt e
vide
nce
asse
ssm
ent o
f the
all-
oral
, bed
aqui
line-
cont
aini
ng s
hort
er re
gim
en h
as s
ome
addi
tiona
l ad
vant
ages
as
com
pare
d w
ith a
ll-or
al lo
nger
regi
men
s, na
mel
y in
term
s of
low
er lo
ss to
follo
w-u
p (d
esira
ble
effe
ct) a
nd o
bvio
us s
hort
er d
urat
ion
(acc
epta
bilit
y).
Whe
n de
cidin
g on
the
stre
ngth
of t
he re
com
men
datio
n, th
e G
DG
reac
hed
a un
anim
ous
decis
ion
on th
e co
nditi
onal
ity o
f the
reco
mm
enda
tion,
mai
nly
attri
bute
d to
the
very
low
cer
tain
ty
in th
e ev
iden
ce a
nd re
quire
men
ts to
bui
ld la
bora
tory
cap
acity
and
ens
ure
DST
.O
ther
gro
unds
for t
he s
treng
th a
nd d
irect
ion
of th
is re
com
men
datio
n ar
e as
follo
ws:
• Th
e an
alys
is co
nduc
ted
to in
form
the
deve
lopm
ent o
f thi
s re
com
men
datio
n w
as b
ased
on
obse
rvat
iona
l pro
gram
mat
ic da
ta fr
om S
outh
Afri
ca w
here
the
stan
dard
ized
sho
rter
, all-
oral
, be
daqu
iline-
cont
aini
ng re
gim
en (B
DQ
-LFX
/MFX
-ETO
-E-Z
-Hh -C
FZ) w
as u
sed
for p
atie
nts
with
MD
R/RR
-TB.
• Th
ough
no
maj
or s
igna
ls of
risk
wer
e ob
serv
ed w
ith th
e us
e of
the
all-o
ral b
edaq
uilin
e-ba
sed
shor
ter r
egim
en, t
here
also
rem
aine
d so
me
unce
rtai
ntie
s gi
ven
the
lack
of s
yste
mat
ic co
llect
ion
of d
ata,
and
the
lack
of c
larit
y as
to a
ny c
hang
es in
the
regi
men
that
cou
ld h
ave
been
info
rmed
by
the
pres
ence
of a
dver
se e
vent
s.•
Cost
–effe
ctiv
enes
s m
odel
ling
of th
e al
l-ora
l, sh
orte
r, be
daqu
iline-
cont
aini
ng re
gim
en s
how
ed ro
bust
cos
t sav
ings
rela
tive
to e
ither
a lo
nger
ora
l reg
imen
or a
sho
rt in
ject
able
-co
ntai
ning
regi
men
.•
The
GD
G ju
dged
that
man
y el
igib
le p
atie
nts
wou
ld p
refe
r the
all-
oral
, bed
aqui
line-
cont
aini
ng re
gim
en o
f 9–1
2 m
onth
s’ du
ratio
n. T
his
is su
ppor
ted
by li
mite
d ob
serv
atio
ns in
volv
ing
16 s
urvi
vors
of d
rug-
resis
tant
TB.
In a
dditi
on, t
his
regi
men
may
hel
p pr
omot
e he
alth
equ
ity o
r miti
gate
the
wor
seni
ng o
f hea
lth in
equi
ties.
How
ever
, the
pan
el re
cogn
ized
that
im
plem
enta
tion
and
scal
e-up
of t
his
regi
men
mig
ht b
e slo
w b
ecau
se o
f pre
requ
isite
s re
gard
ing
labo
rato
ry c
apac
ity a
nd m
onito
ring.
Subg
roup
con
side
ratio
nsTh
e at
tem
pted
to d
escr
ibe
the
bala
nce
of e
ffect
s an
d co
nsid
erat
ions
for v
ario
us s
ubgr
oups
or s
pecia
l pop
ulat
ions
. How
ever
, the
evi
denc
e re
view
ed s
uppo
rted
the
use
of th
is in
the
follo
win
g se
tting
s, w
ith s
pecif
ic ca
veat
s:•
Peop
le li
ving
with
HIV
infe
ctio
n (P
LHIV
): Th
e da
ta e
valu
ated
cor
resp
onde
d to
a s
ettin
g w
ith a
hig
h pr
eval
ence
of H
IV, a
nd o
f par
ticul
ar s
igni
fican
ce, m
ost P
LHIV
(>95
%) w
ho s
tart
ed
the
all-o
ral b
edaq
uilin
e-co
ntai
ning
regi
men
wer
e re
ceiv
ing
antir
etro
vira
l the
rapy
(ART
). In
vie
w o
f the
trea
tmen
t out
com
es d
escr
ibed
in th
e an
alys
is, th
ere
wer
e no
gro
unds
to b
elie
ve
that
the
regi
men
wou
ld p
erfo
rm a
ny d
iffer
ently
in P
LHIV
. It i
s ne
cess
ary
to c
onsid
er s
igni
fican
t clin
ical i
nter
actio
ns th
at m
ay in
crea
se b
edaq
uilin
e ex
posu
re o
r tha
t of o
ther
age
nts
with
po
tent
ial f
or c
ardi
otox
icity
whe
n th
ese
are
co-a
dmin
ister
ed w
ith a
ntire
trovi
rals.
• Ch
ildre
n: A
lthou
gh n
o di
rect
out
com
e es
timat
ions
cou
ld b
e dr
awn
for t
his
popu
latio
n, e
xtra
pola
tion
was
dee
med
reas
onab
le. H
owev
er, b
ecau
se b
edaq
uilin
e is
curre
ntly
reco
mm
ende
d fo
r chi
ldre
n an
d ad
oles
cent
s ag
ed 6
–17
year
s, th
e G
DG
con
clude
d th
at th
e al
l-ora
l bed
aqui
line-
cont
aini
ng re
gim
en m
ay b
e us
ed in
elig
ible
chi
ldre
n w
ithin
this
age
grou
p, ta
king
into
ac
coun
t spe
cifica
tions
for r
egim
en c
ompa
nion
dru
gs, i
n pa
rticu
lar,
beda
quilin
e.•
Preg
nant
and
lact
atin
g w
omen
: Mor
e ev
iden
ce is
nee
ded
to b
ette
r inf
orm
the
use
of th
e al
l-ora
l, be
daqu
iline-
cont
aini
ng s
hort
er re
gim
en (B
DQ
-LFX
/MFX
-ETO
-E-Z
-Hh -C
FZ).
One
of
the
agen
ts in
this
all-o
ral s
hort
er re
gim
en, e
thio
nam
ide,
is u
sual
ly c
ontra
indi
cate
d in
pre
gnan
cy, a
nd w
ithho
ldin
g th
is ag
ent o
r rep
lacin
g it
with
ano
ther
one
cou
ld s
erio
usly
co
mpr
omise
the
effe
ctiv
enes
s of
the
regi
men
. For
pre
gnan
t and
lact
atin
g w
omen
, it i
s th
eref
ore
reco
mm
ende
d th
at a
n in
divi
dual
ized
, all-
oral
long
er re
gim
en (i
nclu
ding
bed
aqui
line)
be
use
d (s
ee R
ecom
men
datio
ns o
n th
e us
e of
long
er re
gim
ens
for M
DR/
RR-T
B).
• Ex
trapu
lmon
ary
dise
ase:
In v
iew
of t
he u
nava
ilabi
lity
of e
vide
nce
rega
rdin
g su
rroga
tes
for s
ever
ity o
r ext
ent o
f dise
ase,
it is
adv
isabl
e to
use
clin
ical j
udge
men
t to
decid
e on
the
use
of
this
regi
men
in p
atie
nts
with
ext
ensiv
e TB
dise
ase
or s
ever
e fo
rms
of e
xtra
pulm
onar
y TB
.
WHO consolidated guidelines on tuberculosis: Online annexes86
Impl
emen
tatio
n co
nsid
erat
ions
The
inte
rest
in re
ducin
g th
e du
ratio
n of
trea
tmen
t for
MD
R/RR
-TB
has
mot
ivat
ed a
num
ber o
f stu
dies
in re
cent
yea
rs o
f tre
atin
g pa
tient
s w
ith s
hort
er re
gim
ens
unde
r pro
gram
mat
ic as
wel
l as
trial
con
ditio
ns. B
ecau
se o
f exp
erie
nces
in v
ario
us s
ettin
gs, [
elig
ible
] pat
ient
s no
w h
ave
an o
ptio
n to
be
treat
ed w
ith a
sho
rter
, inj
ecta
ble-
spar
ing
regi
men
of 9
–12
mon
ths’
dura
tion.
To e
nsur
e th
at th
e re
gim
en a
chie
ves
its d
esira
ble
effe
cts
and
to p
reve
nt th
e ac
quisi
tion
(or a
mpl
ifica
tion)
of a
dditi
onal
dru
g re
sista
nce
(whi
le p
rote
ctin
g re
gim
en c
ompo
nent
s),
coun
tries
are
to c
onsid
er th
e fo
llow
ing:
• Pa
tient
sel
ectio
n an
d de
cisio
ns to
sta
rt th
e al
l-ora
l sho
rter
regi
men
: Pat
ient
s w
ith c
onfir
med
MD
R/RR
-TB
and
with
resis
tanc
e to
fluo
roqu
inol
ones
rule
d ou
t are
exp
ecte
d to
ben
efit
the
mos
t fro
m th
is re
gim
en. P
rope
r pat
ient
sel
ectio
n w
ill no
t onl
y le
ad to
impr
oved
trea
tmen
t out
com
es, b
ut w
ill al
so c
ontri
bute
to a
void
ing
the
deve
lopm
ent o
f res
istan
ce to
bed
aqui
line.
In
this
resp
ect,
the
regi
men
is to
onl
y be
impl
emen
ted
in s
ettin
gs w
here
rout
ine
DST
for r
ifam
picin
and
fluo
roqu
inol
ones
can
be
guar
ante
ed.
–It
is ve
ry im
port
ant t
hat t
he im
plem
enta
tion
of th
ese
reco
mm
enda
tions
is a
ccom
pani
ed b
y co
ntin
ued
effo
rts
to in
crea
se a
cces
s to
DST
for a
ll m
edici
nes
for w
hich
relia
ble
met
hods
ex
ist, a
s w
ell a
s fo
r the
dev
elop
men
t and
rollo
ut o
f DST
met
hods
for n
ewer
med
icine
s. In
the
abse
nce
of a
dru
g-su
scep
tibilit
y te
st, a
ssay
s sp
ecifi
c fo
r bed
aqui
line
resis
tanc
e sh
ould
be
mon
itore
d th
roug
h as
sess
men
t of m
inim
um in
hibi
tory
con
cent
ratio
ns (M
ICs)
of b
edaq
uilin
e. –Re
sista
nce
to o
ther
ant
i-TB
drug
s sh
ould
be
mon
itore
d in
acc
orda
nce
with
WH
O re
com
men
datio
ns.
• Us
e of
line
zolid
: The
evi
denc
e m
ade
avai
labl
e to
info
rm th
is re
com
men
datio
n fo
cuse
d on
the
asse
ssm
ent o
f a re
gim
en c
ompo
sed
of b
edaq
uilin
e, le
voflo
xacin
/mox
iflox
acin
, et
hion
amid
e, e
tham
buto
l, py
razi
nam
ide,
hig
h-do
se is
onia
zid,
clo
fazi
min
e, a
nd p
yraz
inam
ide.
How
ever
, sec
onda
ry a
naly
ses
(onl
y in
long
er re
gim
ens
cont
aini
ng b
edaq
uilin
e an
d be
daqu
iline
plus
line
zolid
) sho
wed
favo
urab
le o
utco
mes
whe
n tre
atm
ent r
egim
ens
inclu
ded
both
line
zolid
and
bed
aqui
line.
The
bas
is fo
r the
add
ition
of l
inez
olid
was
to p
rote
ct
the
regi
men
, in
part
icula
r, be
daqu
iline,
whi
le a
wai
ting
susc
eptib
ility
resu
lts o
n ad
ditio
nal r
esist
ance
to fl
uoro
quin
olon
es a
nd o
ther
dru
gs. T
he G
DG
dec
ided
that
unt
il ne
w e
vide
nce
is av
aila
ble
on s
hort
er re
gim
ens
that
inclu
de b
oth
of th
ese
agen
ts, t
he a
ll-or
al b
edaq
uilin
e-co
ntai
ning
sho
rter
regi
men
adv
ised
here
in s
houl
d no
t inc
lude
line
zolid
. How
ever
, the
gro
up
enco
urag
ed c
ount
ries
to c
onsid
er th
e us
e of
a m
odifie
d al
l-ora
l bed
aqui
line-
and
linez
olid
-con
tain
ing
only
unde
r ope
ratio
nal r
esea
rch
until
new
evid
ence
bec
omes
ava
ilabl
e.•
Patie
nt-c
entre
d ap
proa
ch: E
ffort
s ar
e re
quire
d to
pro
vide
pat
ient
sup
port
to e
nabl
e fu
ll ad
here
nce
to tr
eatm
ent.
Mon
itorin
g an
d ev
alua
tion
• Th
e im
plem
enta
tion
of th
is re
gim
en re
quire
s th
e us
e of
rout
ine
DST
not
onl
y fo
r pat
ient
sel
ectio
n, b
ut a
lso fo
r mon
itorin
g of
the
acqu
isitio
n of
resis
tanc
e.•
Alth
ough
the
data
ass
esse
d di
d no
t une
arth
any
maj
or s
igna
ls of
risk
, act
ive
TB d
rug
safe
ty m
onito
ring
and
man
agem
ent s
yste
ms
mus
t be
func
tiona
l in
orde
r to
cond
uct r
igor
ous
activ
e m
onito
ring
of a
dver
se e
vent
s an
d to
det
ect,
man
age
and
repo
rt s
uspe
cted
or c
onfir
med
dru
g to
xiciti
es in
a ti
mel
y m
anne
r.
Rese
arch
prio
ritie
sM
embe
rs o
f the
GD
G d
iscus
sed
the
rese
arch
gap
s to
info
rm th
e de
velo
pmen
t of p
ublic
hea
lth re
com
men
datio
ns fo
r the
man
agem
ent o
f MD
R/RR
-TB,
and
hig
hlig
hted
the
follo
win
g pr
iorit
ies:
• st
udie
s as
sess
ing
com
paris
ons
of a
ll-or
al s
hort
er re
gim
ens
whi
ch in
clude
bed
aqui
line
and
linez
olid
, in
addi
tion
to o
ther
com
pani
on d
rugs
;•
stud
ies
asse
ssin
g co
mpa
rison
s of
all-
oral
sho
rter
regi
men
s am
ong
diffe
rent
sub
grou
ps a
nd s
pecia
l pop
ulat
ions
, inc
ludi
ng p
regn
ant a
nd la
ctat
ing
wom
en;
• ra
ndom
ized
-con
trolle
d tri
als
or o
pera
tiona
l res
earc
h of
the
effe
ctiv
enes
s an
d sa
fety
of a
ll-or
al s
hort
er re
gim
ens,
incr
easin
g th
e ce
rtai
nty
of th
e ev
iden
ce;
• st
udie
s ex
plor
ing
mec
hani
sms
of a
cqui
sitio
n of
resis
tanc
e to
bed
aqui
line
and
gene
tic m
arke
rs to
iden
tify
resis
tanc
e; a
nd•
effo
rts
to d
eter
min
e be
st w
ays
to s
tand
ardi
ze th
e co
llect
ion
of d
ata
so th
at c
ount
ries
can
cont
ribut
e to
the
deve
lopm
ent o
f glo
bal r
ecom
men
datio
ns.
aOR:
adj
uste
d od
ds ra
tio; A
RT: a
ntire
trovi
ral t
hera
py; d
rug-
susc
eptib
ility
test
ing;
GD
F: G
loba
l Dru
g Fa
cility
; GD
G: G
uide
line
Dev
elop
men
t Gro
up; M
DR/
RR-T
B: m
ultid
rug-
or r
ifam
picin
-res
istan
t TB;
MIC
: min
imum
in
hibi
tory
con
cent
ratio
n; P
LHIV
: peo
ple
livin
g w
ith h
uman
imm
unod
efici
ency
viru
s; TB
: tub
ercu
losis
; WH
O: W
orld
Hea
lth O
rgan
izat
ion.
Annex 4: GRADE evidence-to-decision tables 87
Shou
ld a
n al
l-or
al s
hort
er re
gim
en o
f 9–1
2 m
onth
s’ d
urat
ion
incl
udin
g be
daqu
iline
vs
long
er re
gim
ens
with
out n
ew T
B dr
ugs
be u
sed
for M
DR-
/RR-
TB p
atie
nts
to s
afel
y im
prov
e ou
tcom
es?
POPU
LATI
ON
:M
DR-
/RR-
TB p
atie
nts
to s
afel
y im
prov
e ou
tcom
esIN
TERV
ENTI
ON
:Al
l-ora
l bed
aqui
line-
cont
aini
ng s
hort
er re
gim
en o
f 9–1
2 m
onth
s du
ratio
n (B
DQ
-LFX
/MFX
-ETO
-E-Z
-Hh -C
FZ)
COM
PARI
SON
:Lo
nger
regi
men
s w
ithou
t new
TB
drug
sM
AIN
OUT
COM
ES:
Succ
ess
vs. F
ailu
re/R
ecur
renc
e; S
ucce
ss v
s. D
eath
; Suc
cess
vs.
Failu
re/R
ecur
renc
e/D
eath
; Suc
cess
vs.
All U
nfav
oura
ble;
Los
t vs.
All O
ther
Out
com
es; A
FB
Smea
r Pos
itive
: Suc
cess
vs.
Failu
re/R
ecur
renc
e; A
FB S
mea
r Pos
itive
: Suc
cess
vs.
Dea
th; A
FB S
mea
r Pos
itive
: Suc
cess
vs.
Failu
re/R
ecur
renc
e/D
eath
; AFB
Sm
ear
Posit
ive:
Suc
cess
vs.
All U
nfav
oura
ble;
AFB
Sm
ear P
ositi
ve: L
ost v
s. Al
l Oth
er O
utco
mes
; HIV
-Pos
itive
on
ART:
Suc
cess
vs.
Failu
re/R
ecur
renc
e; H
IV-P
ositi
ve o
n AR
T: S
ucce
ss v
s. D
eath
; HIV
-Pos
itive
on
ART:
Suc
cess
vs.
Failu
re/R
ecur
renc
e/D
eath
; HIV
-Pos
itive
on
ART:
Suc
cess
vs.
All O
ther
Unf
avou
rabl
e; H
IV-P
ositi
ve
on A
RT: L
ost v
s. Al
l Oth
er O
utco
mes
; HIV
Neg
ativ
e: S
ucce
ss v
s. Fa
ilure
/Rec
urre
nce;
HIV
Neg
ativ
e: S
ucce
ss v
s. D
eath
; HIV
Neg
ativ
e: S
ucce
ss v
s. Fa
ilure
/Re
curre
nce/
Dea
th; H
IV N
egat
ive:
Suc
cess
vs.
All O
ther
Out
com
es; H
IV N
egat
ive:
Los
t vs.
All O
ther
Out
com
es.
SETT
ING
:So
uth
Afric
a.
PERS
PECT
IVE:
Publ
ic he
alth
and
hea
lth s
yste
ms
pers
pect
ive
BACK
GRO
UND
:M
ultid
rug-
resis
tant
(MD
R-) a
nd ri
fam
picin
-res
istan
t tub
ercu
losis
(MD
R-/R
R-TB
) is
emer
ging
as
a m
ajor
pro
blem
due
to p
oor m
anag
emen
t of d
rug-
sens
itive
as
wel
l as
drug
-res
istan
t TB.
MD
R-/R
R-TB
is tr
eata
ble,
but
has
requ
ired
the
use
of lo
nger
trea
tmen
t reg
imen
s w
hich
con
tain
pot
entia
lly to
xic d
rugs
. The
in
tere
st in
redu
cing
the
dura
tion
of tr
eatm
ent f
or M
DR-
TB m
otiv
ated
a n
umbe
r of i
nitia
tives
in re
cent
yea
rs to
trea
t pat
ient
s w
ith s
hort
er re
gim
ens
unde
r pr
ogra
mm
atic
as w
ell a
s tri
al c
ondi
tions
. In
2016
, on
the
basis
of d
ata
from
obs
erva
tiona
l stu
dies
of t
he s
hort
er re
gim
ens
in d
iffer
ent A
sian
and
Afric
an
coun
tries
, WH
O s
tart
ed to
reco
mm
end
a st
anda
rdiz
ed s
hort
er M
DR-
TB re
gim
en, c
onta
inin
g an
inje
ctab
le a
gent
, bas
ed o
n th
e on
es u
nder
stu
dy fo
r elig
ible
pa
tient
s. In
201
8, fu
rthe
r mod
ifica
tions
wer
e m
ade
to th
e ea
rlier
reco
mm
ende
d sh
orte
r reg
imen
, rep
lacin
g ka
nam
ycin
by
amika
cin (b
ased
on
evid
ence
from
th
e co
mpa
rativ
e ef
fect
iven
ess
of th
ese
two
inje
ctab
le a
gent
s).
Evid
ence
of p
erm
anen
t effe
cts
attri
bute
d to
the
toxic
ity o
f inj
ecta
ble
agen
ts, h
ave
prom
pted
furt
her a
dvan
ces
in th
e de
velo
pmen
t of n
ew tr
eatm
ents
su
ch a
s sh
orte
r inj
ecta
ble-
spar
ing
regi
men
s. In
par
ticul
ar, o
bser
vatio
nal d
ata
on a
n al
l-ora
l bed
aqui
line-
cont
aini
ng s
hort
er re
gim
en o
f 9–1
2 m
onth
s du
ratio
n be
cam
e av
aila
ble.
Thi
s is
of p
artic
ular
impo
rtan
ce g
iven
that
the
regi
men
may
offe
r pat
ient
s th
e lik
elih
ood
of b
ette
r tol
erat
ing
treat
men
t with
out
signi
fican
t tox
icity.
CON
FLIC
T O
F IN
TERE
STS:
Albe
rto
Piub
ello
.
Ass
essm
ent
Prob
lem
Is th
e pr
oble
m a
prio
rity?
JUD
GEM
ENT
RESE
ARC
H E
VID
ENCE
AD
DIT
ION
AL
CON
SID
ERAT
ION
S○
No
○ P
roba
bly
no
○ P
roba
bly
yes
● Ye
s ○
Var
ies
○ D
on’t
know
Tube
rcul
osis
(TB)
rem
ains
a th
reat
to g
loba
l pub
lic h
ealth
and
is th
e to
pmos
t inf
ectio
us c
ause
of
deat
h in
the
wor
ld. I
n 20
18, a
n es
timat
ed 1
0 m
illion
peo
ple
deve
lope
d TB
and
1.4
milli
on d
ied
from
the
dise
ase.
Abo
ut 5
00 0
00 n
ew c
ases
of m
ultid
rug-
or r
ifam
picin
-res
istan
t TB
(MD
R/RR
-TB)
w
ere
estim
ated
to e
mer
ge in
201
8. A
lthou
gh a
ll of
thes
e w
ould
hav
e be
en e
ligib
le fo
r a s
econ
d-lin
e TB
trea
tmen
t reg
imen
, onl
y 15
6 07
1 en
rolm
ents
in tr
eatm
ent w
ere
repo
rted
by
coun
tries
in
201
8 –
abou
t 30%
of t
he e
stim
ated
cas
eloa
d. D
espi
te th
is, s
igni
fican
t im
prov
emen
ts in
the
avai
labi
lity
of e
nhan
ced
diag
nost
ics a
nd m
ore
effe
ctiv
e m
edici
nes
has
occu
rred
in re
cent
yea
rs
and
has
led
to e
arlie
r det
ectio
n an
d hi
gher
suc
cess
rate
s am
ong
patie
nts
with
MD
R/RR
-TB
in a
nu
mbe
r of n
atio
nal p
rogr
amm
es. H
owev
er, t
hese
suc
cess
es h
ave
not b
een
repr
oduc
ed in
the
rest
of t
he w
orld
, and
the
over
all t
reat
men
t suc
cess
rate
wor
ldw
ide
reac
hed
only
56%
for p
atie
nts
with
MD
R/RR
-TB
who
sta
rted
trea
tmen
t in
2016
, and
onl
y 39
% fo
r pat
ient
s w
ith e
xtre
mel
y dr
ug-
resis
tant
TB
(XD
R-TB
).
WHO consolidated guidelines on tuberculosis: Online annexes88
Des
irab
le E
ffec
tsH
ow s
ubst
antia
l are
the
desi
rabl
e an
ticip
ated
eff
ects
?
JUD
GEM
ENT
RESE
ARC
H E
VID
ENCE
AD
DIT
ION
AL
CON
SID
ERAT
ION
S○
Triv
ial
○ S
mal
l ○
Mod
erat
e ●
Larg
e ○
Var
ies
○ D
on’t
know
The
prim
ary
anal
ysis
also
illu
stra
ted
the
effe
ct o
f an
all-o
ral s
hort
er b
edaq
uilin
e-ba
sed
regi
men
as
com
pare
d w
ith lo
ng re
gim
ens
that
did
not
con
tain
any
new
dru
gs. T
he s
hort
er re
gim
en
perfo
rmed
sig
nific
antly
bet
ter a
cros
s al
l out
com
es a
nd a
ll su
bgro
ups
as c
ompa
red
with
trea
tmen
t ou
tcom
es w
hen
long
er re
gim
es w
ithou
t new
dru
gs w
ere
impl
emen
ted.
Out
com
en/
N
(Bdq
sho
rt)
n/N
(L
ong,
no
new
dru
gs)
Num
ber
of Pairs
aOR
(95%
CI
)aR
D (9
5%
CI)
Succ
ess
vs. F
ailu
re/
Recu
rrenc
e63
1/65
367
9/77
158
03.
7 (2
.2, 6
.3)
8
(5, 1
1)Su
cces
s vs
. Dea
th63
1/79
167
9/10
4474
72.
3 (1
.8, 3
.0)
15
(10,
19)
Succ
ess
vs. F
ailu
re/R
ec./
Dea
th63
1/81
367
9/11
3677
12.
6 (2
.0, 3
.3)
18
(14,
23)
Succ
ess
vs. A
ll Un
favo
rabl
e63
1/89
167
9/14
3785
92.
8 (2
.3, 3
.5)
23
(18,
27)
Lost
vs.
All O
ther
O
utco
mes
88/8
9136
8/14
3785
90.
4 (0
.3, 0
.5)
-14
(-17
, -10
)
Und
esir
able
Eff
ects
How
sub
stan
tial a
re th
e un
desi
rabl
e an
ticip
ated
eff
ects
?
JUD
GEM
ENT
RESE
ARC
H E
VID
ENCE
AD
DIT
ION
AL
CON
SID
ERAT
ION
S○
Lar
ge
○ M
oder
ate
○ S
mal
l ●
Triv
ial
○ V
arie
s ○
Don
’t kn
ow
The
GD
G d
iscus
sed
earli
er re
sults
of t
he in
divi
dual
-pat
ient
dat
a (IP
D) m
eta-
anal
ysis
cond
ucte
d to
as
sess
the
over
all b
alan
ce b
etw
een
bene
fits
and
harm
s of
indi
vidu
al a
gent
s. In
the
anal
ysis,
199
5 pa
tient
s re
ceiv
ed k
anam
ycin
and
268
(13.
4%) e
xper
ienc
ed a
n ad
vers
e ev
ent c
ausin
g pe
rman
ent
drug
disc
ontin
uatio
n; 4
106
patie
nts
rece
ived
am
ikacin
, of w
hom
235
(5.7
%) e
xper
ienc
ed a
n ad
vers
e ev
ent c
ausin
g pe
rman
ent d
rug
disc
ontin
uatio
n; a
dditi
onal
ly, 1
932
rece
ived
cap
reom
ycin
an
d 16
1 (8
.3%
) exp
erie
nced
an
adve
rse
even
t cau
sing
perm
anen
t dru
g di
scon
tinua
tion.
In
cont
rast
, 464
pat
ient
s re
ceiv
ed b
edaq
uilin
e, o
f who
m n
ine
(1.9
%),
nine
(1.9
%) e
xper
ienc
ed a
n ad
vers
e ev
ent c
ausin
g pe
rman
ent d
rug
disc
ontin
uatio
n.
The
GD
G a
gree
d th
at th
ere
is ev
iden
ce o
f pat
ient
s ex
perie
ncin
g ad
vers
e ev
ents
afte
r the
use
of b
edaq
uilin
e. H
owev
er, i
t was
em
phas
ized
that
com
pare
d w
ith th
e al
tern
ativ
e, a
nd o
n th
e ba
sis o
f the
IPD
met
a-an
alys
is, th
ese
even
ts s
eem
to b
e sig
nific
antly
few
er.
Som
e m
embe
rs o
f the
GD
G d
id e
mph
asiz
e th
at a
lthou
gh
the
unde
sirab
le e
ffect
s of
the
all-o
ral b
edaq
uilin
e-co
ntai
ning
sh
orte
r reg
imen
see
med
to b
e tri
vial
com
pare
d w
ith th
ose
of
long
er re
gim
ens
with
out n
ew T
B dr
ugs,
ther
e w
ere
still
adve
rse
even
ts a
ssoc
iate
d w
ith th
e dr
ugs
used
in th
e al
l-ora
l reg
imen
.
Annex 4: GRADE evidence-to-decision tables 89
Cert
aint
y of
evi
denc
eW
hat i
s th
e ov
eral
l cer
tain
ty o
f the
evi
denc
e of
eff
ects
?
JUD
GEM
ENT
RESE
ARC
H E
VID
ENCE
AD
DIT
ION
AL
CON
SID
ERAT
ION
S●
Very
low
○
Low
○
Mod
erat
e ○
Hig
h ○
No
inclu
ded
stud
ies
Th
e G
DG
poi
nted
out
that
on
the
basis
of t
he e
vide
nce
asse
ssed
– n
amel
y ob
serv
atio
nal d
ata
and
pote
ntia
l res
idua
l co
nfou
ndin
g –
the
over
all c
erta
inty
of t
he e
stim
ates
of e
ffect
w
as ju
dged
to b
e “v
ery
low
”, w
ith th
e ef
fect
s fo
r all
outc
omes
al
so ra
ted
as “v
ery
low
”.Al
thou
gh d
oubl
e ad
just
men
t in
prop
ensit
y sc
ore
mat
chin
g an
alys
es w
as c
arrie
d ou
t to
rem
ove
the
effe
cts
of c
onfo
undi
ng,
mem
bers
of t
he G
DG
furt
her n
oted
that
alth
ough
thes
e ef
fort
s co
mpe
nsat
ed fo
r som
e po
tent
ial c
onfo
unde
rs, r
esid
ual b
ias
was
lik
ely
to b
e pr
esen
t. Th
e gr
oup
ackn
owle
dged
that
alth
ough
th
e us
e of
pro
gram
mat
ic da
ta h
olds
gre
at p
rom
ise b
ecau
se
they
bet
ter r
efle
ct re
al p
ract
ice, s
ome
cons
ider
atio
ns in
term
s of
the
exte
nt to
whi
ch th
ese
findi
ngs
coul
d be
app
lied
to
othe
r set
tings
are
to b
e co
ntem
plat
ed, s
uch
as s
pecif
ic cli
nica
l ch
arac
teris
tics
of th
e po
pula
tion
(e.g
. HIV
pre
vale
nce;
dru
g-re
sista
nce
patte
rns)
, as
wel
l as
qual
ity o
f hea
lth c
are
serv
ices,
mod
els
of c
are,
and
trea
tmen
t adh
eren
ce s
trate
gies
.
Valu
esIs
ther
e im
port
ant u
ncer
tain
ty a
bout
or v
aria
bilit
y in
how
muc
h pe
ople
val
ue th
e m
ain
outc
omes
?
JUD
GEM
ENT
RESE
ARC
H E
VID
ENCE
AD
DIT
ION
AL
CON
SID
ERAT
ION
S○
Impo
rtan
t un
cert
aint
y or
va
riabi
lity
○ P
ossib
ly
impo
rtan
t un
cert
aint
y or
va
riabi
lity
○ P
roba
bly
no im
port
ant
unce
rtai
nty
or
varia
bilit
y ●
No
impo
rtan
t un
cert
aint
y or
va
riabi
lity
A qu
alita
tive
stud
y un
dert
aken
to h
ighl
ight
the
pers
pect
ives
of k
ey s
take
hold
ers,
mai
nly
patie
nts
and
civil
socie
ty re
pres
enta
tives
(n =
16)
, loo
ked
at g
ener
al p
refe
renc
es a
nd v
alue
s re
gard
ing
diffe
rent
asp
ects
of t
reat
men
t reg
imen
s fo
r dru
g-re
sista
nt T
B, s
uch
as d
urat
ion,
pill
burd
en, u
se o
f in
ject
able
age
nts,
and
pote
ntia
l for
exp
erie
ncin
g ad
vers
e ev
ents
.Pr
efer
ence
s fo
r tre
atm
ent d
urat
ion
seem
ed to
be
guid
ed fi
rst b
y sid
e-ef
fect
s an
d se
cond
by
effic
acy.
The
qual
itativ
e st
udy,
thou
gh s
mal
l, hi
ghlig
hted
how
mos
t pat
ient
s w
ould
pre
fer a
long
er
regi
men
with
less
sev
ere
side-
effe
cts
over
a s
hort
er re
gim
en w
ith m
ore
seve
re s
ide-
effe
cts..
Pref
eren
ces
rega
rdin
g tre
atm
ent a
ppea
red
to b
e ro
oted
in c
ore
valu
es, i
nclu
ding
min
imal
disr
uptio
n to
nor
mal
life
. Rel
ativ
ely
few
pat
ient
s se
emed
to p
refe
r a s
hort
regi
men
that
was
tied
to
mor
e se
rious
sid
e-ef
fect
s, an
d th
en o
nly
if th
e sid
e-ef
fect
s w
ere
rare
or r
ever
sible
. In
addi
tion,
in te
rms
of th
e du
ratio
n of
trea
tmen
t, pr
efer
ence
s se
emed
to b
e gu
ided
firs
t by
side-
effe
cts
and
seco
nd b
y ef
ficac
y of
trea
tmen
t reg
imen
s.
WHO consolidated guidelines on tuberculosis: Online annexes90
Bala
nce
of e
ffec
tsD
oes
the
bala
nce
betw
een
desi
rabl
e an
d un
desi
rabl
e ef
fect
s fa
vor t
he in
terv
entio
n or
the
com
paris
on?
JUD
GEM
ENT
RESE
ARC
H E
VID
ENCE
AD
DIT
ION
AL
CON
SID
ERAT
ION
S○
Fav
ors
the
com
paris
on
○ P
roba
bly
favo
rs
the
com
paris
on
○ D
oes
not
favo
r eith
er th
e in
terv
entio
n or
the
com
paris
on
○ P
roba
bly
favo
rs
the
inte
rven
tion
● Fa
vors
the
inte
rven
tion
○ V
arie
s ○
Don
’t kn
ow
Th
e di
scus
sed
whe
ther
the
bala
nce
betw
een
desir
able
and
un
desir
able
effe
cts
favo
ured
the
inte
rven
tion.
Dat
a as
sess
ed
show
ed th
at th
e ov
eral
l rat
e of
adv
erse
eve
nts
attri
bute
d to
be
daqu
iline
as c
ompa
red
with
inje
ctab
le a
gent
s w
as tw
o tim
e le
ss. A
t the
sam
e tim
e, th
e G
DG
not
ed a
50%
redu
ctio
n in
de
aths
, attr
ibut
ing
this
effe
ct to
the
addi
tion
of b
edaq
uilin
e.
How
ever
, the
gro
up e
mph
asiz
ed th
e po
tent
ial h
arm
s if
this
beda
quilin
e-co
ntai
ning
regi
men
wer
e to
be
impl
emen
ted
with
out e
nsur
ing
prop
er D
ST, a
nd th
e po
tent
ial f
or a
mpl
ifica
tion
of re
sista
nce
patte
rns.
Reso
urce
s re
quir
edH
ow la
rge
are
the
reso
urce
requ
irem
ents
(cos
ts)?
JUD
GEM
ENT
RESE
ARC
H E
VID
ENCE
AD
DIT
ION
AL
CON
SID
ERAT
ION
S○
Lar
ge c
osts
○
Mod
erat
e co
sts
○ N
eglig
ible
cos
ts
and
savi
ngs
● M
oder
ate
savi
ngs
○ L
arge
sav
ings
○
Var
ies
○ D
on’t
know
Th
e G
DG
did
agr
ee th
at, o
vera
ll, sa
ving
s ca
n be
con
sider
ed
in te
rms
of fu
ture
retre
atm
ents
pre
vent
ed, a
s w
ell a
s re
duce
d ho
spita
lizat
ion
rate
s re
sulti
ng fr
om fe
wer
adv
erse
reac
tions
.
Cert
aint
y of
evi
denc
e of
req
uire
d re
sour
ces
Wha
t is
the
cert
aint
y of
the
evid
ence
of r
esou
rce
requ
irem
ents
(cos
ts)?
JUD
GEM
ENT
RESE
ARC
H E
VID
ENCE
AD
DIT
ION
AL
CON
SID
ERAT
ION
S○
Ver
y lo
w
○ L
ow
● M
oder
ate
○ H
igh
○ N
o in
clude
d st
udie
s
The
GD
G a
ntici
pate
d th
e co
st s
avin
gs to
be
robu
st, w
ith s
avin
gs
on d
rugs
, hea
lth c
are
deliv
ery,
few
er a
dver
se e
vent
s an
d lo
wer
re
treat
men
t and
loss
-to-
follo
w-u
p ra
tes.
Annex 4: GRADE evidence-to-decision tables 91
Cost
eff
ecti
vene
ssD
oes
the
cost
-eff
ectiv
enes
s of
the
inte
rven
tion
favo
r the
inte
rven
tion
or th
e co
mpa
rison
?
JUD
GEM
ENT
RESE
ARC
H E
VID
ENCE
AD
DIT
ION
AL
CON
SID
ERAT
ION
S○
Fav
ors
the
com
paris
on
○ P
roba
bly
favo
rs
the
com
paris
on
○ D
oes
not
favo
r eith
er th
e in
terv
entio
n or
the
com
paris
on
○ P
roba
bly
favo
rs
the
inte
rven
tion
● Fa
vors
the
inte
rven
tion
○ V
arie
s ○
No
inclu
ded
stud
ies
No
cost
–effe
ctiv
enes
s an
alys
is w
as p
erfo
rmed
onl
y fo
r cur
rent
ly re
com
men
ded
com
para
tor
regi
men
s. A
long
er re
gim
en c
onta
inin
g no
new
TB
drug
s w
as n
ot s
epar
atel
y m
odel
led.
Al
thou
gh th
e an
alyt
ic-de
cisio
n m
odel
did
not
focu
s on
co
mpa
ring
cost
sav
ings
and
cos
t–ef
fect
iven
ess
rela
tive
to
long
er re
gim
ens
with
out t
he u
se o
f any
new
dru
gs, t
he G
DG
di
d ac
know
ledg
e th
at th
e sh
orte
ning
of t
he re
gim
en a
nd
the
switc
h fro
m in
ject
able
s to
ora
l dru
gs a
re e
stim
ated
to b
e re
sour
ce s
avin
g as
a re
sult
of s
avin
gs o
n dr
ugs,
heal
th c
are
deliv
ery,
and
redu
ced
rate
s of
adv
erse
eve
nts.
Equi
tyW
hat w
ould
be
the
impa
ct o
n he
alth
equ
ity?
JUD
GEM
ENT
RESE
ARC
H E
VID
ENCE
AD
DIT
ION
AL
CON
SID
ERAT
ION
S○
Red
uced
○
Pro
babl
y re
duce
d ○
Pro
babl
y no
im
pact
○
Pro
babl
y in
crea
sed
● In
crea
sed
○ V
arie
s ○
Don
’t kn
ow
A qu
alita
tive
stud
y un
dert
aken
to h
ighl
ight
the
pers
pect
ives
of k
ey s
take
hold
ers,
mai
nly
patie
nts
and
civil
socie
ty re
pres
enta
tives
(n =
16)
, loo
ked
at g
ener
al p
refe
renc
es a
nd v
alue
s re
gard
ing
diffe
rent
asp
ects
of t
reat
men
t reg
imen
s fo
r dru
g-re
sista
nt T
B, s
uch
as d
urat
ion,
pill
burd
en, u
se o
f in
ject
able
age
nts,
and
pote
ntia
l for
exp
erie
ncin
g ad
vers
e ev
ents
.Pa
rtici
pant
s co
nsid
ered
any
thin
g le
ss th
an u
nive
rsal
and
imm
edia
te a
cces
s to
new
trea
tmen
ts to
be
une
thica
l, bu
t whe
n pr
ompt
ed to
con
sider
this
pref
eren
ce a
gain
st a
lim
ited
supp
ly o
f dru
gs, a
fe
w w
ould
prio
ritiz
e th
e yo
unge
st a
nd s
ickes
t, as
wel
l as
thos
e w
ho w
ere
adhe
rent
and
cou
ld b
e m
onito
red
for a
dver
se e
vent
s. Pa
tient
s w
ho fa
ce s
ocio
econ
omic
chal
leng
es to
adh
eren
ce o
r who
liv
e in
rem
ote,
rura
l, or
poo
rer c
omm
uniti
es th
at la
ck te
chni
cal s
kill o
r equ
ipm
ent f
or tr
eatm
ent
mon
itorin
g co
uld
then
be
disp
ropo
rtio
nate
ly a
nd u
njus
tly p
lace
d at
a d
isadv
anta
ge.
The
GD
G a
gree
d th
at th
e al
l-ora
l sho
rter
regi
men
wou
ld b
e ea
sier t
o de
cent
raliz
e an
d th
eref
ore
mak
e av
aila
ble
to re
mot
e an
d un
ders
ervi
ced
setti
ngs
and
disa
dvan
tage
d po
pula
tions
, he
lpin
g to
alle
viat
e he
alth
ineq
uitie
s, w
ithou
t ant
icipa
ting
diffe
renc
es in
out
com
es in
spe
cific
popu
latio
ns. F
urth
er, t
he
grou
p no
ted
that
bec
ause
aud
iom
etry
wou
ld n
ot b
e re
quire
d,
it m
ight
be
easie
r to
mon
itor i
ndiv
idua
ls, in
spi
te o
f inc
reas
ed
requ
irem
ents
for e
lect
roca
rdio
grap
hy, w
hich
is a
pre
requ
isite
fo
r the
use
of b
edaq
uilin
e-co
ntai
ning
regi
men
s. H
owev
er,
the
grou
p st
ress
ed th
at th
e us
e of
ele
ctro
card
iogr
aphy
sh
ould
not
be
a di
ffere
ntia
ting
elem
ent b
etw
een
thes
e tw
o re
gim
ens,
beca
use
patie
nts
rece
ivin
g in
ject
able
age
nts
such
as
am
ikacin
sho
uld
also
hav
e re
gula
r car
diac
mon
itorin
g. T
he
grou
p ac
know
ledg
ed th
at it
is p
ossib
le th
at, i
n so
me
setti
ngs,
not a
ll pa
tient
s w
ill be
abl
e to
und
ergo
ele
ctro
card
iogr
aphi
c m
onito
ring;
how
ever
, mem
bers
also
not
ed th
at th
e in
crea
sing
acce
ss to
ele
ctro
card
iogr
aphy
at p
erip
hera
l lev
els
mig
ht
impr
ove
equi
ty.
WHO consolidated guidelines on tuberculosis: Online annexes92
Acc
epta
bilit
yIs
the
inte
rven
tion
acce
ptab
le to
key
sta
keho
lder
s?
JUD
GEM
ENT
RESE
ARC
H E
VID
ENCE
AD
DIT
ION
AL
CON
SID
ERAT
ION
S○
No
○ P
roba
bly
no
○ P
roba
bly
yes
● Ye
s ○
Var
ies
○ D
on’t
know
A qu
alita
tive
stud
y un
dert
aken
to h
ighl
ight
the
pers
pect
ives
of k
ey s
take
hold
ers,
mai
nly
patie
nts
and
civil
socie
ty re
pres
enta
tives
(n =
16)
, loo
ked
at g
ener
al p
refe
renc
es a
nd v
alue
s re
gard
ing
diffe
rent
asp
ects
of t
reat
men
t reg
imen
s fo
r dru
g-re
sista
nt T
B, s
uch
as d
urat
ion,
pill
burd
en,
use
of in
ject
able
age
nts,
and
pote
ntia
l for
exp
erie
ncin
g ad
vers
e ev
ents
. The
resu
lts o
f thi
s qu
alita
tive
anal
ysis
sugg
este
d th
at m
ost p
atie
nts
wou
ld p
riorit
ize
a re
gim
en w
ith fe
wer
and
less
se
vere
sid
e-ef
fect
s ab
ove
all e
lse, b
ecau
se it
wou
ld a
llow
them
to c
ontin
ue ro
utin
e ac
tiviti
es. O
f no
te, s
urvi
vors
of d
rug-
resis
tant
TB
rem
arke
d th
at th
ey w
ould
acc
ept a
long
er tr
eatm
ent t
hat
prom
ised
less
sev
ere
adve
rse
effe
cts
over
a s
hort
er re
gim
en ti
ed to
mor
e se
vere
sid
e-ef
fect
s, ev
en if
trea
tmen
t was
exp
erim
enta
l or e
ffica
cy w
as u
ncle
ar. T
his
cont
rast
ed w
ith c
ompa
rativ
ely
few
par
ticip
ants
who
prio
ritiz
ed a
rapi
d re
turn
to n
orm
al li
fe a
nd w
ould
rath
er a
ssum
e th
e ris
k of
mor
e se
rious
sid
e-ef
fect
s w
ithin
a s
hort
er re
gim
en, e
ven
if tre
atm
ent w
as e
xper
imen
tal a
nd
effic
acy
was
unc
lear
.
