Bedaquiline (BDQ) for the treatment of multi-drug resistant ......2016/10/02 · Diagnosis of...
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Bedaquiline (BDQ) for the treatment of multi-drug
resistant tuberculosis: a protocol for an individual
patient data meta-analysis
Version 2
Date: 2016-02-04
Lawrence Mbuagbaw
Joseph Beyene
Mark Loeb
Christian Lienhardt
Licé González-Angulo
Lehana Thabane
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BACKGROUND: The emergence of drug-resistant tuberculosis (TB) is a major threat to global TB care and
control. In 2014, the World Health Organization (WHO) estimated that 480 000 people
developed multidrug-resistant TB (MDR-TB), of which 190 000 died (1). Current treatment
regimens for MDR-TB patients are far from satisfactory. These usually require at least 20
months of treatment with a combination of second-line drugs, that are more toxic and less
effective than the drugs used to treat drug-susceptible TB (2, 3). In the 2012 global cohort of
detected MDR-TB cases, only 50% were successfully treated, as a result of high frequency of
death (16%), treatment failure (10%) and loss to follow-up (16%) commonly associated with
adverse drug reactions, among other factors. One hundred and five countries have reported at
least one case of extensively drug-resistant TB (XDR-TB), a form of MDRTB with additional
resistance to fluoroquinolones and second-line injectable drugs (amikacin, kanamycin or
capreomycin). On average, an estimated 9.7% of MDR-TB cases have XDR-TB. Treatment
options for XDR-TB patients are even more limited with lower cure rates compared to that of
MDR-TB. In a subset of 200 XDR-TB patients in 14 countries, treatment success was achieved
in only 33% of the cases while 26% of the patients died (4).
The landscape of drug development for treatment of TB has evolved dramatically over the last
ten years, and 6 new compounds are in the final stages of clinical development (1). One of
those, bedaquiline, was provided marketing authorisation by the US-FDA under a procedure of
“accelerated approval” for the treatment of MDR-TB, in December 2012 (5). Although limited
data were available, and the drug had not been tested in a full Phase III randomized controlled
trial in humans – but only in a Phase II b trial – in view of the importance of this progress, the
likelihood of this drug to contribute effectively to the treatment of a life-threatening disease, and
the request by member states to get guidance on the way to use the drug, and following the
recommendations of the WHO Guidelines Review Committee (GRC), WHO organised in
January 2013 an expert group meeting to review all available data. Based on available
knowledge about the safety and efficacy of the product, the evaluation of the balance of
potential harms and expected benefit, the target population(s) and the likely conditions of use, in
association with the MDR-TB treatment currently recommended by WHO, the expert group
advised WHO that the drug may be used under five (5) strict conditions (see Box below). This
led to the issuance of an Interim Guidance for the use of bedaquiline in the treatment of MDR-
TB in June 2013 (6). Since then, the drug has been registered in a number of countries
(including the EU, South Africa, Korea, Russia). WHO estimates that, up to now, the drug has
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been introduced and used at least once in 46 countries worldwide, under various mechanisms
of compassionate use, expanded access programme, donation programmes, import waiver and
registered market access (1).
Box — Brief summary of the main recommendations of the Interim Policy Guidance on
the use of bedaquiline for treatment of MDR-TB
WHO recommends that ‘bedaquiline may be added to a WHO-recommended regimen in adult
patients with pulmonary MDR-TB (conditional recommendation, very low confidence in
estimates of effects)’ (6).
The WHO recommendation for the inclusion of bedaquiline in the adult treatment regimen of
MDR-TB is subject to the following five conditions being met:
1. Proper patient inclusion (special caution in persons above 65 years of age or adults
living with HIV; use not advised in pregnant women and children).
2. Signed patient informed consent obtained after detailed explanations on the novel nature
of the drug, the reasons why it is added to the regimen, and its risks and benefits have
all been provided to the patient.