The
GD
G n
oted
that
pat
ient
s re
cogn
ize
that
thei
r exp
erie
nces
an
d pe
rcep
tions
are
hig
hly
pers
on-
and
cont
ext-d
epen
dent
, th
ough
pre
fere
nce
over
this
[sho
rter
] reg
imen
see
med
to b
e co
nditi
onal
upo
n ad
vers
e ev
ents
bei
ng ra
re o
r rev
ersib
le.
Nev
erth
eles
s, ov
eral
l, a
shor
t, in
ject
ion-
free
regi
men
with
few
to
no p
hysic
al a
nd m
enta
l hea
lth s
ide-
effe
cts
and
a lo
w p
ill bu
rden
ap
pear
ed to
be
the
mos
t acc
epta
ble.
Annex 4: GRADE evidence-to-decision tables 93
Feas
ibili
tyIs
the
inte
rven
tion
feas
ible
to im
plem
ent?
JUD
GEM
ENT
RESE
ARC
H E
VID
ENCE
AD
DIT
ION
AL
CON
SID
ERAT
ION
S○
No
○ P
roba
bly
no
○ P
roba
bly
yes
○ Y
es
● Va
ries
○ D
on’t
know
A qu
alita
tive
stud
y un
dert
aken
to h
ighl
ight
the
pers
pect
ives
of k
ey s
take
hold
ers,
mai
nly
patie
nts
and
civil
socie
ty re
pres
enta
tives
(n =
16)
, loo
ked
at g
ener
al p
refe
renc
es a
nd v
alue
s re
gard
ing
diffe
rent
asp
ects
of t
reat
men
t reg
imen
s fo
r dru
g-re
sista
nt T
B, s
uch
as d
urat
ion,
pill
burd
en, u
se o
f in
ject
able
age
nts,
and
pote
ntia
l for
exp
erie
ncin
g ad
vers
e ev
ents
.Th
is st
udy
reve
aled
that
bec
ause
the
regi
men
– in
par
ticul
ar th
e ex
pans
ion
of b
edaq
uilin
e ac
cess
to
all
patie
nts
– is
held
bac
k in
som
e se
tting
s as
a re
sult
of re
stric
tive
elig
ibilit
y (i.
e. p
riorit
izat
ion
of s
pecif
ic gr
oups
) crit
eria
, lac
k of
fund
ing,
or l
ack
of a
dequ
ate
infra
stru
ctur
e in
pla
ce (e
.g.
diag
nost
ics),
the
oper
atio
naliz
atio
n an
d im
med
iate
rollo
ut o
f the
all-
oral
bed
aqui
line-
cont
aini
ng
regi
men
mig
ht b
e ha
mpe
red.
One
impo
rtan
t req
uire
men
t hig
hlig
hted
by
the
GD
G w
as th
at
of e
nsur
ing
the
care
ful s
elec
tion
of p
atie
nts
who
are
to b
enef
it fro
m th
is re
gim
en, c
ondu
ctin
g ra
pid
and
accu
rate
DST
, and
m
onito
ring
beda
quilin
e re
sista
nce.
The
impl
emen
tatio
n of
the
regi
men
may
be
limite
d by
the
need
for i
mpr
oved
labo
rato
ry
infra
stru
ctur
e. A
lthou
gh c
ount
ries
are
impl
emen
ting
rapi
d m
olec
ular
test
s to
iden
tify
rifam
picin
resis
tanc
e, la
bora
tory
ca
pacit
y ne
eds
to b
e ef
fect
ivel
y es
tabl
ished
to c
ondu
ct
geno
typi
c an
d ph
enot
ypic
test
ing
for o
ther
impo
rtan
t age
nts
in th
e re
gim
en. A
lso, a
lthou
gh th
e pr
eval
ence
of i
dent
ified
m
utat
ions
con
ferr
ing
low
-leve
l dru
g re
sista
nce
is ve
ry lo
w,
coun
tries
are
to s
treng
then
labo
rato
ry c
apac
ity a
nd to
mon
itor
the
acqu
isitio
n of
resis
tanc
e to
bed
aqui
line
thou
gh th
eir
natio
nal r
efer
ence
labo
rato
ries
or T
B su
pran
atio
nal r
efer
ence
ne
twor
k sit
es. T
his
is es
pecia
lly im
port
ant g
iven
the
pipe
line
of n
ew a
nti-T
B re
gim
ens
that
are
rely
ing
on b
edaq
uilin
e as
a
back
bone
.Th
e re
mov
al o
f inj
ecta
ble
agen
ts, a
s di
scus
sed
by th
e G
DG
, also
po
inte
d to
war
ds th
e co
nven
ienc
e (fo
r hea
lth c
are
wor
kers
) of
not h
avin
g to
del
iver
dai
ly in
ject
ions
, and
mor
e so
, for
pat
ient
s no
t hav
ing
to e
ndur
e pa
in a
nd o
ther
sig
nific
ant a
dver
se e
vent
s.Th
e im
plem
enta
tion
of th
e re
gim
en is
per
ceiv
ed to
go
beyo
nd
secu
ring
of fu
ndin
g, b
ut it
furt
her r
equi
res
mak
ing
long
-te
rm, s
usta
inab
le s
yste
ms
chan
ges
to e
nsur
e ra
pid
trans
ition
, co
nsid
erin
g th
e re
gist
ratio
n of
bed
aqui
line
and
othe
r new
ag
ents
, uni
nter
rupt
ed s
uppl
y of
qua
lity-
assu
red
drug
s, an
d ac
tive
TB d
rug
safe
ty m
onito
ring
and
man
agem
ent s
yste
m in
co
ordi
natio
n w
ith e
xistin
g ph
arm
acov
igila
nce
stru
ctur
es a
t the
co
untr
y le
vel.
Also
, the
impl
emen
tatio
n of
this
regi
men
(and
any
oth
er n
ovel
re
gim
en) w
ill re
quire
dec
ision
-mak
ing
tow
ards
mul
tisec
tora
l po
licie
s, ta
ilorin
g pa
tient
-cen
tred
prog
ram
mes
that
also
co
nsid
er a
spec
ts s
uch
as m
enta
l hea
lth a
nd m
anag
emen
t of
othe
r com
orbi
ditie
s, fa
cilita
ting
coun
sellin
g an
d su
ppor
t dur
ing
treat
men
t, an
d af
ter c
ompl
etio
n, fa
cilita
ting
full
reco
very
.
WHO consolidated guidelines on tuberculosis: Online annexes94
Sum
mar
y of
judg
emen
ts
JUD
GEM
ENTS
PRO
BLEM
No
Prob
ably
no
Prob
ably
yes
Yes
Varie
sD
on’t
know
DES
IRAB
LE E
FFEC
TSTr
ivia
lSm
all
Mod
erat
eLa
rge
Varie
sD
on’t
know
UND
ESIR
ABLE
EFF
ECTS
Larg
eM
oder
ate
Smal
lTr
ivia
lVa
ries
Don
’t kn
owCE
RTAI
NTY
OF
EVID
ENCE
Very
low
Low
Mod
erat
eH
igh
No
inclu
ded
stud
ies
VALU
ESIm
port
ant
unce
rtai
nty
or
varia
bilit
y
Poss
ibly
impo
rtan
t un
cert
aint
y or
va
riabi
lity
Prob
ably
no
impo
rtan
t un
cert
aint
y or
va
riabi
lity
No
impo
rtan
t un
cert
aint
y or
va
riabi
lity
BALA
NCE
OF
EFFE
CTS
Favo
rs th
e co
mpa
rison
Prob
ably
favo
rs th
e co
mpa
rison
Doe
s no
t fav
or
eith
er th
e in
terv
entio
n or
the
com
paris
on
Prob
ably
favo
rs th
e in
terv
entio
nFa
vors
the
inte
rven
tion
Varie
sD
on’t
know
RESO
URCE
S RE
QUI
RED
Larg
e co
sts
Mod
erat
e co
sts
Neg
ligib
le c
osts
and
sa
ving
sM
oder
ate
savi
ngs
Larg
e sa
ving
sVa
ries
Don
’t kn
ow
CERT
AIN
TY O
F EV
IDEN
CE
OF
REQ
UIRE
D R
ESO
URCE
SVe
ry lo
wLo
wM
oder
ate
Hig
hN
o in
clude
d st
udie
s
COST
EFF
ECTI
VEN
ESS
Favo
rs th
e co
mpa
rison
Prob
ably
favo
rs th
e co
mpa
rison
Doe
s no
t fav
or
eith
er th
e in
terv
entio
n or
the
com
paris
on
Prob
ably
favo
rs th
e in
terv
entio
nFa
vors
the
inte
rven
tion
Varie
sN
o in
clude
d st
udie
s
EQUI
TYRe
duce
dPr
obab
ly re
duce
dPr
obab
ly n
o im
pact
Prob
ably
incr
ease
dIn
crea
sed
Varie
sD
on’t
know
ACCE
PTAB
ILIT
YN
oPr
obab
ly n
oPr
obab
ly y
esYe
sVa
ries
Don
’t kn
owFE
ASIB
ILIT
YN
oPr
obab
ly n
oPr
obab
ly y
esYe
sVa
ries
Don
’t kn
ow
Type
of r
ecom
men
datio
nSt
rong
reco
mm
enda
tion
agai
nst
the
inte
rven
tion
○
Cond
ition
al re
com
men
datio
n ag
ains
t the
inte
rven
tion
○
Cond
ition
al re
com
men
datio
n fo
r eith
er th
e in
terv
entio
n or
the
com
paris
on○
Cond
ition
al re
com
men
datio
n fo
r th
e in
terv
entio
n●
Stro
ng re
com
men
datio
n fo
r the
in
terv
entio
n○
Annex 4: GRADE evidence-to-decision tables 95
Conc
lusi
ons
Reco
mm
enda
tion
A sh
orte
r, al
l-ora
l, be
daqu
iline-
cont
aini
ng re
gim
en o
f 9–1
2 m
onth
s’ du
ratio
n is
reco
mm
ende
d in
elig
ible
pat
ient
s w
ith c
onfir
med
MD
R/RR
-TB
who
hav
e no
t bee
n ex
pose
d to
trea
tmen
t w
ith s
econ
d-lin
e TB
med
icine
s us
ed in
this
regi
men
for m
ore
than
one
mon
th a
nd in
who
m re
sista
nce
to fl
uoro
quin
olon
es h
as b
een
exclu
ded.
(Con
ditio
nal r
ecom
men
datio
n, v
ery
low
cer
tain
ty in
the
evid
ence
)Ju
stifi
catio
nO
vera
ll, th
e G
DG
not
ed th
at th
e ce
rtai
nty
of th
e ev
iden
ce re
gard
ing
the
effic
acy
of th
e al
l-ora
l sho
rter
regi
men
was
“ver
y lo
w”,
attri
buta
ble
nam
ely
to c
once
rns
of s
erio
us ri
sk o
f bia
s, de
spite
effo
rts
to b
alan
ce b
asel
ine
cova
riate
s. H
owev
er, t
he g
roup
reco
gniz
ed th
at th
e cu
rrent
evi
denc
e as
sess
men
t of t
he a
ll-or
al, b
edaq
uilin
e-co
ntai
ning
sho
rter
regi
men
has
som
e ad
ditio
nal a
dvan
tage
s as
com
pare
d w
ith a
ll-or
al lo
nger
regi
men
s, na
mel
y in
term
s of
low
er lo
ss to
follo
w-u
p (d
esira
ble
effe
ct) a
nd o
bvio
us s
hort
er d
urat
ion
(acc
epta
bilit
y).
Whe
n de
cidin
g on
the
stre
ngth
of t
he re
com
men
datio
n, th
e G
DG
reac
hed
a un
anim
ous
decis
ion
on th
e co
nditi
onal
ity o
f the
reco
mm
enda
tion,
mai
nly
attri
bute
d to
the
very
low
cer
tain
ty
in th
e ev
iden
ce a
nd re
quire
men
ts to
bui
ld la
bora
tory
cap
acity
and
ens
ure
DST
.O
ther
gro
unds
for t
he s
treng
th a
nd d
irect
ion
of th
is re
com
men
datio
n ar
e as
follo
ws:
• Th
e an
alys
is co
nduc
ted
to in
form
the
deve
lopm
ent o
f thi
s re
com
men
datio
n w
as b
ased
on
obse
rvat
iona
l pro
gram
mat
ic da
ta fr
om S
outh
Afri
ca w
here
the
stan
dard
ized
sho
rter
, all-
oral
, be
daqu
iline-
cont
aini
ng re
gim
en (B
DQ
-LFX
/MFX
-ETO
-E-Z
-Hh -C
FZ) w
as u
sed
for p
atie
nts
with
MD
R/RR
-TB.
• Th
ough
no
maj
or s
igna
ls of
risk
wer
e ob
serv
ed w
ith th
e us
e of
the
all-o
ral b
edaq
uilin
e-ba
sed
shor
ter r
egim
en, t
here
also
rem
aine
d so
me
unce
rtai
ntie
s gi
ven
the
lack
of s
yste
mat
ic co
llect
ion
of d
ata,
and
the
lack
of c
larit
y as
to a
ny c
hang
es in
the
regi
men
that
cou
ld h
ave
been
info
rmed
by
the
pres
ence
of a
dver
se e
vent
s.•
Cost
–effe
ctiv
enes
s m
odel
ling
of th
e al
l-ora
l, sh
orte
r, be
daqu
iline-
cont
aini
ng re
gim
en s
how
ed ro
bust
cos
t sav
ings
rela
tive
to e
ither
a lo
nger
ora
l reg
imen
or a
sho
rt in
ject
able
-co
ntai
ning
regi
men
.•
The
GD
G ju
dged
that
man
y el
igib
le p
atie
nts
wou
ld p
refe
r the
all-
oral
, bed
aqui
line-
cont
aini
ng re
gim
en o
f 9–1
2 m
onth
s’ du
ratio
n. T
his
is su
ppor
ted
by li
mite
d ob
serv
atio
ns in
volv
ing
16 s
urvi
vors
of d
rug-
resis
tant
TB.
In a
dditi
on, t
his
regi
men
may
hel
p pr
omot
e he
alth
equ
ity o
r miti
gate
the
wor
seni
ng o
f hea
lth in
equi
ties.
How
ever
, the
pan
el re
cogn
ized
that
im
plem
enta
tion
and
scal
e-up
of t
his
regi
men
mig
ht b
e slo
w b
ecau
se o
f pre
requ
isite
s re
gard
ing
labo
rato
ry c
apac
ity a
nd m
onito
ring.
Subg
roup
con
side
ratio
nsTh
e an
alys
is at
tem
pted
to d
escr
ibe
the
bala
nce
of e
ffect
s an
d co
nsid
erat
ions
for v
ario
us s
ubgr
oups
or s
pecia
l pop
ulat
ions
. How
ever
, the
evi
denc
e re
view
ed s
uppo
rted
the
use
of th
is in
th
e fo
llow
ing
setti
ngs,
with
spe
cific
cave
ats:
• Pe
ople
livi
ng w
ith H
IV in
fect
ion
(PLH
IV):
The
data
eva
luat
ed c
orre
spon
ded
to a
set
ting
with
a h
igh
prev
alen
ce o
f HIV
, and
of p
artic
ular
sig
nific
ance
, mos
t PLH
IV (>
95%
) who
sta
rted
th
e al
l-ora
l bed
aqui
line-
cont
aini
ng re
gim
en w
ere
rece
ivin
g an
tiret
rovi
ral t
hera
py (A
RT)..
In v
iew
of t
he tr
eatm
ent o
utco
mes
des
crib
ed in
the
anal
ysis,
ther
e w
ere
no g
roun
ds to
bel
ieve
th
at th
e re
gim
en w
ould
per
form
any
diff
eren
tly in
PLH
IV. I
t is
nece
ssar
y to
con
sider
sig
nific
ant c
linica
l int
erac
tions
that
may
incr
ease
bed
aqui
line
expo
sure
or t
hat o
f oth
er a
gent
s w
ith
pote
ntia
l for
car
diot
oxici
ty w
hen
thes
e ar
e co
-adm
inist
ered
with
ant
iretro
vira
ls.•
Child
ren:
Alth
ough
no
dire
ct o
utco
me
estim
atio
ns c
ould
be
draw
n fo
r thi
s po
pula
tion,
ext
rapo
latio
n w
as d
eem
ed re
ason
able
. How
ever
, bec
ause
bed
aqui
line
is cu
rrent
ly re
com
men
ded
for c
hild
ren
and
adol
esce
nts
aged
6–1
7 ye
ars,
the
GD
G c
onclu
ded
that
the
all-o
ral b
edaq
uilin
e-co
ntai
ning
regi
men
may
be
used
in e
ligib
le c
hild
ren
with
in th
is ag
e gr
oup,
takin
g in
to
acco
unt s
pecif
icatio
ns fo
r reg
imen
com
pani
on d
rugs
, in
part
icula
r, be
daqu
iline.
• Pr
egna
nt a
nd la
ctat
ing
wom
en: M
ore
evid
ence
is n
eede
d to
bet
ter i
nfor
m th
e us
e of
the
all-o
ral,
beda
quilin
e-co
ntai
ning
sho
rter
regi
men
(BD
Q-L
FX/M
FX-E
TO-E
-Z-H
h -CFZ
). O
ne
of th
e ag
ents
in th
is al
l-ora
l sho
rter
regi
men
, eth
iona
mid
e, is
usu
ally
con
train
dica
ted
in p
regn
ancy
, and
with
hold
ing
this
agen
t or r
epla
cing
it w
ith a
noth
er o
ne c
ould
ser
ious
ly
com
prom
ise th
e ef
fect
iven
ess
of th
e re
gim
en. F
or p
regn
ant a
nd la
ctat
ing
wom
en, i
t is
ther
efor
e re
com
men
ded
that
an
indi
vidu
aliz
ed, a
ll-or
al lo
nger
regi
men
(with
inclu
sion
of
beda
quilin
e) b
e us
ed (s
ee R
ecom
men
datio
ns o
n th
e us
e of
long
er re
gim
ens
for M
DR/
RR-T
B).
–Ex
trapu
lmon
ary
dise
ase:
In v
iew
of t
he u
nava
ilabi
lity
of e
vide
nce
rega
rdin
g su
rroga
tes
for s
ever
ity o
r ext
ent o
f dise
ase,
it is
adv
isabl
e to
use
clin
ical j
udge
men
t to
decid
e on
the
use
of th
is re
gim
en in
pat
ient
s w
ith e
xten
sive
TB d
iseas
e or
sev
ere
form
s of
ext
rapu
lmon
ary
TB.
WHO consolidated guidelines on tuberculosis: Online annexes96
Impl
emen
tatio
n co
nsid
erat
ions
The
inte
rest
in re
ducin
g th
e du
ratio
n of
trea
tmen
t for
MD
R/RR
-TB
has
mot
ivat
ed a
num
ber o
f stu
dies
in re
cent
yea
rs to
trea
t pat
ient
s w
ith s
hort
er re
gim
ens
unde
r pro
gram
mat
ic as
wel
l as
tria
l con
ditio
ns. B
ecau
se o
f exp
erie
nces
in v
ario
us s
ettin
gs, [
elig
ible
] pat
ient
s no
w h
ave
an o
ptio
n to
be
treat
ed w
ith a
sho
rter
, inj
ecta
ble-
spar
ing
regi
men
of 9
–12
mon
ths’
dura
tion.
To
ensu
re th
at th
e re
gim
en a
chie
ves
its d
esira
ble
effe
cts
and
prev
ent t
he a
cqui
sitio
n (o
r am
plifi
catio
n) o
f add
ition
al d
rug
resis
tanc
e (w
hile
pro
tect
ing
regi
men
com
pone
nts)
, cou
ntrie
s ar
e to
co
nsid
er th
e fo
llow
ing:
• Pa
tient
sel
ectio
n an
d de
cisio
ns to
sta
rt th
e al
l-ora
l sho
rter
regi
men
: Pat
ient
s w
ith c
onfir
med
MD
R/RR
-TB
and
with
resis
tanc
e to
fluo
roqu
inol
ones
rule
d ou
t are
exp
ecte
d to
ben
efit
the
mos
t fro
m th
is re
gim
en. P
rope
r pat
ient
sel
ectio
n w
ill no
t onl
y le
ad to
impr
oved
trea
tmen
t out
com
es, b
ut w
ill al
so c
ontri
bute
to a
void
ing
the
deve
lopm
ent o
f res
istan
ce to
bed
aqui
line.
In
this
resp
ect,
the
regi
men
is to
onl
y be
impl
emen
ted
in s
ettin
gs w
here
rout
ine
DST
for r
ifam
picin
and
fluo
roqu
inol
ones
can
be
guar
ante
ed.
It is
very
impo
rtan
t tha
t the
impl
emen
tatio
n of
thes
e re
com
men
datio
ns is
acc
ompa
nied
by
cont
inue
d ef
fort
s to
incr
ease
acc
ess
to D
ST fo
r all
med
icine
s fo
r whi
ch re
liabl
e m
etho
ds
exist
, as
wel
l as
for t
he d
evel
opm
ent a
nd ro
llout
of D
ST m
etho
ds fo
r new
er m
edici
nes.
In th
e ab
senc
e of
a d
rug-
susc
eptib
ility
test
, ass
ays
spec
ific
for b
edaq
uilin
e re
sista
nce
shou
ld b
e m
onito
red
thro
ugh
asse
ssm
ent o
f min
imum
inhi
bito
ry c
once
ntra
tions
(MIC
s) o
f bed
aqui
line.
Resis
tanc
e to
oth
er a
nti-T
B dr
ugs
shou
ld b
e m
onito
red
in a
ccor
danc
e w
ith W
HO
reco
mm
enda
tions
.•
Use
of li
nezo
lid: T
he e
vide
nce
mad
e av
aila
ble
to in
form
this
reco
mm
enda
tion
focu
sed
on th
e as
sess
men
t of a
regi
men
com
pose
d of
bed
aqui
line,
levo
floxa
cin/m
oxifl
oxac
in,
ethi
onam
ide,
eth
ambu
tol,
pyra
zina
mid
e, h
igh-
dose
ison
iazi
d, c
lofa
zim
ine,
and
pyr
azin
amid
e. H
owev
er, s
econ
dary
ana
lyse
s (o
nly
in lo
nger
regi
men
s co
ntai
ning
bed
aqui
line
and
beda
quilin
e pl
us li
nezo
lid) s
how
ed fa
vour
able
out
com
es w
hen
treat
men
t reg
imen
s in
clude
d bo
th li
nezo
lid a
nd b
edaq
uilin
e. T
he b
asis
for t
he a
dditi
on o
f lin
ezol
id w
as to
pro
tect
the
regi
men
– in
par
ticul
ar, b
edaq
uilin
e –
whi
le a
wai
ting
susc
eptib
ility
resu
lts o
n ad
ditio
nal r
esist
ance
to fl
uoro
quin
olon
es a
nd o
ther
dru
gs. T
he G
DG
dec
ided
that
unt
il ne
w e
vide
nce
is av
aila
ble
on s
hort
er re
gim
ens
that
inclu
de b
oth
of th
ese
agen
ts, t
he a
ll-or
al b
edaq
uilin
e-co
ntai
ning
sho
rter
regi
men
adv
ised
here
in s
houl
d no
t inc
lude
line
zolid
. How
ever
, the
gro
up
enco
urag
ed c
ount
ries
to c
onsid
er th
e us
e of
a m
odifie
d al
l-ora
l bed
aqui
line-
and
linez
olid
-con
tain
ing
only
unde
r ope
ratio
nal r
esea
rch
until
new
evid
ence
bec
omes
ava
ilabl
e.•
Patie
nt-c
entre
d ap
proa
ch: E
ffort
s ar
e re
quire
d to
pro
vide
pat
ient
sup
port
to e
nabl
e fu
ll ad
here
nce
to tr
eatm
ent.
Mon
itorin
g an
d ev
alua
tion
• Th
e im
plem
enta
tion
of th
is re
gim
en re
quire
s th
e us
e of
rout
ine
DST
not
onl
y fo
r pat
ient
sel
ectio
n, b
ut a
lso fo
r mon
itorin
g of
the
acqu
isitio
n of
resis
tanc
e.•
Alth
ough
the
data
ass
esse
d di
d no
t une
arth
any
maj
or s
igna
ls of
risk
, act
ive
TB d
rug
safe
ty m
onito
ring
and
man
agem
ent s
yste
ms
mus
t be
func
tiona
l in
orde
r to
cond
uct r
igor
ous
activ
e m
onito
ring
of a
dver
se e
vent
s an
d to
det
ect,
man
age
and
repo
rt s
uspe
cted
or c
onfir
med
dru
g to
xiciti
es in
a ti
mel
y m
anne
r.
Rese
arch
prio
ritie
sM
embe
rs o
f the
GD
G d
iscus
sed
the
rese
arch
gap
s to
info
rm th
e de
velo
pmen
t of p
ublic
hea
lth re
com
men
datio
ns fo
r the
man
agem
ent a
nd c
are
of p
atie
nts
with
MD
R/RR
-TB,
and
hi
ghlig
hted
the
follo
win
g pr
iorit
ies:
• st
udie
s as
sess
ing
com
paris
ons
of a
ll-or
al s
hort
er re
gim
ens
whi
ch in
clude
bed
aqui
line
and
linez
olid
, in
addi
tion
to o
ther
com
pani
on d
rugs
;•
stud
ies
asse
ssin
g co
mpa
rison
s of
all-
oral
sho
rter
regi
men
s am
ong
diffe
rent
sub
grou
ps a
nd s
pecia
l pop
ulat
ions
, inc
ludi
ng p
regn
ant a
nd la
ctat
ing
wom
en;
• ra
ndom
ized
-con
trolle
d tri
als
or o
pera
tiona
l res
earc
h of
the
effe
ctiv
enes
s an
d sa
fety
of a
ll-or
al s
hort
er re
gim
ens,
incr
easin
g th
e ce
rtai
nty
of th
e ev
iden
ce;
• st
udie
s ex
plor
ing
mec
hani
sms
of a
cqui
sitio
n of
resis
tanc
e to
bed
aqui
line
and
gene
tic m
arke
rs to
iden
tify
resis
tanc
e; a
nd•
effo
rts
to d
eter
min
e be
st w
ays
to s
tand
ardi
ze th
e co
llect
ion
of d
ata
so th
at c
ount
ries
can
cont
ribut
e to
the
deve
lopm
ent o
f glo
bal r
ecom
men
datio
ns.
aOR:
adj
uste
d od
ds ra
tio; A
RT: a
ntire
trovi
ral t
hera
py; d
rug-
susc
eptib
ility
test
ing;
GD
F: G
loba
l Dru
g Fa
cility
; GD
G: G
uide
line
Dev
elop
men
t Gro
up; M
DR/
RR-T
B: m
ultid
rug-
or r
ifam
picin
-res
istan
t TB;
MIC
: min
imum
in
hibi
tory
con
cent
ratio
n; P
LHIV
: peo
ple
livin
g w
ith h
uman
imm
unod
efici
ency
viru
s; TB
: tub
ercu
losis
; WH
O: W
orld
Hea
lth O
rgan
izat
ion.
Annex 4: GRADE evidence-to-decision tables 97
Shou
ld a
trea
tmen
t reg
imen
last
ing
6–9
mon
ths
com
pose
d of
bed
aqui
line,
pre
tom
anid
and
line
zolid
vs
long
er re
gim
ens
cont
aini
ng b
edaq
uilin
e an
d lin
ezol
id in
add
ition
to
oth
er a
nti-
TB d
rugs
be
used
for X
DR-
TB p
atie
nts
or p
atie
nts
who
are
trea
tmen
t int
oler
ant o
r with
non
-res
pons
ive
MD
R-TB
?PO
PULA
TIO
N:
XDR-
TB p
atie
nts
or p
atie
nts
who
are
trea
tmen
t int
oler
ant o
r with
non
-res
pons
ive
MD
R-TB
INTE
RVEN
TIO
N:
Trea
tmen
t reg
imen
last
ing
6–9
mon
ths
com
pose
d of
bed
aqui
line,
pre
tom
anid
and
line
zolid
CO
MPA
RISO
N:
Long
er re
gim
ens
cont
aini
ng b
edaq
uilin
e an
d lin
ezol
id in
add
ition
to o
ther
ant
i-TB
drug
s M
AIN
OUT
COM
ES:
Succ
ess
vs. F
ailu
re/R
ecur
renc
e; S
ucce
ss v
s. D
eath
; Suc
cess
vs.
Failu
re/R
ecur
renc
e/D
eath
; Suc
cess
vs.
All U
nfav
orab
le; A
dver
se e
vent
s;SE
TTIN
G:
Trea
tmen
t of M
DR-
TB p
atie
nts
with
add
ition
al fl
uoro
quin
olon
e re
sista
nce
and
/ or M
DR-
TB p
atie
nts
who
are
trea
tmen
t int
oler
ant o
r who
had
not
resp
onde
d to
pre
viou
s M
DR-
TB tr
eatm
ent,
usin
g a
shor
ter r
egim
en c
ompo
sed
of b
edaq
uilin
e, p
reto
man
id a
nd li
nezo
lid (B
PaL)
of 6
–9 m
onth
s du
ratio
n in
a c
ombi
natio
n of
hos
pita
l and
am
bula
tory
car
e se
tting
s in
Sou
th A
frica
. The
dat
a w
ere
deriv
ed fr
om th
e N
ix-TB
stu
dy, w
ith 1
08 p
atie
nts
inclu
ded
for a
naly
sis (t
he w
hole
stu
dy
popu
latio
n w
as 1
09 p
atie
nts,
how
ever
one
pat
ient
with
drew
con
sent
and
this
pers
on w
as n
ot in
clude
d in
the
effic
acy
anal
yses
)PE
RSPE
CTIV
E:Pu
blic
heal
th a
nd h
ealth
sys
tem
sBA
CKG
ROUN
D:
Trea
tmen
t of e
xten
sivel
y dr
ug-r
esist
ant f
orm
s of
TB
pres
ents
mul
tiple
cha
lleng
es to
clin
ician
s an
d na
tiona
l TB
prog
ram
mes
bot
h du
e to
the
limite
d ra
nge
of
med
icine
s av
aila
ble
and
the
life-
thre
aten
ing
natu
re o
f the
dise
ase.
Pat
ient
s w
ith M
DR/
RR-T
B an
d ad
ditio
nal f
luor
oqui
nolo
ne re
sista
nce
have
typi
cally
exp
erie
nced
po
or tr
eatm
ent o
utco
mes
sin
ce th
e de
scrip
tion
of X
DR-
TB w
as fi
rst u
sed
in 2
006.
5 Bas
ed o
n da
ta re
port
ed b
y M
embe
r Sta
tes
to W
HO
, for
the
coho
rt o
f XD
R-TB
pa
tient
s w
ho s
tart
ed tr
eatm
ent i
n 20
16 (a
nd fo
r who
m tr
eatm
ent o
utco
mes
wer
e av
aila
ble
in 2
018)
, onl
y 39
% c
ompl
eted
trea
tmen
t suc
cess
fully
, whi
le 2
6% d
ied,
tre
atm
ent f
aile
d fo
r 18%
and
an
addi
tiona
l 18%
wer
e lo
st to
follo
w u
p or
wer
e no
t eva
luat
ed.6 T
he p
ress
ing
need
for m
ore
effe
ctiv
e tre
atm
ent r
egim
ens
for p
atie
nts
with
ext
ensiv
e dr
ug re
sista
nce,
inclu
ding
fluo
roqu
inol
one
resis
tanc
e an
d m
ore
exte
nsiv
e dr
ug re
sista
nce
prof
iles,
has
mot
ivat
ed a
num
ber o
f stu
dies
and
initi
ativ
es
to te
st m
ore
effe
ctiv
e an
d no
vel t
reat
men
t reg
imen
s, in
clusiv
e of
new
er a
nd re
purp
osed
med
icine
s. O
ne su
ch st
udy
is th
e N
ix-TB
stud
y,7 con
duct
ed b
y TB
Allia
nce.
The
Nix-
TB st
udy
was
a o
ne a
rm, p
hase
thre
e, o
pen
labe
l pro
spec
tive
coho
rt st
udy
that
ass
esse
d th
e sa
fety
, effi
cacy
, tol
erab
ility
and
phar
mac
okin
etic
prop
ertie
s of a
6 m
onth
trea
tmen
t reg
imen
com
pose
d of
bed
aqui
line,
pre
tom
anid
8 an
d lin
ezol
id (B
PaL)
, ext
enda
ble
to 9
mon
ths f
or th
ose
who
miss
ed d
oses
or f
or p
atie
nts w
ho re
mai
ned
cultu
re p
ositi
ve o
r rev
erte
d fro
m c
ultu
re n
egat
ive to
pos
itive
bet
wee
n m
onth
s 4 to
6 o
f tre
atm
ent.
The
stud
y w
as c
ondu
cted
bet
wee
n 20
14 a
nd 2
019
at th
ree
stud
y sit
es, a
ll in
Sou
th A
frica
, with
the
first
pat
ient
enr
olle
d in
Apr
il 20
15. E
ligib
le p
atie
nts w
ere
aged
14
year
s and
abo
ve, w
eigh
ed ≥
35kg
, had
a d
ocum
ente
d H
IV re
sult
and
had
bact
erio
logi
cally
con
firm
ed sp
utum
cul
ture
pos
itive
XD
R-TB
or b
acte
riolo
gica
lly
conf
irmed
MD
R/RR
-TB
but w
ho w
ere
treat
men
t int
oler
ant o
r non
-res
pons
ive to
pre
vious
MD
R/RR
-TB
treat
men
t. A
num
ber o
f oth
er in
clusio
n cr
iteria
wer
e ap
plie
d.Pa
tient
s w
ere
follo
wed
up
for a
per
iod
of u
p to
24
mon
ths
post
trea
tmen
t com
plet
ion.
The
prim
ary
outc
ome
mea
sure
was
the
incid
ence
of b
acte
riolo
gic
failu
re o
r re
laps
e or
clin
ical f
ailu
re th
roug
h fo
llow
up
until
6 m
onth
s af
ter t
he e
nd o
f tre
atm
ent (
TB A
llianc
e, N
ix-TB
stu
dy p
roto
col,
avai
labl
e at
: http
s://c
linica
ltria
ls.go
v/ct
2/sh
ow/N
CT02
3337
99).
Seco
ndar
y ou
tcom
e m
easu
res
com
prise
d:
1. In
ciden
ce o
f bac
terio
logi
c fa
ilure
or r
elap
se o
r clin
ical f
ailu
re th
roug
h fo
llow
up
until
24
mon
ths
afte
r the
end
of t
reat
men
t (as
a c
onfir
mat
ory
anal
ysis)
. 2.
Tim
e to
spu
tum
cul
ture
con
vers
ion
to n
egat
ive
stat
us th
roug
h th
e tre
atm
ent p
erio
d.
3. T
he p
ropo
rtio
n of
sub
ject
s w
ith s
putu
m c
ultu
re c
onve
rsio
n to
neg
ativ
e st
atus
at 4
, 6, 8
, 12,
16
and
26 o
r 39
wee
ks.
4. L
inez
olid
dos
ing
(act
ual)
and
effic
acy.
5. C
hang
e fro
m b
asel
ine
in T
B sy
mpt
oms.
6. C
hang
e fro
m b
asel
ine
in P
atie
nt R
epor
ted
Hea
lth S
tatu
s. 7.
Cha
nge
from
bas
elin
e in
wei
ght (
TB A
llianc
e, N
ix-TB
stu
dy p
roto
col,
avai
labl
e at
: http
s://c
linica
ltria
ls.go
v/ct
2/sh
ow/N
CT02
3337
99).
The
Nix-
TB s
tudy
regi
men
com
prise
d pr
etom
anid
adm
inist
ered
at 2
00m
g on
ce d
aily,
bed
aqui
line
adm
inist
ered
at 4
00m
g on
ce d
aily
for t
he fi
rst t
wo
wee
ks o
f tre
atm
ent (
days
1 to
14)
and
then
200
mg
thre
e tim
es a
wee
k th
erea
fter,
and
linez
olid
com
men
ced
at 1
200m
g pe
r day
(add
ition
al in
form
atio
n on
line
zolid
dos
ing
is in
clude
d un
der I
mpl
emen
tatio
n co
nsid
erat
ions
, bel
ow).
Clos
e m
icrob
iolo
gic,
clin
ical a
nd a
dver
se e
vent
mon
itorin
g w
ere
feat
ures
of t
he N
ix-TB
stu
dy.
5 Em
erge
nce
of X
DR-
TB [w
ebsit
e]. G
enev
a, S
witz
erla
nd W
orld
Hea
lth O
rgan
izat
ion
2006
(http
s://w
ww.
who
.int/
med
iace
ntre
/new
s/no
tes/
2006
/np2
3/en
, acc
esse
d 28
Feb
ruar
y 20
20).
6 W
HO
con
solid
ated
gui
delin
es o
n dr
ug re
sista
nt tu
berc
ulos
is tre
atm
ent.
Gen
eva,
Sw
itzer
land
: Wor
ld H
ealth
Org
aniz
atio
n; 2
019
(http
s://a
pps.w
ho.in
t/iri
s/bi
tstre
am/h
andl
e/10
665/
3113
89/9
7892
4155
0529
-eng
.pd
f?ua
=1, a
cces
sed
20 M
arch
202
0).
7 Th
e N
ix-TB
stu
dy p
roto
col i
s av
aila
ble
at: h
ttps:/
/clin
icaltr
ials.
gov/
ct2/
show
/NCT
0233
3799
. A p
ublic
atio
n on
the
resu
lts o
f the
stu
dy is
ava
ilabl
e at
: http
s://w
ww.
nejm
.org
/doi
/full/
10.1
056/
NEJ
Moa
1901
814.
8 Pr
etom
anid
is a
new
che
mica
l ent
ity a
nd a
mem
ber o
f a c
lass
of c
ompo
unds
kno
wn
as n
itroi
mid
azo-
oxaz
ines
, whi
ch p
osse
ss s
igni
fican
t ant
i-TB
activ
ity a
nd a
uni
que
mec
hani
sm o
f act
ion.
WHO consolidated guidelines on tuberculosis: Online annexes98
The
evid
ence
to in
form
this
PICO
que
stio
n w
as d
eriv
ed fr
om th
e N
ix-TB
stu
dy a
nd in
clude
d in
form
atio
n on
108
pat
ient
s. Th
e to
tal s
tudy
pop
ulat
ion
was
109
pa
tient
s; ho
wev
er, o
ne p
atie
nt w
ithdr
ew in
form
ed c
onse
nt to
par
ticip
ate
in th
e st
udy
and
this
pers
on w
as in
clude
d in
saf
ety
anal
yses
but
not
in th
e an
alys
es fo
r ef
fect
iven
ess.
Thes
e da
ta w
ere
com
pare
d to
a s
ubse
t of d
ata
from
the
indi
vidu
al p
atie
nt d
atas
et (I
PD) w
hich
ove
rall
inclu
des
13 2
73 in
divi
dual
pat
ient
reco
rds
from
55
diff
eren
t stu
dies
/cen
tres
in 3
8 co
untri
es. F
or th
e pr
imar
y an
alys
es, t
he c
ompa
rato
r gro
up in
clude
d pa
tient
s fro
m th
e IP
D o
n lo
nger
trea
tmen
t reg
imen
s (w
ith
a m
ean
dura
tion
of tr
eatm
ent o
f 21.
0–25
.5 m
onth
s), w
ho re
ceiv
ed b
oth
beda
quilin
e an
d lin
ezol
id a
s pa
rt o
f the
regi
men
(no
patie
nts
rece
ived
pre
tom
anid
in th
e IP
D).
This
com
paris
on g
roup
inclu
ded
456
patie
nts
who
wer
e tre
ated
in B
elar
us, I
ndia
, Fra
nce,
Rus
sia a
nd in
cou
ntrie
s in
Asia
. The
inte
rven
tion
and
com
paris
on
grou
ps w
ere
mat
ched
exa
ctly
for X
DR,
MD
R an
d flu
oroq
uino
lone
resis
tanc
e an
d H
IV s
tatu
s, w
ith p
rope
nsity
sco
re m
atch
ing
for t
he v
aria
bles
of a
ge, s
ex, b
asel
ine
cultu
re re
sult,
ext
ent o
f dise
ase
(det
erm
ined
by
base
line
AFB
smea
r or c
hest
x-r
ay fi
ndin
gs o
f cav
itatio
n or
bila
tera
l dise
ase
if AF
B sm
ear r
esul
t was
miss
ing)
and
co
untr
y in
com
e le
vel (
Wor
ld B
ank
Atla
s m
etho
d). T
reat
men
t out
com
es u
sed
in th
ese
anal
yses
com
prise
d th
e in
vest
igat
or d
efin
ed o
utco
mes
for t
he in
terv
entio
n gr
oup
(for t
he N
ix-TB
stu
dy) a
nd tr
eatm
ent o
utco
mes
larg
ely
defin
ed a
ccor
ding
to W
HO
def
initi
ons
(Las
erso
n KF
et a
l., 20
05; W
orld
Hea
lth O
rgan
izat
ion,
201
3:
http
s://w
ww.
who
.int/
tb/p
ublic
atio
ns/d
efin
ition
s/en
/) fo
r the
com
para
tor g
roup
(for
the
patie
nts
inclu
ded
in th
e IP
D).
In o
rder
to a
llow
an
equa
l opp
ortu
nity
for
treat
men
t out
com
es to
occ
ur fr
om th
e st
art o
f tre
atm
ent w
hen
com
parin
g th
e tw
o gr
oups
, all
outc
omes
wer
e in
clude
d fro
m th
e st
art o
f tre
atm
ent t
o 24
mon
ths
post
trea
tmen
t sta
rt. T
his
mea
nt th
at in
the
inte
rven
tion
grou
p th
ese
outc
omes
occ
urre
d po
st tr
eatm
ent c
ompl
etio
n an
d fo
r the
com
para
tor g
roup
the
outc
omes
w
ere
end
of tr
eatm
ent o
utco
mes
(as
patie
nts
in th
e IP
D re
ceiv
ed a
long
er re
gim
en a
nd w
ere
not f
ollo
wed
up
post
trea
tmen
t com
plet
ion)
. Thr
ee o
ther
com
para
tor
grou
ps fr
om th
e IP
D in
clude
d pa
tient
s on
long
er tr
eatm
ent r
egim
ens
who
rece
ived
a re
gim
en w
hich
inclu
ded
beda
quilin
e, o
r a re
gim
en w
hich
inclu
ded
linez
olid
, or
a re
gim
en w
ith n
eith
er b
edaq
uilin
e or
line
zolid
inclu
ded.
The
initi
al in
tent
ion
of th
e G
DG
was
to a
sses
s th
e in
terv
entio
n re
gim
en a
gain
st a
ll th
ree
com
paris
on
grou
ps h
owev
er, d
urin
g th
eir d
elib
erat
ions
the
pane
l agr
eed
that
the
judg
emen
ts s
houl
d be
bas
ed o
n th
e co
mpa
rison
gro
up w
ho re
ceiv
ed b
edaq
uilin
e an
d lin
ezol
id a
s pa
rt o
f the
ir re
gim
en, a
s th
ese
patie
nts
mos
t clo
sely
rese
mbl
e pa
tient
s w
ho w
ould
rece
ive
curre
ntly
reco
mm
ende
d lo
nger
regi
men
s co
mpo
sed
with
med
icine
s fro
m G
roup
s A
, B a
nd C
. How
ever
, a d
irect
com
paris
on o
f BPa
L w
ith a
ll-or
al lo
nger
regi
men
s co
nstru
cted
acc
ordi
ng to
the
mos
t rec
ent W
HO
re
com
men
datio
ns is
sued
in M
ay 2
019
was
not
pos
sible
as
thes
e re
gim
ens
may
hav
e on
ly b
een
in u
se s
ince
mid
-201
9, a
nd tr
eatm
ent o
utco
mes
for t
hese
pat
ient
s ar
e no
t yet
ava
ilabl
e. A
dditi
onal
dat
a re
view
ed b
y th
e G
uide
line
Dev
elop
men
t Gro
up re
leva
nt to
this
PICO
que
stio
n w
ere
a co
st e
ffect
iven
ess
anal
ysis,
a s
tudy
on
the
acce
ptab
ility
and
likel
ihoo
d of
impl
emen
tatio
n of
the
BPaL
regi
men
, mod
elle
d ph
arm
aco-
kinet
ic da
ta b
ased
on
the
deve
lopm
ent o
f a p
harm
aco-
kinet
ic to
xicod
ynam
ic m
odel
and
a s
umm
ary
revi
ew o
f pre
clini
cal a
nd e
arly
clin
ical d
ata
on p
reto
man
id. T
he c
ost e
ffect
iven
ess
anal
ysis,
acc
epta
bilit
y st
udy
and
mod
elle
d ph
arm
acok
inet
ic st
udie
s w
ere
cond
ucte
d as
par
t of t
he N
ix-TB
stu
dy a
nd w
ere
spon
sore
d by
TB
Allia
nce.