3. Adherence to principles of designing a WHO-recommended MDR-TB regimen typically
composed of at least pyrazinamide and four second-line drugs that are considered to be
effective based on drug susceptibility test and/or previous use and/or drug resistance
surveillance data: a fluoroquinolone (preferably later generation), a second-line
injectable agent and two bacteriostatic drugs, preferably prothionamide or ethionamide
plus cycloserine or para-aminosalicylic acid. Bedaquiline may be indicated if such a
regimen is not feasible because of: (i) in vitro resistance to fluoroquinolones and/or
second-line injectable drugs; (ii) known adverse reaction, poor tolerance or
contraindication to any component of the combination regimen; or (iii) unavailability or
lack of a guaranteed supply of a drug(s).
4. Treatment administered under closely monitored conditions to enable optimal drug
effectiveness and safety (sound treatment and management protocols must be in place,
preferably submitted and approved by the relevant national ethics authority; review of
treatment and management programmes by an independent group of experts in clinical
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management and public health, such as the national MDR-TB advisory group is
recommended).
5. Active pharmacovigilance and proper management of adverse drug reactions and
prevention of complications from drug–drug interactions.
OBJECTIVES:
Overall aim: To re-evaluate the added benefit of bedaquiline to the treatment of MDR-TB, a life-threatening
form of tuberculosis, and revise the WHO interim guidance issued in June 2013 in view of
updated evidence on its use in conjunction with WHO-recommended MDR-TB treatment
regimens.
Specific objectives: 1. To use individual level patient data to evaluate the harms/benefits ratio of bedaquiline in
combination with currently recommended MDR-TB treatment regimen according to the
following criteria:
(i) for safety, through the evaluation of the type, frequency, severity and
seriousness of adverse events related to the use of bedaquiline;
(ii) for effectiveness, through the evaluation of treatment outcomes in cohorts of
patients treated with bedaquiline in addition to (optimised) background regimen,
in comparison with similar cohorts or programmatically available data;
(iii) for survival, through evaluation of the mortality rates when receiving
bedaquiline (and related causes of death).
2. Based on this evaluation, to update the interim guidance on the use of bedaquiline as
part of WHO-recommended MDR-TB treatment regimens, as appropriate.
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METHODS:
Overview:
The overall approach for this update is to conduct a systematic review of cohorts of MDR-TB
patients treated with bedaquiline, obtain individual patient data, and compare key safety,
effectiveness and survival data with cohorts of patients treated for MDR-TB in the absence of
bedaquiline, to complete relevant GRADE evidence tables and inform policy revision.
Literature search strategy: Bibliographic searches for this systematic review included MEDLINE®, Embase® and the
Cochrane Central Register of Controlled Trials. Furthermore, the drug manufacturer was
contacted for unpublished data on file. Conference proceedings and reference lists were also
searched as an additional technique to identify published studies that were not retrieved in the
initial search (See Annex 1: Search strategies for studies retrieval).
Limits such as age and language were not used in this search. Concepts or “facets” (topic
specific terms) included in the PICO (Participants, Intervention, Comparison, Outcome) question
were combined with Boolean operators to develop an optimal search strategy.
Inclusion criteria:
Humans, no age limit
Diagnosis of multi-drug resistant tuberculosis (pulmonary and extrapulmonary)
Bedaquiline added to background MDR-TB regimen for at least 6 months
Studies implementing drug-monitoring, at least at baseline and at end of treatment
Individual patient data available
Exclusion criteria:
Studies not relevant to the main subject (title-screened)
Studies conducted in animals
PK-PD studies
Studies of only-bedaquiline therapy
Studies not providing information on background therapy (WHO recommended or
any other)
Studies not providing outcome information
Samples size: Case reports or other observational studies with samples less than 10
participants
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Outcome different to safety and effectiveness
Quantitative data reports
Full texts were not available
Repetitive publications (Duplicates)
Language limitation (no translation possible by the time of data extraction)
Preliminary search synthesis: Through the preliminary search, a total of 687 studies have been identified (CENTRAL, 10
records; PubMed/MEDLINE®, 92 records; and Embase®, 572 records). Additionally, 13 studies
have been identified through supplementary sources, namely conference proceedings and data
from drug manufacturer.
Two (2) reviewers have been assigned to independently screen and assess the methodological
quality of all identified studies (CL and LGA). Currently, one reviewer (LGA) has examined the
records identified through searching CENTRAL and PubMed/MEDLINE®. Embase® search
was also conducted, but studies are pending to be screened. In case of disagreement in the
selection and inclusion of studies, agreement will be sought through a third reviewer (NG). The
authors of eligible studies were contacted to retrieve individual patient data.
Included studies/data sources: To date, we have identified four studies of patients who received bedaquiline for whom
individual patient data is available. They include an industry funded phase II multisite trial
conducted in 11 countries, a retrospective cohort in France, a prospective cohort in Armenia
and an interim cohort analysis conducted in South Africa. The key features of these studies are
summarised in table 1.
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Table 1: Intervention group: Studies of Bedaquiline use in MDR-TB patients
Janssen
2013(7)
Guglielmetti
2015(8)
MSF 2015(9) Ndjeka 2015(10)
Design A phase II,
single arm
open label trial
Retrospective
cohort
Prospective cohort Interim cohort
analysis
Location 31 sites, 11
countries
France Armenia South Africa
Inclusion
criteria
Sputum smear
positive
pulmonary
infection with
MDR-TB
MDR-TB
receiving BDQ
for
compassionate
use
MDR-TB patients with
additional resistance to
either a
fluoroquinolone or both
XDR-TB and failures of
MDR-TB treatment
Pulmonary XDR-
or pre-XDR-TB
Sample size 233 35 62 91+
Intervention Weeks 1-2:
BDQ* 400mg
once daily
Weeks 3-24:
BDQ 200mg
thrice a week
BDQ* 400mg
once daily for
2 weeks, then
200mg thrice a
week
BDQ* for 24 weeks as
part of a regimen
constructed according
to WHO
Recommendations&
BDQ* 400mg
once daily for 2
weeks, then
200mg thrice a
week for 22
weeks
Co-
intervention
Baseline
Regimen
BDQ* given as
part of an
individualised
anti-TB
regimen
At least four other
effective drugs
Optimised
Baseline Regimen
Duration of
follow-up
96 weeks 30 months 24 weeks. 18 months
Ethics
approval
An
Independent
Ethics
Committee
Institutional
review board
of
the Bligny
Hospital
The NTP (National TB control Programme) formed an Ethic Committee to review bedaquiline use for patients with TB (2012) Ethic Committee and MOH approved Bedaquiline importation for humanitarian reasons (2013)
Universities of
Witwatersrand
and Cape Town
and Pharma-
Ethics
*Bedaquiline; & At least 4 effective drugs including a FQ and injectable if possible; +Data from
more than 91 patients may be available at time of retrieval
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Given the limitations of using only observational cohorts for this update, we sought for and
identified two suitable comparator cohorts of patients treated for MDR-TB without Bedaquiline
(11) (12). See Table 2.