CON
FLIC
T O
F IN
TERE
STS:
Susa
n AB
DEL
-RAH
MAN
, Dan
iela
CIR
ILLO
, Agn
es G
EBH
ARD,
Ale
na S
KRAH
INA
, And
rew
VER
NO
N
Annex 4: GRADE evidence-to-decision tables 99
Ass
essm
ent
Prob
lem
Is th
e pr
oble
m a
prio
rity?
JUD
GEM
ENT
RESE
ARC
H E
VID
ENCE
AD
DIT
ION
AL
CON
SID
ERAT
ION
S○
No
○ P
roba
bly
no
○ P
roba
bly
yes
● Ye
s ○
Var
ies
○ D
on’t
know
Tube
rcul
osis
(TB)
rem
ains
a th
reat
to g
loba
l pub
lic h
ealth
and
is th
e to
p in
fect
ious
cau
se o
f dea
th in
the
wor
ld. I
n 20
18, a
n es
timat
ed 1
0 m
illion
peo
ple
deve
lope
d TB
and
1.4
milli
on d
ied
from
the
dise
ase.
Abo
ut 5
00 0
00 n
ew c
ases
of
mul
tidru
g- o
r rifa
mpi
cin-r
esist
ant T
B (M
DR/
RR-T
B) w
ere
estim
ated
to e
mer
ge in
20
18. W
hile
all
of th
ese
wou
ld h
ave
been
elig
ible
for a
sec
ond-
line
TB tr
eatm
ent
regi
men
, onl
y 15
6 07
1 en
rolm
ents
on
treat
men
t wer
e re
port
ed b
y co
untri
es
in 2
018
– ab
out 3
0% o
f the
est
imat
ed c
asel
oad.
In a
dditi
on, t
he a
vera
ge
prop
ortio
n of
MD
R-TB
cas
es w
ith e
xten
sivel
y dr
ug-r
esist
ant T
B (X
DR-
TB) i
s ap
prox
imat
ely
6.2%
(95%
con
fiden
ce in
terv
al [C
I]: 4
.4–8
.2%
). D
espi
te th
is,
signi
fican
t im
prov
emen
ts in
the
avai
labi
lity
of e
nhan
ced
diag
nost
ics a
nd m
ore
effe
ctiv
e m
edici
nes
has
occu
rred
in re
cent
yea
rs, a
nd h
as le
d to
ear
lier d
etec
tion
and
high
er s
ucce
ss ra
tes
amon
g pa
tient
s w
ith M
DR/
RR-T
B in
a n
umbe
r of
natio
nal p
rogr
amm
es. H
owev
er, t
hese
suc
cess
es h
ave
not b
een
repr
oduc
ed in
th
e re
st o
f the
wor
ld, a
nd th
e ov
eral
l tre
atm
ent s
ucce
ss ra
te w
orld
wid
e re
ache
d on
ly 5
6% fo
r MD
R/RR
-TB
patie
nts
who
sta
rted
on
treat
men
t in
2016
, and
onl
y 39
% fo
r pat
ient
s w
ith X
DR-
TB.
WHO consolidated guidelines on tuberculosis: Online annexes100
Des
irab
le E
ffec
tsH
ow s
ubst
antia
l are
the
desi
rabl
e an
ticip
ated
eff
ects
?
JUD
GEM
ENT
RESE
ARC
H E
VID
ENCE
AD
DIT
ION
AL
CON
SID
ERAT
ION
S○
Triv
ial
○ S
mal
l ●
Mod
erat
e ○
Lar
ge
○ V
arie
s ○
Don
’t kn
ow
Out
com
es
With
long
er
regi
men
s co
ntai
ning
be
daqu
iline
an
d lin
ezol
id
in a
dditi
on to
ot
her a
nti-
TB
drug
s
With
trea
tmen
t re
gim
en la
stin
g 6–
9 m
onth
s co
mpo
sed
of
beda
quili
ne,
pret
oman
id
and
linez
olid
Diff
eren
ce
Rela
tive
effe
ct
(95%
CI
)
Succ
ess
vs. F
ailu
re/
Recu
rrenc
e fo
llow
up:
mea
n 24
mon
ths
92 p
er 1
0097
per
100
(9
0 to
99)
6 m
ore
per
100
(2 fe
wer
to
8 m
ore)
OR
3.3
(0.8
to
13.7
)
Succ
ess
vs.
Dea
th
follo
w u
p: m
ean
24 m
onth
s
92 p
er 1
0092
per
100
(5
3 to
99)
0 fe
wer
pe
r 10
0 (3
9 fe
wer
to
7 m
ore)
OR
1.0
(0.1
to
8.2)
Succ
ess
vs. F
ailu
re/
Recu
rrenc
e/D
eath
fo
llow
up:
mea
n 24
mon
ths
85 p
er 1
0091
per
100
(8
0 to
96)
6 m
ore
per
100
(5 fe
wer
to
11 m
ore)
OR
1.8
(0.7
to
4.4)
Succ
ess
vs. A
ll Un
favo
rabl
e fo
llow
up:
mea
n 24
mon
ths
82 p
er 1
0085
per
100
(7
0 to
93)
3 m
ore
per
100
(12
few
er to
11
mor
e)
OR
1.2
(0.5
to
3.1)
Adve
rse
even
tsBP
aL re
gim
en: 1
(0.9
%) p
atie
nt d
ied,
27
(25%
) pat
ient
s ex
perie
nced
oth
er s
erio
us a
dver
se e
vent
s in
cludi
ng
hosp
italiz
atio
ns a
nd li
fe-t
hrea
teni
ng e
vent
s, an
d 53
(49%
) pa
tient
s ex
perie
nced
at l
east
one
Gra
de 3
–4 a
dver
se e
vent
s. D
rug
disc
ontin
uatio
n fo
r adv
erse
eve
nts:
rela
ted
to a
ll th
ree
drug
s in
1 p
atie
nt, a
nd re
late
d to
line
zolid
(ini
tial d
ose
1200
m
g/da
y) d
iscon
tinue
d in
ano
ther
35
(32%
) pat
ient
s. O
nly
20
(18%
) pat
ient
s co
mpl
eted
a fu
ll co
urse
of 1
200
mg/
day.
In th
e IP
D s
tudi
es (9
0% re
ceiv
ed ≤
600m
g/da
y), t
he p
oole
d ra
te o
f lin
ezol
id p
erm
anen
t disc
ontin
uatio
n w
as 1
7.9%
, and
in th
e En
dTB
stud
y (a
ll pa
tient
s re
ceiv
ed 6
00 m
g/da
y or
less
), th
e ra
te o
f lin
ezol
id d
iscon
tinua
tion
was
13.
1%. I
n En
dTB:
9 o
ut
of 1
094
part
icipa
nts
(0.8
%) d
ied
of a
pos
sibly
or p
roba
bly
drug
rela
ted
adve
rse
even
t, in
cludi
ng tw
o pa
rtici
pant
s w
ith
sudd
en c
ardi
ac d
eath
and
QT
prol
onga
tion.
The
GD
G p
anel
not
ed th
at th
e ev
iden
ce w
as u
ncer
tain
, ref
lect
ed in
the
cert
aint
y ra
ting
of “v
ery
low
”. Th
ey a
lso a
ckno
wle
dged
the
over
all h
igh
succ
ess
rate
s in
th
e N
ix-TB
stu
dy.
The
pane
l vot
ed o
n th
e m
agni
tude
of t
he d
esira
ble
effe
cts,
with
17
votin
g “s
mal
l” an
d 7
votin
g “tr
ivia
l”. O
ne a
bsta
ined
, and
5 re
port
ed c
onfli
cts
of in
tere
st.
The
pane
l the
n re
-eva
luat
ed th
e di
ffere
ntia
l des
irabl
e ef
fect
s of
the
shor
ter
regi
men
with
rega
rd to
bur
den
(whi
ch is
a d
esira
ble
effe
ct if
is re
duce
d by
th
e in
terv
entio
n). T
his
re-e
valu
atio
n w
as b
roug
ht u
p w
hen
the
bala
nce
of th
e ef
fect
s w
as fo
und
to b
e in
cons
isten
t with
the
crite
ria n
oted
und
er d
esira
ble
and
unde
sirab
le e
ffect
s.Pa
tient
repr
esen
tativ
es ra
ised
the
issue
s of
oth
er c
onse
quen
ces
of a
long
er
dura
tion
of tr
eatm
ent;
thes
e in
clude
a la
rger
pill
burd
en a
nd m
ay in
clude
de
pres
sion
and
othe
r und
esira
ble
effe
cts.
The
pane
l not
ed th
at lo
ss to
follo
w-u
p do
es n
ot c
aptu
re a
ll of
the
burd
en o
f diff
erin
g M
DR/
RR-T
B re
gim
ens
on p
atie
nts.
Afte
r the
se a
dditi
onal
disc
ussio
ns, t
he G
DG
cam
e to
con
sens
us (t
hrou
gh v
otin
g)
that
the
diffe
renc
e in
the
desir
able
effe
cts
wer
e m
oder
ate.
The
vot
es w
ere
tallie
d as
5 fo
r “sm
all”
and
18 fo
r “m
oder
ate”
. One
mem
ber a
bsta
ined
and
5 m
embe
rs
repo
rted
con
flict
s of
inte
rest
; ano
ther
GD
G m
embe
r was
not
pre
sent
at t
he
mee
ting
by th
is po
int.
Addi
tiona
l evi
denc
e pr
esen
ted
inclu
ded
mod
elle
d ph
arm
acok
inet
ic da
ta b
ased
on
the
deve
lopm
ent o
f a p
harm
acok
inet
ic–to
xicod
ynam
ic m
odel
des
igne
d to
qua
ntify
the
rela
tions
hip
betw
een
phar
mac
okin
etic
and
toxic
qua
litie
s of
lin
ezol
id a
s pa
rt o
f a 6
-mon
th B
PaL
regi
men
. The
se a
naly
ses
wer
e sp
onso
red
by th
e TB
Allia
nce
and
wer
e ba
sed
on d
ata
from
the
Nix-
TB s
tudy
. Inf
orm
atio
n on
mod
elle
d da
ta fr
om 8
8 pa
tient
s w
ho re
ceiv
ed li
nezo
lid in
the
Nix-
TB s
tudy
w
as p
rese
nted
. Thi
s pa
tient
pop
ulat
ion
inclu
ded
info
rmat
ion
on 7
pat
ient
s w
ho h
ad d
ied;
21
indi
vidu
als
from
the
Nix-
TB s
tudy
wer
e ex
clude
d fro
m th
ese
anal
yses
bec
ause
16
had
inco
mpl
ete
dosin
g hi
stor
ies
(i.e.
they
wer
e re
ceiv
ing
ongo
ing
treat
men
t at t
he ti
me
of a
naly
sis) a
nd 5
had
unv
erifi
able
dos
ing
hist
orie
s. Am
ong
the
109
patie
nts
in th
e N
ix-TB
stu
dy, a
naem
ia w
as re
port
ed
in 3
7% a
nd p
erip
hera
l sen
sory
neu
ropa
thy
was
repo
rted
in 6
9%. O
n th
e ba
sis
of th
e m
odel
led
data
, it w
as c
onclu
ded
that
the
phar
mac
okin
etics
rela
ted
to
linez
olid
are
non
linea
r in
patie
nts
with
XD
R-TB
and
that
indi
vidu
al li
nezo
lid
conc
entra
tion
times
are
the
best
pre
dict
or o
f tox
icity.
Hig
her t
oxici
ty ra
tes
wer
e ob
serv
ed a
t hig
her t
otal
dai
ly d
oses
, with
com
para
ble
toxic
ity ra
tes
for B
ID a
nd
QD
dos
ing
sche
dule
s. An
aem
ia c
an b
e m
anag
ed b
y clo
sely
mon
itorin
g ch
ange
s in
hae
mog
lobi
n ov
er th
e fir
st 4
wee
ks o
f tre
atm
ent (
in p
artic
ular
, cha
nges
in
haem
oglo
bin
that
repr
esen
t a >
10%
incr
ease
from
bas
elin
e sh
ould
trig
ger a
re
duct
ion
in th
e do
se o
f lin
ezol
id –
hae
mog
lobi
n le
vels
reco
ver w
ell a
fter d
ose
redu
ctio
ns).
Perip
hera
l neu
ropa
thy
shou
ld b
e clo
sely
mon
itore
d; w
hen
it do
es
occu
r, it
is re
vers
ible
for m
ost p
atie
nts
with
in 3
mon
ths.
Thro
mbo
cyto
peni
a is
pote
ntia
lly n
ot a
maj
or c
once
rn w
ith h
igh-
dose
line
zolid
for p
atie
nts
with
XD
R-TB
.
Annex 4: GRADE evidence-to-decision tables 101
Des
irab
le E
ffec
tsH
ow s
ubst
antia
l are
the
desi
rabl
e an
ticip
ated
eff
ects
?
JUD
GEM
ENT
RESE
ARC
H E
VID
ENCE
AD
DIT
ION
AL
CON
SID
ERAT
ION
S○
Triv
ial
○ S
mal
l ●
Mod
erat
e ○
Lar
ge
○ V
arie
s ○
Don
’t kn
ow
Out
com
es
With
long
er
regi
men
s co
ntai
ning
be
daqu
iline
an
d lin
ezol
id
in a
dditi
on to
ot
her a
nti-
TB
drug
s
With
trea
tmen
t re
gim
en la
stin
g 6–
9 m
onth
s co
mpo
sed
of
beda
quili
ne,
pret
oman
id
and
linez
olid
Diff
eren
ce
Rela
tive
effe
ct
(95%
CI
)
Succ
ess
vs. F
ailu
re/
Recu
rrenc
e fo
llow
up:
mea
n 24
mon
ths
92 p
er 1
0097
per
100
(9
0 to
99)
6 m
ore
per
100
(2 fe
wer
to
8 m
ore)
OR
3.3
(0.8
to
13.7
)
Succ
ess
vs.
Dea
th
follo
w u
p: m
ean
24 m
onth
s
92 p
er 1
0092
per
100
(5
3 to
99)
0 fe
wer
pe
r 10
0 (3
9 fe
wer
to
7 m
ore)
OR
1.0
(0.1
to
8.2)
Succ
ess
vs. F
ailu
re/
Recu
rrenc
e/D
eath
fo
llow
up:
mea
n 24
mon
ths
85 p
er 1
0091
per
100
(8
0 to
96)
6 m
ore
per
100
(5 fe
wer
to
11 m
ore)
OR
1.8
(0.7
to
4.4)
Succ
ess
vs. A
ll Un
favo
rabl
e fo
llow
up:
mea
n 24
mon
ths
82 p
er 1
0085
per
100
(7
0 to
93)
3 m
ore
per
100
(12
few
er to
11
mor
e)
OR
1.2
(0.5
to
3.1)
Adve
rse
even
tsBP
aL re
gim
en: 1
(0.9
%) p
atie
nt d
ied,
27
(25%
) pat
ient
s ex
perie
nced
oth
er s
erio
us a
dver
se e
vent
s in
cludi
ng
hosp
italiz
atio
ns a
nd li
fe-t
hrea
teni
ng e
vent
s, an
d 53
(49%
) pa
tient
s ex
perie
nced
at l
east
one
Gra
de 3
–4 a
dver
se e
vent
s. D
rug
disc
ontin
uatio
n fo
r adv
erse
eve
nts:
rela
ted
to a
ll th
ree
drug
s in
1 p
atie
nt, a
nd re
late
d to
line
zolid
(ini
tial d
ose
1200
m
g/da
y) d
iscon
tinue
d in
ano
ther
35
(32%
) pat
ient
s. O
nly
20
(18%
) pat
ient
s co
mpl
eted
a fu
ll co
urse
of 1
200
mg/
day.
In th
e IP
D s
tudi
es (9
0% re
ceiv
ed ≤
600m
g/da
y), t
he p
oole
d ra
te o
f lin
ezol
id p
erm
anen
t disc
ontin
uatio
n w
as 1
7.9%
, and
in th
e En
dTB
stud
y (a
ll pa
tient
s re
ceiv
ed 6
00 m
g/da
y or
less
), th
e ra
te o
f lin
ezol
id d
iscon
tinua
tion
was
13.
1%. I
n En
dTB:
9 o
ut
of 1
094
part
icipa
nts
(0.8
%) d
ied
of a
pos
sibly
or p
roba
bly
drug
rela
ted
adve
rse
even
t, in
cludi
ng tw
o pa
rtici
pant
s w
ith
sudd
en c
ardi
ac d
eath
and
QT
prol
onga
tion.
The
GD
G p
anel
not
ed th
at th
e ev
iden
ce w
as u
ncer
tain
, ref
lect
ed in
the
cert
aint
y ra
ting
of “v
ery
low
”. Th
ey a
lso a
ckno
wle
dged
the
over
all h
igh
succ
ess
rate
s in
th
e N
ix-TB
stu
dy.
The
pane
l vot
ed o
n th
e m
agni
tude
of t
he d
esira
ble
effe
cts,
with
17
votin
g “s
mal
l” an
d 7
votin
g “tr
ivia
l”. O
ne a
bsta
ined
, and
5 re
port
ed c
onfli
cts
of in
tere
st.
The
pane
l the
n re
-eva
luat
ed th
e di
ffere
ntia
l des
irabl
e ef
fect
s of
the
shor
ter
regi
men
with
rega
rd to
bur
den
(whi
ch is
a d
esira
ble
effe
ct if
is re
duce
d by
th
e in
terv
entio
n). T
his
re-e
valu
atio
n w
as b
roug
ht u
p w
hen
the
bala
nce
of th
e ef
fect
s w
as fo
und
to b
e in
cons
isten
t with
the
crite
ria n
oted
und
er d
esira
ble
and
unde
sirab
le e
ffect
s.Pa
tient
repr
esen
tativ
es ra
ised
the
issue
s of
oth
er c
onse
quen
ces
of a
long
er
dura
tion
of tr
eatm
ent;
thes
e in
clude
a la
rger
pill
burd
en a
nd m
ay in
clude
de
pres
sion
and
othe
r und
esira
ble
effe
cts.
The
pane
l not
ed th
at lo
ss to
follo
w-u
p do
es n
ot c
aptu
re a
ll of
the
burd
en o
f diff
erin
g M
DR/
RR-T
B re
gim
ens
on p
atie
nts.
Afte
r the
se a
dditi
onal
disc
ussio
ns, t
he G
DG
cam
e to
con
sens
us (t
hrou
gh v
otin
g)
that
the
diffe
renc
e in
the
desir
able
effe
cts
wer
e m
oder
ate.
The
vot
es w
ere
tallie
d as
5 fo
r “sm
all”
and
18 fo
r “m
oder
ate”
. One
mem
ber a
bsta
ined
and
5 m
embe
rs
repo
rted
con
flict
s of
inte
rest
; ano
ther
GD
G m
embe
r was
not
pre
sent
at t
he
mee
ting
by th
is po
int.
Addi
tiona
l evi
denc
e pr
esen
ted
inclu
ded
mod
elle
d ph
arm
acok
inet
ic da
ta b
ased
on
the
deve
lopm
ent o
f a p
harm
acok
inet
ic–to
xicod
ynam
ic m
odel
des
igne
d to
qua
ntify
the
rela
tions
hip
betw
een
phar
mac
okin
etic
and
toxic
qua
litie
s of
lin
ezol
id a
s pa
rt o
f a 6
-mon
th B
PaL
regi
men
. The
se a
naly
ses
wer
e sp
onso
red
by th
e TB
Allia
nce
and
wer
e ba
sed
on d
ata
from
the
Nix-
TB s
tudy
. Inf
orm
atio
n on
mod
elle
d da
ta fr
om 8
8 pa
tient
s w
ho re
ceiv
ed li
nezo
lid in
the
Nix-
TB s
tudy
w
as p
rese
nted
. Thi
s pa
tient
pop
ulat
ion
inclu
ded
info
rmat
ion
on 7
pat
ient
s w
ho h
ad d
ied;
21
indi
vidu
als
from
the
Nix-
TB s
tudy
wer
e ex
clude
d fro
m th
ese
anal
yses
bec
ause
16
had
inco
mpl
ete
dosin
g hi
stor
ies
(i.e.
they
wer
e re
ceiv
ing
ongo
ing
treat
men
t at t
he ti
me
of a
naly
sis) a
nd 5
had
unv
erifi
able
dos
ing
hist
orie
s. Am
ong
the
109
patie
nts
in th
e N
ix-TB
stu
dy, a
naem
ia w
as re
port
ed
in 3
7% a
nd p
erip
hera
l sen
sory
neu
ropa
thy
was
repo
rted
in 6
9%. O
n th
e ba
sis
of th
e m
odel
led
data
, it w
as c
onclu
ded
that
the
phar
mac
okin
etics
rela
ted
to
linez
olid
are
non
linea
r in
patie
nts
with
XD
R-TB
and
that
indi
vidu
al li
nezo
lid
conc
entra
tion
times
are
the
best
pre
dict
or o
f tox
icity.
Hig
her t
oxici
ty ra
tes
wer
e ob
serv
ed a
t hig
her t
otal
dai
ly d
oses
, with
com
para
ble
toxic
ity ra
tes
for B
ID a
nd
QD
dos
ing
sche
dule
s. An
aem
ia c
an b
e m
anag
ed b
y clo
sely
mon
itorin
g ch
ange
s in
hae
mog
lobi
n ov
er th
e fir
st 4
wee
ks o
f tre
atm
ent (
in p
artic
ular
, cha
nges
in
haem
oglo
bin
that
repr
esen
t a >
10%
incr
ease
from
bas
elin
e sh
ould
trig
ger a
re
duct
ion
in th
e do
se o
f lin
ezol
id –
hae
mog
lobi
n le
vels
reco
ver w
ell a
fter d
ose
redu
ctio
ns).
Perip
hera
l neu
ropa
thy
shou
ld b
e clo
sely
mon
itore
d; w
hen
it do
es
occu
r, it
is re
vers
ible
for m
ost p
atie
nts
with
in 3
mon
ths.
Thro
mbo
cyto
peni
a is
pote
ntia
lly n
ot a
maj
or c
once
rn w
ith h
igh-
dose
line
zolid
for p
atie
nts
with
XD
R-TB
.
The
GD
G c
onsid
ered
the
desir
able
effe
ct o
f tre
atm
ent s
ucce
ss, w
hich
was
hig
her
in th
e in
terv
entio
n gr
oups
than
in th
e co
mpa
rato
r gro
ups,
for a
ll fo
ur tr
eatm
ent
outc
omes
that
wer
e as
sess
ed. O
vera
ll, w
hen
com
parin
g tre
atm
ent s
ucce
ss w
ith
failu
re/r
ecur
renc
e, th
e tre
atm
ent s
ucce
ss ra
te in
the
Nix-
TB s
tudy
was
97.
0%,
com
pare
d w
ith 9
1.7%
in th
e co
mpa
rato
r gro
up (r
esul
ting
in 6
mor
e tre
atm
ent
succ
esse
s pe
r 100
pat
ient
s). F
or tr
eatm
ent s
ucce
ss v
ersu
s de
ath,
trea
tmen
t su
cces
s w
as 9
3.2%
in th
e N
ix-TB
stu
dy c
ompa
red
with
91.
9% in
the
com
para
tor
grou
p (re
sulti
ng in
1 m
ore
treat
men
t suc
cess
per
100
pat
ient
s). T
he G
DG
co
nsid
ered
rate
s of
loss
to fo
llow
-up
to b
e a
desir
able
effe
ct; t
he p
ropo
rtio
n of
pa
tient
s w
ho w
ere
lost
to fo
llow
-up
was
low
er in
the
inte
rven
tion
grou
p (1
.8%
) co
mpa
red
with
the
com
paris
on g
roup
(3.1
%).
The
unce
rtai
nty
in th
e ev
iden
ce
was
ack
now
ledg
ed b
y th
e pa
nel w
hen
mak
ing
thei
r jud
gem
ent o
n th
e de
sirab
le
(and
und
esira
ble)
effe
cts.
The
BPaL
regi
men
was
ass
ocia
ted
with
a h
igh
rate
of a
dver
se e
vent
s, co
nsid
ered
to
be
rela
ted
to th
e st
udy
drug
s. Th
is in
clude
d th
e de
ath
of 1
(0.9
%) p
artic
ipan
t; ot
her s
erio
us a
dver
se e
vent
s (in
cludi
ng h
ospi
taliz
atio
ns a
nd li
fe-t
hrea
teni
ng
even
ts) i
n 27
(25%
) par
ticip
ants
and
at l
east
one
Gra
de 3
–4 a
dver
se e
vent
in 5
3 (4
9%) p
artic
ipan
ts. T
his
led
to d
iscon
tinua
tion
of a
ll th
ree
drug
s fo
r 1 p
atie
nt,
and
disc
ontin
uatio
n of
line
zolid
(ini
tial d
ose
1200
mg/
day)
for a
noth
er 3
5 (3
2%) p
atie
nts.
Onl
y 18
(17%
) pat
ient
s co
mpl
eted
a fu
ll co
urse
of l
inez
olid
at
1200
mg/
day.
The
GD
G n
oted
that
it is
diff
icult
to c
ompa
re th
ese
adve
rse
even
t rat
es w
ith
othe
r stu
dies
bec
ause
of m
ajor
and
impo
rtan
t diff
eren
ces
in a
dver
se e
vent
as
cert
ainm
ent,
asse
ssm
ent,
and
repo
rtin
g. H
owev
er, i
n th
e IP
D s
tudi
es (w
here
90
% o
f pat
ient
s re
ceiv
ed a
line
zolid
dos
e of
≤60
0 m
g/da
y), t
he p
oole
d ra
te
of p
erm
anen
t disc
ontin
uatio
n of
line
zolid
was
17.
9%, a
nd in
the
EndT
B tri
al
(whe
re a
ll pa
tient
s re
ceiv
ed ≤
600
mg/
day
of li
nezo
lid),
the
rate
of l
inez
olid
di
scon
tinua
tion
was
13.
1%. I
n bo
th o
f the
se s
tudi
es, >
80%
of p
atie
nts
rece
ived
a
star
ting
dose
of l
inez
olid
of 6
00 m
g/da
y. In
the
EndT
B st
udy,
prel
imin
ary
anal
yses
su
gges
ted
that
9 o
f 109
4 pa
rtici
pant
s (0
.8%
) die
d of
a p
ossib
ly o
r pro
babl
y dr
ug-r
elat
ed a
dver
se e
vent
, inc
ludi
ng 2
par
ticip
ants
with
sud
den
card
iac
deat
h
WHO consolidated guidelines on tuberculosis: Online annexes102
Und
esir
able
Eff
ects
How
sub
stan
tial a
re th
e un
desi
rabl
e an
ticip
ated
eff
ects
?
JUD
GEM
ENT
RESE
ARC
H E
VID
ENCE
AD
DIT
ION
AL
CON
SID
ERAT
ION
S○
Lar
ge
● M
oder
ate
○ S
mal
l ○
Triv
ial
○ V
arie
s ○
Don
’t kn
ow
Out
com
es
With
long
er
regi
men
s co
ntai
ning
be
daqu
iline
an
d lin
ezol
id
in a
dditi
on to
ot
her a
nti-
TB
drug
s
With
tr
eatm
ent
regi
men
la
stin
g 6–
9 m
onth
s co
mpo
sed
of
beda
quili
ne,
pret
oman
id
and
linez
olid
Diff
eren
ce
Rela
tive
effe
ct
(95%
CI
)
Succ
ess
vs. F
ailu
re/
Recu
rrenc
e fo
llow
up:
m
ean
24
mon
ths
92 p
er 1
0097
per
100
(9
0 to
99)
6 m
ore
per
100
(2 fe
wer
to
8 m
ore)
OR
3.3
(0.8
to
13.7
)
Succ
ess
vs.
Dea
th
follo
w u
p:
mea
n 24
m
onth
s
92 p
er 1
0092
per
100
(5
3 to
99)
0 fe
wer
pe
r 10
0 (3
9 fe
wer
to
7 m
ore)
OR
1.0
(0.1
to
8.2)
Succ
ess
vs. F
ailu
re/
Recu
rrenc
e/D
eath
fo
llow
up:
m
ean
24
mon
ths
85 p
er 1
0091
per
100
(8
0 to
96)
6 m
ore
per
100
(5 fe
wer
to
11 m
ore)
OR
1.8
(0.7
to
4.4)
Succ
ess
vs. A
ll Un
favo
rabl
e fo
llow
up:
m
ean
24
mon
ths
82 p
er 1
0085
per
100
(7
0 to
93)
3 m
ore
per
100
(12
few
er to
11
mor
e)
OR
1.2
(0.5
to
3.1)
The
issue
of s
erio
us a
dver
se e
vent
s, pa
rticu
larly
thos
e re
late
d to
line
zolid
, and
po
tent
ial s
afet
y sig
nals
rela
ted
to m
ale
infe
rtilit
y ob
serv
ed in
ani
mal
(mur
ine)
m
odel
s, w
ere
of c
once
rn to
the
pane
l. Th
e G
DG
hig
hlig
hted
the
pote
ntia
l di
fficu
lties
in m
onito
ring
of in
fert
ility
in a
pro
gram
mat
ic se
tting
. Add
ition
al
hum
an s
perm
stu
dies
reco
mm
ende
d by
the
US F
ood
and
Dru
g Ad
min
istra
tion
will
be c
arrie
d ou
t by
the
TB A
llianc
e; h
owev
er, t
hese
dat
a w
ere
not a
vaila
ble
for
the
GD
G to
con
sider
at t
he ti
me
of th
e m
eetin
g (a
nd th
ey w
ill no
t be
avai
labl
e fo
r a fe
w y
ears
). Th
e G
DG
det
erm
ined
that
infe
rtilit
y is
a se
rious
issu
e be
caus
e it
affe
cts
not o
nly
patie
nts
but a
lso th
eir f
amilie
s. Th
e G
DG
also
ack
now
ledg
ed
that
, at t
he ti
me
the
Nix-
TB s
tudy
sta
rted
, the
re w
ere
few
trea
tmen
t opt
ions
for
patie
nts
and
ther
e w
as a
hig
h ca
se fa
talit
y ra
te, w
hich
mea
ns th
at p
atie
nts
mig
ht
have
pla
ced
a di
ffere
nt v
alue
on
pote
ntia
l mal
e in
fert
ility
than
they
mig
ht n
ow.
Addi
tiona
l evi
denc
e pr
esen
ted
inclu
ded
mod
elle
d ph
arm
acok
inet
ic da
ta b
ased
on
the
deve
lopm
ent o
f a p
harm
acok
inet
ic–to
xicod
ynam
ic m
odel
des
igne
d to
qua
ntify
the
betw
een
phar
mac
okin
etics
and
toxic
ity o
f lin
ezol
id a
s pa
rt o
f a
6-m
onth
BPa
L re
gim
en. T
hese
ana
lyse
s w
ere
spon
sore
d by
the
TB A
llianc
e an
d w
ere
base
d on
dat
a fro
m th
e N
ix-TB
stu
dy. I
nfor
mat
ion
on m
odel
led
data
fro
m 8
8 pa
rtici
pant
s w
ho re
ceiv
ed li
nezo
lid in
the
Nix-
TB s
tudy
was
pre
sent
ed.
The
info
rmat
ion
on th
is po
pula
tion
inclu
ded
data
on
7 pa
tient
s w
ho h
ad d
ied.
Tw
enty
-one
indi
vidu
als
from
the
Nix-
TB s
tudy
wer
e ex
clude
d fro
m th
ese
anal
yses
be
caus
e 16
had
inco
mpl
ete
dosin
g hi
stor
ies
(i.e.
they
wer
e re
ceiv
ing
ongo
ing
treat
men
t at t
he ti
me
of a
naly
sis) a
nd 5
had
unv
erifi
able
dos
ing
hist
orie
s. Am
ong
the
109
patie
nts
in th
e N
ix-TB
stu
dy, a
naem
ia w
as re
port
ed in
37%
of
pat
ient
s an
d pe
riphe
ral s
enso
ry n
euro
path
y w
as re
port
ed in
69%
. On
the
basis
of t
he m
odel
led
data
, it w
as c
onclu
ded
that
the
phar
mac
okin
etics
rela
ted
to li
nezo
lid a
re n
onlin
ear i
n pa
tient
s w
ith X
DR-
TB a
nd th
at in
divi
dual
line
zolid
co
ncen
tratio
n tim
es a
re th
e be
st p
redi
ctor
of t
oxici
ty. H
ighe
r tox
icity
rate
s w
ere
obse
rved
at h
ighe
r tot
al d
aily
dos
es, w
ith c
ompa
rabl
e to
xicity
rate
s fo
r BID
and
Q
D d
osin
g sc
hedu
les.
Anae
mia
can
be
man
aged
by
close
ly m
onito
ring
chan
ges
in h
aem
oglo
bin
over
the
first
4 w
eeks
of t
reat
men
t (in
par
ticul
ar, i
ncre
ases
in
haem
oglo
bin
of >
10%
ove
r bas
elin
e sh
ould
trig
ger a
redu
ctio
n in
the
dose
of
linez
olid
; hae
mog
lobi
n le
vels
reco
ver w
ell a
fter d
ose
redu
ctio
ns).
Perip
hera
l ne
urop
athy
sho
uld
be c
lose
ly m
onito
red;
whe
n it
does
occ
ur, i
t is
reve
rsib
le fo
r m
ost p
atie
nts
with
in 3
mon
ths.
Thro
mbo
cyto
peni
a is
pote
ntia
lly n
ot a
maj
or
conc
ern
with
hig
h-do
se li
nezo
lid fo
r pat
ient
s w
ith X
DR-
TB.
Annex 4: GRADE evidence-to-decision tables 103
Und
esir
able
Eff
ects
How
sub
stan
tial a
re th
e un
desi
rabl
e an
ticip
ated
eff
ects
?
JUD
GEM
ENT
RESE
ARC
H E
VID
ENCE
AD
DIT
ION
AL
CON
SID
ERAT
ION
S○
Lar
ge
● M
oder
ate
○ S
mal
l ○
Triv
ial
○ V
arie
s ○
Don
’t kn
ow
Out
com
es
With
long
er
regi
men
s co
ntai
ning
be
daqu
iline
an
d lin
ezol
id
in a
dditi
on to
ot
her a
nti-
TB
drug
s
With
tr
eatm
ent
regi
men
la
stin
g 6–
9 m
onth
s co
mpo
sed
of
beda
quili
ne,
pret
oman
id
and
linez
olid
Diff
eren
ce
Rela
tive
effe
ct
(95%
CI
)
Succ
ess
vs. F
ailu
re/
Recu
rrenc
e fo
llow
up:
m
ean
24
mon
ths
92 p
er 1
0097
per
100
(9
0 to
99)
6 m
ore
per
100
(2 fe
wer
to
8 m
ore)
OR
3.3
(0.8
to
13.7
)
Succ
ess
vs.
Dea
th
follo
w u
p:
mea
n 24
m
onth
s
92 p
er 1
0092
per
100
(5
3 to
99)
0 fe
wer
pe
r 10
0 (3
9 fe
wer
to
7 m
ore)
OR
1.0
(0.1
to
8.2)
Succ
ess
vs. F
ailu
re/
Recu
rrenc
e/D
eath
fo
llow
up:
m
ean
24
mon
ths
85 p
er 1
0091
per
100
(8
0 to
96)
6 m
ore
per
100
(5 fe
wer
to
11 m
ore)
OR
1.8
(0.7
to
4.4)
Succ
ess
vs. A
ll Un
favo
rabl
e fo
llow
up:
m
ean
24
mon
ths
82 p
er 1
0085
per
100
(7
0 to
93)
3 m
ore
per
100
(12
few
er to
11
mor
e)
OR
1.2
(0.5
to
3.1)
The
issue
of s
erio
us a
dver
se e
vent
s, pa
rticu
larly
thos
e re
late
d to
line
zolid
, and
po
tent
ial s
afet
y sig
nals
rela
ted
to m
ale
infe
rtilit
y ob
serv
ed in
ani
mal
(mur
ine)
m
odel
s, w
ere
of c
once
rn to
the
pane
l. Th
e G
DG
hig
hlig
hted
the
pote
ntia
l di
fficu
lties
in m
onito
ring
of in
fert
ility
in a
pro
gram
mat
ic se
tting
. Add
ition
al
hum
an s
perm
stu
dies
reco
mm
ende
d by
the
US F
ood
and
Dru
g Ad
min
istra
tion
will
be c
arrie
d ou
t by
the
TB A
llianc
e; h
owev
er, t
hese
dat
a w
ere
not a
vaila
ble
for
the
GD
G to
con
sider
at t
he ti
me
of th
e m
eetin
g (a
nd th
ey w
ill no
t be
avai
labl
e fo
r a fe
w y
ears
). Th
e G
DG
det
erm
ined
that
infe
rtilit
y is
a se
rious
issu
e be
caus
e it
affe
cts
not o
nly
patie
nts
but a
lso th
eir f
amilie
s. Th
e G
DG
also
ack
now
ledg
ed
that
, at t
he ti
me
the
Nix-
TB s
tudy
sta
rted
, the
re w
ere
few
trea
tmen
t opt
ions
for
patie
nts
and
ther
e w
as a
hig
h ca
se fa
talit
y ra
te, w
hich
mea
ns th
at p
atie
nts
mig
ht
have
pla
ced
a di
ffere
nt v
alue
on
pote
ntia
l mal
e in
fert
ility
than
they
mig
ht n
ow.
Addi
tiona
l evi
denc
e pr
esen
ted
inclu
ded
mod
elle
d ph
arm
acok
inet
ic da
ta b
ased
on
the
deve
lopm
ent o
f a p
harm
acok
inet
ic–to
xicod
ynam
ic m
odel
des
igne
d to
qua
ntify
the
betw
een
phar
mac
okin
etics
and
toxic
ity o
f lin
ezol
id a
s pa
rt o
f a
6-m
onth
BPa
L re
gim
en. T
hese
ana
lyse
s w
ere
spon
sore
d by
the
TB A
llianc
e an
d w
ere
base
d on
dat
a fro
m th
e N
ix-TB
stu
dy. I
nfor
mat
ion
on m
odel
led
data
fro
m 8
8 pa
rtici
pant
s w
ho re
ceiv
ed li
nezo
lid in
the
Nix-
TB s
tudy
was
pre
sent
ed.
The
info
rmat
ion
on th
is po
pula
tion
inclu
ded
data
on
7 pa
tient
s w
ho h
ad d
ied.
Tw
enty
-one
indi
vidu
als
from
the
Nix-
TB s
tudy
wer
e ex
clude
d fro
m th
ese
anal
yses
be
caus
e 16
had
inco
mpl
ete
dosin
g hi
stor
ies
(i.e.
they
wer
e re
ceiv
ing
ongo
ing
treat
men
t at t
he ti
me
of a
naly
sis) a
nd 5
had
unv
erifi
able
dos
ing
hist
orie
s. Am
ong
the
109
patie
nts
in th
e N
ix-TB
stu
dy, a
naem
ia w
as re
port
ed in
37%
of
pat
ient
s an
d pe
riphe
ral s
enso
ry n
euro
path
y w
as re
port
ed in
69%
. On
the
basis
of t
he m
odel
led
data
, it w
as c
onclu
ded
that
the
phar
mac
okin
etics
rela
ted
to li
nezo
lid a
re n
onlin
ear i
n pa
tient
s w
ith X
DR-
TB a
nd th
at in
divi
dual
line
zolid
co
ncen
tratio
n tim
es a
re th
e be
st p
redi
ctor
of t
oxici
ty. H
ighe
r tox
icity
rate
s w
ere
obse
rved
at h
ighe
r tot
al d
aily
dos
es, w
ith c
ompa
rabl
e to
xicity
rate
s fo
r BID
and
Q
D d
osin
g sc
hedu
les.
Anae
mia
can
be
man
aged
by
close
ly m
onito
ring
chan
ges
in h
aem
oglo
bin
over
the
first
4 w
eeks
of t
reat
men
t (in
par
ticul
ar, i
ncre
ases
in
haem
oglo
bin
of >
10%
ove
r bas
elin
e sh
ould
trig
ger a
redu
ctio
n in
the
dose
of
linez
olid
; hae
mog
lobi
n le
vels
reco
ver w
ell a
fter d
ose
redu
ctio
ns).
Perip
hera
l ne
urop
athy
sho
uld
be c
lose
ly m
onito
red;
whe
n it
does
occ
ur, i
t is
reve
rsib
le fo
r m
ost p
atie
nts
with
in 3
mon
ths.
Thro
mbo
cyto
peni
a is
pote
ntia
lly n
ot a
maj
or
conc
ern
with
hig
h-do
se li
nezo
lid fo
r pat
ient
s w
ith X
DR-
TB.
Adve
rse
even
tsBP
aL re
gim
en: 1
(0.9
%) p
atie
nt d
ied,
27
(25%
) pat
ient
s ex
perie
nced
oth
er s
erio
us a
dver
se e
vent
s in
cludi
ng
hosp
italiz
atio
ns a
nd li
fe-t
hrea
teni
ng e
vent
s, an
d 53
(49%
) pa
tient
s ex
perie
nced
at l
east
one
Gra
de 3
–4 a
dver
se e
vent
s. D
rug
disc
ontin
uatio
n fo
r adv
erse
eve
nts:
rela
ted
to a
ll th
ree
drug
s in
1 p
atie
nt, a
nd re
late
d to
line
zolid
(ini
tial d
ose
1200
m
g/da
y) d
iscon
tinue
d in
ano
ther
35
(32%
) pat
ient
s. O
nly
20
(18%
) pat
ient
s co
mpl
eted
a fu
ll co
urse
of 1
200
mg/
day.
In
the
IPD
stu
dies
(90%
rece
ived
600
mg/
day
or le
ss),
the
pool
ed
rate
of L
ZD p
erm
anen
t disc
ontin
uatio
n w
as 1
7.9%
, and
in th
e En
dTB
stud
y (a
ll pa
tient
s re
ceiv
ed 6
00m
g/da
y or
less
), th
e ra
te o
f LZD
disc
ontin
uatio
n w
as 1
3.1%
. In
EndT
B: 9
per
sons
ou
t of 1
094
(0.8
%) d
ied
of a
pos
sibly
/pro
babl
y dr
ug re
late
d AE
, inc
ludi
ng tw
o pe
rson
s w
ith s
udde
n ca
rdia
c de
ath
and
QT
prol
onga
tion.
Anot
her u
ndes
irabl
e ef
fect
that
the
GD
G c
onsid
ered
was
the
inco
nsist
ency
of
evid
ence
on
the
reve
rsib
ility
of p
erip
hera
l neu
ropa
thy;
the
evid
ence
sug
gest
ed
eith
er c
ompl
ete
or in
com
plet
e re
vers
ibilit
y of
per
iphe
ral n
euro
path
y. Bo
th
patie
nts
and
clini
cians
who
wer
e pa
nel m
embe
rs d
escr
ibed
the
pote
ntia
lly
debi
litat
ing
effe
cts
of ir
reve
rsib
le p
erip
hera
l neu
ropa
thy,
whi
ch w
ere
of c
once
rn.
GD
G m
embe
rs a
lso c
onsid
ered
the
fact
that
long
er re
gim
ens
for M
DR/
RR-T
B ca
rry
a su
bsta
ntia
lly h
ighe
r pill
burd
en, w
hich
may
be
view
ed a
s un
desir
able
for
man
y pa
tient
s.Ri
sk o
f bia
s w
ith re
gard
to th
e co
mpa
rison
was
men
tione
d by
pan
el m
embe
rs
(mon
itorin
g of
adv
erse
effe
cts
was
mor
e fre
quen
t in
the
Nix-
TB s
tudy
than
in th
e co
mpa
rison
gro
up, w
hich
inclu
des
prog
ram
mat
ic da
ta).
This
was
not
nec
essa
rily
a pr
oble
m w
ith th
e IP
D c
ohor
ts, b
ut p
osed
a p
robl
em w
ith th
e la
ck o
f a c
ontro
l gr
oup
in th
e st
udy
that
test
ed th
e in
terv
entio
n.
The
GD
G c
onsid
ered
the
desir
able
effe
ct o
f tre
atm
ent s
ucce
ss, w
hich
was
hig
her
in th
e in
terv
entio
n gr
oups
than
in th
e co
mpa
rato
r gro
ups,
for a
ll fo
ur tr
eatm
ent
outc
omes
that
wer
e as
sess
ed. O
vera
ll, w
hen
com
parin
g tre
atm
ent s
ucce
ss w
ith
failu
re/r
ecur
renc
e, th
e tre
atm
ent s
ucce
ss ra
te in
the
Nix-
TB s
tudy
was
97.
0%,
com
pare
d w
ith 9
1.7%
in th
e co
mpa
rato
r gro
up (r
esul
ting
in 6
mor
e tre
atm
ent
succ
esse
s pe
r 100
pat
ient
s). F
or tr
eatm
ent s
ucce
ss v
ersu
s de
ath,
trea
tmen
t su
cces
s w
as 9
3.2%
in th
e N
ix-TB
stu
dy c
ompa
red
with
91.
9% in
the
com
para
tor
grou
p (re
sulti
ng in
1 m
ore
treat
men
t suc
cess
per
100
pat
ient
s). T
he G
DG
co
nsid
ered
rate
s of
loss
to fo
llow
-up
to b
e a
desir
able
effe
ct; t
he p
ropo
rtio
n of
pa
tient
s w
ho w
ere
lost
to fo
llow
-up
was
low
er in
the
inte
rven
tion
grou
p (1
.8%
) co
mpa
red
with
the
com
paris
on g
roup
(3.1
%).
The
unce
rtai
nty
in th
e ev
iden
ce
was
ack
now
ledg
ed b
y th
e pa
nel w
hen
mak
ing
thei
r jud
gem
ent o
n th
e de
sirab
le
(and
und
esira
ble)
effe
cts.
The
BPaL
regi
men
was
ass
ocia
ted
with
a h
igh
rate
of a
dver
se e
vent
s, co
nsid
ered
to
be
rela
ted
to th
e st
udy
drug
s. Th
is in
clude
d th
e de
ath
of 1
(0.9
%) p
artic
ipan
t; ot
her s
erio
us a
dver
se e
vent
s (in
cludi
ng h
ospi
taliz
atio
ns a
nd li
fe-t
hrea
teni
ng
even
ts) i
n 27
(25%
) par
ticip
ants
and
at l
east
one
Gra
de 3
–4 a
dver
se e
vent
in 5
3 (4
9%) p
artic
ipan
ts. T
his
led
to d
iscon
tinua
tion
of a
ll th
ree
drug
s fo
r 1 p
atie
nt,
and
disc
ontin
uatio
n of
line
zolid
(ini
tial d
ose
1200
mg/
day)
for a
noth
er 3
5 (3
2%) p
atie
nts.
Onl
y 18
(17%
) pat
ient
s co
mpl
eted
a fu
ll co
urse
of l
inez
olid
at
1200
mg/
day.
The
GD
G n
oted
that
it is
diff
icult
to c
ompa
re th
ese
adve
rse
even
t rat
es w
ith
othe
r stu
dies
bec
ause
of m
ajor
and
impo
rtan
t diff
eren
ces
in a
dver
se e
vent
as
cert
ainm
ent,
asse
ssm
ent,
and
repo
rtin
g. H
owev
er, i
n th
e IP
D s
tudi
es (w
here
90
% o
f pat
ient
s re
ceiv
ed a
line
zolid
dos
e of
≤60
0 m
g/da
y), t
he p
oole
d ra
te
of p
erm
anen
t disc
ontin
uatio
n of
line
zolid
was
17.
9%, a
nd in
the
EndT
B tri
al
(whe
re a
ll pa
tient
s re
ceiv
ed ≤
600
mg/
day
of li
nezo
lid),
the
rate
of l
inez
olid
di
scon
tinua
tion
was
13.
1%. I
n bo
th o
f the
se s
tudi
es, >
80%
of p
atie
nts
rece
ived
a
star
ting
dose
of l
inez
olid
of 6
00 m
g/da
y. In
the
EndT
B st
udy,
prel
imin
ary
anal
yses
su
gges
ted
that
9 o
f 109
4 pa
rtici
pant
s (0
.8%
) die
d of
a p
ossib
ly o
r pro
babl
y dr
ug-r
elat
ed a
dver
se e
vent
, inc
ludi
ng 2
par
ticip
ants
with
sud
den
card
iac
deat
h
WHO consolidated guidelines on tuberculosis: Online annexes104
Cert
aint
y of
evi
denc
eW
hat i
s th
e ov
eral
l cer
tain
ty o
f the
evi
denc
e of
eff
ects
?
JUD
GEM
ENT
RESE
ARC
H E
VID
ENCE
AD
DIT
ION
AL
CON
SID
ERAT
ION
S●
Very
low
○
Low
○
Mod
erat
e ○
Hig
h ○
No
inclu
ded
stud
ies
The
prim
ary
sour
ce o
f evi
denc
e fo
r thi
s PI
CO q
uest
ion
is th
e N
ix-TB
stu
dy,
whi
ch w
as c
ompo
sed
of 1
09 p
atie
nts
recr
uite
d in
a o
ne-a
rm, p
hase
III,
open
-la
bel s
tudy
that
ass
esse
d th
e sa
fety
, effi
cacy
, tol
erab
ility,
and
phar
mac
okin
etic
prop
ertie
s of
a 6
-mon
th tr
eatm
ent r
egim
en c
ompo
sed
of b
edaq
uilin
e,
pret
oman
id a
nd li
nezo
lid (B
PaL)
in S
outh
Afri
ca. T
he e
vide
nce
was
gen
erat
ed,
in th
e co
ntex
t of t
horo
ugh
mon
itorin
g an
d fo
llow
-up,
at b
asel
ine,
thro
ugho
ut
treat
men
t, an
d fo
r 24
mon
ths
afte
r tre
atm
ent c
ompl
etio
n. T
here
wer
e 10
9 pa
tient
s in
the
inte
ntio
n-to
-tre
at p
opul
atio
n an
d 10
8 in
the
mod
ified
inte
ntio
n-to
-tre
at p
opul
atio
n. T
hese
dat
a w
ere
com
pare
d w
ith th
e da
ta fr
om th
e IP
D
beca
use
the
stud
y w
as n
ot a
rand
omiz
ed, c
ontro
lled
trial
. Ove
rall,
the
cert
aint
y of
the
evid
ence
was
cla
ssifi
ed a
s “v
ery
low
”. Th
e ch
air o
f the
GD
G p
anel
not
ed
that
con
fiden
ce in
terv
als
(CIs)
aro
und
the
estim
ates
of e
ffect
hav
e lim
ited
appl
icatio
n in
the
cont
ext o
f ver
y lo
w e
vide
nce.
Valu
esIs
ther
e im
port
ant u
ncer
tain
ty a
bout
or v
aria
bilit
y in
how
muc
h pe
ople
val
ue th
e m
ain
outc
omes
?
JUD
GEM
ENT
RESE
ARC
H E
VID
ENCE
AD
DIT
ION
AL
CON
SID
ERAT
ION
S○
Impo
rtan
t un
cert
aint
y or
va
riabi
lity
● Po
ssib
ly
impo
rtan
t un
cert
aint
y or
va
riabi
lity
○ P
roba
bly
no im
port
ant
unce
rtai
nty
or
varia
bilit
y ○
No
impo
rtan
t un
cert
aint
y or
va
riabi
lity
No
rese
arch
evi
denc
e w
as id
entif
ied.
Al
thou
gh n
o re
sear
ch e
vide
nce
was
iden
tifie
d, th
e pa
nel f
elt t
hat t
here
was
po
ssib
ly im
port
ant u
ncer
tain
ty o
r var
iabi
lity
in h
ow m
uch
peop
le w
ould
val
ue
the
mai
n ou
tcom
es. F
ertil
ity w
as ra
ised
as a
n ou
tcom
e fo
r whi
ch th
ere
is le
ss
info
rmat
ion.
The
pan
el th
ough
t tha
t thi
s w
ould
incr
ease
the
com
plex
ity o
f the
ju
dgem
ent a
bout
how
muc
h pe
ople
wou
ld v
alue
the
outc
omes
. The
GD
G
dete
rmin
ed th
at in
fert
ility
is a
serio
us is
sue
beca
use
it af
fect
s no
t onl
y pa
tient
s bu
t also
thei
r fam
ilies.
The
pane
l not
ed th
at th
ere
are
othe
r saf
ety
outc
omes
(e.g
. ot
her a
dver
se e
vent
s, in
cludi
ng p
erip
hera
l neu
ropa
thy)
that
may
var
y an
d th
at
peop
le m
ay v
alue
diff
eren
tly.
Indi
rect
evi
denc
e w
as c
onsid
ered
by
the
pane
l in
the
form
of a
sep
arat
e qu
alita
tive
stud
y co
nduc
ted
amon
g 16
pat
ient
s w
ith d
rug-
resis
tant
TB
who
wer
e fro
m h
igh
TB b
urde
n co
untri
es (w
hich
info
rmed
the
judg
emen
ts o
n PI
CO 1
). Th
e ai
m o
f the
stu
dy w
as to
det
erm
ine
the
mos
t acc
epta
ble
treat
men
t reg
imen
for
drug
-res
istan
t TB.
On
the
basis
of t
he re
sults
of t
his
stud
y, th
e pr
efer
red
regi
men
w
as s
hort
and
inje
ctio
n-fre
e w
ith fe
w to
no
phys
ical o
r men
tal h
ealth
sid
e-ef
fect
s an
d w
ith a
low
pill
burd
en. R
anke
d pr
efer
ence
s fo
r tre
atm
ent o
f dru
g-re
sista
nt T
B in
clude
d (1
) adv
erse
eve
nts,
(2) d
urat
ion,
(3) i
njec
tion
(free
) and
(4) p
ill bu
rden
.
Annex 4: GRADE evidence-to-decision tables 105
Bala
nce
of e
ffec
tsD
oes
the
bala
nce
betw
een
desi
rabl
e an
d un
desi
rabl
e ef
fect
s fa
vor t
he in
terv
entio
n or
the
com
paris
on?
JUD
GEM
ENT
RESE
ARC
H E
VID
ENCE
AD
DIT
ION
AL
CON
SID
ERAT
ION
S○
Fav
ors
the
com
paris
on
○ P
roba
bly
favo
rs
the
com
paris
on
● D
oes
not
favo
r eith
er th
e in
terv
entio
n or
the
com
paris
on
○ P
roba
bly
favo
rs
the
inte
rven
tion
○ F
avor
s th
e in
terv
entio
n ○
Var
ies
○ D
on’t
know
The
pane
l not
ed th
e m
oder
ate
desir
able
effe
cts
and
the
mod
erat
e un
desir
able
ef
fect
s (a
nd th
e lo
w c
erta
inty
of t
he e
vide
nce
over
all).
and
took
this
into
acc
ount
w
hen
mak
ing
thei
r jud
gem
ent a
bout
the
bala
nce
of e
ffect
s, w
hich
wer
e fe
lt to
no
t fav
our e
ither
the
inte
rven
tion
or th
e co
mpa
rison
.
The
pane
l con
sider
ed a
t len
gth
the
desir
able
and
und
esira
ble
effe
cts
and
the
bala
nce
of th
ese
effe
cts,
notin
g th
e ve
ry lo
w c
erta
inty
of t
he e
vide
nce
and
ackn
owle
dgin
g th
e ef
fort
s to
mat
ch p
atie
nts
in th
e in
terv
entio
n an
d co
mpa
rato
r gr
oups
(thr
ough
exa
ct a
nd p
rope
nsity
sco
re-b
ased
mat
chin
g). T
he G
DG
not
ed
that
rand
omiz
ed, c
ontro
lled
trial
s ar
e ne
eded
in th
e fu
ture
, whi
ch m
ay a
llow
fo
r a m
ore
close
ly a
ligne
d co
mpa
rison
gro
up w
ith le
ss p
oten
tial f
or re
sidua
l co
nfou
ndin
g. T
hrou
gh a
vot
ing
proc
ess,
the
pane
l con
clude
d th
at th
e ba
lanc
e of
effe
cts
does
not
favo
ur e
ither
the
inte
rven
tion
or th
e co
mpa
rison
. Fift
een
pane
l mem
bers
vot
ed th
at th
e ba
lanc
e of
effe
cts
does
not
favo
ur e
ither
the
inte
rven
tion
or th
e co
mpa
rison
, 5 v
oted
that
the
bala
nce
of e
ffect
s pr
obab
ly
does
favo
ur th
e co
mpa
rison
and
4 v
oted
that
they
did
not
kno
w. O
ne m
embe
r ab
stai
ned,
and
5 re
port
ed c
onfli
cts
of in
tere
st.
WHO consolidated guidelines on tuberculosis: Online annexes106
Reso
urce
s re
quir
edH
ow la
rge
are
the
reso
urce
requ
irem
ents
(cos
ts)?
JUD
GEM
ENT
RESE
ARC
H E
VID
ENCE
AD
DIT
ION
AL
CON
SID
ERAT
ION
S○
Lar
ge c
osts
○
Mod
erat
e co
sts
○ N
eglig
ible
cos
ts
and
savi
ngs
○ M
oder
ate
savi
ngs
● La
rge
savi
ngs
○ V
arie
s ○
Don
’t kn
ow
No
rese
arch
evi
denc
e w
as id
entif
ied.
Th
e G
DG
con
sider
ed e
vide
nce
from
a c
ost–
effe
ctiv
enes
s an
alys
is st
udy
whi
ch
was
con
duct
ed b
y st
aff f
rom
the
Lond
on S
choo
l of H
ygie
ne &
Trop
ical M
edici
ne
on b
ehal
f of t
he T
B Al
lianc
e. T
he G
DG
not
ed th
at th
e an
alys
is w
as n
ot d
one
for t
his
–evi
denc
e to
dec
ision
fram
ewor
k –
that
is, u
ndes
irabl
e ef
fect
s w
ere
not
cons
ider
ed a
ccor
ding
to th
e G
DG
’s ju
dgem
ents
. Thi
s m
ade
the
cost
–effe
ctiv
enes
s an
alys
es in
form
ativ
e bu
t not
dire
ctly
bas
ed o
n th
e ev
iden
ce th
at th
e G
DG
w
as a
sses
sing.
The
anal
yses
wer
e ba
sed
on G
eorg
ia, t
he P
hilip
pine
s, an
d So
uth
Afric
a. T
he
aim
s of
the
rese
arch
wer
e to
est
imat
e th
e co
st–e
ffect
iven
ess
of a
new
regi
men
co
ntai
ning
bed
aqui
line,
pre
tom
anid
, and
line
zolid
(BPa
L) c
ompa
red
with
the
stan
dard
of c
are
at a
giv
en p
rice,
and
to e
stim
ate
the
max
imum
dru
g pr
ice a
t w
hich
the
BPaL
regi
men
cou
ld b
e co
nsid
ered
cos
t-effe
ctiv
e or
cos
t-neu
tral i
n ea
ch s
ettin
g. T
he p
ersp
ectiv
e ta
ken
was
a h
ealth
ser
vice
one
, and
the
stud
y as
sum
ed B
PaL
to b
e ef
fect
ive.
Whe
n as
sess
ing
the
pote
ntia
l cos
t–ef
fect
iven
ess
of B
PaL
for t
he tr
eatm
ent o
f XD
R-TB
, the
GD
G o
bser
ved
that
in a
ll th
ree
setti
ngs
this
regi
men
has
the
pote
ntia
l to
be c
ost-s
avin
g at
a g
iven
dru
g pr
ice o
f US$
364
pe
r tre
atm
ent c
ours
e fo
r pre
tom
anid
. The
stu
dy fo
und
that
cos
t-sav
ings
are
a
func
tion
of th
e co
st o
f car
e an
d th
e m
agni
tude
of X
DR-
TB b
urde
n, a
nd a
re
abou
t US$
449
0 –
not i
nclu
ding
ant
iretro
vira
l the
rapy
(ART
) cos
ts –
in S
outh
Af
rica;
US$
406
0 in
Geo
rgia
and
US$
386
0 in
the
Philip
pine
s. In
hig
h H
IV-T
B pr
eval
ence
set
tings
suc
h as
Sou
th A
frica
, rel
ated
futu
re c
osts
suc
h as
thos
e fro
m
the
HIV
pro
gram
me
(ART
cos
ts) r
educ
e th
e m
agni
tude
of e
xpec
ted
cost
sav
ings
to
US$
140
0 pe
r pat
ient
. Ove
rall,
whe
n BP
aL is
intro
duce
d to
a la
rger
pop
ulat
ion
(inclu
ding
thos
e w
ith M
DR-
TB tr
eatm
ent f
ailu
re a
nd th
ose
with
trea
tmen
t in
tole
ranc
e), t
he G
DG
obs
erve
d an
incr
ease
in th
e in
crem
enta
l ben
efits
, bot
h in
te
rms
of d
eath
s an
d di
sabi
lity
adju
sted
life
-yea
rs a
vert
ed a
nd in
crem
enta
l cos
ts.
Food
cos
ts w
ere
not i
nclu
ded
in th
e co
st–e
ffect
iven
ess
anal
ysis
and
wou
ld n
eed
to b
e co
nsid
ered
whe
n BP
aL is
impl
emen
ted.
Dur
ing
the
Nix-
TB s
tudy
, all
stud
y m
edica
tions
wer
e ad
min
ister
ed w
ith fo
od (b
ecau
se o
f the
adm
inist
ratio
n of
be
daqu
iline,
whi
ch w
ill al
so n
ow fe
atur
e as
a c
ore
med
icine
in lo
nger
trea
tmen
t re
gim
ens
for M
DR/
RR-T
B). T
he c
ost o
f the
BPa
L re
gim
en is
US$
104
0 ac
cord
ing
to th
e G
loba
l Dru
g Fa
cility
(GFD
), ba
sed
on G
DF-
wei
ghte
d av
erag
e ta
blet
pric
e.
Cert
aint
y of
evi
denc
e of
req
uire
d re
sour
ces
Wha
t is
the
cert
aint
y of
the
evid
ence
of r
esou
rce
requ
irem
ents
(cos
ts)?
JUD
GEM
ENT
RESE
ARC
H E
VID
ENCE
AD
DIT
ION
AL
CON
SID
ERAT
ION
S○
Ver
y lo
w
○ L
ow
○ M
oder
ate
○ H
igh
● N
o in
clude
d st
udie
s
No
rese
arch
evi
denc
e w
as id
entif
ied.
Annex 4: GRADE evidence-to-decision tables 107
Cost
eff
ecti
vene
ssD
oes
the
cost
-eff
ectiv
enes
s of
the
inte
rven
tion
favo
r the
inte
rven
tion
or th
e co
mpa
rison
?
JUD
GEM
ENT
RESE
ARC
H E
VID
ENCE
AD
DIT
ION
AL
CON
SID
ERAT
ION
S○
Fav
ors
the
com
paris
on
○ P
roba
bly
favo
rs
the
com
paris
on
○ D
oes
not
favo
r eith
er th
e in
terv
entio
n or
the
com
paris
on
○ P
roba
bly
favo
rs
the
inte
rven
tion
○ F
avor
s th
e in
terv
entio
n ○
Var
ies
● N
o in
clude
d st
udie
s
No
rese
arch
evi
denc
e w
as id
entif
ied.
Th
e G
DG
con
sider
ed e
vide
nce
from
a c
ost–
effe
ctiv
enes
s an
alys
is st
udy
that
was
co
nduc
ted
by s
taff
from
the
Lond
on S
choo
l of H
ygie
ne &
Trop
ical M
edici
ne o
n be
half
of th
e TB
Allia
nce.
The
GD
G n
oted
that
the
cost
–effe
ctiv
enes
s an
alys
is w
as
not d
one
for t
his
evid
ence
to d
ecisi
on fr
amew
ork
– th
at is
, und
esira
ble
effe
cts
wer
e no
t con
sider
ed a
ccor
ding
to th
e G
DG
’s ju
dgem
ents
. Thi
s m
ade
the
cost
–ef
fect
iven
ess
anal
yses
info
rmat
ive
but n
ot d
irect
ly b
ased
on
the
evid
ence
that
the
GD
G w
as a
sses
sing.
The
anal
yses
wer
e ba
sed
on G
eorg
ia, t
he P
hilip
pine
s, an
d So
uth
Afric
a. T
he
aim
s of
the
rese
arch
wer
e to
est
imat
e th
e co
st–e
ffect
iven
ess
of a
new
regi
men
co
ntai
ning
bed
aqui
line,
pre
tom
anid
and
line
zolid
(BPa
L) c
ompa
red
with
the
stan
dard
of c
are
at a
giv
en p
rice,
and
to e
stim
ate
the
max
imum
dru
g pr
ice a
t w
hich
the
BPaL
regi
men
cou
ld b
e co
nsid
ered
cos
t-effe
ctiv
e or
cos
t-neu
tral i
n ea
ch s
ettin
g. T
he p
ersp
ectiv
e ta
ken
was
a h
ealth
ser
vice
one
, and
the
stud
y as
sum
ed B
PaL
to b
e ef
fect
ive.
Whe
n as
sess
ing
the
pote
ntia
l cos
t–ef
fect
iven
ess
of B
PaL
for t
he tr
eatm
ent o
f XD
R-TB
, the
GD
G o
bser
ved
that
in a
ll th
ree
setti
ngs,
this
regi
men
has
the
pote
ntia
l to
be c
ost s
avin
g at
a g
iven
dru
g pr
ice o
f US$
364
pe
r tre
atm
ent c
ours
e fo
r pre
tom
anid
. The
stu
dy fo
und
that
cos
t sav
ings
are
a
func
tion
of th
e co
st o
f car
e an
d th
e m
agni
tude
of X
DR-
TB b
urde
n, a
nd a
re
abou
t US$
449
0 –
not i
nclu
ding
ant
iretro
vira
l the
rapy
(ART
) cos
ts –
in S
outh
Af
rica;
US$
406
0 in
Geo
rgia
and
US$
386
0 in
the
Philip
pine
s.. In
hig
h H
IV-T
B pr
eval
ence
set
tings
, suc
h as
Sou
th A
frica
, rel
ated
futu
re c
osts
suc
h as
thos
e fro
m th
e H
IV p
rogr
amm
e (A
RT c
osts
) red
uce
the
mag
nitu
de o
f exp
ecte
d co
st
savi
ngs
to U
S$ 1
400
per p
atie
nt. O
vera
ll, w
hen
BPaL
is in
trodu
ced
to a
larg
er
popu
latio
n (in
cludi
ng p
atie
nts
with
failu
re o
f MD
R-TB
trea
tmen
t and
thos
e w
ho
cann
ot to
lera
te tr
eatm
ent),
the
GD
G o
bser
ved
an in
crea
se in
the
incr
emen
tal
bene
fits,
both
in te
rms
of d
eath
s an
d di
sabi
lity
adju
sted
life
yea
rs a
vert
ed a
nd
incr
emen
tal c
osts
.Fo
od c
osts
wer
e no
t inc
lude
d in
the
cost
–effe
ctiv
enes
s an
alys
is an
d w
ould
nee
d to
be
cons
ider
ed w
hen
BPaL
is im
plem
ente
d. D
urin
g th
e N
ix-TB
stu
dy, a
ll st
udy
med
icatio
ns w
ere
adm
inist
ered
with
food
(bec
ause
of t
he a
dmin
istra
tion
of
beda
quilin
e, w
hich
will
also
now
feat
ure
as a
cor
e m
edici
ne in
long
er tr
eatm
ent
regi
men
s fo
r MD
R/RR
-TB)
.
WHO consolidated guidelines on tuberculosis: Online annexes108
Equi
tyW
hat w
ould
be
the
impa
ct o
n he
alth
equ
ity?
JUD
GEM
ENT
RESE
ARC
H E
VID
ENCE
AD
DIT
ION
AL
CON
SID
ERAT
ION
S○
Red
uced
○
Pro
babl
y re
duce
d ○
Pro
babl
y no
im
pact
●
Prob
ably
in
crea
sed
○ In
crea
sed
○ V
arie
s ○
Don
’t kn
ow
No
rese
arch
evi
denc
e w
as id
entif
ied.
Alth
ough
no
rese
arch
evi
denc
e w
as id
entif
ied,
the
GD
G p
anel
felt
that
the
impa
ct o
n he
alth
equ
ity w
ould
be
a pr
obab
le in
crea
se, g
iven
the
optio
n of
a
shor
ter r
egim
en th
at c
ould
be
avai
labl
e gl
obal
ly (i
.e. a
vaila
ble
to a
ll pa
tient
s).
The
GD
F ha
s id
entif
ied
a pr
ice fo
r pre
tom
anid
and
sta
ted
that
it w
ill m
ake
the
BPaL
regi
men
ava
ilabl
e to
nat
iona
l TB
prog
ram
mes
, dep
ende
nt u
pon
the
reco
mm
enda
tion
from
the
pane
l. Th
e G
DF
repr
esen
tativ
e no
ted
that
two
bottl
es o
f bed
aqui
line
will
need
to b
e or
dere
d fo
r any
one
who
is re
ceiv
ing
the
BPaL
regi
men
. Chi
ldre
n an
d pr
egna
nt w
omen
wer
e in
elig
ible
for i
nclu
sion
in
the
Nix-
TB s
tudy
and
ther
efor
e w
ill no
t be
an e
ligib
le p
opul
atio
n fo
r BPa
L if
it is
reco
mm
ende
d, w
hich
may
be
an e
quity
issu
e.
Annex 4: GRADE evidence-to-decision tables 109
Acc
epta
bilit
yIs
the
inte
rven
tion
acce
ptab
le to
key
sta
keho
lder
s?
JUD
GEM
ENT
RESE
ARC
H E
VID
ENCE
AD
DIT
ION
AL
CON
SID
ERAT
ION
S○
No
○ P
roba
bly
no
● Pr
obab
ly y
es
○ Y
es
○ V
arie
s ○
Don
’t kn
ow
The
GD
G p
anel
thou
ght t
hat t
he ju
dgem
ent w
as p
roba
bly
yes b
ecau
se th
e co
ncer
ns re
gard
ing
repr
oduc
tive
toxic
ities
wer
e no
t disc
usse
d as
par
t of t
he
acce
ptab
ility
stud
y co
nduc
ted
by K
NCV
(bec
ause
this
was
not
kno
wn
to th
e st
udy
inve
stig
ator
s at
the
time)
and
the
com
para
tor u
sed
in th
is st
udy
was
not
th
e sa
me
as th
at fo
r the
evi
denc
e th
at w
as a
sses
sed.
The
GD
G c
onsid
ered
evi
denc
e fro
m a
n ac
cept
abilit
y an
d fe
asib
ility
stud
y co
nduc
ted
by K
NCV
on
beha
lf of
the
TB A
llianc
e. T
he o
bjec
tives
of t
he s
tudy
w
ere
to a
sses
s th
e ac
cept
abilit
y an
d lik
elih
ood
of im
plem
enta
tion
of th
e BP
aL
regi
men
as
antic
ipat
ed b
y ke
y st
akeh
olde
rs a
nd b
ased
on
a nu
mbe
r of c
riter
ia
(inclu
ding
the
perc
eive
d be
nefit
s an
d ch
alle
nges
of i
mpl
emen
tatio
n of
BPa
L an
d lo
nger
indi
vidu
aliz
ed tr
eatm
ent r
egim
ens,
and
othe
r pra
ctica
l req
uire
men
ts o
f im
plem
enta
tion)
. The
stu
dy w
as a
mixe
d-m
etho
ds, m
ultic
ount
ry, c
ross
-sec
tiona
l in
vest
igat
ion
cond
ucte
d in
–20
18–2
019
amon
g st
akeh
olde
rs in
Indo
nesia
, Ky
rgys
tan
and
Nig
eria
. Vie
ws
wer
e of
fere
d by
a to
tal o
f 188
par
ticip
ants
, in
cludi
ng c
areg
iver
s, pr
ogra
mm
atic
stak
ehol
ders
(inc
ludi
ng n
atio
nal a
nd
inte
rnat
iona
l pro
gram
mat
ic st
akeh
olde
rs a
nd p
atie
nt-a
dvoc
acy
grou
ps) a
nd
publ
ic an
d pr
ivat
e la
bora
tory
sta
keho
lder
s. O
n th
e ba
sis o
f sev
en a
sses
smen
t ca
tego
ries
(rang
ing
from
pat
ient
frie
ndlin
ess
to tr
eatm
ent s
afet
y m
onito
ring)
, th
e ac
cept
abilit
y of
BPa
L w
hen
com
pare
d w
ith a
long
er tr
eatm
ent r
egim
en fo
r M
DR-
TB w
as h
ighe
r for
eve
ry c
ateg
ory.
Acce
ptab
ility
was
hig
her f
or B
PaL
than
fo
r the
long
er M
DR-
TB re
gim
ens
in s
ix of
the
seve
n ca
tego
ries
asse
ssed
, with
the
exce
ptio
n of
trea
tmen
t saf
ety
mon
itorin
g, w
here
the
diffe
renc
e w
as n
eglig
ible
. Th
e m
ain
driv
ers
of a
ccep
tabi
lity
of B
PaL
wer
e th
e sh
orte
r dur
atio
n, a
bsen
ce o
f in
ject
able
s, lo
wer
pill
burd
en, a
ntici
pate
d pa
tient
pre
fere
nces
and
low
er fi
nanc
ial
burd
en fo
r pat
ient
s, an
ticip
ated
hig
her t
reat
men
t suc
cess
, low
er c
osts
for t
he
heal
th s
yste
m, m
inim
al a
dditi
onal
requ
irem
ents
for d
iagn
ostic
pro
cess
es, a
nd
a lo
wer
ant
icipa
ted
per-p
atie
nt b
urde
n to
the
TB la
bora
tory
for b
acte
riolo
gica
l tre
atm
ent m
onito
ring.
Indi
rect
evi
denc
e w
as c
onsid
ered
by
the
pane
l in
the
form
of
a s
epar
ate
qual
itativ
e st
udy
cond
ucte
d am
ong
16 p
atie
nts
with
dru
g-re
sista
nt
TB w
ho w
ere
from
hig
h bu
rden
cou
ntrie
s (w
hich
info
rmed
the
judg
emen
ts o
n PI
CO 1
). Th
e ai
m o
f the
stu
dy w
as to
det
erm
ine
the
mos
t acc
epta
ble
treat
men
t re
gim
en fo
r dru
g-re
sista
nt T
B. O
n th
e ba
sis o
f the
resu
lts o
f thi
s st
udy,
the
pref
erre
d re
gim
en w
as s
hort
and
inje
ctio
n-fre
e w
ith fe
w to
no
phys
ical o
r men
tal
heal
th s
ide-
effe
cts
and
a lo
w p
ill bu
rden
. Ran
ked
pref
eren
ces
for d
rug
resis
tant
TB
trea
tmen
t wer
e as
follo
ws:
(1) a
dver
se e
vent
s, (2
) dur
atio
n, (3
) inj
ectio
n (fr
ee)
and
(4) p
ill bu
rden
.
WHO consolidated guidelines on tuberculosis: Online annexes110
Feas
ibili
tyIs
the
inte
rven
tion
feas
ible
to im
plem
ent?
JUD
GEM
ENT
RESE
ARC
H E
VID
ENCE
AD
DIT
ION
AL
CON
SID
ERAT
ION
S○
No
○ P
roba
bly
no
● Pr
obab
ly y
es
○ Y
es
○ V
arie
s ○
Don
’t kn
ow
The
GD
G c
onsid
ered
evi
denc
e fro
m a
n ac
cept
abilit
y an
d fe
asib
ility
stud
y co
nduc
ted
by K
NCV
on
beha
lf of
the
TB A
llianc
e. T
he o
bjec
tives
of t
he s
tudy
w
ere
to a
sses
s th
e ac
cept
abilit
y an
d lik
elih
ood
of im
plem
enta
tion
of th
e BP
aL
regi
men
as
antic
ipat
ed b
y ke
y st
akeh
olde
rs a
nd o
n th
e ba
sis o
f a n
umbe
r of
crite
ria, i
nclu
ding
the
perc
eive
d be
nefit
s an
d ch
alle
nges
of i
mpl
emen
tatio
n of
BPa
L an
d lo
nger
indi
vidu
aliz
ed tr
eatm
ent r
egim
ens,
and
othe
r pra
ctica
l re
quire
men
ts o
f im
plem
enta
tion.
The
stu
dy w
as a
mixe
d-m
etho
ds, m
ultic
ount
ry,
cros
s-se
ctio
nal i
nves
tigat
ion
cond
ucte
d in
201
8–20
19 a
mon
g st
akeh
olde
rs
in In
done
sia, K
yrgy
zsta
n an
d N
iger
ia. A
tota
l of 1
88 p
artic
ipan
ts o
ffere
d th
eir
view
s, in
cludi
ng c
areg
iver
s, pr
ogra
mm
atic
stak
ehol
ders
(inc
ludi
ng n
atio
nal a
nd
inte
rnat
iona
l pro
gram
mat
ic st
akeh
olde
rs a
nd p
atie
nt-a
dvoc
acy
grou
ps),
and
publ
ic an
d pr
ivat
e la
bora
tory
sta
keho
lder
s. O
n th
e ba
sis o
f sev
en a
sses
smen
t ca
tego
ries (
rang
ing
from
frie
ndlin
ess f
or p
atie
nts t
o tre
atm
ent s
afet
y m
onito
ring)
, th
e ac
cept
abilit
y of
BPa
L w
hen
com
pare
d w
ith a
long
er tr
eatm
ent r
egim
en fo
r M
DR-
TB w
as h
ighe
r for
eve
ry c
ateg
ory.
Acce
ptab
ility
was
hig
her f
or B
PaL
than
fo
r the
long
er M
DR-
TB re
gim
ens
in s
ix of
the
seve
n ca
tego
ries
asse
ssed
, with
the
exce
ptio
n of
trea
tmen
t saf
ety
mon
itorin
g, w
here
the
diffe
renc
e w
as n
eglig
ible
. In
line
with
the
over
all h
igh
acce
ptab
ility
of th
e BP
aL re
gim
en, t
he o
vera
ll lik
elin
ess
of im
plem
entin
g th
e BP
aL re
gim
en a
s a
stan
dard
of c
are
for t
he tr
eatm
ent o
f pa
tient
s w
ith X
DR-
TB a
nd M
DR-
TB tr
eatm
ent f
ailu
re/in
tole
ranc
e sc
ored
at 8
8;
only
1%
of t
he 1
66 p
artic
ipan
ts s
core
d th
at im
plem
enta
tion
as “u
nlike
ly,” a
nd
11%
had
a n
eutra
l opi
nion
. The
like
lines
s of
impl
emen
tatio
n w
as s
imila
r (84
%) t
o th
at fo
r the
BPa
L re
gim
en a
s a
stan
dard
of c
are
for p
atie
nts
with
MD
R-TB
with
flu
oroq
uino
lone
resis
tanc
e, re
gard
less
of a
dditi
onal
resis
tanc
e to
sec
ond-
line
inje
ctab
les.
This
indi
cate
d th
at th
e re
gim
en m
ay b
e fe
asib
le to
impl
emen
t fro
m
the
pers
pect
ive
of th
ose
inte
rvie
wed
.
Annex 4: GRADE evidence-to-decision tables 111
Sum
mar
y of
judg
emen
ts
JUD
GEM
ENT
PRO
BLEM
No
Prob
ably
no
Prob
ably
yes
Yes
Varie
sD
on’t
know
DES
IRAB
LE E
FFEC
TSTr
ivia
lSm
all
Mod
erat
eLa
rge
Varie
sD
on’t
know
UND
ESIR
ABLE
EFF
ECTS
Larg
eM
oder
ate
Smal
lTr
ivia
lVa
ries
Don
’t kn
owCE
RTAI
NTY
OF
EVID
ENCE
Very
low
Low
Mod
erat
eH
igh
No
inclu
ded
stud
ies
VALU
ESIm
port
ant
unce
rtai
nty
or
varia
bilit
y
Poss
ibly
impo
rtan
t un
cert
aint
y or
va
riabi
lity
Prob
ably
no
impo
rtan
t un
cert
aint
y or
va
riabi
lity
No
impo
rtan
t un
cert
aint
y or
va
riabi
lity
BALA
NCE
OF
EFFE
CTS
Favo
rs th
e co
mpa
rison
Prob
ably
favo
rs th
e co
mpa
rison
Doe
s no
t fav
or
eith
er th
e in
terv
entio
n or
the
com
paris
on
Prob
ably
favo
rs th
e in
terv
entio
nFa
vors
the
inte
rven
tion
Varie
sD
on’t
know
RESO
URCE
S RE
QUI
RED
Larg
e co
sts
Mod
erat
e co
sts
Neg
ligib
le c
osts
and
sa
ving
sM
oder
ate
savi
ngs
Larg
e sa
ving
sVa
ries
Don
’t kn
ow
CERT
AIN
TY O
F EV
IDEN
CE
OF
REQ
UIRE
D R
ESO
URCE
SVe
ry lo
wLo
wM
oder
ate
Hig
hN
o in
clude
d st
udie
s
COST
EFF
ECTI
VEN
ESS
Favo
rs th
e co
mpa
rison
Prob
ably
favo
rs th
e co
mpa
rison
Doe
s no
t fav
or e
ither
th
e in
terv
entio
n or
th
e co
mpa
rison
Prob
ably
favo
rs th
e in
terv
entio
nFa
vors
the
inte
rven
tion
Varie
sN
o in
clud
ed
stud
ies
EQUI
TYRe
duce
dPr
obab
ly re
duce
dPr
obab
ly n
o im
pact
Prob
ably
incr
ease
dIn
crea
sed
Varie
sD
on’t
know
ACCE
PTAB
ILIT
YN
oPr
obab
ly n
oPr
obab
ly y
esYe
sVa
ries
Don
’t kn
owFE
ASIB
ILIT
YN
oPr
obab
ly n
oPr
obab
ly y
esYe
sVa
ries
Don
’t kn
ow
Type
of r
ecom
men
datio
nSt
rong
reco
mm
enda
tion
agai
nst
the
inte
rven
tion
○
Cond
ition
al re
com
men
datio
n ag
ains
t the
inte
rven
tion
○
Cond
ition
al re
com
men
datio
n fo
r eith
er th
e in
terv
entio
n or
the
com
paris
on●
Cond
ition
al re
com
men
datio
n fo
r th
e in
terv
entio
n○
Stro
ng re
com
men
datio
n fo
r the
in
terv
entio
n○
WHO consolidated guidelines on tuberculosis: Online annexes112
Conc
lusi
ons
Reco
mm
enda
tion
A tre
atm
ent r
egim
en la
stin
g 6–
9 m
onth
s co
mpo
sed
of b
edaq
uilin
e, p
reto
man
id a
nd li
nezo
lid (B
PaL)
may
be
used
und
er o
pera
tiona
l res
earc
h co
nditi
ons
in M
DR-
TB p
atie
nts
with
TB
that
is re
sista
nt to
fluo
roqu
inol
ones
who
hav
e ha
d no
pre
viou
s ex
posu
re to
bed
aqui
line
and
linez
olid
for m
ore
than
two
wee
ks (c
ondi
tiona
l rec
omm
enda
tion,
ver
y lo
w c
erta
inty
in th
e es
timat
es o
f effe
ct).
Just
ifica
tion
Trea
tmen
t of p
atie
nts
with
form
s of
ext
ensiv
ely
drug
-res
istan
t TB
(XD
R-TB
) pre
sent
s m
ultip
le c
halle
nges
to c
linici
ans
and
natio
nal T
B pr
ogra
mm
es, b
oth
beca
use
of th
e lim
ited
rang
e of
med
icine
s av
aila
ble
and
the
life-
thre
aten
ing
natu
re o
f the
dise
ase.
Pat
ient
s w
ith M
DR/
RR-T
B an
d ad
ditio
nal f
luor
oqui
nolo
ne re
sista
nce
have
typi
cally
exp
erie
nced
poo
r tre
atm
ent
outc
omes
sin
ce th
e de
scrip
tion
of X
DR-
TB w
as fi
rst u
sed
in 2
006.
9 The
dat
a re
port
ed b
y m
embe
r sta
tes
to W
HO
, for
the
coho
rt o
f pat
ient
s w
ith X
DR-
TB w
ho s
tart
ed tr
eatm
ent i
n 20
16 (a
nd fo
r who
m tr
eatm
ent o
utco
mes
wer
e av
aila
ble
in 2
018)
sho
w th
at o
nly
39%
com
plet
ed tr
eatm
ent s
ucce
ssfu
lly, w
here
as 2
6% d
ied,
18%
exp
erie
nced
trea
tmen
t fai
lure
, and
an
add
ition
al 1
8% w
ere
lost
to fo
llow
-up
or w
ere
not e
valu
ated
.10 T
he p
ress
ing
need
for m
ore
effe
ctiv
e tre
atm
ent r
egim
ens
for p
atie
nts
with
ext
ensiv
e dr
ug re
sista
nce,
inclu
ding
flu
oroq
uino
lone
resis
tanc
e an
d m
ore
exte
nsiv
e dr
ug re
sista
nce
prof
iles,
has
mot
ivat
ed a
num
ber o
f stu
dies
and
initi
ativ
es to
test
mor
e ef
fect
ive
and
nove
l tre
atm
ent r
egim
ens,
inclu
ding
ne
wer
and
repu
rpos
ed m
edici
nes.
One
suc
h st
udy
is th
e N
ix-TB
stu
dy, c
ondu
cted
by
the
TB A
llianc
e. T
he N
ix-TB
stu
dy w
as a
one
-arm
, pha
se II
I, op
en-la
bel p
rosp
ectiv
e co
hort
stu
dy th
at a
sses
sed
the
safe
ty, e
ffica
cy,
tole
rabi
lity,
and
phar
mac
okin
etic
prop
ertie
s of
a 6
-mon
th tr
eatm
ent r
egim
en c
ompo
sed
of b
edaq
uilin
e, p
reto
man
id a
nd li
nezo
lid (B
PaL)
, ext
enda
ble
to 9
mon
ths
for t
hose
who
miss
ed
dose
s or
for p
atie
nts
who
rem
aine
d cu
lture
pos
itive
or r
ever
ted
from
cul
ture
neg
ativ
e to
cul
ture
pos
itive
bet
wee
n m
onth
s 4
and
6 of
trea
tmen
t. Th
e st
udy
was
con
duct
ed b
etw
een
2014
an
d 20
19 a
t thr
ee s
tudy
site
s, al
l in
Sout
h Af
rica,
with
the
first
pat
ient
enr
olle
d in
Apr
il 20
15. E
ligib
le p
atie
nts
wer
e ag
ed 1
4 ye
ars
or o
lder
, wei
ghed
≥35
kg,
had
a d
ocum
ente
d H
IV re
sult,
an
d ha
d ba
cter
iolo
gica
lly c
onfir
med
spu
tum
cul
ture
pos
itive
XD
R-TB
or b
acte
riolo
gica
lly c
onfir
med
MD
R/RR
-TB
but c
ould
not
tole
rate
trea
tmen
t or h
ad d
iseas
e th
at d
id n
ot re
spon
d to
pr
evio
us M
DR/
RR-T
B tre
atm
ent.
A nu
mbe
r of o
ther
inclu
sion
crite
ria w
ere
appl
ied.
Patie
nts
wer
e fo
llow
ed u
p fo
r a p
erio
d of
up
to 2
4 m
onth
s af
ter c
ompl
etio
n of
trea
tmen
t. Th
e pr
imar
y ou
tcom
e m
easu
re w
as th
e in
ciden
ce o
f bac
terio
logi
cal f
ailu
re o
r rel
apse
or c
linica
l fa
ilure
thro
ugh
follo
w-u
p un
til 6
mon
ths
afte
r the
end
of t
reat
men
t.11 S
econ
dary
out
com
e m
easu
res
wer
e as
follo
ws:
1. In
ciden
ce o
f bac
terio
logi
cal f
ailu
re o
r rel
apse
or c
linica
l fai
lure
thro
ugh
follo
w u
p un
til 2
4 m
onth
s af
ter t
he e
nd o
f tre
atm
ent (
as a
con
firm
ator
y an
alys
is).
2. T
ime
to s
putu
m c
ultu
re c
onve
rsio
n to
neg
ativ
e st
atus
thro
ugh
the
treat
men
t per
iod.
3. P
ropo
rtio
n of
sub
ject
s w
ith s
putu
m c
ultu
re c
onve
rsio
n to
neg
ativ
e st
atus
at 4
, 6, 8
, 12,
16
and
26 o
r 39
wee
ks.
4. L
inez
olid
dos
ing
(act
ual)
and
effic
acy.
5. C
hang
e fro
m b
asel
ine
in T
B sy
mpt
oms.
6. C
hang
e fro
m b
asel
ine
in p
atie
nt re
port
ed h
ealth
sta
tus.
7. C
hang
e fro
m b
asel
ine
in w
eigh
t (TB
Allia
nce,
Nix-
TB s
tudy
pro
toco
l, av
aila
ble
at: h
ttps:/
/clin
icaltr
ials.
gov/
ct2/
show
/NCT
0233
3799
).Th
e N
ix-TB
stu
dy re
gim
en c
ompr
ised
pret
oman
id a
dmin
ister
ed a
t 200
mg/
day,
beda
quilin
e ad
min
ister
ed a
t 400
mg/
day
for t
he fi
rst 2
wee
ks o
f tre
atm
ent (
days
1–1
4) a
nd 2
00 m
g th
ree
times
a w
eek
ther
eafte
r, an
d lin
ezol
id c
omm
encin
g at
120
0 m
g/da
y (a
dditi
onal
info
rmat
ion
on li
nezo
lid d
osin
g is
inclu
ded
unde
r “Im
plem
enta
tion
cons
ider
atio
ns”).
Clo
se m
icrob
iolo
gic,
cli
nica
l and
adv
erse
eve
nt m
onito
ring
wer
e fe
atur
es o
f the
Nix-
TB s
tudy
.
9 Em
erge
nce
of X
DR-
TB. G
enev
a, S
witz
erla
nd W
orld
Hea
lth O
rgan
izat
ion
2006
(http
s://w
ww.
who
.int/
med
iace
ntre
/new
s/no
tes/
2006
/np2
3/en
, acc
esse
d 28
Feb
ruar
y 20
20).