Table 2: Comparator group: Studies using conventional MDR-TB treatment (or other regimens)
Ahuja 2012 (11) Cegielski 2015 (PETTS) (12)
Design Systematic review and individual
patient data meta-analysis
Prospective cohort study
Location Canada, USA, Taiwan, Uzbekistan,
Mexico, Spain, The Netherlands,
South Africa, South Korea, Latvia,
Estonia, Iran, Italy, Peru, UK,
Argentina, South Korea, Vietnam,
South Africa, Russian Federation,
Japan, Philippines, France,
Bangladesh, Hong Kong
Estonia, Latvia, Philippines,
Peru, Russia, South Africa, South
Korea, Taiwan, and Thailand
Inclusion criteria Studies published after 1970 that
reported original data of treatment
of patients with microbiologically
confirmed pulmonary MDR-TB. *
Patients with microbiologically
confirmed MDR tuberculosis
starting second-line drug treatment
Sample size 32 cohorts, 9898 patients 1244 patients
Intervention WHO groups 1-5 drugs Treatment according to national
standards of care with 5
drugs, including an SLI, for a 6–8-
month intensive phase, followed by
a continuation phase of 3–4 drugs
for a total of 20–24 months
Duration of follow-
up
? Till end of treatment or end of study
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Ethics approval Research Ethics Board of the
Montreal Chest Institute, McGill
University Health Centre and local
ethics boards
Centers for Disease Control and
Prevention
(CDC)
*Patients within these datasets were excluded if they had only extra-pulmonary TB, had
extensive drug resistance (XDR-TB, as defined elsewhere
Collaboration: The principal investigators of all the included studies will be invited to be co-authors of any
published manuscripts, along with three members of their respective teams. They will be
provided with monthly updates on progress with the analysis. All research teams and data
sources will be fully acknowledged in the final report.
Data management: For each study, we will collect baseline data, and outcome variables. We will store all retrieved
data on a controlled-access computer at the Biostatistics Unit of the Father Sean O’Sullivan
Research Centre/McMaster University. Our computers are equipped with cloud drives with local
and remote servers to prevent any accidental data losses. All data files will be stored in their
original form but converted to suit our choice of analytical software. Prior to analysis, files will be
checked for missing data and compared to published (or unpublished) reports when available.
Any discrepancies will be resolved by contacting the corresponding authors or custodian of the
data. In order to merge the files, common variables will be converted to a pre-specified format
and given new names. Each data source will have a unique identifier in the merged data set,
and another identifier indicating the presence or absence Bedaquiline. Data retrieved for this
analysis will be used only for this purpose, and will be completely deleted as soon as the final
reports have been completed.
Data merging procedures: We will provide a list of variables of interest to all investigator teams (See Table 3). Variables
that may be categorised or measured differently will be recoded to standard WHO definitions.
To make studies more comparable, primary analyses will be restricted to variables available in
all cohorts. Further analyses with subsets of the data will be conducted if pertinent questions
cannot be answered by the whole data set.
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Table 3: Variables of interest
Variables Measure Type
Study level data
Country Country name Nominal
Duration of follow-up Months Continuous
Individual level data
Baseline
Age Years Continuous
Sex Male/Female Binary
HIV status Yes/No Binary
Ethnicity (if available) Ethnic group Nominal
Type of TB Pulmonary/extra pulmonary Binary
Date of diagnosis of TB Date Continuous
Severity of TB (cavities) Yes/No Binary
Susceptibility to drugs in OBR/resistance profile (or other MDR
treatment)
List Nominal
Associated medical conditions (and other risk factors, if available) List Nominal
Composition (type of drugs) of OBR (and doses) List Nominal
Date treatment started Date Continuous
Date treatment ended Date Continuous
Treatment with bedaquiline Yes/No Binary
Date BDQ started Date Continuous
BDQ dose Numerical Continuous
Date BDQ ended Date Continuous
Changes to treatment Yes/No Binary
Drugs added List Nominal
Drugs stopped List Nominal
Outcome data
Safety*
Number of adverse events per patient Numerical Continuous
Severity Mild/moderate/severe Ordinal
Seriousness Yes/No Binary
Number with at least one adverse event Numerical Continuous
Number with at least one severe adverse event Numerical Continuous
Number with at least one serious adverse event Numerical Continuous
All events Yes/No Binary
Gastrointestinal symptoms Yes/No Binary
Nausea Yes/No Binary
Diarrhea Yes/No Binary