10
Glo
bal t
uber
culo
sis re
port
201
9 (W
HO
/CD
S/TB
/201
9.15
). G
enev
a, S
witz
erla
nd W
orld
Hea
lth O
rgan
izat
ion;
201
9 (h
ttps:/
/ww
w.w
ho.in
t/tb
/pub
licat
ions
/glo
bal_r
epor
t/en
/, ac
cess
ed 2
9 M
ay 2
020)
.11
Sa
fety
and
effi
cacy
of v
ario
us d
oses
and
trea
tmen
t dur
atio
ns o
f lin
ezol
id p
lus b
edaq
uilin
e an
d pr
etom
anid
in p
artic
ipan
ts w
ith p
ulm
onar
y TB
, XD
R-TB
, Pre
- XD
R-TB
or n
on-r
espo
nsiv
e/In
tole
rant
MD
R-TB
(ZeN
iX)
[web
site]
. Mar
ylan
d, U
nite
d St
ates
of A
mer
ica U
.S. N
atio
nal L
ibra
ry o
f Med
icine
; 201
7 (h
ttps:/
/clin
icaltr
ials.
gov/
ct2/
show
/NCT
0308
6486
, acc
esse
d 20
Mar
ch 2
020)
.
Annex 4: GRADE evidence-to-decision tables 113
The
evid
ence
to in
form
this
PICO
que
stio
n w
as d
erive
d fro
m th
e N
ix-TB
stud
y an
d in
clude
d in
form
atio
n on
108
pat
ient
s. Th
e to
tal s
tudy
pop
ulat
ion
was
109
pat
ient
s; ho
wev
er, 1
pat
ient
w
ithdr
ew in
form
ed c
onse
nt to
par
ticip
ate
in th
e st
udy
and
was
inclu
ded
in sa
fety
ana
lyses
but
not
in a
nalys
es fo
r effe
ctive
ness
. The
se d
ata
wer
e co
mpa
red
with
a su
bset
of d
ata
from
the
IPD,
whi
ch o
vera
ll in
clude
s 13
273
indi
vidua
l pat
ient
reco
rds f
rom
55
diffe
rent
stud
ies o
r cen
tres i
n 38
cou
ntrie
s. Fo
r the
prim
ary
anal
yses
, the
com
para
tor g
roup
inclu
ded
patie
nts f
rom
the
IPD
rece
iving
long
er tr
eatm
ent r
egim
ens (
with
a m
ean
dura
tion
of tr
eatm
ent r
angi
ng b
etw
een
21.0
–25.
5 m
onth
s), w
ho re
ceive
d bo
th b
edaq
uilin
e an
d lin
ezol
id a
s par
t of t
he re
gim
en (n
o pa
tient
s rec
eive
d pr
etom
anid
in th
e IP
D).
This
com
paris
on g
roup
inclu
ded
456
patie
nts w
ho w
ere
treat
ed in
Bel
arus
(Rep
ublic
of),
Fra
nce,
Indi
a, a
nd R
ussia
, and
in c
ount
ries i
n As
ia. T
he
inte
rven
tion
and
com
paris
on g
roup
s wer
e m
atch
ed e
xact
ly fo
r XD
R-TB
stat
us, M
DR-
TB st
atus
, flu
oroq
uino
lone
resis
tanc
e, a
nd H
IV st
atus
, with
pro
pens
ity sc
ore
mat
chin
g fo
r the
var
iabl
es
of a
ge, s
ex, b
asel
ine
cultu
re re
sult,
ext
ent o
f dise
ase
(det
erm
ined
by
base
line
AFB
smea
r or c
hest
X-r
ay fi
ndin
gs o
f cav
itatio
n or
by
bila
tera
l dise
ase
if AF
B sm
ear r
esul
t was
miss
ing)
and
co
untr
y in
com
e le
vel (
Wor
ld B
ank
Atla
s met
hod)
. Tre
atm
ent o
utco
mes
use
d in
thes
e an
alys
es c
ompr
ised
the
inve
stig
ator
-def
ined
out
com
es fo
r the
inte
rven
tion
grou
p (fo
r the
Nix-
TB
stud
y) a
nd tr
eatm
ent o
utco
mes
larg
ely
defin
ed a
ccor
ding
to W
HO
def
initi
ons12
for t
he c
ompa
rato
r gro
up (f
or th
e pa
tient
s inc
lude
d in
the
IPD
). To
allo
w a
n eq
ual o
ppor
tuni
ty fo
r tre
atm
ent
outc
omes
to o
ccur
from
the
star
t of t
reat
men
t whe
n co
mpa
ring
the
two
grou
ps, a
ll ou
tcom
es w
ere
inclu
ded
from
the
star
t of t
reat
men
t to
24 m
onth
s afte
r the
star
t of t
reat
men
t. Th
is m
eant
that
, in
the
inte
rven
tion
grou
p, th
ese
outc
omes
occ
urre
d af
ter c
ompl
etio
n of
trea
tmen
t, an
d fo
r the
com
para
tor g
roup
, the
out
com
es w
ere
end-
of-t
reat
men
t out
com
es (b
ecau
se
patie
nts i
n th
e IP
D re
ceive
d a
long
er re
gim
en a
nd w
ere
not m
onito
red
afte
r tre
atm
ent c
ompl
etio
n). T
hree
oth
er c
ompa
rato
r gro
ups f
rom
the
IPD
inclu
ded
patie
nts r
ecei
ving
long
er
treat
men
t reg
imen
s whi
ch in
clude
d be
daqu
iline,
or a
regi
men
whi
ch in
clude
d lin
ezol
id, o
r a re
gim
en w
ith n
eith
er b
edaq
uilin
e or
line
zolid
inclu
ded.
The
initi
al in
tent
ion
of th
e G
DG
was
to
asse
ss th
e in
terv
entio
n re
gim
en a
gain
st a
ll th
ree
com
paris
on g
roup
s; ho
wev
er, d
urin
g th
eir d
elib
erat
ions
the
pane
l agr
eed
that
the
judg
emen
ts sh
ould
be
base
d on
the
com
paris
on g
roup
w
ho re
ceive
d be
daqu
iline
and
linez
olid
as p
art o
f the
ir re
gim
en, b
ecau
se th
ese
patie
nts m
ost c
lose
ly re
sem
bled
pat
ient
s who
wou
ld re
ceive
cur
rent
ly re
com
men
ded
long
er re
gim
ens
com
pose
d of
med
icine
s fro
m G
roup
s A–C
. How
ever
, a d
irect
com
paris
on o
f BPa
L w
ith a
ll-or
al lo
nger
regi
men
s con
stru
cted
acc
ordi
ng to
the
mos
t rec
ent W
HO
reco
mm
enda
tions
issu
ed in
M
ay 2
019
was
not
pos
sible
, bec
ause
thes
e re
gim
ens m
ight
hav
e be
en in
use
onl
y sin
ce m
id-2
019,
and
trea
tmen
t out
com
es fo
r the
se p
atie
nts a
re n
ot y
et a
vaila
ble.
Addi
tiona
l dat
a re
view
ed b
y th
e G
DG
rele
vant
to th
is PI
CO q
uest
ion
wer
e a
cost
–effe
ctiv
enes
s an
alys
is, a
stu
dy o
n th
e ac
cept
abilit
y an
d lik
elih
ood
of im
plem
enta
tion
of th
e BP
aL re
gim
en,
mod
elle
d ph
arm
acok
inet
ic da
ta b
ased
on
the
deve
lopm
ent o
f a p
harm
acok
inet
ic–to
xicod
ynam
ic m
odel
, and
a s
umm
ary
revi
ew o
f pre
clini
cal a
nd e
arly
clin
ical d
ata
on p
reto
man
id. T
he
cost
–effe
ctiv
enes
s an
alys
is, a
ccep
tabi
lity
stud
y, an
d m
odel
led
phar
mac
okin
etic
stud
ies
wer
e co
nduc
ted
as p
art o
f the
Nix-
TB s
tudy
and
wer
e sp
onso
red
by th
e TB
Allia
nce.
The
GD
G c
onsid
ered
the
desir
able
effe
ct o
f tre
atm
ent s
ucce
ss, w
hich
was
hig
her i
n th
e in
terv
entio
n gr
oup
whe
n co
mpa
red
with
the
com
para
tor,
for a
ll fo
ur tr
eatm
ent o
utco
mes
that
w
ere
asse
ssed
. Ove
rall,
whe
n co
mpa
ring
treat
men
t suc
cess
ver
sus
failu
re/r
ecur
renc
e, th
e tre
atm
ent s
ucce
ss ra
te in
the
Nix-
TB s
tudy
was
97.
0% c
ompa
red
with
91.
7% in
the
com
para
tor
grou
p (re
sulti
ng in
6 m
ore
outc
omes
of t
reat
men
t suc
cess
per
100
pat
ient
s). F
or th
e co
mpa
rison
of t
reat
men
t suc
cess
ver
sus
deat
h, tr
eatm
ent s
ucce
ss w
as 9
3.2%
in th
e N
ix-TB
stu
dy
com
pare
d w
ith 9
1.9%
in th
e co
mpa
rato
r gro
up (r
esul
ting
in 1
mor
e ou
tcom
e of
trea
tmen
t suc
cess
per
100
pat
ient
s). F
or th
e co
mpa
rison
s of
trea
tmen
t suc
cess
ver
sus
failu
re/r
ecur
renc
e/de
ath
and
treat
men
t suc
cess
ver
sus
all u
nfav
oura
ble
outc
omes
com
bine
d (i.
e. fa
ilure
/rel
apse
/dea
th a
nd lo
ss to
follo
w-u
p), t
he p
ropo
rtio
ns o
f pat
ient
s w
ith tr
eatm
ent s
ucce
ss in
the
inte
rven
tion
and
com
para
tor g
roup
s w
ere
90.5
% v
ersu
s 84
.8%
(6 m
ore
outc
omes
of t
reat
men
t suc
cess
per
100
pat
ient
s) a
nd 8
8.9%
ver
sus
82.2
% (2
mor
e ou
tcom
es o
f tre
atm
ent
succ
ess
per 1
00 p
atie
nts)
, res
pect
ivel
y. O
n th
e ba
sis o
f the
se fi
gure
s, th
e pr
imar
y an
alys
is yi
elde
d ad
just
ed o
dds
ratio
s (a
ORs
) of 3
.3 fo
r tre
atm
ent s
ucce
ss (v
ersu
s th
e co
mbi
ned
outc
ome
of fa
ilure
and
recu
rrenc
e; 9
5% C
I: 0.
8–13
.7),
1.0
for s
ucce
ss v
ersu
s de
ath
(95%
CI:
0.1–
8.2)
, 1.8
for s
ucce
ss v
ersu
s fa
ilure
/rel
apse
/dea
th (9
5% C
I: 0.
7–4.
4), a
nd 1
.2 fo
r suc
cess
ver
sus
all u
nfav
oura
ble
outc
omes
(95%
CI:
0.5–
3.1)
, with
a m
ean
dura
tion
of fo
llow
-up
of 2
4 m
onth
s (ra
nge,
21–
25.5
mon
ths)
, whe
n BP
aL w
as c
ompa
red
with
long
er re
gim
ens
cont
aini
ng
beda
quilin
e an
d lin
ezol
id. T
he G
DG
con
sider
ed ra
tes
of lo
ss to
follo
w-u
p to
be
a de
sirab
le e
ffect
; the
pro
port
ion
of p
atie
nts
who
wer
e lo
st to
follo
w-u
p w
as lo
wer
in th
e in
terv
entio
n (B
PaL)
gro
up (1
.8%
) tha
n in
the
com
paris
on g
roup
(3.1
%);
how
ever
, thi
s di
ffere
nce
was
not
con
sider
ed b
y th
e pa
nel t
o be
larg
e. T
he p
anel
also
con
sider
ed a
sho
rten
ed d
urat
ion
of
treat
men
t and
less
dru
g ex
posu
re to
be
desir
able
effe
cts
of th
e in
terv
entio
n, a
nd n
oted
that
thes
e w
ere
both
com
pone
nts
of th
e ov
eral
l bur
den
of a
giv
en M
DR/
RR-T
B tre
atm
ent
regi
men
, whi
ch m
ay n
ot b
e w
holly
refle
cted
in ra
tes
of lo
ss to
follo
w-u
p al
one.
Spe
cifie
d su
bgro
up a
naly
ses
wer
e un
able
to b
e un
dert
aken
bec
ause
of l
imita
tions
in th
e sa
mpl
e siz
e.
12
Lase
rson
KF,
Thor
pe L
E, L
eim
ane
V, W
eyer
K, M
itnick
CD,
Rie
kstin
a V
et a
l. Sp
eakin
g th
e sa
me
lang
uage
: tre
atm
ent o
utco
me
defin
ition
s for
mul
tidru
g-re
sista
nt tu
berc
ulos
is. In
t J Tu
berc
Lun
g D
is. 2
005;
9(6)
:640
–5.
and
Def
initi
ons
and
repo
rtin
g fra
mew
ork
for t
uber
culo
sis –
201
3 re
visio
n (u
pdat
ed D
ecem
ber 2
014)
[WH
O/H
TM/T
B/20
13.2
]. G
enev
a, S
witz
erla
nd: W
orld
Hea
lth O
rgan
izat
ion;
201
3 (h
ttps:/
/app
s.who
.int/
iris/
bits
tream
/han
dle/
1066
5/79
199/
9789
2415
0534
5_en
g.pd
f?se
quen
ce=1
, acc
esse
d 20
Mar
ch 2
020)
.
WHO consolidated guidelines on tuberculosis: Online annexes114
The
BPaL
regi
men
was
also
ass
ocia
ted
with
a h
igh
rate
of a
dver
se e
vent
s, co
nsid
ered
to b
e re
late
d to
the
stud
y dr
ugs,
whi
ch w
as a
con
cern
for G
DG
mem
bers
. Of t
he 1
09 p
atie
nts
in
the
Nix-
TB s
tudy
, 28
(25.
7%) e
xper
ienc
ed a
t lea
st o
ne s
erio
us a
dver
se e
vent
. Thi
s in
clude
d 1
deat
h (0
.9%
) rel
ated
to a
cute
hae
mor
rhag
ic pa
ncre
atiti
s, 27
(25%
) oth
er s
erio
us a
dver
se
even
ts in
cludi
ng h
ospi
taliz
atio
ns a
nd li
fe-t
hrea
teni
ng e
vent
s, an
d 2
(1.8
%) a
dver
se e
vent
s th
at re
sulte
d in
per
siste
nt o
r sig
nific
ant d
isabi
lity
or in
capa
city.
Fifty
-thr
ee p
artic
ipan
ts (4
9%)
expe
rienc
ed a
t lea
st o
ne G
rade
3–4
adv
erse
eve
nt c
onsid
ered
to b
e re
late
d to
the
stud
y dr
ugs,
com
prisi
ng 2
5 w
ith p
erip
hera
l neu
ropa
thy
(reso
lved
in 1
1), 1
6 w
ith in
crea
sed
hepa
tic
trans
amin
ases
(res
olve
d in
13)
, 9 w
ith h
aem
atol
ogica
l adv
erse
eve
nts
(reso
lved
in a
ll), 8
who
had
incr
ease
d pa
ncre
atic
enzy
mes
(res
olve
d in
7),
and
2 w
ith o
ptic
neur
itis
(reso
lved
in
bot
h). T
his
led
to d
rug
disc
ontin
uatio
n of
all
thre
e dr
ugs
for 1
par
ticip
ant,
and
linez
olid
(ini
tial d
ose:
120
0 m
g/da
y) w
as d
iscon
tinue
d in
ano
ther
35
part
icipa
nts
(32%
). O
nly
18
part
icipa
nts
(17%
) com
plet
ed a
full
cour
se o
f lin
ezol
id a
t 120
0 m
g/da
y. Th
e G
DG
not
ed th
at it
is d
ifficu
lt to
com
pare
thes
e ad
vers
e ev
ent r
ates
with
oth
er s
tudi
es b
ecau
se o
f maj
or a
nd
impo
rtan
t diff
eren
ces
in a
scer
tain
men
t, as
sess
men
t, an
d re
port
ing
of a
dver
se e
vent
s. H
owev
er, i
n th
e IP
D s
tudi
es (w
here
90%
of p
artic
ipan
ts re
ceiv
ed a
line
zolid
dos
e of
≤60
0 m
g/da
y),
the
pool
ed ra
te o
f per
man
ent d
iscon
tinua
tion
of li
nezo
lid w
as 1
7.9%
, and
in th
e En
dTB
obse
rvat
iona
l stu
dy (w
here
all
patie
nts
rece
ived
≤60
0 m
g/da
y of
line
zolid
), th
e ra
te o
f lin
ezol
id
disc
ontin
uatio
n w
as 1
3.1%
. In
both
of t
hese
stu
dies
, >80
% o
f par
ticip
ants
rece
ived
a s
tart
ing
dose
of l
inez
olid
of 6
00 m
g/da
y. In
pre
limin
ary
anal
yses
of t
he E
ndTB
obs
erva
tiona
l stu
dy,
9 of
109
4 pa
rtici
pant
s (0
.8%
) die
d of
a p
ossib
ly o
r pro
babl
y dr
ug-r
elat
ed a
dver
se e
vent
, inc
ludi
ng 2
par
ticip
ants
with
sud
den
card
iac
deat
h; th
ese
patie
nts
wer
e re
ceiv
ing
beda
quilin
e,
clofa
zim
ine,
cap
reom
ycin
, and
p-a
min
osal
icylic
acid
(PAS
) and
had
hyp
okal
aem
ia.
Info
rmat
ion
pres
ente
d fro
m th
e in
depe
nden
t rev
iew
of t
he p
recli
nica
l dat
a an
d ea
rly-p
hase
clin
ical d
ata
high
light
ed th
at p
reto
man
id p
osse
sses
act
ivity
aga
inst
repl
icatin
g an
d no
nrep
licat
ing
bacil
li th
at is
bot
h co
ncen
tratio
n an
d do
se d
epen
dent
. A c
ompr
ehen
sive
desc
riptio
n of
the
safe
ty s
igna
ls w
as re
port
ed, m
any
of th
ese
signa
ls w
ere
obse
rved
at e
xpos
ures
th
at a
re h
ighe
r tha
n w
ould
be
used
in h
uman
s; ho
wev
er, s
afet
y sig
nals
of n
ote
inclu
de li
ver t
oxici
ties
(hyp
ertro
phy
of h
epat
ocyt
es, t
rans
amin
ase
elev
atio
n, a
nd in
crea
sed
liver
wei
ght,
obse
rved
at h
ighe
r dos
es in
rode
nts
and
low
er d
oses
in m
onke
ys) a
nd re
prod
uctiv
e to
xiciti
es in
mal
es o
bser
ved
in a
nim
al (m
urin
e an
d sim
ian)
mod
els,
whi
ch a
ppea
r to
be b
oth
time
and
dose
dep
ende
nt. T
hese
obs
erva
tions
in m
onke
ys m
ight
hav
e be
en a
ttrib
uted
to th
e ge
nera
l dec
line
of h
ealth
in th
ese
anim
als;
how
ever
, the
sam
e sig
nals
wer
e ob
serv
ed in
rode
nt
mod
els
with
som
e ev
iden
ce th
at th
ese
effe
cts
mig
ht b
e irr
ever
sible
. In
mou
se m
odel
s, th
ese
effe
cts
wer
e ob
serv
ed a
t exp
osur
es th
at w
ould
be
used
in h
uman
s. Re
prod
uctiv
e to
xiciti
es
wer
e al
so o
bser
ved
in fe
mal
es.
Addi
tiona
l inf
orm
atio
n on
adv
erse
eve
nts
pres
ente
d to
the
GD
G in
clude
d th
e re
sults
of a
pha
rmac
okin
etic–
toxic
odyn
amic
mod
el (S
avic
R, u
npub
lishe
d da
ta, U
nive
rsity
of C
alifo
rnia
Sa
n Fr
ancis
co, N
ovem
ber 2
019)
. On
the
basis
of t
hese
dat
a, it
was
con
clude
d th
at th
e ph
arm
acok
inet
ics re
late
d to
line
zolid
are
non
linea
r in
patie
nts
with
XD
R-TB
and
that
indi
vidu
al
linez
olid
con
cent
ratio
n tim
es a
re th
e be
st p
redi
ctor
of t
oxici
ty. H
ighe
r tox
icity
rate
s w
ere
obse
rved
at h
ighe
r tot
al d
aily
dos
es, w
ith c
ompa
rabl
e to
xicity
rate
s fo
r BID
and
QD
dos
ing
sche
dule
s. Th
e re
sults
of t
he m
odel
led
data
hig
hlig
hted
that
ana
emia
can
be
man
aged
by
close
ly m
onito
ring
chan
ges
in h
aem
oglo
bin
over
the
first
4 w
eeks
of t
reat
men
t (in
par
ticul
ar,
chan
ges
in h
aem
oglo
bin
that
repr
esen
t a >
10%
dec
reas
e fro
m b
asel
ine
shou
ld tr
igge
r a re
duct
ion
in th
e do
se o
f lin
ezol
id; h
aem
oglo
bin
leve
ls re
cove
r wel
l afte
r dos
e re
duct
ions
). Th
rom
bocy
tope
nia
was
pot
entia
lly n
ot a
maj
or c
once
rn. T
he s
tudy
inve
stig
ator
s re
com
men
ded
that
per
iphe
ral n
euro
path
y be
clo
sely
mon
itore
d, a
nd n
oted
that
the
mod
elle
d da
ta
show
ed th
at, w
hen
it di
d oc
cur,
it w
as re
vers
ible
for m
ost p
atie
nts,
with
in 3
mon
ths.
Annex 4: GRADE evidence-to-decision tables 115
Subg
roup
con
side
ratio
nsCh
ildre
n. C
hild
ren
(age
d 0–
13 y
ears
) wer
e ex
clude
d fro
m th
e N
ix-TB
stu
dy; t
here
fore
, no
anal
ysis
spec
ific
to th
is su
bgro
up o
f pat
ient
s co
uld
be p
erfo
rmed
. It i
s re
com
men
ded
that
ch
ildre
n w
ith p
ulm
onar
y M
DR/
RR-T
B w
ith a
dditi
onal
resis
tanc
e to
fluo
roqu
inol
ones
be
give
n th
e sa
me
cons
ider
atio
n fo
r lon
ger t
reat
men
t reg
imen
s as
adu
lts, t
o in
clude
com
pone
nts
with
a s
afet
y pr
ofile
that
is b
ette
r est
ablis
hed.
Bed
aqui
line
is cu
rrent
ly re
com
men
ded
only
for c
hild
ren
aged
6 y
ears
or o
lder
. It i
s ac
know
ledg
ed th
at a
dditi
onal
dat
a on
the
use
of B
PaL
in
child
ren,
whe
n el
igib
le, w
ould
be
usef
ul; t
his
may
be
a fe
atur
e of
car
eful
ly p
lann
ed a
nd m
onito
red
futu
re re
sear
ch.
PLH
IV: P
LHIV
repr
esen
ted
half
of th
ose
enro
lled
in th
e N
ix-TB
stu
dy; h
owev
er, i
t was
impo
ssib
le to
per
form
any
adj
uste
d st
ratif
ied
anal
yses
for P
LHIV
bec
ause
of t
he s
ampl
e siz
e.
PLH
IV w
ere
elig
ible
to e
nrol
in th
e N
ix-TB
stu
dy if
they
had
a C
D4
coun
t of >
50 c
ells/
µL a
nd if
they
wer
e us
ing
perm
itted
ant
iretro
vira
l med
icatio
ns.13
It is
impo
rtan
t to
note
dru
g–dr
ug
inte
ract
ions
whe
n ad
min
ister
ing
TB a
nd H
IV m
edica
tions
in c
ombi
natio
n, in
cludi
ng th
e do
cum
ente
d in
tera
ctio
ns b
etw
een
beda
quilin
e an
d ef
avire
nz.14
Efa
vire
nz a
lso re
duce
s pr
etom
anid
ex
posu
res
signi
fican
tly; t
here
fore
, an
alte
rnat
ive
antir
etro
vira
l age
nt s
houl
d be
con
sider
ed if
pre
tom
anid
or t
he B
PaL
regi
men
is to
be
used
.15 R
egim
ens
inclu
ding
zid
ovud
ine
shou
ld b
e us
ed w
ith s
pecia
l cau
tion
beca
use
zido
vudi
ne a
nd li
nezo
lid m
ay b
oth
caus
e pe
riphe
ral n
erve
toxic
ity a
nd a
re k
now
n to
hav
e m
yelo
supp
ress
ion
cros
s-to
xicity
. Pr
egna
nt a
nd la
ctat
ing
wom
en w
ere
exclu
ded
from
the
Nix-
TB s
tudy
; the
refo
re, n
o an
alys
is sp
ecifi
c to
this
subg
roup
of p
atie
nts
coul
d be
per
form
ed. F
or s
uch
patie
nts,
it is
reco
mm
ende
d th
at a
long
er re
gim
en b
e in
divi
dual
ized
to in
clude
com
pone
nts
with
a s
afet
y pr
ofile
that
is b
ette
r est
ablis
hed.
Whe
n th
is is
the
case
, the
out
com
es o
f tre
atm
ent a
nd
preg
nanc
y (in
cludi
ng in
fant
cha
ract
erist
ics),
and
post
part
um s
urve
illanc
e fo
r con
geni
tal a
nom
alie
s, sh
ould
be
docu
men
ted
to h
elp
info
rm fu
ture
reco
mm
enda
tions
for M
DR-
TB tr
eatm
ent
durin
g pr
egna
ncy.
The
use
of b
edaq
uilin
e in
pre
gnan
cy h
as b
een
show
n to
be
asso
ciate
d w
ith in
fant
s bo
rn w
ith a
low
er m
ean
birt
h w
eigh
t, w
hen
com
pare
d w
ith in
fant
s w
hose
mot
hers
w
ho d
id n
ot ta
ke b
edaq
uilin
e; h
owev
er, t
his
did
not a
ppea
r to
be a
clin
ically
sig
nific
ant f
indi
ng w
hen
infa
nts
wer
e fo
llow
ed u
p ov
er ti
me.
Bre
astfe
edin
g is
not r
ecom
men
ded
for w
omen
ta
king
BPaL
.16
Extr
apul
mon
ary
TB: P
artic
ipan
ts w
ith e
xtra
pulm
onar
y TB
wer
e ex
clude
d fro
m th
e N
ix-TB
stu
dy; t
here
fore
, no
anal
ysis
spec
ific
to th
is su
bgro
up o
f pat
ient
s co
uld
be p
erfo
rmed
. The
W
HO
reco
mm
enda
tions
for l
onge
r MD
R-TB
regi
men
s ap
ply
to p
atie
nts
with
ext
rapu
lmon
ary
dise
ase,
inclu
ding
thos
e w
ith T
B m
enin
gitis
. The
re a
re fe
w d
ata
on th
e ce
ntra
l ner
vous
sy
stem
pen
etra
tion
of b
edaq
uilin
e or
pre
tom
anid
.Pa
tient
s w
ith v
ery
limite
d tr
eatm
ent o
ptio
ns: I
n so
me
inst
ance
s, pa
tient
s w
ill ha
ve e
xten
sive
drug
resis
tanc
e pr
ofile
s th
at m
ay m
ake
it di
fficu
lt (o
r im
poss
ible
) to
cons
truct
a re
gim
en
base
d on
exis
ting
WH
O re
com
men
datio
ns. I
n su
ch s
ituat
ions
, the
pat
ient
’s lif
e m
ay b
e en
dang
ered
. The
refo
re, f
or in
divi
dual
pat
ient
s fo
r who
m th
e de
sign
of a
n ef
fect
ive
regi
men
ba
sed
on e
xistin
g re
com
men
datio
ns is
not
pos
sible
,17 th
e BP
aL re
gim
en m
ay b
e co
nsid
ered
a la
st re
sort
und
er p
reva
iling
ethi
cal s
tand
ards
. For
suc
h pa
tient
s, th
e us
e of
BPa
L sh
ould
be
acco
mpa
nied
by
indi
vidu
al p
atie
nt in
form
ed c
onse
nt, a
dequ
ate
coun
sellin
g on
the
pote
ntia
l ben
efits
and
har
ms,
and
activ
e m
onito
ring
and
man
agem
ent o
f adv
erse
eve
nts.
Patie
nts
shou
ld a
lso b
e ad
vise
d th
at re
prod
uctiv
e to
xiciti
es h
ave
been
obs
erve
d in
ani
mal
stu
dies
, and
that
the
pote
ntia
l effe
cts
on h
uman
mal
e fe
rtilit
y ha
ve n
ot b
een
adeq
uate
ly e
valu
ated
at
this
time.
13
The
perm
itted
ant
iretro
viral
trea
tmen
ts w
ere
as fo
llow
s: (1
) nev
irapi
ne in
com
bina
tion
with
any
NRT
Is; (2
) lop
inav
ir/rit
onav
ir in
com
bina
tion
with
any
NRT
Is; (3
) ten
ofov
ir/la
mivu
dine
/aba
cavir
(if n
orm
al re
nal f
unct
ion)
; (4
) trip
le N
RTI t
hera
py c
onsis
ting
of z
idov
udin
e, la
miv
udin
e, a
nd a
baca
vir (
notin
g th
e in
crea
sed
risk
of p
erip
hera
l ner
ve to
xicity
with
zid
ovud
ine
and
linez
olid
); an
d (5
) ral
tegr
avir
in c
ombi
natio
n w
ith N
RTIs.
14
HIV
dru
g in
tera
ctio
ns [w
ebsit
e]. L
iver
pool
, Uni
ted
King
dom
Uni
vers
ity o
f Liv
erpo
ol 2
020
(http
s://w
ww.
hiv-
drug
inte
ract
ions
.org
/che
cker
, acc
esse
d 11
Mar
ch 2
020)
.15
D
rug
appr
oval
pac
kage
: Pre
tom
anid
[web
site]
. Mar
yland
, Uni
ted
Stat
es o
f Am
erica
: U.S
. Foo
d an
d D
rug
Adm
inist
ratio
n; 2
019
(http
s://w
ww.
acce
ssda
ta.fd
a.go
v/dr
ugsa
tfda_
docs
/nda
/201
9/21
2862
Orig
1s00
0TO
C.cf
m, a
cces
sed
28 F
ebru
ary
2020
).16
D
rug
appr
oval
pac
kage
: Pre
tom
anid
[web
site]
. Mar
yland
, Uni
ted
Stat
es o
f Am
erica
: U.S
. Foo
d an
d D
rug
Adm
inist
ratio
n; 2
019
(http
s://w
ww.
acce
ssda
ta.fd
a.go
v/dr
ugsa
tfda_
docs
/nda
/201
9/21
2862
Orig
1s00
0TO
C.cf
m, a
cces
sed
28 F
ebru
ary
2020
).17
Us
ually
this
grou
p of
pat
ient
s w
ould
inclu
de th
ose
with
an
exte
nsiv
e dr
ug re
sista
nce
prof
ile w
ho h
ave
very
lim
ited
treat
men
t opt
ions
as
part
of a
long
er tr
eatm
ent r
egim
en.
WHO consolidated guidelines on tuberculosis: Online annexes116
Impl
emen
tatio
n co
nsid
erat
ions
Giv
en th
e pa
ucity
of e
vide
nce
on th
e us
e of
BPa
L, a
nd th
e co
ncer
ns m
entio
ned
abov
e, m
embe
rs o
f the
GD
G s
ugge
sted
that
its
use
shou
ld b
e co
nditi
onal
upo
n im
plem
enta
tion
in
the
cont
ext o
f ope
ratio
nal r
esea
rch
only.
The
GD
G e
mph
asiz
ed th
at, d
espi
te th
e pr
omisi
ng tr
eatm
ent s
ucce
ss ra
tes
obse
rved
in th
e N
ix-TB
stu
dy, t
he re
gim
en m
ay n
ot b
e co
nsid
ered
fo
r pro
gram
mat
ic us
e w
orld
wid
e un
til a
dditi
onal
evi
denc
e on
effi
cacy
and
saf
ety
has
been
gen
erat
ed. T
he G
DG
mem
bers
em
phas
ized
the
need
for t
his
rese
arch
to ta
ke th
e fo
rm o
f ra
ndom
ized
, con
trolle
d tri
als
as w
ell a
s ob
serv
atio
nal s
tudi
es. G
iven
the
cond
ition
ality
of t
his
reco
mm
enda
tion
in th
e co
ntex
t of a
dditi
onal
rese
arch
, cer
tain
sta
ndar
ds a
nd p
rincip
les
are
prer
equi
sites
for t
he im
plem
enta
tion
of B
PaL.
Fur
ther
, the
GD
G e
mph
asiz
ed th
at in
any
ope
ratio
nal r
esea
rch
stud
y in
volv
ing
BPaL
, the
prin
ciple
s of
goo
d cli
nica
l pra
ctice
sho
uld
appl
y.O
vera
ll, to
repr
oduc
e th
e tre
atm
ent s
ucce
ss ra
tes
obse
rved
in th
e N
ix-TB
stu
dy, a
ll ef
fort
s ne
ed to
be
mad
e to
car
eful
ly s
elec
t elig
ible
pat
ient
s an
d th
en, o
nce
they
are
enr
olle
d, to
pr
ovid
e ef
fect
ive
patie
nt s
uppo
rt to
ena
ble
adhe
renc
e to
trea
tmen
t, as
wel
l as
close
mon
itorin
g fo
r adv
erse
eve
nts,
resp
onse
to tr
eatm
ent,
and
emer
ging
dru
g re
sista
nce.
All
effo
rts
shou
ld b
e m
ade
to d
o th
e fo
llow
ing:
• En
sure
pro
per p
atie
nt in
clusio
n (u
se is
not
adv
ised
in p
regn
ant a
nd la
ctat
ing
wom
en a
nd in
chi
ldre
n, n
otin
g th
e ot
her i
nclu
sion
and
exclu
sion
crite
ria o
f the
Nix-
TB s
tudy
). Al
thou
gh
DST
is a
n im
port
ant c
ompo
nent
of p
atie
nt s
elec
tion
for t
he B
PaL
regi
men
(des
crib
ed b
elow
), an
othe
r key
impl
emen
tatio
n co
nsid
erat
ion
is pr
ior T
B tre
atm
ent h
istor
y. Pa
tient
s ar
e el
igib
le fo
r the
BPa
L re
gim
en o
nly
if th
ey h
ave
not r
ecei
ved
beda
quilin
e or
line
zolid
for 2
wee
ks o
r mor
e pr
evio
usly,
and
this
was
an
elig
ibilit
y cr
iterio
n of
the
Nix-
TB s
tudy
. Giv
en
that
the
curre
nt W
HO
reco
mm
enda
tion
for l
onge
r tre
atm
ent r
egim
ens
for M
DR/
RR-T
B in
clude
s be
daqu
iline
and
linez
olid
as
prio
rity
med
icine
s in
Gro
up A
, som
e pa
tient
s w
ho
have
pre
viou
sly s
tart
ed tr
eatm
ent w
ith a
long
er M
DR/
RR-T
B re
gim
en m
ay in
fact
be
inel
igib
le fo
r BPa
L sh
ould
they
late
r dev
elop
fluo
roqu
inol
one
resis
tanc
e. T
his
reaf
firm
s pr
evio
us
stat
emen
ts b
y W
HO
on
the
need
to c
aref
ully
sel
ect e
ligib
le p
atie
nts
for l
onge
r or s
hort
er M
DR/
RR-T
B tre
atm
ent r
egim
ens,
and
then
, onc
e pa
tient
s ar
e re
ceiv
ing
a re
gim
en, t
o en
sure
pa
tient
sup
port
and
clo
se m
onito
ring
and
follo
w-u
p, in
cludi
ng m
onito
ring
for t
reat
men
t fai
lure
and
rela
pse,
and
em
ergi
ng d
rug
resis
tanc
e, w
ith D
ST p
erfo
rmed
whe
n in
dica
ted.
If
resis
tanc
e is
susp
ecte
d du
ring
treat
men
t and
DST
is n
ot a
vaila
ble,
the
stra
ins
shou
ld b
e co
nser
ved
and
refe
rred
to a
WH
O s
upra
natio
nal T
B re
fere
nce
labo
rato
ry fo
r fur
ther
test
ing.
Ea
ch o
pera
tiona
l res
earc
h pr
otoc
ol o
n th
e us
e of
BPa
L in
a g
iven
set
ting
will
need
to in
clude
det
aile
d in
clusio
n an
d ex
clusio
n cr
iteria
.•
Obt
ain
signe
d pa
tient
info
rmed
con
sent
afte
r det
aile
d ex
plan
atio
ns o
n th
e no
vel n
atur
e of
the
regi
men
and
pre
tom
anid
, inc
ludi
ng th
e ris
ks a
nd b
enef
its o
f the
regi
men
. The
GD
G
mem
bers
thou
ght t
hat a
lthou
gh in
divi
dual
pat
ient
info
rmed
con
sent
is n
eces
sary
, it s
houl
d no
t be
over
ly b
urde
nsom
e fo
r pat
ient
s; th
eref
ore,
con
sent
form
s sh
ould
be
adap
ted,
co
ntex
tual
ized
, stre
amlin
ed a
nd p
rovi
ded
in th
e lo
cal l
angu
age(
s) s
o th
at th
ey a
re e
asy
for p
atie
nts
to u
nder
stan
d. N
ever
thel
ess,
the
GD
G a
lso n
oted
that
pat
ient
s sh
ould
be
fully
in
form
ed a
bout
the
regi
men
, giv
en th
at it
also
inclu
des
a ne
w c
ompo
und,
pre
tom
anid
. As
part
of t
he in
form
ed c
onse
nt p
roce
ss, p
atie
nts
shou
ld b
e of
fere
d su
fficie
nt in
form
atio
n on
po
tent
ial a
dver
se e
vent
s, in
cludi
ng lo
w b
lood
cel
l cou
nts
(e.g
. ana
emia
, thr
ombo
cyto
peni
a, n
eutro
peni
a), l
iver
toxic
ities
, and
per
iphe
ral a
nd o
ptic
neur
opat
hy. P
atie
nts
shou
ld a
lso
be a
dvise
d th
at re
prod
uctiv
e to
xiciti
es h
ave
been
obs
erve
d in
ani
mal
stu
dies
and
that
the
pote
ntia
l effe
cts
on h
uman
mal
e fe
rtilit
y ha
ve n
ot b
een
adeq
uate
ly e
valu
ated
at t
his
time.
Pa
tient
s sh
ould
also
be
info
rmed
that
pre
tom
anid
is e
xcre
ted
in b
reas
t milk
, and
its
safe
ty in
infa
nts
and
child
ren
has
not b
een
adeq
uate
ly e
valu
ated
.18 A
med
icatio
n gu
ide
is av
aila
ble
as p
art o
f the
pre
tom
anid
pro
duct
labe
l tha
t may
be
used
whe
n in
form
ing
patie
nts
abou
t the
BPa
L re
gim
en a
s pa
rt o
f a re
sear
ch s
tudy
.•
Trea
tmen
t mus
t be
adm
inist
ered
und
er c
lose
ly m
onito
red
cond
ition
s, to
ena
ble
optim
al d
rug
effe
ctiv
enes
s an
d sa
fety
, and
to m
onito
r for
the
acqu
isitio
n of
em
ergi
ng d
rug
resis
tanc
e, s
houl
d it
arise
. Giv
en th
at th
e re
gim
en is
sho
rter
, tha
t it i
nclu
des
a ne
w c
ompo
und
(pre
tom
anid
), an
d th
at it
s im
plem
enta
tion
is in
the
cont
ext o
f res
earc
h, it
may
be
espe
cially
impo
rtan
t tha
t clin
ical p
rogr
ess
is m
onito
red
afte
r com
plet
ion
of tr
eatm
ent,
to e
nsur
e re
laps
e fre
e cu
re. O
ther
des
ign
feat
ures
of t
he N
ix-TB
stu
dy h
ave
impl
icatio
ns fo
r its
im
plem
enta
tion
unde
r ope
ratio
nal r
esea
rch
cond
ition
s. In
the
Nix-
TB s
tudy
, all
med
icatio
ns w
ere
adm
inist
ered
with
food
thro
ugho
ut, a
nd s
tudy
med
icatio
ns w
ere
supe
rvise
d ac
cord
ing
to lo
cal s
ite p
ract
ices,
as a
form
of p
atie
nt s
uppo
rt. P
reve
ntin
g tre
atm
ent i
nter
rupt
ion
is im
port
ant f
or in
crea
sing
the
likel
ihoo
d of
trea
tmen
t suc
cess
. Mea
sure
s to
sup
port
pat
ient
ad
here
nce,
eith
er b
y fa
cilita
ting
patie
nt v
isits
to h
ealth
car
e fa
ciliti
es o
r hom
e vi
sits
by h
ealth
car
e st
aff,
or b
y us
ing
digi
tal t
echn
olog
ies
for d
aily
com
mun
icatio
n, m
ay b
e im
port
ant f
or
rete
ntio
n of
pat
ient
s in
trea
tmen
t, ev
en th
ough
the
regi
men
is c
ompa
rativ
ely
shor
t.19 W
HO
reco
mm
enda
tions
on
the
care
and
sup
port
of p
atie
nts
with
MD
R/RR
-TB
are
prov
ided
in th
e W
HO
con
solid
ated
gui
delin
es o
n dr
ug-r
esist
ant T
B tre
atm
ent.20
• Ac
tive
phar
mac
ovig
ilanc
e an
d pr
oper
man
agem
ent o
f adv
erse
dru
g re
actio
ns a
nd p
reve
ntio
n of
com
plica
tions
from
dru
g–dr
ug in
tera
ctio
ns. T
he n
atio
nal T
B pr
ogra
mm
e sh
ould
act
ively
mon
itor d
rug
safe
ty to
ens
ure
prop
er p
atie
nt c
are,
to re
port
any
adv
erse
dru
g re
actio
ns to
the
resp
onsib
le d
rug
safe
ty a
utho
rity
in th
e co
untr
y, an
d to
info
rm n
atio
nal a
nd g
loba
l pol
icy.
18
Dru
g ap
prov
al p
acka
ge: P
reto
man
id [w
ebsit
e]. M
aryla
nd, U
nite
d St
ates
of A
mer
ica: U
.S. F
ood
and
Dru
g Ad
min
istra
tion;
201
9 (h
ttps:/
/ww
w.ac
cess
data
.fda.
gov/
drug
satfd
a_do
cs/n
da/2
019/
2128
62O
rig1s
000T
OC.
cfm
, acc
esse
d 28
Feb
ruar
y 20
20).
19
Gui
delin
es fo
r tre
atm
ent o
f dru
g-su
scep
tible
tube
rcul
osis
and
patie
nt c
are,
201
7 up
date
(WH
O/H
TM/T
B/20
17.0
5). G
enev
a, S
witz
erla
nd: W
orld
Hea
lth O
rgan
izat
ion;
201
7 (h
ttps:/
/app
s.who
.int/
iris/
bits
tream
/han
dle/
1066
5/25
5052
/978
9241
5500
00-e
ng.p
df?s
eque
nce=
1, a
cces
sed
20 M
arch
202
0).
20
WH
O c
onso
lidat
ed g
uide
lines
on
drug
resis
tant
tube
rcul
osis
treat
men
t. G
enev
a, S
witz
erla
nd: W
orld
Hea
lth O
rgan
izat
ion;
201
9 (h
ttps:/
/app
s.who
.int/
iris/
bits
tream
/han
dle/
1066
5/31
1389
/978
9241
5505
29-e
ng.
pdf?
ua=1
, acc
esse
d 20
Mar
ch 2
020)
.
Annex 4: GRADE evidence-to-decision tables 117
The
impl
emen
tatio
n of
the
BPaL
regi
men
in th
e co
ntex
t of o
pera
tiona
l res
earc
h im
plie
s th
at:
• a
stud
y pr
otoc
ol h
as b
een
deve
lope
d by
app
ropr
iate
ly s
kille
d an
d ex
perie
nced
rese
arch
ers;
• th
is re
sear
ch p
roto
col i
s su
bmitt
ed to
a n
atio
nal e
thics
boa
rd o
r oth
er e
thica
l app
rova
l com
mitt
ees;
• th
ere
are
pre-
spec
ified
inclu
sion
and
exclu
sion
crite
ria in
pla
ce (n
otin
g th
e cr
iteria
use
d fo
r the
Nix-
TB s
tudy
);21
• th
ere
is an
app
ropr
iate
sch
edul
e of
saf
ety
mon
itorin
g an
d re
port
ing
in p
lace
, inc
ludi
ng a
ctiv
e dr
ug s
afet
y m
onito
ring
(aD
SM) –
usu
ally
ove
rsee
n by
a d
ata
safe
ty m
onito
ring
boar
d or
sim
ilar i
ndep
ende
nt re
sear
ch g
over
nanc
e co
mm
ittee
);•
ther
e is
a pr
edef
ined
sch
edul
e of
clin
ical a
nd m
icrob
iolo
gica
l mon
itorin
g in
pla
ce, p
refe
rabl
y in
cludi
ng fo
llow
-up
afte
r com
plet
ion
of tr
eatm
ent;
• in
divi
dual
pat
ient
info
rmed
con
sent
is o
btai
ned;
• pa
tient
sup
port
is p
rovi
ded;
and
• st
anda
rdiz
ed re
port
ing
and
reco
rdin
g is
used
, inc
ludi
ng fo
r adv
erse
eve
nts.
Revi
ew o
f tre
atm
ent a
nd m
anag
emen
t pro
toco
ls by
an
inde
pend
ent g
roup
of e
xper
ts in
clin
ical m
anag
emen
t and
pub
lic h
ealth
, suc
h as
the
natio
nal M
DR-
TB a
dviso
ry g
roup
, is
reco
mm
ende
d.D
rug-
susc
eptib
ility
test
ing
is an
impo
rtan
t im
plem
enta
tion
cons
ider
atio
n th
at w
ill ne
ed fu
rthe
r enh
ance
men
t in
man
y co
untri
es, g
iven
the
incr
easin
g po
tent
ial u
se o
f bed
aqui
line
and
linez
olid
(eve
n fo
r lon
ger r
egim
ens
for M
DR/
RR-T
B) a
nd th
e in
clusio
n of
new
med
icine
s –
such
as
pret
oman
id –
in M
DR-
TB tr
eatm
ent r
egim
ens.
Base
line
DST
will
conf
irm e
ligib
ility
for
the
BPaL
regi
men
; the
refo
re, t
he e
stab
lishm
ent a
nd s
treng
then
ing
of d
rug-
susc
eptib
ility
test
ing
serv
ices
will
be a
vita
l im
plem
enta
tion
cons
ider
atio
n. In
pat
ient
s w
ith b
acte
riolo
gica
lly
conf
irmed
MD
R/RR
-TB,
22 th
e M
TBD
Rsl a
ssay
may
be
used
as
the
initi
al te
st, i
n pr
efer
ence
to c
ultu
re a
nd p
heno
typi
c D
ST, t
o de
tect
resis
tanc
e to
fluo
roqu
inol
ones
(con
ditio
nal
reco
mm
enda
tion;
cer
tain
ty o
f evi
denc
e fo
r dire
ct te
stin
g of
spu
tum
from
low
to m
oder
ate.
23 In
set
tings
in w
hich
labo
rato
ry c
apac
ity fo
r DST
to fl
uoro
quin
olon
es is
not
yet
ava
ilabl
e, o
r ca
nnot
be
acce
ssed
, it w
ill be
diff
icult
to c
arry
out
ope
ratio
nal r
esea
rch
on B
PaL.
If te
stin
g fo
r sus
cept
ibilit
y to
bed
aqui
line
or li
nezo
lid is
ava
ilabl
e, it
is h
ighl
y de
sirab
le th
at th
is is
also
ca
rrie
d ou
t at b
asel
ine;
how
ever
, thi
s ne
ed n
ot b
e a
prer
equi
site
for t
reat
men
t ini
tiatio
n, n
or n
eed
it be
so
in th
e ab
senc
e of
cul
ture
con
vers
ion
durin
g tre
atm
ent.
DST
for p
reto
man
id is
no
t yet
ava
ilabl
e. C
urre
ntly,
ther
e is
limite
d ca
pacit
y gl
obal
ly to
car
ry o
ut D
ST fo
r bed
aqui
line
and
linez
olid
; how
ever
, lab
orat
ory
capa
city
shou
ld b
e st
reng
then
ed in
this
area
as
thes
e m
edici
nes
and
regi
men
s be
com
e m
ore
wid
ely
used
. Nat
iona
l and
refe
renc
e la
bora
torie
s w
ill ne
ed to
hav
e th
e m
edici
ne p
owde
rs a
vaila
ble
to e
nabl
e D
ST to
be
carr
ied
out a
nd w
ill ne
ed d
ata
on th
e m
inim
um in
hibi
tory
con
cent
ratio
n (M
IC) d
istrib
utio
n of
all
Myc
obac
teriu
m tu
berc
ulos
is lin
eage
s th
at a
re c
ircul
atin
g gl
obal
ly. If
resis
tanc
e to
any
of t
he c
ompo
nent
m
edici
nes
in th
e BP
aL re
gim
en is
det
ecte
d, th
e pa
tient
sho
uld
com
men
ce tr
eatm
ent w
ith a
long
er M
DR-
TB re
gim
en. W
HO
Sup
rana
tiona
l Ref
eren
ce L
abor
ator
y N
etw
ork
is av
aila
ble
to
supp
ort n
atio
nal T
B re
fere
nce
labo
rato
ries
in p
erfo
rmin
g qu
ality
-ass
ured
DST
. A W
HO
tech
nica
l con
sulta
tion
in 2
017
esta
blish
ed c
ritica
l con
cent
ratio
ns fo
r DST
for t
he fl
uoro
quin
olon
es,
beda
quilin
e, d
elam
anid
, clo
fazi
min
e an
d lin
ezol
id.24
Met
hods
for t
estin
g pr
etom
anid
sus
cept
ibilit
y ar
e cu
rrent
ly u
nder
dev
elop
men
t.
21
The
prot
ocol
for t
he N
ix-TB
stu
dy is
ava
ilabl
e at
: http
s://c
linica
ltria
ls.go
v/ct
2/sh
ow/N
CT02
3337
9922
M
DR/
RR-T
B is
usua
lly c
onfir
med
by
rapi
d m
olec
ular
test
s tha
t det
ect r
esist
ance
to ri
fam
picin
and
M. t
uber
culo
sis. C
urre
nt W
HO
reco
mm
enda
tions
stat
e th
at th
e Xp
ert M
TB/R
IF a
ssay
shou
ld b
e us
ed ra
ther
than
co
nven
tiona
l micr
osco
py, c
ultu
re, a
nd D
ST a
s th
e in
itial
dia
gnos
tic te
st in
adu
lts s
uspe
cted
of h
avin
g M
DR-
TB o
r HIV
-ass
ocia
ted
TB (s
trong
reco
mm
enda
tion;
hig
h-qu
ality
evi
denc
e). T
he X
pert
MTB
/RIF
ass
ay
shou
ld b
e us
ed r
athe
r th
an c
onve
ntio
nal m
icros
copy
, cul
ture
, and
DST
as
the
initi
al d
iagn
ostic
test
in c
hild
ren
susp
ecte
d of
hav
ing
MD
R-TB
or
HIV
-ass
ocia
ted
TB (s
trong
reco
mm
enda
tion;
ver
y lo
w-q
ualit
y ev
iden
ce) –
Aut
omat
ed re
al-t
ime
nucle
ic ac
id a
mpl
ifica
tion
tech
nolo
gy fo
r rap
id a
nd s
imul
tane
ous
dete
ctio
n of
tube
rcul
osis
and
rifam
picin
resis
tanc
e: X
pert
MTB
/RIF
ass
ay fo
r the
dia
gnos
is of
pul
mon
ary
and
extra
pulm
onar
y TB
in a
dults
and
chi
ldre
n (W
HO
/HTM
/TB/
2013
.16)
. Gen
eva,
Sw
itzer
land
: Wor
ld H
ealth
Org
aniz
atio
n; 2
013
(http
s://a
pps.w
ho.in
t/iri
s/bi
tstre
am/h
andl
e/10
665/
1124
72/9
7892
4150
6335
_eng
.pd
f?se
quen
ce=1
, acc
esse
d 20
Mar
ch 2
020)
. A re
cent
WH
O ra
pid
com
mun
icatio
n re
info
rced
the
high
dia
gnos
tic a
ccur
acy
and
impr
oved
pat
ient
out
com
es o
f rap
id m
olec
ular
dia
gnos
tic te
sts s
uch
as X
pert
MTB
/RI
F, Xp
ert M
TB/R
IF U
ltra,
and
Tru
eNat
– R
apid
com
mun
icatio
n: m
olec
ular
ass
ays
as in
itial
test
s fo
r the
dia
gnos
is of
tube
rcul
osis
and
rifam
picin
resis
tanc
e. G
enev
a, S
witz
erla
nd W
orld
Hea
lth O
rgan
izat
ion
2020
(h
ttps:/
/app
s.who
.int/
iris/
bits
tream
/han
dle/
1066
5/33
0395
/978
9240
0003
39-e
ng.p
df, a
cces
sed
20 M
arch
202
0).
23
The
use
of m
olec
ular
line
pro
be a
ssay
s fo
r the
det
ectio
n of
resis
tanc
e to
sec
ond-
line
anti-
tube
rcul
osis
drug
s: po
licy
guid
ance
[WH
O/H
TM/T
B/20
16.0
7]. G
enev
a, S
witz
erla
nd: W
orld
Hea
lth O
rgan
izat
ion;
201
6 (h
ttps:/
/app
s.who
.int/
iris/
bits
tream
/han
dle/
1066
5/24
6131
/978
9241
5105
61-e
ng.p
df?s
eque
nce=
1, a
cces
sed
20 M
arch
202
0).
24
Auto
mat
ed re
al-t
ime
nucle
ic ac
id a
mpl
ifica
tion
tech
nolo
gy fo
r rap
id a
nd si
mul
tane
ous d
etec
tion
of tu
berc
ulos
is an
d rif
ampi
cin re
sista
nce:
Xpe
rt M
TB/R
IF a
ssay
for t
he d
iagn
osis
of p
ulm
onar
y an
d ex
trapu
lmon
ary
TB in
adu
lts a
nd c
hild
ren
(WH
O/H
TM/T
B/20
13.1
6). G
enev
a, S
witz
erla
nd: W
orld
Hea
lth O
rgan
izat
ion;
201
3 (h
ttps:/
/app
s.who
.int/
iris/
bits
tream
/han
dle/
1066
5/11
2472
/978
9241
5063
35_e
ng.p
df?s
eque
nce=
1,
acce
ssed
20
Mar
ch 2
020)
.
WHO consolidated guidelines on tuberculosis: Online annexes118
Dos
ing
of li
nezo
lid: T
he li
nezo
lid d
osag
e us
ed in
the
Nix-
TB s
tudy
was
120
0 m
g/da
y. In
itial
ly, a
ll st
udy
part
icipa
nts
rece
ived
600
mg
of li
nezo
lid B
D b
ecau
se th
at w
as th
e ap
prov
ed d
ose
used
to tr
eat b
acte
rial i
nfec
tions
for u
p to
28
days
at t
he ti
me
the
stud
y co
mm
ence
d. H
owev
er, i
n M
ay 2
018,
the
prot
ocol
was
cha
nged
to a
dos
ing
of 1
200
mg
OD.
Acc
ordi
ng to
the
prot
ocol
, dos
e re
duct
ion
to 6
00 m
g da
ily a
nd fu
rthe
r to
300
mg
daily
or t
empo
rary
ces
satio
n of
line
zolid
was
per
mitt
ed fo
r up
to 3
5 co
nsec
utiv
e da
ys, f
or a
ny k
now
n lin
ezol
id a
dver
se
reac
tions
of m
yelo
supp
ress
ion,
per
iphe
ral n
euro
path
y an
d op
tic n
euro
path
y. If
toxic
ity p
rohi
bite
d fu
rthe
r tre
atm
ent w
ith li
nezo
lid, t
hen
patie
nts
coul
d co
ntin
ue to
take
bed
aqui
line
and
pret
oman
id, p
rovi
ded
that
they
had
rece
ived
the
1200
mg/
day
dose
for a
t lea
st th
e fir
st 4
con
secu
tive
wee
ks, w
ere
sput
um s
mea
r-neg
ativ
e an
d w
ere
resp
ondi
ng to
trea
tmen
t as
indi
cate
d by
clin
ical m
onito
ring
and
follo
w-u
p. M
issed
dos
es o
f lin
ezol
id w
ere
not m
ade
up d
urin
g th
e N
ix-TB
stu
dy, a
nd d
ose
mod
ifica
tions
for b
edaq
uilin
e an
d pr
etom
anid
wer
e no
t al
low
ed. O
vera
ll, 18
pat
ient
s (1
7.3%
) in
the
Nix-
TB s
tudy
com
plet
ed a
full
cour
se o
f lin
ezol
id a
t the
120
0-m
g do
se, 3
8 (3
6.5%
) com
plet
ed w
ith a
600
-mg
dose
, 16
(15.
4%) c
ompl
eted
with
a
300-
mg
dose
, and
32
(30.
7%) s
topp
ed li
nezo
lid e
arly
bec
ause
of a
n ad
vers
e ev
ent.
In v
iew
of t
he e
xper
ienc
e of
the
Nix-
TB s
tudy
, it m
ay b
e ne
cess
ary
to m
odify
the
dose
of l
inez
olid
du
ring
treat
men
t on
the
basis
of a
dver
se e
vent
s, hi
ghlig
htin
g th
e im
port
ance
of c
lose
mon
itorin
g, p
atie
nt fo
llow
-up
and
aDSM
. Add
ition
al s
tudi
es –
suc
h as
the
ZeN
ix st
udy
(TB
Allia
nce)
–
are
unde
rway
to a
sses
s th
e op
timal
dos
ing
and
dura
tion
of li
nezo
lid fo
r the
trea
tmen
t of d
rug-
resis
tant
TB;
how
ever
, the
resu
lts o
f the
se s
tudi
es a
re n
ot y
et a
vaila
ble
for r
evie
w. To
da
te, t
he B
PaL
regi
men
has
bee
n st
udie
d as
a s
tand
ardi
zed
cour
se o
f tre
atm
ent.
Mod
ifica
tion
of th
e re
gim
en th
roug
h ea
rly d
iscon
tinua
tion
or re
plac
emen
t of a
ny o
f the
com
pone
nt
med
icine
s m
ay re
sult
in p
oor t
reat
men
t out
com
es. T
he p
reto
man
id p
rodu
ct la
bel r
ecom
men
ds th
at if
eith
er b
edaq
uilin
e or
pre
tom
anid
tabl
ets
are
disc
ontin
ued,
the
entir
e BP
aL re
gim
en
shou
ld a
lso b
e di
scon
tinue
d. If
line
zolid
is p
erm
anen
tly d
iscon
tinue
d du
ring
the
initi
al 4
con
secu
tive
wee
ks o
f tre
atm
ent,
then
bed
aqui
line
and
pret
oman
id s
houl
d al
so b
e di
scon
tinue
d.
If lin
ezol
id is
disc
ontin
ued
afte
r the
initi
al 4
wee
ks o
f con
secu
tive
treat
men
t, cli
nicia
ns s
houl
d co
ntin
ue a
dmin
ister
ing
beda
quilin
e an
d pr
etom
anid
, con
siste
nt w
ith th
e N
ix-TB
stu
dy
prot
ocol
. In
the
Nix-
TB s
tudy
, it w
as n
eces
sary
for p
atie
nts
to c
ompl
ete
6 m
onth
s of
the
regi
men
(i.e
. 26
wee
ks o
f pre
scrib
ed d
oses
) with
in 8
mon
ths,
and
for t
hose
who
had
trea
tmen
t ex
tend
ed, i
t was
nec
essa
ry fo
r pat
ient
s to
com
plet
e 9
mon
ths
of tr
eatm
ent (
i.e. 3
9 w
eeks
of p
resc
ribed
dos
es) w
ithin
12
mon
ths.
Patie
nts
who
rem
aine
d cu
lture
pos
itive
or w
ho re
vert
ed
to b
eing
cul
ture
pos
itive
bet
wee
n m
onth
s 4
and
6, a
nd w
hose
clin
ical c
ondi
tion
sugg
este
d th
ey m
ight
hav
e on
goin
g TB
infe
ctio
n, h
ad tr
eatm
ent e
xten
ded
to a
tota
l of 9
mon
ths.
Mon
itorin
g an
d ev
alua
tion
Patie
nts
who
rece
ive
BPaL
(or a
ny s
hort
er re
gim
en fo
r the
trea
tmen
t of M
DR/
RR-T
B) n
eed
to b
e te
sted
at b
asel
ine
and
then
mon
itore
d du
ring
treat
men
t usin
g sc
hedu
les
of re
leva
nt
clini
cal a
nd la
bora
tory
test
ing.
Acc
ordi
ng to
the
prod
uct l
abel
for p
reto
man
id, b
asel
ine
asse
ssm
ents
bef
ore
initi
atio
n of
the
BPaL
regi
men
inclu
de a
sses
smen
ts fo
r sym
ptom
s an
d sig
ns
of li
ver d
iseas
e (e
.g. f
atig
ue, a
nore
xia, n
ause
a, ja
undi
ce, d
ark
urin
e, li
ver t
ende
rnes
s an
d he
pato
meg
aly)
and
the
cond
uct o
f lab
orat
ory
test
s (a
lani
ne a
min
otra
nsfe
rase
[ALT
], as
part
ate
amin
otra
nsfe
rase
[AST
], al
kalin
e ph
osph
atas
e, a
nd b
ilirub
in, c
ompl
ete
bloo
d co
unt a
nd s
erum
pot
assiu
m, c
alciu
m, a
nd m
agne
sium
, whi
ch s
houl
d be
cor
rect
ed if
abn
orm
al).
Trea
ting
clini
cians
sho
uld
also
obt
ain
an e
lect
roca
rdio
gram
bef
ore
initi
atio
n of
trea
tmen
t. Th
e ba
selin
e m
onito
ring
sche
dule
of t
he N
ix-TB
stu
dy w
as m
uch
mor
e co
mpr
ehen
sive
than
this,
and
in
clude
d a
thor
ough
bas
elin
e cli
nica
l ass
essm
ent,
follo
wed
by
a sc
hedu
le o
f wee
kly p
atie
nt m
onito
ring
until
wee
k 20
and
then
mon
itorin
g ev
ery
4 to
6 w
eeks
ther
eafte
r, pa
rtly
dep
ende
nt
on w
heth
er th
e pa
tient
had
trea
tmen
t for
6 m
onth
s in
tota
l or w
heth
er tr
eatm
ent w
as e
xten
ded
by a
noth
er 3
mon
ths
(to 9
mon
ths
in to
tal).
Giv
en th
at th
e BP
aL re
gim
en is
new
and
is b
eing
impl
emen
ted
unde
r ope
ratio
nal r
esea
rch
cond
ition
s, it
is al
so im
port
ant t
o fo
llow
up
with
pat
ient
s af
ter t
he c
ompl
etio
n of
trea
tmen
t for
po
ssib
le re
laps
e. In
the
Nix-
TB s
tudy
, mon
itorin
g af
ter c
ompl
etio
n of
trea
tmen
t was
car
ried
out m
onth
ly fo
r mon
ths
1 to
3, a
nd th
en e
very
3 m
onth
s th
erea
fter.
Follo
w-u
p af
ter t
reat
men
t co
mpl
etio
n w
as fo
r a to
tal o
f 24
mon
ths;
how
ever
, at t
he ti
me
of d
ata
anal
ysis,
abo
ut h
alf o
f the
pat
ient
s ha
d be
en fo
llow
ed u
p fo
r thi
s pe
riod.
The
ana
lysis
of t
he N
ix-TB
stu
dy d
ata
indi
cate
d th
at th
ere
was
trea
tmen
t fai
lure
or r
ecur
renc
e in
3 p
atie
nts
(2.8
% o
f pat
ient
s ov
eral
l), ta
king
into
acc
ount
the
perio
d of
pos
t tre
atm
ent c
ompl
etio
n fo
llow
-up.
Det
aile
d sc
hedu
les
of b
asel
ine
and
follo
w-u
p m
onito
ring,
inclu
ding
pos
t tre
atm
ent c
ompl
etio
n, s
houl
d be
dev
elop
ed fo
r any
BPa
L op
erat
iona
l res
earc
h pr
otoc
ol, w
ith s
tand
ardi
zed
mea
sure
s fo
r rec
ordi
ng a
dver
se e
vent
s. Th
e W
HO
fram
ewor
k fo
r aD
SM n
eeds
to b
e ap
plie
d to
pat
ient
s re
ceiv
ing
any
type
of M
DR-
TB re
gim
en, t
o en
sure
app
ropr
iate
act
ion
and
an
acce
ptab
le le
vel o
f mon
itorin
g fo
r and
pro
mpt
resp
onse
to a
dver
se e
vent
s –
alon
gsid
e m
onito
ring
for t
reat
men
t out
com
es, i
nclu
ding
ear
ly m
onito
ring
for t
reat
men
t fai
lure
. Add
ition
al
evid
ence
gen
erat
ed o
n ad
vers
e ev
ents
will
be im
port
ant f
or b
uild
ing
the
evid
ence
bas
e on
the
safe
ty o
f the
BPa
L re
gim
en in
var
ied
setti
ngs.
Mon
itorin
g of
cha
nges
in d
osin
g an
d du
ratio
n of
line
zolid
in p
artic
ular
(whe
n ne
eded
) will
also
be
impo
rtan
t for
info
rmin
g th
e fu
ture
evi
denc
e ba
se o
n th
e w
ider
use
of t
he B
PaL
regi
men
and
the
tole
rabi
lity
of li
nezo
lid in
th
is re
gim
en.
Annex 4: GRADE evidence-to-decision tables 119
Rese
arch
prio
ritie
s•
Rese
arch
on
the
use
of B
PaL
to c
ompa
re e
ffica
cy, s
afet
y an
d to
lera
bilit
y to
oth
er a
ll-or
al re
gim
ens.
• D
ata
from
oth
er re
gion
s an
d co
untri
es (b
eyon
d So
uth
Afric
a).
• D
escr
iptio
n of
the
mec
hani
sm a
nd m
olec
ular
mar
kers
of p
reto
man
id re
sista
nce.
Sur
veilla
nce
for t
he d
evel
opm
ent o
f res
istan
ce, w
ith a
dequ
ate
cons
ider
atio
n pa
id to
the
impa
ct o
f se
lect
ed m
utat
ions
. •
Doc
umen
ting
of th
e fu
ll ad
vers
e ef
fect
pro
file
of p
reto
man
id, a
nd th
e fre
quen
cy o
f rel
evan
t adv
erse
effe
cts,
with
a fo
cus
on h
epat
otox
icity
and
repr
oduc
tive
toxic
ity in
hum
ans.
Repr
oduc
tive
toxic
ities
of p
reto
man
id h
ave
been
sig
nalle
d in
ani
mal
stu
dies
but
pot
entia
l effe
cts
of th
is m
edici
ne o
n hu
man
fert
ility
have
not
bee
n ad
equa
tely
eva
luat
ed a
nd re
quire
ap
prop
riate
rese
arch
. •
Expl
orin
g th
e re
lativ
e ef
ficac
y (a
nd a
dded
val
ue in
mul
tidru
g re
gim
ens)
of p
reto
man
id a
nd d
elam
anid
.•
Rese
arch
on
optim
al d
ose
and
dura
tion
of li
nezo
lid u
se in
dru
g-re
sista
nt T
B re
gim
ens
(ZeN
ix st
udy)
.
AFB:
acid
-fas
t bac
illus;
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.
WHO consolidated guidelines on tuberculosis: Online annexes120
A4.2 WHO treatment guidelines for isoniazid-resistant tuberculosis, 2018Refer to Annex 6: GRADE evidence-to-decision tables in the WHO treatment guidelines for isoniazid-resistant tuberculosis (https://www.who.int/tb/publications/2018/WHO_treatment_guidelines_ isoniazid_resistant_TB_Online_GRADE_tables_Annexes.pdf, accessed 2 March 2019).
A4.3 WHO treatment guidelines for multidrug- and rifampicin-resistant tuberculosis, 2018 updateRefer to Annex 9: GRADE evidence-to-decision tables in the WHO treatment guidelines for multidrug-and rifampicin-resistant tuberculosis, 2018 update (https://www.who.int/tb/areas-of-work/drug-resistant-tb/ Annexes_8–10.pdf, accessed 2 March 2019).
A4.4 Guidelines for the programmatic management of drug-resistant tuberculosis, 2011 updateRefer to Annex 2: GRADE glossary and summary of evidence tables (questions 6 and 7) in the Guidelines for the programmatic management of drug-resistant tuberculosis, 2011 update (https://apps.who. int/iris/bitstream/handle/10665/70677/WHO_HTM_TB_2011.6b_eng.pdf, accessed 2 March 2019), where the content of the evidence-to-decision process was summarized in the remarks relating to each recommendation.
A4.5 WHO treatment guidelines for drug-resistant tuberculosis, 2016 updateRefer to Annex 5: Evidence-to-decision tables (question 4) in the WHO treatment guidelines for drug- resistant tuberculosis, 2016 update (https://apps.who.int/iris/bitstream/handle/10665/250125/ 9789241549639-webannexes-eng.pdf, accessed 2 March 2019).
A4.6 Guidelines for treatment of drug-susceptible tuberculosis and patient care, 2017 updateRefer to Annex 4: Evidence-to-decision tables (questions 10 and 11) in the Guidelines for treatment of drug-susceptible tuberculosis and patient care, 2017 update (https://www.who.int/tb/publications/2017/ dstb_guidance_2017/en/, accessed 2 March 2019)
Annex 5: Summaries of unpublished data 121
Annex 5: Summaries of unpublished data
A5.1 WHO treatment guidelines for multidrug- and rifampicin-resistant tuberculosis, 2020 updateA5.1.1: Summary review for the GDG of preclinical and early clinicl data on pretomanid for use in MDR and XDR-TB: CPMT Project No.: 19010 By Professor Susan M Abdel-Rahman
Overview:
Pretomanid (Pa) was granted approval by the U.S. FDA in August 2019 to be used as part of a bedaquiline, pretomanid, linezolid (BPaL) regimen. This document summarizes a broader report to WHO detailing background information on Pa including pre-clinical dat and early phase clinical safety and efficacy.
Chemistry:
Pa represents a class of nitroimidazopyrans arising from the naturally occurring nitroimidazole, azomycin, and its synthetic derivative metronidazole. It bears structural similarity to the nitroimidazooxazole, delamanid.[1–4]
Putative mechanisms of action for Pa include; 1) reductive activation to reactive nitro radical anion intermediates, 2) nitric oxide release, 3) ketomycolic acid depletion, and 4) toxic methylglyoxal accumulation.[1, 5–7] The cofactor F420 mediated redox system is integral to the activity of Pa and sequence variations in MTb proteins that are involved with the synthesis, oxidation or reduction of this cofactor are linked to resistance. These include Ddn (Rv3547), Fgd (Rv0407), fbiA (Rv3261), fbiB (Rv3262), fbiC (Rv1173), and fbiD (Rv2983).[1, 8–14] With limited exception, these proteins are not required for the growth/survival of MTb and their disruption does not limit mycobacterial fitness.[15–19]
The frequency of spontaneous Pa resistance in vitro (10–5 to 10–7) is influenced by the concentration to which the isolates are exposed and the starting mycobacterial inoculum. Estimates are greater than that of rifampin but comparable to other agents including isoniazid, ethambutol, and pyrazinamide.[20] Spontaneous resistance rates in vivo are variable (~10–3–10–5) and increase in direct proportion with dose; however, they drop in combination with INH.[13, 21–23]
Cross resistance to other antimycobacterial agents is rare with the exception of delamanid for which it is common but incomplete.[24] Cross resistance has also been documented with the more recently discovered nitrofuranylamides and 5-nitrothiophenes which share structural features with Pa and delamanid.[25,26]
WHO consolidated guidelines on tuberculosis: Online annexes122
Microbiology:
MIC for Pa against drug-susceptible, monoresistant, MDR, and XDR isolates of MTb (0.005–0.48 μg/mL) suggest that resistance phenotype has limited impact on Pa activity.[24] MICs against MTb increase in low oxygen conditions and in the presence of human albumin/serum.[24, 27–28] Pa demonstrates activity against other species in the Mycobacterium tuberculosis complex including M. bovis, M. africanum, and M. pinnipedii (MIC range <0.0312 to 0.125 μg/mL);however, there is little to no activity in other mycobacterial and non-mycobacterial species.[24]
In vitro, Pa appears to exhibit both concentration- and time-dependent bactericidal activity.[24] Intracellular potency appears comparable to INH and inferior to delamanid and rifampin, though intracellular to extracellular ratios vary by drug and incubation condition.[29–31]
Murine models support a dose-response relationship for Pa with a minimum effective dose of 12.5 mg/kg and a minimum bactericidal dose of 100 mg/kg. At this dose, CFU reductions in the lung and spleen comparable to INH (25 mg/kg), gatifloxacin (100 mg/kg) and moxifloxacin (100 mg/kg).[1, 21, 32]. Monotherapy with Pa at 50 mg/kg fails to achieve a sterile cure, though combinations with bedaquiline and an oxazolidinone achieve CFU reductions that are a full order of magnitude lower than achieved with Pa alone.[26, 33–35] The combination PaMZ is similarly effective in the guinea pig model.[1, 36] Dose fractionation studies in these animal models suggest that %T>MIC demonstrates the strongest association with CFU count reduction.[37]
In humans, 14-day single-dose studies suggest no appreciable increase in EBA above 200 mg.[38–39] When administered in combination, EBA observed in regimens containing Pa did not appear inferior to combinations without this agent. Pa-based regimens also outperformed standard HRZE treatment regimens in select studies, though none of the combinations tested reflect the FDA approved BPaL regimen.[40–43]
Pharmacology/Toxicology:
Information relevant to understanding the disposition of Pa and its drug-interaction potential derives largely from the CDER review [44] and are summarized as follows:
• Absolute bioavailability in non-human primate is less than 50%• Protein binding ranges from 86.3 to 86.5% with a low potential for partitioning into red blood cells.• Pa undergoes biotransformation by multiple P450 and non-P450 pathways with CYP3A4 the only
relevant P450 accounting for up to 20% the drugs metabolism. • In vitro studies demonstrate the potential for Pa to inhibit CYP3A4/5, though at concentrations
in excess of those observed with routine dosing. Recorded IC50 values suggest DDI mediated via other P450 isoforms is unlikely.
• The potential for pretomanid to induce CYP3A4 appears to be negligible.• Pa does not appear to be a substrate for transporters evaluated to date; however, it does inhibit
the renal tubular uptake transporter OAT3 at clinically relevant concentrations. • Clinically relevant in vivo DDI observed in humans are limited to a drop in Pa exposure when
co-administered with CYP3A inducers (e.g. rifampin, efavirenz, lopinavir/ritonavir).[45–48] • Pa does appear to increase in moxifloxacin exposures in rats; however, the mechanism and relevance
to humans is unclear.• Drug-food interactions are marked by an increase in Pa exposures (Cmax and AUC) when
co-administered with a high-fat meal. The relative increase in bioavailability gets disproportionately larger with increasing dose.[49]
• Cardiac toxicity mediated by hERG inhibition (IC50 was 17.3 μM) is not likely to be relevant at labeled doses.
• Carcinogenicity and mutagenicity risk also appear low.[24, 44] However, safety signals in animals have been observed in various organ systems the most relevant of which is hepatotoxicity at labeled
Annex 5: Summaries of unpublished data 123
doses.[24, 44] Testicular toxicity has also been observed at lower exposures and the uncertain human implications have lead the FDA to require additional post-marketing studies.
Clinical Pharmacokinetics:
In healthy volunteers, Pa concentrations peak between 4–5 hours post-dose with a less-than proportional relationship between dose and exposure through 600 to 1000 mg after which point increasing dose produces no corresponding increase in exposure.[50–51] Mean Pa half-life ranges from 15–20 hours explaining a doubling in the extent of exposure at steady state.[50]
Efficacy/Safety:
Nix-TB [24]: This non-comparative study of BPaL in 109 individuals reported favorable outcomes in 89%, 91% and 92% of their ITT, MITT, and PP populations respectively. No appreciable differences in response were observed as a function of HIV status, linezolid regimen (BID vs. QD), age, gender, race, cavitation, or time to positivity at baseline. All participants (100%) experienced at least 1 treatment emergent adverse event (TEAE), 99% of which were considered related to study regimen. The most frequently reported AE can be identified in the clinicaltrials.gov URL referenced above. Those most likely associated with Pa based on preclinical data include: dermatitis/eczema (53.2%), non-infective gastrointestinal upset (48.6%), hepatic disorder (38.5%), headache (29.4%), lens disorder (13.8%), severe cutaneous reaction (6.4%), and convulsions (1.8%). There were 8 deaths in the trial 7 of which led to premature discontinuation of the study and TEAE in an additional 5 patients that led to treatment discontinuation.
STAND [52]: In this trial of PaMZ, the rate of unfavorable outcomes for the primary measure exceeded those of the standard HRZE treatment group. At the point of analysis, the Pa containing regimens failed non-inferiority criterion prompting early discontinuation of the trial. Note that this was preceded by a clinical hold from the FDA owing to 3 hepatotoxicity associated deaths. TEAE rates ranged from 87–94% in the Pa containing arms compared with 91% in standard treatment arm. The only SAE observed in more than 1 individual across all pretomanid containing regimens include increases in ALT/AST and seizures. Additional AE observed with more than a 2-fold higher rate in the Pa groups (vs. HRZE) were gastrointestinal (nausea, vomiting, diarrhea) and pulmonary (pleuritic pain, hemoptysis, URI).
ZeNix [53]: In this ongoing trial of BPaL, 83.6% of 61 participants have experienced at least one TEAE, 55.7% of which were considered related to study drug. The most frequently reported AE parallel those reported in Nix-TB. To date, TEAE have led to permanent discontinuation in 2 participants.
Early Clinical Trials [38–43]: In the 14-day EBA monotherapy studies, reported SAE were restricted to complications of the underlying disease (pneumonia, pneumothorax, hemoptysis). The only non-serious AE experienced by more than one individual across all treatment arms was nausea, vomiting, headache, pruritis, rash, and iron deficiency anemia. In the 8-week BA studies, TEAE rates approximated those of the efficacy studies described above. When the regimens are broadly combined, and non-serious AE are evaluated against the standard HRZE regimen, neurologic and hepatic disturbances appeared to be more prevalent in the Pa containing regimens. Early clinical studies also identified a relationship between trough Pa concentrations and an increase in circulating serum creatinine levels which resolved after discontinuation of the drug.[50] Subsequent exploratory studies suggests that these changes are likely the result of inhibition of creatinine secretion at the level of the renal proximal tubule.[51]
References:
1. Stover CK, et al. Nature. 2000 Jun 22; 405(6789): 962–6.2. Thompson AM, et al. ACS Med Chem Lett. 2017 Nov 13;8(12):1275–1280.3. Bahuguna A, et al. Med Res Rev. 2019 Jun 28. [Epub ahead of print]
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4. Zhang J, et al. Eur J Med Chem. 2019 Oct 1;179:376–388.5. Moreno SN, et al. Environ Health Perspect. 1985 Dec;64:199–208.6. Yuan Y, et al. Proceedings of the National Academy of Sciences Nov 1996, 93 (23) 12828–128337. Baptista R, et al. Sci Rep. 2018 Mar 23;8(1):5084.8. Singh R, et al. Science. 2008 Nov 28;322(5906):1392–5.9. Purwantini E, et al. PLoS One. 2013 Dec 11;8(12):e81985.10. Haver HL, et al. Antimicrob Agents Chemother. 2015 Sep;59(9): 5316–23.11. Manjunatha UH, et al. Proc Natl Acad Sci U S A. 2006 Jan 10; 103(2): 431–6.12. Wen S, et al. Eur J Clin Microbiol Infect Dis. 2019 Jul;38(7):1293–129613. Rifat D, et al. bioRxiv 457754; Posted October 31, 2018. doi: https://doi.org/10.1101/45775414. Bashiri G, et al. Nat Commun. 2019 Apr 5;10(1):1558.15. Sassetti CM, et al. Mol Microbiol. 2003 Apr;48(1):77–84.16. Sassetti CM, et al. Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):12989–94.17. Rengarajan J, et al. Proc Natl Acad Sci U S A. 2005 Jun 7;102(23):8327–32.18. Dutta NK, et al. J Infect Dis. 2010 Jun 1;201(11):1743–52.19. Zhang YJ, et al. PLoS Pathog. 2012 Sep;8(9):e1002946.20. McGrath M, et al, J Antimicrob Chemother. 2014 Feb;69(2): 292–302.21. Tyagi S, et al. Antimicrob Agents Chemother. 2005 Jun; 49(6): 2289–93.22. Harper J, et al. J Infect Dis. 2012 Feb 15;205(4):595–602.23. Li SY, et al. Antimicrob Agents Chemother. 2017 Aug 24;61(9).24. Data on File, TB Alliance.25. Hurdle JG, et al. J Antimicrob Chemother. 2008 Nov;62(5):1037–45.26. Hartkoorn RC, et al. Antimicrob Agents Chemother. 2014 May;58(5): 2944–7.27. Franzblau SG, et al. Tuberculosis (Edinb). 2012 Nov;92(6):453–88. 28. Upton AM, et al. Antimicrob Agents Chemother. 2015 Jan;59(1):136–44.29. Matsumoto M, et al. PLoS Med. 2006 Nov;3(11):e466.30. Stott KE, eta al. J Antimicrob Chemother. 2018 Sep 1;73(9):2305–2313.31. Daskapan A, et al. Clin Pharmacokinet. 2019 Jun;58(6):747–766.32. Lenaerts AJ, et al. Antimicrob Agents Chemother. 2005 Jun;49(6):2294–30133. Dutta NK, et al. Int J Antimicrob Agents. 2014 Dec;44(6):564–634. Lanoix JP, et al. Antimicrob Agents Chemother. 2014;58(4):2316–21. 35. Tasneen R, et al. Antimicrob Agents Chemother. 2015 Oct 26;60(1):270–7.36. Dutta NK, et al. Antimicrob Agents Chemother. 2013 Aug;57(8):3910–6.37. Ahmad Z, et al. Antimicrob Agents Chemother. 2011 Jan;55(1):239–45.38. NCT00944021 (https://clinicaltrials.gov/ct2/show/NCT00944021?term=NCT00944021&draw=2&rank=1)39. NCT00567840 (https://clinicaltrials.gov/ct2/show/NCT00567840?term=NCT00567840&draw=2&rank=1)40. NCT01215851 (https://clinicaltrials.gov/ct2/show/NCT01215851?term=NCT01215851&draw=2&rank=1)41. NCT01691534 (https://clinicaltrials.gov/ct2/show/NCT01691534?term=NCT01691534&draw=2&rank=1)42. NCT01498419 (https://clinicaltrials.gov/ct2/show/NCT01498419?term=NCT01498419&draw=2&rank=1)43. NCT02193776 (https://clinicaltrials.gov/ct2/show/NCT02193776?term=NCT02193776&draw=2&rank=1)44. CDER. Multidisciplinary review for Application 212862Orig1s000. August 13, 2019.45. Dooley KE, et al. Antimicrob Agents Chemother. 2014 Sep;58(9):5245–52. 46. Winter H, et al. Antimicrob Agents Chemother. 2013 Aug;57(8):3699–703.47. Wang L, et al. J Pharm Biomed Anal. 2014 Aug;97:1–8. 48. Wang L, et al. J Chromatogr Sci. 2018 Apr 1;56(4):327–335
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49. Winter H, et al. Antimicrob Agents Chemother. 2013 Nov;57(11):5516–2050. Ginsberg AM, et al. Antimicrob Agents Chemother. 2009 Sep;53(9):3720–5. 51. Ginsberg AM, et al. Antimicrob Agents Chemother. 2009 Sep;53(9):3726–33.52. NCT02342886 (https://clinicaltrials.gov/ct2/show/NCT02342886?term=NCT02342886&draw=2&rank=1)53. NCT03086486 (https://clinicaltrials.gov/ct2/show/NCT03086486?term=NCT03086486&draw=2&rank=1)
A5.1.2: Model-based projections of costs and cost effectiveness of changes in MDR/RR-TB regimensBy Dr Emily A Kendall, MD PhD
Background:
Changes in recommended MDR/RR-TB treatment are likely to have economic consequences, through their effects on drug costs, drug delivery (for example, injections), safety monitoring requirements, numbers of follow-up visits, or (via changes in treatment outcomes) the number of TB patients who will require treatment in the future. Changes to recommended regimens might be cost-saving under common conditions, or might result in cost increases and potential access concerns that need to be weighed against clinical advantages. We developed a model to estimate the costs and cost-effectiveness of three potential changes to recommended treatments for MDR/RR TB.
Methods:
A single decision analytic modeling framework was developed to evaluate multiple regimen comparisons that were under consideration by the Guidelines Development Group (GDG). For PICO question 1, the costs and effectiveness of a shorter (9–12 month), all-oral, bedaquiline-containing regimen (modeled as based on South African guidelines) were compared to two types of currently recommended MDR/RR-TB regimens: (a) a longer (18–20 month), bedaquiline-containing oral regimen (modeled as consisting of WHO class A and B drugs bedaquiline, linezolid, levofloxacin, clofazimine, and terizidone), or (b) a 9–12 month, injectable-containing regimen (modeled as evaluated in STREAM). For PICO 3 (use of bedaquiline for longer than 6 months in longer oral regimens), use of bedaquiline for 6 months in the 18–20 month regimen described above was compared to use for the duration of treatment. For PICO 4 (concurrent use of delamanid and bedaquiline), use of delamanid was modeled in two ways: (a) as an addition to the 18–20 month oral regimen (thus potentially increasing efficacy while adding cost) or (b) as a replacement for linezolid (with main goal to reduce toxicity).
Each pair of regimens was compared in a population of adult patients with MDR/RR (not pre-XDR/XDR) pulmonary TB. Modeled differences in TB outcomes between regimens (differences in relapse/failure, mortality, and loss to follow up) were based on the statistical analyses of individual patient data performed for the GDG by Drs. J Campbell and R Menzies. Differences in cost, in 2019 US dollars, were evaluated from a health system perspective, accounting for resources required to manage current and future TB (including drugs, office visits and hospitalizations, safety monitoring, recurrences and secondary cases) and adverse events. Future non-TB health care costs (e.g. of ART) incurred as a result of preventing deaths were excluded. Serious adverse event risks were estimated per drug-month using data from a global surveillance project. Differences in effectiveness, in disability-adjusted life years (DALYs) averted, accounted for estimated morbidity and mortality during and after treatment (with disability weights13 for TB disease, drug side effects, treatment burden, and health status, and with 3%/year discounting of DALYs and costs). Primary analyses were based in South Africa, and sensitivity analyses explored the range of health care costs, drug costs, and HIV co-prevalence expected across low- and middle-income countries.
WHO consolidated guidelines on tuberculosis: Online annexes126
Results:
PICO 1: A shorter, all-oral, bedaquiline-containing regimen was projected to be cost-saving relative to either comparator regimen: by nearly $3,000 per patient when compared to a longer, all-oral regimen, and by $1,000 per patient when compared to a short, injectable-containing regimen (both in South Africa). Compared to the longer oral regimen, the majority of the resource savings associated with the shorter all-oral regimen were due to reduced costs of drugs, but savings were also projected in costs of health care delivery, adverse events, and future retreatments and secondary cases. Compared to the short, injectable-containing regimen, the shorter all-oral regimen did not reduce drug costs, but it provided similar projected resources savings in other categories. The shorter all-oral regimen was also projected to be more effective than either comparator.
In sensitivity analyses, the resource savings of the shorter all-oral regimen relative to a longer all-oral regimen appeared extremely robust to country setting and underlying assumptions. The greatest variations in (cost savings) were seen with a two-fold decrease or increase in drug costs (cost savings $2000 and $4600, respectively) and with a two-fold decrease or increase in all non-drug healthcare costs (cost savings $2300 and $4000). The resource savings of the shorter all-oral regimen relative to the shorter injectable-containing regimen were nearly as robust, with the shorter all-oral regimen ceasing to be cost-saving (but remaining cost-effective, at < $400 per DALY averted) only when we assumed a large (four-fold) isolated increase in the cost of the drug bedaquiline.
PICO 3: Extending the duration of bedaquiline treatment, from six months to the full 18–20 month duration of a longer all-oral regimen, was expected to add approximately $500 per patient to health system costs (at current drug prices). Cost-effectiveness depended heavily on the magnitude of the clinical benefit of extending treatment, and a sufficiently large benefit to achieve cost-effectiveness when used for all patients could not be observed in available data. If patients could be identified who would derive a clinically meaningful efficacy benefit (e.g. odds ratio of 0.6 for treatment success), then extending the duration of bedaquiline might be cost effective for those patients, at an estimated incremental cost effectiveness ratio in South Africa of $1,200 per DALY averted.
PICO 4: Current high delamanid prices made cost-effectiveness difficult to achieve, whether delamanid was considered for inclusion in MDR/RR-TB treatment regimens in order to enhance efficacy (analysis a) or to prevent toxicity from another drug through substitution (assuming no significant loss of efficacy, analysis b). When adding delamanid to an otherwise-optimized longer all-oral regimen that already contained bedaquiline, the best-case incremental cost effectiveness ratio was $2,000 per DALY averted in South Africa, at the most optimistic data-consistent estimate of the efficacy benefit that delamanid might provide to patients. Data also supported an outcome of additional cost with no benefit, if true efficacy gains were minimal. When delamanid replaced a more toxic drug (e.g. linezolid) without changing regimen efficacy, then at current drug prices, the most optimistic incremental cost effectiveness ratio achievable in sensitivity analyses was $16,000 per DALY averted; this required assuming a serious adverse event rate of 0.7%/month for the drug that was replaced by delamanid (at the high end of the uncertainty range supported by data for linezolid), and high acute DALY impact per serious adverse event (0.4 DALYs each, similar to one full year with symptomatic active TB), and a high management cost of $17,000 per averted serious adverse event.
Conclusions:
A 9–12 all-oral regimen was projected to be both cost-saving and effective, relative to either a longer all-oral regimen or a shorter injectable-containing regimen, and cost savings were robust to setting-dependent variables and parameter uncertainty.
On the other hand, extending the duration of bedaquiline or adding delamanid within longer MDR/RR-TB regimens added substantial cost, and these changes were unlikely to be cost-effective at current prices when implemented for all patients, because of the relatively small effectiveness benefits
Annex 5: Summaries of unpublished data 127
expected. However, moderate cost effectiveness was possible when used for select patients for whom effective regimens could not otherwise be composed.
A5.1.3: Patient perspectives on DR-TB treatment: a summary report prepared for the November 2019 WHO GDG Meeting
Introduction
Patient values and preferences for treatment, and perspectives on treatment acceptability, feasibility and equity are key to the World Health Organization’s Evidence to Decision framework for drug-resistant tuberculosis (DR-TB) treatment interventions. A qualitative study was undertaken to illuminate patient perspectives and inform discussions for a November 2019 Guidelines Development Group (GDG) meeting for updated DR-TB treatment guidelines. A summary of the study is provided here.
Methods
Private in-depth interviews were held with persons who had received M/XDR-TB treatment in or after 2012, and were at least 18 years old and not receiving any form of TB treatment at the time of the study. They were recruited by referral from non-governmental organizations, as well as former patients with public profiles, from high DR-TB burden countries. Representation was sought from women, men, and people who had received newer or repurposed drugs for DR-TB. Interviews were conducted by phone in English, Russian, Mandarin or Spanish, and audio-recorded. Interview topics included: experiences with DR-TB treatment; preferences for treatment regimens; and the real or perceived acceptability of newer regimens, including perspectives on access and delivery. Recordings were transcribed, translated and identifiers removed. Data were thematically analyzed using OneNote to develop insights on patient values and preferences (characteristics, concerns and expectations of treatment that are considered to be most important); acceptability (appropriateness of treatment based on anticipated or experienced physical, cognitive and emotional effects); feasibility (practical considerations related to taking treatment); and equity (perceived or potential impacts on health and social inequalities). Ethics approval was granted by the Office of Research Ethics, York University, Canada.
Findings
Sixteen participants (44% female) of median age 29.5 years (range 22–64) were interviewed over two weeks in Oct 2019, from Africa (4), Asia (5), Eastern Europe (5) and South America (2). Nine (56%) participants began treatment for MDR-TB and 7 (44%) for pre-XDR or XDR-TB between 2011 to 2017. All had received longer regimens, from 1.5 up to 3 years. Most (96%) participants had experience with a second-line injectable and 40% with at least one of the new or repurposed drugs. One participant received bedaquiline as first-line therapy. Two participants were treated when they were adolescents. Few participants reported a co-morbidity: HIV (1), diabetes (2), chronic kidney illness (1).
Participants’ acceptability and preferences for DR-TB treatment were rooted in the following core values: minimal disruption to normal life and independence during treatment, and full physical and mental recovery post treatment. A short, injection-free regimen with few to no side effects and a low pill burden was considered to be the most acceptable treatment for DR-TB. Barring the fulfillment of all these characteristics, a regimen with least side effects was prioritized, as side effects were considered to be the most disruptive aspect of treatment. This was followed by a shorter regimen, no injections, and fewer pills, in that order.
Side effects that tended to resolve themselves over the course of a day or over the course of treatment (nausea, mild vomiting, body aches and pains, fatigue, and ringing in the ears) were disliked but tolerated. By contrast, severe and persistent vomiting, intense mental health effects ( severe depression including suicidal ideation, and severe anxiety including delusional thoughts), and any side effect that
WHO consolidated guidelines on tuberculosis: Online annexes128
could result in organ or sensory damage (hearing or vision loss, major damage to organs such as the kidney or heart, jaundice, and severe neuropathy or burning) were all considered unacceptable, even if they were short-term and reversible. Severe mental health problems and any loss of hearing and vision were described as the worst side effects. Skin pigmentation and injection pain were highly undesirable; they were accepted in the short-term only if there was no other treatment choice.
There were caveats and nuances to participants’ priorities, as well as important differences in acceptability, based on personal experiences with treatment, and the environment and context in which DR-TB care was received. Consequently, informed patient choice was considered a highly valuable component of the treatment decision-making process. Other elements valued by participants and considered crucial to acceptability of DR-TB treatment regimens were tight monitoring of serious adverse events, mental health counselling and support, ability to receive treatment in one’s own community (e.g., decentralized care), and universal access to new drugs and regimens.
These values and preferences have implications for the feasibility of new DR-TB treatment interventions. Some patient values may conflict due to feasibility challenges, for example if treatment monitoring cannot be reasonably provided in the community. Feasibility issues give way to equity considerations if patient preferences are not upheld across all communities, or place certain populations at a disadvantage, such as those living in remote or rural locations where provision of new drugs or treatment monitoring may be difficult.
Study attributes and limitations
Open ended in-depth inquiry was key to uncovering the dynamic subjectivity of patient values and preferences. Saturation was likely not achieved with regards to the perspective of people with co-morbidities, permanent clinical sequalae, and experience with shorter, non-injectable regimens as first-line treatment. The sample was enriched by the voices of several participants who were TB peer educators and patient advocates and brought the experience of current patients into their narratives.
Conclusion
The study, rooted in the recent lived experience of people who were treated for DR-TB in a number of high burden countries, illuminates novel insights into patients’ core values, ranked preferences, and comparative risk perceptions and acceptability related to DR-TB treatment. Insights gained may inform patient-centred treatment guidelines for DR-TB.
Acknowledgements
The study was conducted by Amrita Daftary and Stephanie Law in preparation for the WHO GDG for updated DR-TB treatment in November 2019. AD is based at the School of Global Health & Dahdaleh Institute of Global Health Research, York University, Canada, and appointed to the Centre for the AIDS Programme of Research in South Africa (CAPRISA). SL is postdoctoral fellow at the Department of Global Health and Social Medicine, Harvard Medical School, Boston, USA. The researchers wish to acknowledge and sincerely thank the people who participated in this study, as well as referring organizations and persons.
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Annex 6: Statistical analysis plans
A6.1 WHO treatment guidelines for multidrug- and rifampicin-resistant tuberculosis, 2020 updateA6.1.1: PICO question 1: In MDR/RR-TB patients, does an all-oral treatment regimen lasting 9-12 months safely improve outcomes when compared with other regimens conforming to WHO guidelines?
Effectiveness of an all-oral MDR/RR-TB regimen lasting 9–12 months in South Africa: Statistical Analysis Plan (draft)Prepared by Jonathon Campbell & Dick Menzies, McGill University: April 15, 2020
Overarching PICO Question (PICO 1)
In MDR/RR-TB patients, does an all-oral, bedaquiline-containing regimen lasting 9–12 months safely improve outcomes when compared with other regimens conforming to current WHO guidelines?
Population Intervention Comparator Outcomes
MDR/RR-TB patientsa. without additional drug
resistanceb. with additional drug resistance
patterns (for FLDs and/or SLDs; if specific mutation data is available in dataset).
c. with FQ resistanced. with severe disease
(i.e. cavitary disease on radiography or SS+)
e. previously treated with 2nd line drugs or not
f. children (0–14y) / adults (adolescents 10–19y if available)
g. persons with HIV (+/- ARVs)h. pregnant womeni. with extrapulmonary diseasej. with comorbidities (e.g.
diabetes mellitus; malnutrition; mental disorders)
– An all-oral shorter regimen of 9–12 months duration including bedaquiline
1. Shorter regimen recommended by WHO
2. Old longer regimens without new drugs in the IPD dataset
3. Longer regimens with new TB drugs from the IPD dataset
4. Longer regimens with use of new drugs from the EndTB dataset.
• Successful completion of treatment (or lack of successful completion)
• Bacteriological cure by end of treatment
• Adherence to treatment (or treatment interruption due to non-adherence)
• Treatment failure or relapse
• Survival (or death)• Adverse reactions from anti-TB medicines
• Acquisition (amplification) of drug resistance
• Relapse free cure
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Research Questions
Primary – intervention and comparator populations from South Africa data
1. Relative to the WHO recommended short-regimen lasting 9–12 months, does a bedaquiline-containing all-oral regimen lasting 9–12 months have the same or better outcomes?
2. Relative to a regimen lasting ≥18 months without the use of new TB drugs (e.g. does not contain bedaquiline, linezolid, delamanid, or carbapenems), does a bedaquiline-containing all-oral regimen lasting 9–12 months have the same or better outcomes?
3. Relative to a regimen lasting ≥18 months with new TB drugs (e.g. contains bedaquiline), does a bedaquiline-containing all-oral regimen lasting 9–12 months have the same or better outcomes?
Secondary – intervention population from South Africa data, and comparator populations are from IPDinMDR – 2019 or the EndTB observational study
1. Relative to people in the IPDinMDR – 2019 data set receiving a regimen lasting ≥18 months without the use of new TB drugs (e.g. does not contain bedaquiline, linezolid, delamanid, or carbapenems), does a bedaquiline-containing all-oral regimen lasting 9–12 months have the same or better outcomes?
2. Relative to people in the IPDinMDR – 2019 data set receiving a regimen lasting ≥18 months with new TB drugs (e.g. contains bedaquiline), does a bedaquiline-containing all-oral regimen lasting 9–12 months have the same or better outcomes?
3. Relative to people in the EndTB data set receiving a regimen lasting ≥18 months with bedaquiline and/or delamanid (for a maximum of 6-months), does a bedaquiline-containing all-oral regimen lasting 9–12 months have the same or better outcomes?
Background and Rationale
The use of shorter (9–12 months) regimens, in particular the new all-oral regimens for MDR/RR-TB, is presumed to have more benefits as compared to longer regimens lasting ≥18 months; as well as to other shorter injectable-containing regimens. Primarily, the shorter duration puts a lower burden on patients and reduces the direct and indirect costs (both to the patient and the healthcare system) associated with treatment since MDR/RR-TB treatment is usually delivered through directly observed therapy. Secondly, injectable-agents are among the most toxic drugs used for MDR/RR-TB, have poor efficacy against TB and can lead to irreversible adverse events. While treatment & care delivery for TB25, including patients with drug-resistant TB can be community-based, usually injection-containing regimens must be administered at health facilities, adding travel and waiting time to the discomfort and inconvenience, and potentially contributing to poor treatment adherence in some cases. Thus, there are several advantages to a shorter all-oral regimen if they are as effective as regimens that (a) last longer and/or (b) contain an injectable.
To date, shorter regimens have only been recommended for individuals who have not been exposed to second-line TB drugs (i.e. are new patients or have only received first-line TB drugs) and whose TB isolates have proven susceptibility to fluoroquinolones and second-line injectables. Given the nature of programmatic data, this latter criterion often simplifies to “not proven resistant” – i.e., their drug susceptibility test result is ‘susceptible’ or ‘not performed’ for these two classes of drugs, although in ideal settings, drug susceptibility results would be available. However, generally this means that patients with MDR/RR-TB that qualify for a shorter regimen are much less “complex”, than patients with MDR -TB with additional resistance patterns26 and XDR-TB, or that have been previously treated with second-line TB drugs. This makes comparisons of treatment of these two groups at very high-risk
25 Treatment & care delivery for TB is used in this context to refer to the administration of “Directly Observed Therapy [DOT]”.26 MDR -TB with additional resistance patterns refers to MDR-TB cases which present MDR-TB plus resistance to fluoroquinolones (MDR-
TB+FQ) or additional resistance to injectable agents (MDR-TB+SLI). This term does NOT mean MDR with resistance to PZA, EMB, Ethionamide Cycloserine or other similar and commonly used second-line drugs.
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of bias. Thus, for the purposes of this PICO question, we will exclude patients from all data sources (detailed below in Section 3.1) who have been exposed to second line drugs previously or who are MDR-TB with additional resistance to a second-line injectable and/or a fluoroquinolone. The number of patients excluded will be quantified, but are expected to be minimal, with only 4% and 1.5% of patients treated with a short regimen in South Africa previously receiving second-line drugs and having MDR -TB with additional resistance patterns or XDR, respectively, in a prior analysis of 2014–2015 data.
Within South Africa, over 10,000 people initiate MDR/RR-TB treatment each year. Both shorter (9–12 months) and longer (≥18 months) regimens have been used and, over the last 2–3 years, there has been a transition from the WHO recommended short, injectable-containing regimen, to one that has replaced the injectable with bedaquiline. Thus, the data from South Africa presents a unique opportunity to compare patient important outcomes with four different types of regimens27 delivered concurrently in the same settings, by the same providers, faced with the same health system resources and constraints. The comparisons within the South Africa data set are thus considered the primary analysis.
In addition to comparison within South Africa, use of patients from the IPDinMDR – 2019 database and/or from the EndTB observational study allow comparisons between settings and patients with different characteristics. If findings are similar, we can be more confident in their generalizability. Due to many potentially confounding differences between health systems and patients with MDR/RR-TB, within South Africa, and other settings, the comparisons between South African cohorts and other cohorts will be considered secondary.
Data Sources
South Africa
All data for MDR/RR-TB patients who initiated treatment within South Africa is housed within the Electronic Drug Resistant TB register (EDRWeb). This register includes information such as age, sex, facility of treatment, previous treatment history, HIV co-infection, ART use, every drug received during treatment, individual culture and smear results during treatment, drug-resistance testing (both genotypic and phenotypic), regimen type (short or long), and end-of-treatment outcomes.
We plan to use data from every individual in South Africa who initiated any short-regimen between Jan 1 and Dec 31, 2017 (N=3772) and data from every individual in South Africa who initiated a “long”-regimen in Q1 and Q2 2017 (Jan 1 to June 30, 2017) (N=3722). We selected the year 2017 for the short, injectable-free regimen as this was the first year this short-regimen had been widely used throughout the country. As well, regardless of the date a person started treatment that year, every individual should have at least 6 months of post treatment follow-up for possible relapse (data extraction for relapse is being performed in August 2019). We selected the first two quarters of 2017 (1 January to 30 June) for the long regimen as these patients would be receiving treatment concurrently with the short regimen patients and 95% of patients initiating therapy within this interval should have had an end of treatment outcome by 31 December 2018, allowing at least 6 months of follow-up for possible relapse. There may be concerns regarding selection of individuals to a short or long regimen when both were systematically offered in 2017. To examine this, we will also compare outcomes with the BDQ short regimen received in 2017 with outcomes among patients who received the conventional (long) regimen in 2016 for a second comparison. In 2016 only 213 of 13,193 (1.6%) persons starting RR/MDR-TB treatment received a short regimen, suggesting that selection bias should have been minimal in 2016, compared to 2017.
As many of the regimens being compared are significantly different in duration, accounting for relapse and death non-differentially presents a challenge. For example deaths during treatment may occur up to 18 or even 24 months after initiation of a conventional ‘long’ regimen, but only up to 12 months with
27 All-oral 9–12 month regimen; WHO recommended 9–12 month regimen; Longer regimen without new drugs; Longer regimen with new drugs.
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the short regimen. Therefore, death in Months 12–24 will be counted as ‘deaths during TB treatment’ with the long regimen, even if unrelated to TB, whereas they would not be classified as such with the short regimen. Similarly, a patient could have culture reversion at month 15 of a long regimen and be classified as a treatment failure, but such a late reversion would not detected with the short regimen (unless relapse was carefully measured). In both situations, knowledge of post-treatment relapse and death outcomes is crucial to minimize differential outcome ascertainment. We plan to detect relapses within EDRWeb by cross-matching all names of those treated in 2016 and 2017 with EDRWeb to ascertain if any patients who are classified as treatment success are subsequently restarted on MDR/RR treatment. We will detect these relapses by probabilistically matching patients within EDRWeb. However, as deaths following treatment completion are not recorded with EDRWeb (treatment must be initiated to be entered in this system), we will link all patients who started treatment in Jan 1 to June 30 2017, and those who started the short regimen from July 1 to Dec 31 2017 and successfully completed treatment with the South African MRC using their South Africa ID number to see if death occurred after treatment completion. Information about the South Africa ID within EDRWeb is ~90% complete, so we expect this should result in a fairly complete capture of deaths post-treatment.
IPDinMDR – 2019
In 2018 an IPD was assembled of 53 data sets from 40 countries/regions containing records for more than 13,000 patients with MDR-TB. This IPD-2018 data set was analyzed to answer a number of PICO questions developed by a WHO MDR-TB guidelines development group (GdG). These guidelines have since been published. This IPD-2018 itself was based on an IPD data set assembled in 2016–17 to answer questions of a GdG of the CDC/ATS/IDSA/ERS. These guidelines have not yet been published, but the analyses that informed this set of guidelines were published in the Lancet in Sept 2018. This database contains records of~150 patients from the EndTB study, who will be removed and updated with the more complete data set (see below). Further, the IPD-2018 contains about 3,500 records from South Africa, which we will exclude for the purposes of the secondary analyses.
Within this iteration of the IPD – 2019, we anticipate adding data from a public call executed by the WHO, however at the time of writing we are unsure of the type, number, and treatment regimens of patients who might be added.
EndTB Observational Study
The EndTB observational study includes 1094 patients with MDR-TB who were treated with bedaquiline- and/or delamanid-containing long regimens between 1 April 2015 and 31 March 2017 in 17 countries28. They were followed as part of an observational study – executed by three institutions – PIH, MSF and IRD. There is comprehensive data capture on all important variables within the data set, including detailed information on treatment associated adverse events.
Considerations for the IPDinMDR – 2019 and EndTB Observational Study Data Sets
Within the IPDinMDR – 2019 and EndTB data sets, there are important differences when compared to the South Africa cohorts from 2016 and 2017 that willl be analyzed. Firstly, these data sets contain patients treated from 2000–2017. We will only include patients initiating treatment from 1 January 2013 onwards to ensure comparability with the patients treated in 2016 and 2017 in South Africa. Further, it is important to compare patients treated in similar resource settings. The primary analysis will include patients treated in all settings, and in sensitivity analyses we will restrict the comparators to patients treated in other World Bank classified upper-middle-income countries, as is this is the category South Africa belongs to. We will quantify how many patients this represents and compare them to those we included from both studies.
28 Armenia, Bangladesh, Belarus, Democratic People’s Republic of Korea (DPRK), Ethiopia, Georgia, Haiti, Indonesia, Kazakhstan, Kenya, Kyrgyzstan, Lesotho, Myanmar, Pakistan, Peru, South Africa and Vietnam; (http://endtb.org/about)
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Defining Regimens
As the treatment trajectory of MDR/RR-TB represents the complex interaction of patient, provider and health system capacities and constraints, there may be deviations from intended durations of therapy and number of drugs used. We will examine descriptively the distribution of treatment duration for all persons who received long or short regimens, as well as the distribution of treatment duration for persons with successful treatment who received a long or a short regimen. Based on these descriptive analyses, we will select cut-points (ideally using inter-modal points) that appear to best define the duration of treatment that can be called ‘short’ and ‘long’ (e.g. how far before or after the ‘planned’ duration of ‘short’ treatment do we accept as still meeting the definition of a short regimen to include in this analysis?).
Therefore, we propose to establish criteria to classify people within regimen types. For data from South Africa, we plan to classify people who received a long-regimen as those who: (i) were classified as receiving a long-regimen within EDRWeb; (ii) had treatment duration not exceeding 24 months; (iii) received ≥4 TB drugs (any drugs, regardless of susceptibility for this definition) during treatment, regardless of whether they were effective and; (iv) if given an outcome of cure or complete, had a treatment duration ≥17.5 months. For data from IPDinMDR – 2019 and the EndTB data set, all patients received a long regimen, therefore we will include people conforming to criteria (ii), (iii), and (iv).
We plan to classify people who received a short-regimen as those who: (i) were classified as received a short-regimen within EDRWeb; (ii) had a treatment duration not exceeding 12 months; (iii) received ≥6 drugs during treatment and; (iv) if given an outcome of cure or complete, had a treatment duration ≥8.5 months. These duration cut-points are subject to change pending the distribution of treatment durations we find. The short regimen target duration is 9 months, but a 3-month (33%) extension is permissible by PICO definition, similarly, a long regimen target duration is 18 months, so the equivalent extension permissible is 24 months. Further, for the minimum treatment durations for success in the 2018 MDR Guideline Update, the 17.5 month cut-point for the long-regimen was used. A similar two-week period should be used for the short-regimen, which may reflect simply differences in dispensation of prescriptions (e.g. 36 weeks of meds vs. 270 days) or deviations in timing of visits and pills dispensed. We will describe any patients excluded because their treatment duration does not fall within these limits.
Regimen Classifications
Intervention Regimen
All-Oral Short Bedaquiline-Containing Regimen: The intervention in each analysis will be individuals who receive a short regimen (lasting 9–12 months) who did not receive any injectable during treatment and received bedaquiline.
Comparator Regimens
1. WHO Recommended Short-Regimen: The first comparator is the WHO recommended short-regimen, which consists of pyrazinamide, ethambutol, moxifloxacin/levofloxacin, and clofazimine given for 9–11 months with high-dose isoniazid, amikacin (if given kanamycin or capreomycin – these will be included), and ethionamide or prothionamide given in the first 4–6 months of treatment.
2. Long Regimen Without New TB Drugs: The second comparator is a long regimen given for a duration of 18–20 months, which does not contain one of the new TB drugs: bedaquiline, delamanid, linezolid, clofazimine, or carbapenems. The target duration of the regimen may not be reached due to treatment non-response, death, or loss to follow-up. Hence, we refer to long regimens as those intended to be given for ≥18 months in our analysis plan.
3. Long Regimen Containing New TB Drugs: The third comparator is a long regimen given for a duration of 18–20 months, which contains at least one of the new TB drugs: bedaquiline,
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delamanid, linezolid, clofazimine, or carbapenems. The target duration of the regimen may not be reached due to treatment non-response, death, or loss to follow-up. Hence, we refer to long regimens as those intended to be given for ≥18 months in our analysis plan.
Regimens Excluded from Analysis
a. Short-Regimen without Bedaquiline and Not Conforming to WHO Recommendations: It is possible patients are treated with a regimen lasting 9–12 months that does not conform to the WHO recommended regimen and does not contain bedaquiline. Individuals receiving a regimen falling into this category will be classified uniquely. We will compare characteristics and outcomes of these patients to others receiving a short regimen descriptively, but they will be excluded from analysis.
b. Short-Regimen with Bedaquiline and an Injectable: It is possible patients began a short-regimen with an injectable, only to have it stopped and replaced with bedaquiline. Individuals receiving a regimen falling into this category will be classified uniquely. We will compare characteristics and outcomes of these patients to others receiving a short regimen descriptively, but they will be excluded from analysis.
Analysis of Outcomes
The PICO lists eight distinct outcomes: (i) Successful completion of treatment, (ii) Bacteriological cure by end of treatment, (iii) Adherence to treatment (or treatment interruption due to non-adherence)29; (iv) Treatment failure or relapse, (v) Death during treatment, (vi) Adverse reactions from anti-TB medicines, (vii) Acquisition (amplification) of drug resistance, and (viii) Sustained bacteriological cure at least 6 months after successful treatment
We will combine failure and relapse, and also combine completion and cure as success. We will estimate odds of relapse free treatment success vs several combinations of poor outcomes, and also examine loss to follow-up (LTFU) vs other outcomes – as summarized below. Adverse reactions from anti-TB medicines, and acquisition of drug resistance during treatment can NOT be analyzed using South Africa data as this information is not routinely captured in South Africa’s EDRWeb.
Comparisons analyzed:
1. Relapse free treatment success (cure + treatment completion) up to 24* months post treatment initiation vs. failure/relapse
2. Relapse free treatment success (cure + treatment completion) up to 24* months post treatment initiation vs. failure/relapse and death during treatment.
3. Relapse free treatment success (cure + treatment completion) up to 24* months post treatment initiation vs. all other outcomes (fail/relapse, death, and loss to FU).
4. Lost to follow-up during treatment vs. all other outcomes.
* The follow-up periods were selected as this will give follow-up times that are comparable for both regimens. A key consideration is that the first patient in our analysis initiates treatment in January 2017 and follow-up ends in June 2019 (30 months elapsing from the time of the first patient recruited until follow-up ends). This time elapsed necessarily shrinks as the year progresses. Thus, setting a limit of 24 months post-treatment initiation for follow-up, and censoring events occurring beyond this period, maximizes the study population for comparison. As this limitation necessarily excludes all patients initiating treatment beyond June 2017, we will conduct sensitivity analyses, examining outcomes 18-months post treatment initiation and 21-months post treatment initiation. Therefore, we will have three comparisons described in the table below:
29 This correlates with loss to follow-up
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Months of Follow-up Post-Treatment Initiation
Dates of Patients Included Receiving Short Regimen
Dates of Patients Included Receiving Long Regimen
18 months January to December 2017 January to June 2017
21 months January to September 2017 January to June 2017
24 months January to June 2017 January to June 2017
Outcomes are clinician defined within South Africa and from our experience largely reflect Laserson (WHO 2005) criteria; this is how the majority of outcomes have been defined in IPDinMDR – 2019 (44/53 studies). Within EndTB, outcomes are coded as per WHO 2013 outcomes, however we will also create outcomes based on microbiologic data to align with WHO 2005 for comparability.
Summary of Approach for Each Research Question
We will conduct all main analyses described in sections 5.1.1, 5.2.1, and 5.3.1 using the concurrent long regimen controls (from Q1 and Q2 2017) and the historical long regimen controls (from all of 2016). These estimates will be shown separately. We will only conduct sensitivity analyses in these sections on the concurrent long regimen controls. For the outcomes described in section 4.0, we will conduct sensitivity analyses examining outcomes up to 18-months and 21-months post-treatment initiation in addition to those at 24 months post-treatment initiation.
Overall Descriptive Analysis
Before analysis of each research question, we will conduct a descriptive analysis for each of the reference and exposure group (detailed below), looking at key characteristics including: age (continuous and 0–14 vs. 14+ and 10–19 vs. 19+), sex, previous treatment history (drugs received and outcome), baseline acid-fast bacilli smear result, number of drugs received during treatment, total number and type of drugs resistant to (not double-counting ‘similar ’ drugs of ethionamide/prothionamide and cycloserine/terizidone, for example), presence of specific drugs in the regimens (e.g. bedaquiline, linezolid, clofazimine, moxifloxacin/levofloxacin, delamanid), and province of treatment. This will help clarify if there are systematic differences between the people who received each regimen, possible differences in where each regimen was used, and provincial differences in overall treatment outcomes. The information elicited from this analysis will be used to inform further variables for matching and/or adjustment described below – for example, addition of a random-effect for province of treatment (or exact matching within the province). Thus, within the approach for each question, the listed variables are an a priori list for inclusion, but may be modified based on data completeness and availability, and further sensitivity analyses including/excluding other variables may be developed based on the results of the descriptive analyses.
The descriptive analysis is also intended to determine how many individuals would be excluded due to regimen composition. We will see if there are any important differences between those included and excluded from analysis.
Primary Analysis (within South Africa only)
Primary Analysis Question 1
Relative to the WHO recommended short-regimen lasting 9–12 months, does a bedaquiline-containing all-oral regimen lasting 9–12 months have the same or better outcomes?
Intervention: All-Oral Short Bedaquiline-Containing Regimen 9–12 months in duration Comparator: WHO Recommended Short-Regimen
WHO consolidated guidelines on tuberculosis: Online annexes136
Approach
Our approach will be to use a combination of exact matching and propensity score-based matching on several covariates to create two groups that are as comparable as possible, and thereby minimize bias and confounding. Between the intervention and comparator groups, we will perform exact matching on HIV co-infection/ART-use, previous TB treatment history (a 2 level variable – never and prior 1st line [recall, all people who previously received 2nd line TB treatment will be excluded]), and total number of drugs the strain was resistant to – this latter covariate is key to ensure the groups are comparable with regard to the full resistance patterns. We will further perform propensity score-based matching on age, sex, and baseline sputum AFB smear result. This matching process will be conducted with replacement using a caliper distance of 0.02 during the propensity score-based matching. We will examine the distribution of the matched covariates within the intervention and comparator groups to assess the fidelity of the matching process.
For each outcome described in section 4.0, within our ‘matched’ population we will conduct logistic regression using mixed-models including random-intercepts for each matched ‘pair ’ and, depending on what we find for the descriptive analysis, for province of treatment. We will not include random-slopes as our experience is that there are significant model convergence issues when these random-effects are included. The logistic regression analysis will calculate adjusted odds ratios and associated 95% confidence intervals. We will further conduct binomial regression, using only fixed effects, on the matched population to calculate adjusted risk differences and their associated 95% confidence intervals.
Primary Analysis Question 2
Relative to a regimen lasting ≥18 months without the use of new TB drugs (e.g. does not contain bedaquiline, linezolid, delamanid, or carbapenems), does a bedaquiline-containing all-oral regimen lasting 9–12 months have the same or better outcomes?
Intervention: All-Oral Short Bedaquiline-Containing Regimen 9–12 months in duration Comparator: Long Regimen Without New TB Drugs
Approach
We will utilize the same approach described in section 5.1.1 to compare outcomes among people receiving the intervention and comparator regimens.
Primary Analysis Question 3
Relative to a regimen lasting ≥18 months with new TB drugs (e.g. contains bedaquiline), does a bedaquiline-containing all-oral regimen lasting 9–12 months have the same or better outcomes?
Intervention: All-Oral Short Bedaquiline-Containing Regimen 9–12 months in duration Comparator: Long Regimen Containing New TB Drugs
Approach
We will utilize the same approach described in section 5.1.1 to compare outcomes among people receiving the intervention and comparator regimens.
If there are enough patients, we will conduct sensitivity analyses within sub-groups defined by use of specific drugs, or combinations of drugs. For example, the sub-group of patients who received, or did not receive linezolid, or delamanid, or bedaquiline, or carbapenems, as part of a long regimen. If any of the subgroup analyses result in <100 patients being included in the analysis population, we will not conduct analyses. We will further conduct a sensitivity analysis repeating the approach in section 5.1.1 for other new or repurposed drugs: delamanid, linezolid, and carbapenems.
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Secondary Analysis (Comparing to IPDinMDR – 2019 or EndTB Data Sets)
Secondary Analysis Question 1
Relative to people in the IPDinMDR – 2019 data set receiving a regimen lasting ≥18 months without the use of new TB drugs (e.g. does not contain bedaquiline, linezolid, delamanid, or carbapenems), does a bedaquiline-containing all-oral regimen lasting 9–12 months have the same or better outcomes?
Intervention: All-Oral Short Bedaquiline-Containing Regimen 9–12 months in duration Comparator: Long Regimen Without New TB Drugs
Approach
We will utilize the same approach as described in section 5.1.1 to compare outcomes among people receiving the intervention and comparator regimens. Recall that we will only include people from the IPDinMDR – 2019 data set who began treatment from the year 2013 onward and who were treated in an upper-middle income country. We will conduct a sensitivity analysis relaxing the criteria for country-level income and report the outcomes.
Secondary Analysis Question 2
Relative to people in the IPDinMDR – 2019 data set receiving a regimen lasting ≥18 months with new TB drugs (e.g. contains bedaquiline), does a bedaquiline-containing all-oral regimen lasting 9–12 months have the same or better outcomes?
Intervention: All-Oral Short Bedaquiline-Containing Regimen 9–12 months in duration Comparator: Long Regimen Containing New TB Drugs
Approach
We will utilize the same approach as described in section 5.1.1 to compare outcomes among people receiving the intervention and comparator regimens. Recall that we will only include people from the IPDinMDR – 2019 data set who began treatment from the year 2013 onward and who were treated in an upper-middle income country. We will conduct a sensitivity analysis relaxing the criteria for country-level income and report the outcomes.
If there are enough patients, we will conduct further sensitivity analyses within sub-groups defined by use of specific drugs, or combinations of drugs. For example, the sub-group of patients who received, or did not receive linezolid, or clofazimine, or delamanid, or bedaquiline, or carbapenems, as part of a long regimen. If any of the subgroup analyses result in <100 patients being included in the analysis population, we will not conduct analyses. We will further conduct a sensitivity analysis repeating the approach in section 5.1.1 for other new or repurposed drugs: delamanid, linezolid, and carbapenems.
Secondary Analysis Question 3
Relative to people in the EndTB data set receiving a regimen lasting ≥18 months with bedaquiline and/or delamanid (for a maximum of 6-months), does a bedaquiline-containing all-oral regimen lasting 9–12 months have the same or better outcomes?
Intervention: All-Oral Short Bedaquiline-Containing Regimen 9–12 months in duration Comparator: Long Regimen Containing New TB Drugs
Approach
We will utilize the same approach as described in section 5.1.1 to compare outcomes among people receiving the intervention and comparator regimens. Recall that we will only include people from the EndTB observational study data set who began treatment from the year 2013 onward and who
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were treated in an upper-middle income country. We will conduct a sensitivity analysis relaxing the criteria for country-level income and report the outcomes.
As all patients in EndTB observational study data set received bedaquiline and/or delamanid, we will conduct further sensitivity analyses within sub-groups defined by use of these specific drugs. These will include patients who received, or did not receive, bedaquiline, or delamanid, or both bedaquiline and delamanid. If any of the subgroup analyses result in <100 patients being included in the analysis population, we will not conduct analyses.
Limitations
Within the South Africa cohorts, drug resistance testing is reflexive and generally relies solely on genotypic drug resistance tests: Xpert MTB/RIF for rifampicin and line probe assays for isoniazid and rifampicin (GenoType MTBDRplus) and fluoroquinolones and second-line injectables (GenoType MTBDRsl). Because of this, resistance to drugs commonly used in short regimens (pyrazinamide, clofazimine, ethambutol, and ethionamide/prothionamide) is likely not available for most patients. As we are matching patients exactly on previous treatment history and pre-XDR/XDR phenotypes are excluded (as they would not be eligible for a short-regimen), we expect these unknown resistances to be similar between the groups being compared.
We do not have chest radiographic results at baseline which may have influenced a clinician’s decision to treat patient with a short or long regimen. Hence this must be considered an unmeasured confounder.
Adverse events and acquisition (or amplification) of drug resistance are not reported in the South Africa cohorts, so analyses of these important outcomes are not possible.
Co-morbidities of diabetes, mental health disorders, and others are not routinely captured within EDRWeb, so the potential impact of these disorders on treatment outcomes cannot be analyzed. Extrapulmonary TB is not included in the IPDinMDR – 2019 data set and represents only 2% of patients receiving a short regimen in a previous extract of EDRWeb, so they cannot be analyzed as a subgroup as well. However bacteriologic confirmation of cure or failure/relapse is rarely obtained, which makes analysis of these outcomes more subject to observer bias. And, in drug sensitive TB results of RCT in pulmonary TB have been successfully applied to treatment of extra-pulmonary TB.
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A6.1.2: PICO question 2: In XDR-TB patients or patients who are treatment intolerant or with non-responsive MDR-TB, does a treatment regimen lasting 6-9 months composed of bedaquiline, pretomanid and linezolid safely improve outcomes when compared with other regimens conforming to WHO guidelines?
Comparative analysis of outcomes and safety between current XDR-TB treatments and a new regimen of bedaquiline, pretomanid, and linezolid.
Statistical Analysis Plan, Draft. Prepared by Dick Menzies, Nicholas Winters and Jonathon Campbell, McGill University.
PICO Question (WHO):
In XDR-TB patients or patients who are treatment intolerant or with non-responsive MDR-TB, does a treatment regimen lasting 6–9 months composed of bedaquiline, pretomanid and linezolid safely improve outcomes when compared with other regimens conforming to current WHO guidelines?
Population Intervention Comparator Outcomes
XDR/TB patients or and/ or those who are treatment intolerant or with non-responsive MDR-TB:a. with additional drug resistance patternsb. with severe disease (i.e. cavitary disease on radiography or SS+)c. previously treated with 2nd line drugs or not persons with HIV (+/- ARVs)d. adults (adolescents 10–19y if available)e. With comorbidities (e.g. diabetes mellitus; malnutrition; mental disorders)
– Nix-TB trial regimen containing bedaquiline, pretomanid and linezolid given for 6 to 9 months
– Using matched controls from the individual patient dataset (*current WHO recommendations)[1]
• Successful completion of treatment (or lack of successful completion)
• Bacteriological cure by end of treatment
• Adherence to treatment (or treatment interruption due to non-adherence)
• Treatment failure or relapse
• Survival (or death)• Adverse reactions from anti-TB medicines
• Acquisition (amplification) of drug resistance
Research Questions:
1. Do patients receiving BPaL have the same or better outcomes 24 months post treatment start compared to patients receiving non-pretomanid regimens containing BDQ/LZD, with total duration of treatment of 24 months (within an allowed range of 22.5 to 25.5 months)
2. Do patients receiving BPaL have the same or better outcomes 18 months post treatment start compared to patients receiving non-pretomanid regimens containing BDQ/LZD for with total duration of treatment of 18 months (within an allowed range of 17 to 19 months – see Page 6)
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3. What is the occurrence of Grade 3–5 adverse events (AE), serious AE, and AE resulting in permanent discontinuation of at least one of the three component drugs of the Nix-TB regimen. (This is descriptive only, and ideally these rates of AE would be compared to rates with a WHO recommended BDQ/LZD containing regimen, but the comparator would have to come from a data set with equally careful and thorough ascertainment of treatment associated AEs.)
Rationale:
Despite global advances in controlling Tuberculosis (TB), this remains one of the most important communicable diseases in the world, accounting for an estimated 10 million cases and 1.6 million deaths in 2017 [WHO TB Report 2018]. Treatment of drug sensitive TB is highly effective in randomized controlled trials, however, treatment is much less effective for drug resistant strains of TB, particularly multidrug resistant TB (MDR-TB), defined as TB that is resistant to both rifampicin (Rif ) and Isoniazid (INH). As TB strains become more resistant, the treatment is increasingly difficult. MDR-TB patients with additional resistance to at least one fluoroquinolone and one second-line injectable, termed extensively drug resistant TB (XDR-TB), are an increasing public health concern. There were an estimated 600,000 cases of MDR-TB in 2016, of which approximately 6.2% were XDR-TB [WHO TB report 2018].
Currently, for treatment of XDR-TB the WHO recommends the use of at least five drugs in the intensive phase and four in the continuation phase, with durations ranging from 18–24 months. In the XDR-TB patients notified to the WHO in 2015, only 34% completed treatment and 26% died. These poor outcomes are in large part due to a lack of novel drugs, as well as lengthy treatment duration and frequent drug toxicity that result in low adherence. In order to combat XDR-TB and prevent possible devastating epidemics, new drugs as well as shorter regimens that increase the likelihood of adherence are needed.
A novel, all-oral, treatment regimen consisting of bedaquiline, pretomanid and linezolid (BPaL) for 6 months has been assessed in an open-label trial. However, the trial had no comparison group. To adequately assess the efficacy and safety of this new regimen in the context of current XDR-TB treatment, it is essential to compare outcomes in NIX-TB trial patients with similar patients who received different regimens. To do this we plan to use an individual patient dataset, contributed over the past 3 years by more than 55 centres. This data now includes more than 13,000 patients with MDR and more than 3,000 patients with pre-XDR and XDR TB.
Data Sources:
Intervention group: the Nix-TB study was a one arm, phase 3, open labeled trial assessing the safety and efficacy of BPaL in patients > 14 years of age with confirmed sputum culture-positive XDR-TB or treatment intolerant/non-responsive MDR-TB. The trial was conducted between 2014 and 2019 in South Africa. The data from this trial that will be used in our analyses includes, but is not limited to: age, sex, race, medical history (BMI, diabetes, alcohol), TB treatment history, AFB smear microscopy results, Gene Xpert results, HIV and ART use, chest x-ray results, sputum culture result, patient reported severity of TB symptoms and health status, hematology/CBC/FBC, clinical chemistry, urinalysis, DST results (phenotypic), adverse events (AE) and serious AE based on DMID severity scale.
Control or comparison group: Patients included in an individual patient data meta-analysis (IPD-MA) study, that included MDR/XDR-TB patients from 53 studies/centres in 40 countries. The included patients began treatment between 1993 and 2016, but we will select patients treated after BDQ was approved for treatment of MDR-TB in 2013 (of the XDR or pre-XDR patients there were 1007 on Bdq and 956 on Lzd). These patients will be matched to patients in the Nix-TB trial, on the basis of patients’ characteristics, DST, drugs used, and other factors that will affect treatment propensity (described in detail below).
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Regimens:
Intervention: The Nix-TB regimen consists of bedaquiline (Bdq, at a 400 mg once daily for 2 weeks then 200 mg 3 times per week), pretomanid (200 mg once daily) and linezolid (Lzd, at a daily dose of 1200 mg/day) for 6–9 months (9 months if sputum culture positive at 4 months). These patients were followed for up to 24 months after treatment end.
Comparison (control): 4 comparator regimens will be assessed. Patients receiving regimens for up to 25.5 months (Q1) or 19.0 months (Q2) that contained:
Bdq plus Lzd plus other anti-TB drugs, Bdq plus others, Lzd plus others, Neither Bdq nor Lzd, but other drugs.
No patients in the IPD received pretomanid. In the Nix-TB trial there are treatment start and stop dates, and in the MDR IPD we have precise total/planned treatment duration until outcome. Thus, analyses will be conducted comparing patients in both regimens from time of treatment start to outcome or end of the specified analytical duration.
The regimens used in the IPD-MA for XDR-TB are significantly longer than the 6–9mo BPaL regimen in the Nix-TB study. This will present difficulties in comparing end-of-treatment outcomes, particularly failure and death. Patients treated with the conventional longer regimens have a much longer time during which they could die (of TB or other causes) or fail. Patients treated with conventional 18 or 24 months regimens may have sputum culture conversion at 6 months, but later revert to culture positivity. If treatment had been only 6 months, they would have been considered a ‘cure’, and then a relapse. Similarly, if a patient dies in the 15th month of conventional XDR treatment, that is, by definition a ‘death during treatment’ whereas if the regimen had been only 6 or 9 months, this would not have been a death during treatment. It is therefore necessary to assess outcomes from treatment start to a specified duration of time where after any events that occur in the comparator groups are censored, as diagramed below (Tx = treatment). Therefore in our analyses of treatment outcomes, all relapses or deaths (regardless of cause) occurring post-treatment in NIX-TB patients, up to 25.5 months (Question 1) or up to 19.0 months (Question 2) post treatment start, will be considered to have the outcomes of failure/relapse, or death and considered equivalent to “during treatment” failure or deaths with conventional regimens.
Tx start
Comparator Tx end
6months 18months 24months
BPaL Tx end
Duration used in analysis
Question 1
BPaL
Comparator
BPaL
Comparator
Tx start
ComparatorTx end
6months 18months 24months
BPaL Tx end
Duration used in analysis
Question 2
Censored (excluded)
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Outcome Definitions:
The PICO lists seven distinct outcomes: (i) Successful completion of treatment, (ii) Bacteriological cure by end of treatment, (iii) Adherence to treatment (or treatment interruption due to non-adherence); (iv) Treatment failure or relapse, (v) Death during treatment, (vi) Adverse reactions from anti-TB medicines, and, (vii) Acquisition (amplification) of drug resistance
In the analyses, we will combine failure and relapse, and also combine completion and cure as success. We will estimate odds of relapse free treatment success vs several combinations of poor outcomes, and also examine LTFU vs other outcomes – as summarized below.
Adverse reactions from anti-TB medicines, and Acquisition of drug resistance during treatment can NOT be analyzed using the IPD data as this information is not routinely captured in many data sets. These two outcomes were measured in the NixTB study carefully, so can be described. As discussed below a different source of comparator data would be ideal. This has been discussed and agreed upon in principle by investigators with the EndTB and the Alliance, and is now described briefly in the sensitivity analyses.
The outcomes are defined in the Nix-TB protocol as follows:
Bacteriologic failure: during the treatment period = failure to attain culture conversion to negative; bacteriologic relapse: during the follow-up period = failure to maintain culture conversion to negative status in culture, with culture conversion to positive status with a Mycobacterium tuberculosis (M.tb.) strain that is genetically identical to the infecting strain at baseline;
Clinical failure: a change from protocol-specified TB treatment due to treatment failure, retreatment for TB during follow up, or TB-related death.
In the IPD cohorts treatment outcomes were defined according to the WHO guidelines, summarized below:
WHO 2005 (Laserson) Outcome Definitions (44/53 studies in our IPD used these definitions or definitions based on bacteriologic criteria)
Outcome Definition
Cure Completed treatment according to program protocol and has at least five consecutive negative cultures from samples collected at least 30 days apart in the final 12 months of treatment. If only one positive culture is reported during that time, and there is no concomitant clinical evidence of deterioration, a patient may still be considered cured, provided that this positive culture is followed by a minimum of three consecutive negative cultures taken at least 30 days apart.
Complete Completed treatment according to program protocol but does not meet the definition for cure because of lack of bacteriological results (i.e. fewer than five cultures were performed in the final 12 months of treatment).
Failure Treatment will be considered to have failed if two or more of the five cultures recorded in the final 12 months of therapy are positive, or if any one of the final three cultures is positive. (Treatment will also be considered to have failed if a clinical decision has been made to terminate treatment early because of poor clinical or radiological response or adverse events).
Death A patient who dies for any reason during the course of MDR/RR-TB treatment
Lost to Follow-up A patient whose treatment was interrupted for two or more consecutive months for any reason without medical approval.
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WHO 2013 Outcome Definitions: 9/53 studies in our IPD used these definitions
Outcome Definition
Cure Treatment completed as recommended by the national policy without evidence of failure AND three or more consecutive cultures taken at least 30 days apart are negative after the intensive phase (or Month 8 if no intensive phase).
Complete Treatment completed as recommended by the national policy without evidence of failure BUT no record that three or more consecutive cultures taken at least 30 days apart are negative after the intensive phase (or Month 8 if no intensive phase).
Failure Treatment terminated or need for permanent regimen change of at least two anti-TB drugs because of: (1) lack of conversion by the end of the intensive phase, or (2) bacteriological reversion in the continuation phase after conversion to negative, or (3) evidence of additional acquired resistance to fluoroquinolones or second-line injectable drugs, or (4) adverse drug reactions.
Death A patient who dies for any reason during the course of treatment
Lost to Follow-up A patient whose treatment was interrupted for 2 consecutive months or more.
For our analysis, we will use different outcome definitions for patients in the Nix-TB trial from patients in the IPD-2019. For Nix-TB, the detailed clinical and microbiologic data will be used to verify the investigator defined end-of-treatment outcomes. Assuming they match their definition outlined in their protocol, we will use their investigator defined end-of-treatment outcomes, plus account for relapse during up to 18 months of post-treatment follow-up. For the EOT outcomes in the IPD-2019, we will use the investigator defined outcomes as well. In the data set we have now, 44/53 data sets used 2005 WHO guidelines to define these outcomes, and 9/53 stated they used WHO2013, but all data sets contained sufficient information to verify that almost all patients met microbiologic outcome definitions (ie fit WHO2005). Therefore we have already redefined the outcomes of the nine studies that used the 2013 guidelines to conform to the 2005 WHO criteria. In summary, within the IPD-2019 data set, we will verify investigator defined outcomes, reclassify if applicable to meet microbiologic criteria (WHO 2005 criteria) and compare these end-of treatment outcomes in the analysis to the NixTB investigator defined outcomes (including relapse as above). The coding of all information from the Nix-TB study will be verified with Alliance staff, and all discordant outcomes will also be verified manually (ie if a specific patient is classified as having treatment success in the original data set but does not meet that definition using the data we have – this will be manually checked)
Analytic approach:
Descriptive statistics:
Treatment outcomes: as described above, the treatment outcomes assigned to patients in the NixTB trial will be reclassified (potentially) according to WHO 2005 definitions, using the detailed clinical and microbiological information available from the Alliance. The concordance of these outcome swill be verified as a first step. Any discordance will be verified manually and the data and programming may also be verified with the Alliance.
Duration: As the treatment trajectory of MDR/RR-TB represents the complex interaction of patient, provider and health system capacities and constraints, there may be deviations from intended durations of therapy and number of drugs used. In the IPD data, we will examine descriptively the
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distribution of treatment duration for persons with successful treatment who received one of the four comparator regimens. Based on these descriptive analyses, we will select cut-points (ideally using inter-modal points) that appear to best define the duration of treatment that can be called ‘18 months’ and ’24 months’ (e.g. how far before or after the exact duration of 18 or 24 months do we accept as still meeting the definition of a regimen of 18 or 24 months to include in this analysis?). A second issue is the planned duration in persons who die, or are lost to follow-up (‘default’), or fail and therapy is stopped early. These patients will not have an actual treatment duration of 18 or 24 months, but of course must be included in the analyses to avoid bias. To identify persons with these outcomes we will use the planned duration (listed in many data sets). In some data sets planned duration is not given. In these we will examine the frequency distribution of duration in those patients treated successfully at the same centres. If this is unimodal, then the mode will be considered the planned duration. If this is a more complex distribution then we will predict the duration based on key predictors of duration (age, extent of resistance, extent of disease and specific drugs used) at that centre.
Patient populations Before analysis of each research question, we will conduct a descriptive analysis for the BPal and four comparator groups (detailed below), looking at key characteristics including: age (continuous and 0–14 vs. 14+ and 10–19 vs. 19+), sex, previous treatment history (drugs received and outcome), baseline acid-fast bacilli smear result, number of drugs received during treatment, total number and type of drugs resistant to (not double-counting ‘similar ’ drugs of ethionamide/prothionamide and cycloserine/terizidone, for example), presence of specific drugs in the regimens (e.g. bedaquiline, linezolid, clofazimine, moxifloxacin/levofloxacin, delamanid), and country of treatment. This will help clarify if there are systematic differences between the people who received each regimen, and possible differences in characteristics and outcomes where each regimen was used. The information elicited from this analysis will be used to inform further variables for matching and/or adjustment described below, and addition of a random-effect for country of treatment (or exact matching by country). Thus, within the approach for each question, the listed variables are an a priori list for inclusion, but may be modified based on data completeness and availability, and further sensitivity analyses including/excluding other variables may be developed based on the results of the descriptive analyses. The descriptive analysis is also intended to determine how many individuals would be included, and excluded due to regimen composition. In addition, for non-Nix-TB patients we will include the number of drugs received during treatment and presence of specific drugs in the regimens (e.g. Bdq, Lzd, clofazimine, moxifloxacin/levofloxacin, delamanid).
Comparing efficacy of regimens::
Q1: Do patients receiving BPaL have the same or better outcomes 24 months post treatment start compared to patients receiving one of 4 comparator non-pretomanid containing regimens, with total duration of treatment of 24 months (within an allowed range of 22.5 to 25.5 months). These four comparators are: (1) Bdq+Lzd+others, (2) Bdq+others, (3) Lzd+others, and (4) neither Bdq or Lzd containing regimens.
Comparisons:
1. Relapse free treatment success (defined as cure or treatment completion) vs. bacteriological/clinical failure or relapse.
2. Relapse free treatment success vs. death
3. Relapse free treatment success vs. clinical/bacteriological failure or relapse, or death.
4. Relapse free treatment success vs. clinical/bacteriological failure or death or relapse or lost to follow-up/default.
Our approach will use a combination of exact matching and propensity score-based matching on several covariates to select comparator groups from the IPD-MA that are as comparable as possible to the patients who received BPal, and thereby minimize bias and confounding. All patient matching
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will be performed by an algorithm in our statistical software that will randomly select from the best patient matches. This algorithm will not include outcome. The variables used for exact matching will depend on the distribution of characteristics in the Nix-TB data and will be finalized once we are able to explore this in detail. For exact matching, we anticipate matching on two variables we consider critical: (1) XDR vs non-responsive/intolerant MDR-TB; and, (2) HIV infection and ART-use. Once we have matched on these two critical variables, we intend to further match exactly, if possible, based on the following important variables: (3) number of drugs to which the patient’s isolate is resistant, and, (4) previous FLD/SLD use, and if the data allows, also (5) disease severity (indicated by one of: AFB smear, cavitary and/or Bilateral disease),. These variables will ensure that patients with clinical profiles which predict their treatment outcomes will be compared. There may be issues with identifying patients in the IPD cohort who have non-responsive/intolerant MDR-TB. If so, we will select IPD patients who have previous SLD use. In addition, we will match patients based on PS, calculated using age, sex, and remaining variables of the three important variables listed above which could not be used for exact matching (AFB smear, Cavitation, number of drugs resistant to, etc). We will allow a calliper distance equal to 0.2 of the standard deviation of the logit of the propensity score. Matching will be done with replacement. If no potential matches fall within the calliper distance, the next closest match to 0.2 of the standard deviation will be selected. We will assess the success of matching by assessing the balance of confounders between the two groups. Additionally, we will determine how many patients were matched more than once to different patients in Nix-TB. This will indicate the need for consideration of methods to control for the effects of independence and increased variance on model fit, from having multiple matches.
The power of this analysis is limited by the small number of patients in the NixTB study. To enhance power, we will match up to 4 controls from the IPD to each Nix-TB patient, depending on whether there are sufficient numbers of suitable matches to each NixTB patient (Four is considered the optimal number to enhance power, after which little added power is gained by matching further controls).
For each outcome, we will conduct logistic regression using mixed-models including random-intercepts for each matched ‘pair ’ and, depending on what we find for the descriptive analysis, for country of treatment. We will not include random-slopes as our experience is that there are significant convergence issues when these random-effects are also included. Outcomes will be dichotomous (i.e. the outcome occurred during the specified analysis duration = 1 vs. the outcome not occurring = 0). The logistic regression analysis will calculate adjusted odds ratios and associated 95% confidence intervals. We will further conduct binomial regression, using fixed effects, on the ‘matched’ group to calculate adjusted risk differences and their associated 95% confidence intervals.
For post-treatment relapse, we will first determine in which data sets of IPD-2019 this outcome was assessed. Then we will obtain information from the study authors on the methods of ascertainment, the intensity of follow-up visits, and the duration of follow-up. This will give us an idea of the comparability of this outcome with that of the NixTB study. In addition duration of follow-up and timimg of relapse may not be available for all individuals or centres. Therefore we will present cumulative incidence of relapse in each study as the proportion of patients relapsing out of the total number of patients that succssfully completed treatment.
This analysis will be repeated for each of the four comparisons listed above.
Q2: Do patients receiving BPaL have the same or better outcomes 18 months post treatment start compared to patients receiving non-pretomanid regimens containing BDQ/LZD for with total duration of treatment of 18 months (within an allowed range of 17 to 19 months)
We will use the same methods outlined in Q1, except that duration used in the analyses will be 18 months, and any event occurring in post treatment follow-up of the BPal group after this period will be censored.
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Q3: Descriptive analysis of the occurrence of Grade 3–5 adverse events (AE), serious AE, and AE resulting in permanent discontinuation of at least one of the three component drugs of the Nix-TB regimen. Three separate but related outcomes.
We will describe the occurrence of any of the secondary outcomes listed above to present results on the safety related measures recorded in the Nix-TB data. Permanent discontinuation of each component drug of the BPaL regimen will be analysed, and the stoppage of one drug but continuation of the others will be considered a drug associated AE for the drug that was stopped. In addition, we will also investigate the effects of dose reduction. We will use proportions or mean (standard deviations) where appropriate. This will not be compared to any of the comparator groups in our IPD listed above.
Comparator: As noted earlier, this safety analysis is limited by the lack of an adequate comparator population, as AE’s were not ascertained with the same methods in the IPD-MA studies. Ideally these rates of AE would be compared to rates with a WHO recommended BDQ/LZD containing regimen, but the comparator would have to come from a data set with equally careful and thorough ascertainment of treatment associated AEs. The only data set to which we have access with comparable methods of systematically assessing AEs is the EndTB data set. We suggest that the AEs’ reported – in patients who received one of the 4 types of regimens listed above in the EndTb study, would be compared with the AEs reported in NixTB. Note that this suggestion would require the agreement of the EndTB investigators as well as the Alliance)
Sensitivity analyses:
We will conduct the same analyses outlined in Q1 and 2 using different subpopulations of patients to select comparators:
(1) Match patients in the Nix-TB trial to patients in IPD-2019, using ONLY South African cohorts. By limiting to South African cohorts, we will match to patients from the same region, which may account for unique characteristics of the patient populations.
(2) Match patients in the Nix-TB trial to patients who received treatment ONLY in high income countries. This may result in a better match on the basis of resources available for follow-up.
(3) Limit comparisons to patients from studies where relapse was ascertained for at least 6 months of follow-up post treatment end. We will contact authors from these studies to obtain any additional information re definition and methods for ascertainment for relapse.
(4) to compare AE between Nix-TB and a suitable comparator group, we need to ensure we have patient populations that are comparable, but also that AE are ascertained in a similar way. In the IPD-2019 we did not have systematic methods to detect, define, investigate manage or report AEs. Thus, we will match patients in the Nix-TB trial to those from the EndTB data, as AE were collected and documented with similar intensity of monitoring to Nix-TB.
Limitations:
There may have been substantial selection bias into the Nix-TB trial, as there was no randomization. Hence participation could have been influenced by physician selection of patients judged better able to tolerate the regimen, or that were sicker, with fewer treatment options (i.e. selection bias could go either way). There is also the potential for bias in the comparison of patients in NixTB with the IPD patients due to differences in loss to follow up. We can lessen, but not eliminate the impact of these biases, by exact and propensity score matching patients in the Nix-TB study to patients in the MDR IPD. This matching should result in patient groups that are balanced with respect to measured confounding factors, which should enhance clinical utility of the results. There may also be limitations in achieving four exact matches on all variables for each NixTB patient. This is why we have listed variables in order of their importance, and PS matching on the same variables will be used if exact
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matching cannot be achieved. In addition, we will use PS matching with a wider caliper distance to achieve matching, if necessary.
Additionally, as noted above, the data on safety is limited in our IPD, and so we will be unable to compare the secondary safety outcomes between patients in NixTB and the IPD.
Relapse was not measured systematically in most studies included in the IPD-2019. Hence this may have been under-estimated. As well for patients treated for 24 months, they finish treatment at the same time as post treatment follow-up ends for the NIXTB patients. So to include post-treatment follow-up will bias results as different lengths of Follow-up can lead to differences in outcomes due to other events. Relapse can be measured for 6 months if treatment is only 18 months, but early relapse rates tend to be highest – so this may overestimate cumulative relapse rates.
Sept 6, 2019
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A6.1.3: PICO questions 3: In MDR/RR-TB patients, does a treatment regimen containing bedaquiline for more than six months safely improve outcomes when compared with bedaquiline for up to six months as part of longer regimens otherwise conforming to WHO guidelines? and 4: In MDR/RR-TB patients, does concurrent use of bedaquiline and delamanid safely improve outcomes when compared with other treatment regimen options otherwise conforming to WHO guidelines?
Statistical Analysis Plan (draft) for PICO 3 & 4 using the EndTB observational study and the IPD2019 data: prepared by Dick Menzies & Jonathon Campbell, McGill University: Sept. 6, 2019
WHO Guidelines group – PICO questions
Question 3. In MDR/RR-TB patients, does treatment with bedaquiline for more than six months safely improve outcomes when compared with treatment up to six months as part of regimens otherwise conforming to current WHO guidelines?
Population Intervention Comparator Outcome
MDR/RR-TB patients:a. Simple MDR-TB (no additional resistance, risk factors)-b. with additional drug resistance patterns, but not XDRc. with XDR-TBd. with severe disease (i.e. cavitary disease on radiography or SS+)e. previously treated with 2nd line drugs or notf. children (0–14y) / adults (adolescents 10–19y if available)g. persons with HIV (+/- ARVs)h. pregnant womeni. people with diabetes mellitus j. extrapulmonary diseasek. malnutrition
- Use of bedaquiline as part of the treatment regimen beyond six months of treatment
- A regimen containing bedaquiline for six months of treatment only
• Successful completion of treatment (or lack of successful completion)
• Bacteriological cure by end of treatment
• Adherence to treatment (or treatment interruption due to non-adherence)
• Treatment failure or relapse
• Survival (or death)• Adverse events with anti-TB medicines
• Acquisition (amplification) of drug resistance
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(PICO 3) Effectiveness of prolongation of bedaquiline beyond 24 weeks:
Three specific questions – related to use of different information sources
1. Relative to bedaquiline (BDQ) use for 24 weeks (6 months), does prolongation of bedaquiline beyond 24 weeks (within properly designed regimens) result in improved treatment outcomes for patients with RR-TB in the EndTB observational study?
2. In the IPD-2019 data set, are treatment outcomes improved in patients who take more than 6 months of BDQ compared to BDQ for 6 months, and to no BDQ?
3. In the combined IPD-2019 and EndTB data sets, are treatment outcomes improved in patients who take more than 6 months of BDQ compared to BDQ for 6 months, and to no BDQ?
Five Outcomes of interest for the Proposed Analyses:
End of treatment:
1. Relapse free treatment success (or simply success, if relapse not assessed) vs fail/relapse
2. Relapse free treatment success (or simply success if relapse not assessed) vs fail/relapse/death
3. Relapse free treatment success (or simply success if relapse not assessed) vs death alone
4. Relapse free treatment success (or simply success if relapse not assessed) vs fail/relapse/death/LTFU (i.e. good vs all bad combined)
During therapy:
5. Adverse events (AE) – defined as serious AEs that resulted in permanent discontinuation of that medication.
• This information is available in considerable detail in the EndTB data following the MSF severity scale – definitions provided at the end of the document. It is less consistently available [~8000 patients in 30 datasets] and defined as grade 3–5 or serious AE that resulted in permanent discontinuation of that medication and may be differentially ascertained in the IPD2019. This may confound comparisons of AE rates – particularly for drugs that are used more, or less in the two datasets.
• If permission granted from all parties, we will also compare AE in EndTB data set with AE detected in NixTB study. These two studies had more comparable intensity of AE detection, although different definitions, and methods for AE.
N.B. Adherence (as % doses taken or other measure) is available in the EndTB data set, but not the IPD2019. Thus, this will only be described for the EndTB data set.
DATA SETS to be used in PICO 3 analyses:
IPD2019
In 2018 an IPD was assembled of 53 data sets from 40 countries/regions containing records for 13,000 patients with MDR-TB. This IPD-2018 data set was analyzed to answer a number of PICO questions developed by a WHO MDR-TB guidelines development group (GdG). These guidelines have since been published. This IPD-2018 was itself was based on an IPD data set assembled in 2016–17 to answer questions of a GdG of the CDC/ATS/IDSA/ERS. These guidelines have not yet been published, but the analyses that informed this set of guidelines were published in the Lancet in Sept 2018.
Hence the IPD-2019 represents an update of the IPD-2018. We anticipate adding data from one national surveillance programs – in South Africa. We will delete the previous records of patients treated in the EndTB observational study, that were included in the IPD-2018, to avoid duplication and overlap with the new data set from EndTB. We may also add two other data sets – provided in response to a public call for data contributions.
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EndTB:
1094 patients with MDR-TB were treated with bedaquiline- and/or delamanid-containing regimens between 1 April 2015 and 31 March 2017. They were followed as part of an observational study – executed by three NGO’s – PIH, MSF and IRD.
Rationale
Why the question of optimal duration of BDQ is challenging.
There are several important potential sources of bias in analysis of duration of therapy in observational studies. We note 2 examples here:
i) Patients who live longer on RR-TB treatment can be treated longer with bedaquiline. Simply comparing the outcomes among people who survive to receive the longer treatment to those who didn’t receive the longer treatment can result in an overestimate of the benefits of the longer treatment. This bias is called “immortal time bias”.
ii) Bedaquiline prolongation varied by patient factors and by country and time. Bedaquiline was prolonged most often in patients with baseline and on-treatment risk factors for poor outcome, i.e., patients whose initial response to treatment was poor, whose regimens without bedaquiline were considered weak, or whose resistance profile or treatment-emergent toxicities limited treatment options. Simply comparing the outcomes among people who got prolonged bedaquiline to those who did not could underestimate the benefits of prolonged bedaquiline. This bias is called (time-varying) confounding by indication.
In the EndTB study, across countries and over time, the use of prolonged bedaquiline varied. Some countries prolonged bedaquiline in nearly all patients, while in other countries, bedaquiline prolongation was not permitted by national guidance. At other sites, bedaquiline prolongation became more common over time as clinicians became more comfortable with the drug.
It’s important to acknowledge the focus on bedaquiline (and delamanid) duration is exceptional, as other drugs (i.e. linezolid) have analogous issues in that people can receive them longer if they don’t experience treatment-limiting toxicity, which in linezolid’s case is ~1 in 5 people. Thus, while the analysis approach that we propose attempts to minimize many sources of bias, we acknowledge it may not be possible to manage all biases.
Defining ‘margins’ in duration analyses:
Since start dates and end-dates of specific drugs are available in the EndTB dataset the duration can be defined to the precise number of days. But, in reality, the precise duration depends on timing of visits, and events such as missed visits, cancelled clinics, holidays or even just bad weather can result in variation of up to a month around the time when a specific drug is stopped. Hence we will first define a frequency distribution of duration for BDQ, in order to define the optimal cut-points for each duration. As an example, from recent analysis of one data set – the frequency of actual duration in days of one drug is plotted (see Annex 1). This plot shows a large number of persons with duration centred around 6 months, but we would conclude that for our purposes “6 months” duration should include patients with duration of 150 to 200 days.
Therefore, in this SAP when we refer to duration of “24 weeks”, or “36 weeks”, or “52 weeks” we mean N weeks + NN weeks, with the value of NN to be determined from the initial descriptive analysis.
Challenges in comparing results using the EndTB data, and the IPD2019 data:
There are several important potential differences between the patient populations, treatment, and other factors between these two sources of individual patient data.
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i) The EndTB study was conducted by agencies and at centres with different patient populations, as well as resources and clinical expertise, from those in the IPD-2019. The IPD-2019 contains data from a greater variety of settings including samples of patients included in national MDR surveillance systems. Hence outcomes may be different in the IPD data-set – independent of measured clinical and treatment characteristics due to unmeasured confounding. While for some datasets in the IPD there may also be differences in outcomes, we will quantify differences between the IPD and EndTB descriptively. As we have done in the past, mixed models will be used to account for heterogeneity between datasets.
ii) There is a perception that the EndTB sites have more complicated patients who have comorbidities and other challenges (homelessness, hx of incarceration, IV drug and alcohol use) that make developing an effective regimen especially difficult;
iii) the extent and quality of data, particularly on-treatment, longitudinal observations; follow-up for recurrent disease (ie for relapse);
iv) methods for collection and reporting of safety data;
v) extent of prolongation of Bdq;
vi) In the EndTB data set all patients received DLM or BDQ or both. But none got neither of these drugs – in contrast to large numbers of patients in the IPD data set who received neither. If DLM is very effective, this could substantially affect comparisons of the no BDQ group in the IPD2019 cohort to the no BDQ group in the EndTB data set since all these patients received DLM. We will, therefore, control for exposure to DLM in all analyses.
vii) overall willingness to use Bdq/Dlm;
viii) outcome classification.
Some of these differences are sources of variability within the IPD as well (e.g., bdq use, outcome classification, safety, etc). However, the IPD2019 data set includes data from over 13,000 patients, treated in 53 studies in 40 countries/regions. The diversity of patients, disease, providers, and treatments provides an excellent opportunity to compare and contrast treatment related covariates in very different settings and should result in more generalizable findings.
The results from Questions 1 and 2 will see if the effect of bedaquiline use beyond six-months is similar in EndTB and the IPD, after accounting for numerous possible confounders. Any confounding effect of DLM will be managed by controlling for delamanid in all analyses. The analysis for Question 3 will analyze the benefit of BDQ for 6 months, vs longer vs a group that did not receive BDQ while adjusting for use of delamanid as well as the data source or study (ie EndTB or IPD2019) and other covariates. In other words, in this analysis the reference group (comparator) will be the group who received BDQ for 6 months. While the IPD2019 data set has important limitations, compared to the EndTB data set, we believe there are important advantages of conducting the analyses of BDQ duration using both the IPD2019 data set and the EndTB dataset. These advantages include the greater diversity of settings and patients in which this question can be addressed – enhancing the generalizability of results. As well the diversity of settings increases the likelihood of diversity in patients receiving longer duration of BDQ – potentially reducing unmeasured confounding relative to actual differences in detectable treatment benefits. Finally, this should increase the number of patients who received any single regimen/combination of medications/duration of BDQ, so simply enhancing power.
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Overview of the analyses for the three specific Questions (end of treatment outcomes)
Q1: Relative to bedaquiline (BDQ) cessation at 24 weeks, does prolongation of bedaquiline result in improved treatment outcomes for patients with RR-TB in the EndTB observational study?
Comparator: use of bedaquiline for 24 weeks in EndTB
Intervention: use of bedaquiline for >24 weeks in EndTB
Sensitivity analysis comparator: use of bedaquiline for 24–36 weeks in EndTB
Sensitivity analysis Intervention: use of bedaquiline for >36 weeks in EndTB
Defining a Time Cut-Off for Bedaquiline Use
As discussed above, it seems likely that BDQ use will not be precisely 24 weeks in many patients, due to the vagaries of dates of visits, drug supply, delays in starting, or stopping, or missed doses. We want to know, as best as we can, if 6 months, or 9 months is planned – what, in reality is the duration? If we restricted analysis to those who got exactly 180 or 270 days – we would have about 20 people. So, we need to account for some variation in actual duration. Hence, we propose to examine the frequency distribution of duration of BDQ to attempt to find ‘inter-modal’ cut-points that best discriminate patients treated with BDQ for ’24 weeks’, or 36 weeks, or 52 weeks. ONLY TO DEFINE THIS CUT-POINT, we will exclude patients who died or were lost to follow-up to ensure that the population assessed are only those who could have received the drug to this point. This will also be done for the sensitivity analysis population. It should be recognized that any selected timepoint will necessarily dichotomize some patients who received only a few days difference of bedaquiline treatment, however by selecting the inter-modal points, this problem should be minimized. The rest of this plan below is written assuming 24 weeks is selected but will be adjusted based on our findings here and may represent a range (e.g., 20–26 weeks of bedaquiline).
Step 1: Descriptive Analysis of the Population Subgroups
We will then undertake descriptive analysis to characterize those who did not receive BDQ, those who received BDQ for at least one month, but <6 months, and those who received at least 24 weeks – divided into two groups: (BDQ for 24 weeks; and BDQ for >24 weeks). We will also sub-divide the group with BDQ for >24 weeks into persons who were treated with BDQ for 24–36 weeks, and those who received BDQ for >36 weeks. The description will include: site where treated, baseline/pre-treatment characteristics: sex, age, HIV and ART treatment, other comorbidities, prior TB treatment, AFB smear, CXR results, DST results (both in terms of resistance patterns and total number of drugs resistant to), year of starting treatment, and number of likely effective drugs used initially. Consideration of the total number of drugs resistant warrants further explanation. It is possible that for drugs with DST that is perceived to be unreliable (e.g. cycloserine, PAS), in the event they were found susceptible, they were reinforced, or in the event they were found resistant, the drug was used anyways. Likewise, there may be reasons some drugs had DST done on them, perhaps due to previous exposure or a regimen was failing. Thus, for these reasons it is important to consider the total number of drugs a patient is resistant to, as well, the more drugs a person is resistant to, the more limited treatment options are, and the more probable it is that bedaquiline is extended. So, we plan to adjust for this covariate in statistical analysis. Because of this, we propose to count the number of drugs individuals are resistant to drugs other than fluoroquinolones and second-line injectables (which will be accounted for in the composite resistance pattern of MDR, pre-XDR, and XDR) – we will assume cross-resistance to similar drugs (e.g. ethionamide and prothionamide or cycloserine and terizidone, or amikacin and kanamycin – unless there is DST for both drugs). There are also sensitivity analyses surrounding this, detailed in the appropriate section below. We are also interested in events during treatment that would affect clinical decisions at the time points of interest – meaning at 6, 9 and 12 months. These would include: culture and DST results indicating any newly detected drug resistance from cultures
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of samples collected prior to the end of week 16 (we assume that at the time of the 6-months evaluation, that cultures and DST would be available only for samples collected prior to weeks 16 and 12 respectively. We would examine AFB smear and CXR results from 24 weeks, as well as number of drugs permanently stopped due to intolerance / AEs up to 24 weeks – all of which information would be available at the 6-month evaluation and could be indications for extension of BDQ. This descriptive analysis will be further stratified by site to determine if there are unique site characteristics. We will further describe exact resistance patterns of all drugs (Resistant, Susceptible, Not Done/Unknown) to see how common testing was and prevalent resistances were when testing was done. We will repeat the descriptive analysis using appropriate time-points for the proposed sensitivity analysis.
Step 2: Exploring the use of delamanid – descriptively
In the same way as bedaquiline, we will descriptively examine the characteristics of people who received delamanid (no BDQ) or did not receive delamanid, and compare those to patients who received DLM and BDQ and to patients who received BDQ alone. One issue that will be explored is whether delamanid was used from the start, or introduced after, since many patients received DLM after several months of therapy. This raises the possibility of indication bias, since those who had DLM added are likely to have been responding poorly, but on the other hand, also immortal time bias since patients had to survive longer to have a chance of later introduction of delamanid. (This is where separate analyses of failure, and death may be especially helpful). Thus we will describe median (IQR) time of delamanid start after treatment start and also how many started within 0–3 months, 4–6 months, 7–9 months, or 9+ months after treatment start. We will also look at these characteristics by site, as policies regarding use may vary between sites, and could be an important potential determinant of use. We will examine whether characteristics of patients was ‘balanced’ between the treatment groups as defined above. Even if there is no evidence of substantial confounding of patient characteristics with DLM use, we will consider delamanid as a unique drug given and adjust for its use in the multivariable analyses described below (like LZD or later generation FQN, for example).
Step 3: Analysis of duration of BDQ
To assess the benefit of bedaquiline extension beyond 24 weeks, we plan two analytical methods and will compare the results. We will do this for each of the four outcomes defined above each method will be repeated for sensitivity analysis.
Method 1: Exact and Propensity score matching. Patient characteristics at baseline that are missing will be imputed using multivariate imputation via chained equations. Note – exposure and outcome data will never be imputed. We will match persons who received bedaquiline for 24 weeks to those who received it longer using a combination of exact and propensity score based matching for covariates that are likely to influence treatment extension at week 24. These covariates include: Baseline characteristics: Resistance to FQ or SLI, total Number of drugs resistant to, AFB smear, Cavitation on CXR, HIV-coinfection and ART use, previous treatment history (first-line drugs only or also second-line), age and sex. During-treatment characteristics: culture status at 12 and 16 weeks (ie culture conversion or non-conversion), number of acquired/new resistances at 16 weeks (0, 1, or 2+), cumulative number of drugs stopped due to adverse events at week 24 (0,1 or 2+), radiologic findings at week 24, treatment at Week 24 including use of receipt of fluoroquinolone, linezolid, and delamanid and number of other likely effective medications. As we have done in past analyses, we attempt to match exactly on as many covariates as possible (recognizing that within the EndTB data set this may be challenging), and propensity score match on the remainder. The covariates selected for exact matching are those with strongest association with the outcomes of interest for that analysis. We will propensity score match on the remaining covariates listed above. We again will consider clustering by site and further adjustment by year of treatment start and/or country level income. We will estimate adjusted odds ratios and associated 95% CI. For each analysis, the matched groups will be examined in standard reports looking at the improvement (or not) in balance of characteristics between the two groups from the matching algorithm.
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Method 2: Survival Analysis using inverse probability of treatment weighting (IPTW) and inverse probability of censor weighting (IPCW). The survival analysis will begin with everyone included in the analysis population who received treatment with bedaquiline for at least six months (i.e., baseline=month 6). We will examine exposure in two ways. (1) Dichotomous: received only six-months of BDQ vs. received more than six-months of BDQ; (2) Continuous: treating months of BDQ beyond six as a continuous variable. The outcome of interest will be failure/relapse/death (composite). We will treat loss to follow-up as a censoring event. We will include patient time until the end of follow-up for relapse. We will construct a baseline patient profile based on what would be clinically known at month 6, including time-fixed covariates of age, sex, previous treatment history, etc. From here, we will update information each month for patients that is time-varying: receipt of concomitant drugs (type and number), number of AE requiring drugs to be stopped, culture status, radiologic findings. Using these time-fixed and time-varying covariates, we will estimate the IPCW for the population (i.e., for LTFU). We will also estimate the IPTW based on timing of BDQ stop (i.e, for people stopping BDQ at month 6, IPTW will be estimated for all time points; for people continuing to receive BDQ beyond month 6, IPTW will be estimated until the time of BDQ stop, then considered constant). We will then run a survival analysis, clustering by patients and centre and incorporating the calculated IPCW and IPTW weights. This analysis will be run for both dichotomous and continuous outcome. For the continuous outcome, please see sensitivity analyses where we consider the benefit of bedaquiline to be non-linear and we describe alternate analytic methods to be explored (e.g. g-formula).
Q2: In IPD-2019 data set, are treatment outcomes improved in patients who take more than 6 months of BDQ compared to no BDQ and BDQ for 6 months?
Exposure 1: No use of Bedaquiline (defined as <30 days) in IPD2019
Reference (comparator) 1: Use of bedaquiline for 24 weeks in IPD2019 (exact duration based on descriptive analysis as in Q1).
Exposure 2: Use of bedaquiline for >24 weeks in IPD2019 (exact duration based on descriptive analysis as in Q1).
We propose three analyses: No BDQ to 24 weeks, and 24 weeks to BDQ to >24 weeks, plus a combined – where BDQ use is a 3-level categorical variable (none, 24 weeks, and >24 weeks). Since this is all within IPD2019 – We propose to match patients exactly on the baseline characteristics of fluoroquinolone and second line injectable resistance, HIV co-infection and ART use, and country-level income (using World Bank categories). We will match patients further using propensity score matching on age, sex, previous TB treatment (first line and second line drugs), extent of disease (AFB smear and/or cavitation on CXR), use of linezolid, use of fluoroquinolones, use of delamanid, BMI (dichotomized as underweight or not), and number of other effective drugs used in the initial regimen. Because of limitations of lack of detailed information about changes and events during therapy, we cannot include these variables in this analysis.
Q3: In the combined IPD-2019 and EndTB data sets, are treatment outcomes improved in patients who take more than 6 months of BDQ compared to no BDQ and BDQ for 6 months?
Exposure 1: No use of Bedaquiline (defined as <30 days) in IPD2019
Reference (comparator) 1: Use of bedaquiline for 24 weeks in IPD2019 (exact duration considered 24 weeks based on descriptive analysis as in Q1).
Exposure 2: Use of bedaquiline for >24 weeks EndTB and in IPD2019
In the analysis strategy deployed, the “exposure” will be BDQ use for 24 weeks or >24 weeks, as treatment in the combined data set of EndTB and IPD2019. The comparator will be BDQ use for <30
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days in IPD2019. Our analytic approach will follow the same approach as described in Q2 comparing the reference to exposure 1 and exposure 2, and when comparing exposure 1 to exposure 2.
Outcome 5: Analysis of adverse events:
The analysis plan for adverse events is made somewhat difficult by the fact that we are not yet certain of the data available from the EndTB study. In the IPD2019 we have information on type of adverse events, and the drug considered responsible by the treating team, as well as whether that drug was permanently stopped – in 30 studies with >8000 patients. We did not have much information on the severity of the AE (i.e. few studies provided information on the Grade), so the analysis was simply the cumulative percent of patients who received at least 1 month of the drug, and the drug was stopped permanently because of an AE, as well as type of AE in most of these studies. Using this we calculated a proportion stopping each drug in each study.
We propose to try three approaches to analyze the occurrence of AE. First, we will perform standard aggregate data meta-analysis for proportions. The estimated proportion of patients within each cohort in whom each specific drug was stopped permanently (out of all patients in the cohort receiving that drug) because of an AE ( AE incidence) . Then AE proportion for each drug from each cohort will be estimated using generalized linear mixed model with random effects at cohort level using the “metaprop” function within R package “meta”, then pooled using standard aggregate data random effects meta-analysis. To address the PICO question, we will sub-divide each cohort into ‘comparator = 6 months BDQ’ and ‘intervention = BDQ longer’. This analysis will be conducted without adjustment for confounders, then we will assess the relationship of covariates (especially age, sex, HIV status, and extent of disease indicators) to AE, and repeat the analysis with adjustment for these confounders.
Second, we can perform an arm-based network meta-analysis using the “nma.ab.bin” function within R package “pcnetmeta” (ref ). In this approach, drugs not used in a study or cohort will be considered as missing at random. The use of a multivariate Bayesian mixed model allows estimation of the population averaged treatment specific event proportions. This model will account for the correlation between different treatments within each cohort as compared to the above approach that estimated drug-specific event proportions based solely on cohorts that used the particular drug. Absolute risk of AE for each drug will be estimated using a random effects model within the Bayesian framework, and the median value with 95% credible interval and mean value with standard deviation reported.
A third approach is to use a ranking-based non-parametric method, as this should more accurately assess the relative toxicity of shorter and longer BDQ vs other drugs in different studies (i.e. if comparing AE in IPD2019 and EndTB. In the first step, within each cohort the drugs used were ranked in the order of observed AE incidence of each drug, from one to N (representing the total number of distinct drugs prescribed). If more than one drug was stopped, they received a proportion of a point (e.g. if two drugs stopped 0.5, if three drugs stopped 0.33, etc.) Note that ‘incidence’ refers to cumulative incidence in the IPD2019 – as we may not have adequate information on drug duration, so we have used the proportion who stopped among those who received the drug for at least 1 month. If two or more drugs had the same AE incidence in a study, the drugs were assigned tied ranks. Next, the raw ranks were adjusted by the maximum distinct number of drugs of all cohorts. In a third step, the unweighted average rank for each drug was calculated across all cohorts using the drug, with equal weight ascribed to each cohort. The weighted average rank for each drug will be estimated in the same way except a weight will be assigned for each cohort based on the number of patients using the drug in that cohort; however, cohorts with large sample size will have a dominant influence on the average ranks; therefore, the unweighted ranking will be considered the primary approach. For this PICO, we will assess the ranking of BDQ in those who received BDQ for 6 months (reference or comparator), vs more than 6 months. A change in ranking would imply greater or lesser AE in the intervention group. An improved AE ranking might suggest selection – since those who tolerate a drug are more likely to continue it.
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Limitations (PICO 3 analysis)
As noted above, patients may receive prolonged bedaquiline, because they were sicker, or had fewer treatment options (AE, or more resistance ). Indeed, information from the investigators indicates that all EndTB countries initiated BDQ use in the patients with the worst MDRTB and the least treatment options – many after prior treatment failures. Early in the EndTB project, countries were very conservative to use BDQ therefore it was included only when cases were desperate and late in the treatment. Second, across countries and over time, the use of prolonged bedaquiline may have varied. However, this is in fact an advantage, as some differences in bedaquiline prescription and duration may have had less to do with patient characteristics, and more to do with local policy, physicians’ beliefs, and BDQ availability – creating a quasi-experimental situation – with less confounding due to patient characteristics. We will use two methods to control for confounding; however, we will not be able to completely control all possible confounding, especially unmeasured confounding. But we expect that if unmeasured confounding is related to indication, then this will act to underestimate the benefit of bedaquiline if sicker patients or those with fewer effective drugs are more likely to receive prolonged bedaquiline.
Potential Sensitivity analyses
1. Analyses repeated but accounting for missed doses (due to non-adherence) from the 24 weeks of initial bedaquiline exposure in EndTB.
2. Assess time to loss-to FU/dropout/default, inpatients who take no BDQ, 6 months BDQ and >6 months BDQ. Compare time to LTFU in EndTB and IPD2019 in same sub-groups based on BDQ duration.
3. Examine whether the effect of prolongation depends on specific other drugs used in the treatment regimen (eg, Dlm, clofazimine, PZA or cycloserine).
4. Assess whether Bdq prolongation is more effective than no Bdq prolongation in patients with an indication for prolongation, i.e., patients whose regimen would be compromised if Bdq were withdrawn (resistance, toxicity, culture positivity, etc). It’s very possible that Bdq prolongation is not helpful in patients who don’t need it after 6 months. Including these patients in an analysis of effectiveness of Bdq prolongation could underestimate the contribution of prolongation. To analyze the effect of prolongation in those who need prolongation would require establishing the risk group based on patient characteristics after 6 months of Bdq, not only those at baseline.
5. For Question 1, Method 2: We will consider modelling time non-linearly using a spline or by including a second quadratic term for duration. Further, we will also use g-formula to calculate the expected probabilities of our outcome, which would reduce biases introduced due to people surviving longer can receive bedaquiline longer. Finally, we will consider LTFU an outcome, and not a censoring event, since LTFU may be due to undetected, clinically important reasons of long duration and/or toxicity.
6. For Question 1: We will not consider the number of drugs a person is resistant to, but instead consider drugs with perceived unreliable DST (notably E, Z, PAS, Eto/Pto, Cs/Trd) as (a) susceptible regardless of result and (b) resistant regardless of result.
7. For AE: Compare frequency of specific drug related AE in EndTB and NixTB studies.
Adverse Event Definitions in EndTB
EndTB AEs are classified using severity grades 1–5 according to the MSF severity scale. They use the commonly-accepted (ICH-GCP among others) criteria to classify events as serious: results in death; is life-threatening (places the subject at immediate risk of death from the event as it occurred); results in inpatient hospitalization or prolongation of existing hospitalization; results in a persistent or significant disability/incapacity; results in a congenital anomaly/birth defect; or is otherwise medically significant: based upon appropriate medical judgment, may jeopardize the subject’s health and may require medical or surgical intervention to prevent one of the other outcomes listed in this definition.
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Question 4. In MDR/RR-TB patients, does concomitant use of bedaquiline and delamanid safely improve outcomes when compared with other treatment options in regimens otherwise conforming to current WHO guidelines?
Population Intervention Comparator Outcomes
MDR/RR-TB patients a. with additional drug resistance patternsb. with XDR-TBc. with severe disease (i.e. cavitary disease on radiography or SS+)d. previously treated with 2nd line drugs or note. children (0–14y) / adults (adolescents 10–19y if available)f. persons with HIV (+/- ARVs)g. pregnant womenh. people with diabetes mellitus i. extrapulmonary diseasej. malnutrition
– Concomitant use of bedaquiline and delamanid, given for six months of treatment
– A regimen without concomitant use of bedaquiline and delamanid for six months of treatment
• Successful completion of treatment (or lack of successful completion)
• Bacteriological cure by end of treatment
• Adherence to treatment (or treatment interruption due to non-adherence)
• Treatment failure or relapse
• Survival (or death)• Adverse events with anti-TB medicines
• Acquisition (amplification) of drug resistance
(PICO 4) Adding Delamanid to bedaquiline: specific questions
1. In the EndTB data set are treatment outcomes improved with concomitant use of BDQ and DLM compared to use of BDQ without DLM (in addition to other components of an adequate MDR regimen)?
2. In the combined IPD-2019 and EndTB data sets, are treatment outcomes improved with concomitant use of BDQ and DLM compared to use of other treatment options?
Challenges in this analysis:
In the EndTB study, DLM use varied between sites, and may have been started at beginning, or given later in therapy, even given as ‘salvage therapy’. If added later, DLM may have been added because of local or individual preference/protocol, or based on response to therapy to that point. Hence, we will begin this analysis with a careful descriptive analysis (as described above as Step 2 for PICO 3) – comparing those who received DLM to those who did not – separately within the EndTB data set. We will also perform the same descriptive analyses for the IPD2019 (where same problems likely applied). This will include an assessment of timing of DLM start, and duration of use.
Study population/data sources (PICO 4):
IPD-2019.
In 2018 an IPD was assembled of 53 data sets from 40 countries/regions containing records for 13,000 patients with MDR-TB. This IPD-2018 data set was analyzed to answer a number of PICO questions developed by a WHO MDR-TB guidelines development group (GdG). These guidelines have since been published. This IPD-2018 was itself was based on an IPD data set assembled in 2016–17 to answer questions of a GdG of the CDC/ATS/IDSA/ERS. These guidelines have not yet been published, but the analyses that informed this set of guidelines were published in the Lancet in Sept 2018.
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Hence the IPD-2019 represents an update of the IPD-2018. We anticipate adding data from one national surveillance programs – in South Africa. We will delete the previous records of patients treated in the EndTB observational study, that were included in the IPD-2018, to avoid duplication and overlap with the new data set from EndTB. We may also add two other data sets – provided in response to a public call for data contributions.
EndTB:
1094 patients with MDR-TB were treated with bedaquiline- and/or delamanid-containing regimens between 1 April 2015 and 31 March 2017. They were followed as part of an observational study – executed by three NGO’s – PIH, MSF and IRD.
Approach
As with PICO 3, the approach here will have the same outcomes. We will again observe the distribution of ‘duration’ for people receiving BDQ and DLM to define cut-points to call the duration six-months. We will perform the same descriptive analyses described in Question 1 of PICO 3 for the intervention population receiving BDQ and DLM to six months and perform the same statistical analyses comparing it to the comparator populations of (1) people who received only Bdq; (2) people who received only Dlm; (3) people who received BDQ and Dlm for <6 months and; (4) people who received BDQ and Dlm for more than 6 months. We will limit analyses within EndTB as this data set is the only one with enough detail to adequate control for the numerous time-varying confounders that may influence which patients fell into the intervention group or one of the four comparator groups.
Limitations – PICO 4
Many of the same limitations apply to PICO 4 as PICO 3, except that in addition there were fewer patients treated – in IPD2019 or end-TB data sets – limiting ability to match on key confounding covariates and limiting power as well to detect small benefits (or harms). In addition, there may have been even greater selection biases (and immortal time bias) affecting estimates of effect of DLM on outcomes.
A6.2 WHO treatment guidelines for multidrug- and rifampicin-resistant tuberculosis, 2018 updateRefer to Annex 10: Summaries of unpublished data and analysis plans used for the recommendations in the WHO treatment guidelines for multidrug- and rifampicin-resistant tuberculosis, 2018 update (https://www.who.int/tb/areas-of-work/drug-resistant-tb/Annexes_8-10.pdf, accessed 2 March 2019).
A6.3 Guidelines for treatment of drug-susceptible tuberculosis and patient care, 2017 updateRefer to Annex 5: Reports of the systematic reviews (reports on systematic reviews for: adherence interventions in tuberculosis treatment and decentralized treatment and care for multidrug-resistant tuberculosis patients) in the Guidelines for treatment of drug-susceptible tuberculosis and patient care, 2017 update (https://www.who.int/tb/publications/2017/dstb_guidance_2017/en/, accessed 2 March 2019). The systematic reviews have subsequently been published (37,38)