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Vomiting Yes/No Binary
Infections and infestations Yes/No Binary
Investigations Yes/No Binary
Metabolisms and nutrition disorders Yes/No Binary
Hyperuriceamia Yes/No Binary
Musculoskeletal and connective tissue disorders Yes/No Binary
Arthralgia Yes/No Binary
Nervous system disorders (dizziness, headache) Yes/No Binary
Headache Yes/No Binary
Skin and subcutaneous tissue disorders Yes/No Binary
Rash Yes/No Binary
Pruritus Yes/No Binary
General disorders and administration site conditions Yes/No Binary
Respiratory, thoracic and mediastinal disorders Yes/No Binary
Ear and labyrinth disorders Yes/No Binary
Eye disorders Yes/No Binary
Psychiatric disorders Yes/No Binary
Blood and lymphatic system disorders Yes/No Binary
Cardiac disorders Yes/No Binary
Reproductive system and breast disorders Yes/No Binary
ECG changes (QTc prolongation) Yes/No Binary
QTc measurement Numerical Continuous
Major laboratory disorders (> grade II modifications) Yes/No Binary
Laboratory signs of hepatitis Numerical Continuous
ALAT Numerical Continuous
ASAT Numerical Continuous
Bilirubin Numerical Continuous
Laboratory signs of pancreatitis Numerical Continuous
Amylase Numerical Continuous
Lipase Numerical Continuous
Effectiveness
Culture conversion at 6 months Yes/No Binary
Time to culture conversion Time-to-event Continuous
Cure (sustained microbiological conversion at end of treatment) Yes/No Binary
Treatment success Yes/No Binary
Death Yes/No Binary
Cause of death Cause reported Nominal
*Counts and severity will also be collected.
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Statistical methods:
Descriptive statistics: Baseline covariates will be summarised as counts (percentage) for categorical variables, mean
(standard deviation) or median (first quartile, third quartile) for continuous or discrete variables
as appropriate depending on the distribution. Baseline covariates and outcomes will be
analysed individually for each cohort, and then according to the presence or absence of
bedaquiline.
Primary analysis: We will use random-effects logistic regression to determine the effects on safety outcomes
among participants who received bedaquiline versus those that did not receive bedaquiline,
adjusting for baseline characteristics—in particular, age, sex, HIV status, ethnicity, components
of baseline regimen, type of TB, susceptibility to drugs in baseline regimen, associated medical
conditions, changes to treatment. In this analysis, study will be used as a random-effect. For this
analysis we will use the PETTS study as the comparator group (12) because it is a more
homogenous cohort in terms of participants, interventions, outcomes and follow-up time. These
analyses will be replicated for the effectiveness and survival outcomes—with the latter based on
random-effects Cox-regression approach.
Sensitivity analysis: In order to test the robustness of our analyses, we will repeat the analysis using the Ahuja et al
study as a comparator group. It is a more heterogeneous data set including 32 cohorts (9898
patients) from different countries. (11)
Subgroup analyses: We will investigate subgroup effects by introducing interaction terms into our models for age,
sex, HIV status, type and severity of TB. These analyses will be based on adding interactions
between each subgroup variable and the treatment group in the primary analysis models.
All statistical analyses will be two-sided with α levels set at 0.05. The results for all analyses will
be reported as odds ratio (OR), corresponding 95% confidence interval (CI) and associated p-
values. All p-values will be reported to three decimal places with those less 0.001 reported as
p<0.001. We will also examine the model assumptions including collinearity and goodness-of-
fits as appropriate for all the analyses. Data will be analysed using SPSS (IBM Corp. Released
2013. IBM SPSS Statistics for Windows, Version 22.0. Armonk, NY: IBM Corp.). An overview of
out statistical approach can be seen in Figure 1.
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Figure 1: Overview of analytical plan
Investigation of heterogeneity: The included studies will be examined carefully for any clinical differences related to the
participants, interventions and outcomes that might affect treatment outcomes. Possible
differences include the population studied and the duration of follow-up. Between study
heterogeneity will be assessed using intraclass correlation coefficients.
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Assessment of study quality: The quality of reporting for published studies will be assessed using the New Castle Ottawa
Scale (NOS).(13) The NOS can be used to assess the quality of cohort studies by allocating
stars based on the selection of participants for the cohort, the comparability of the cohorts on
the basis of design or analysis and how outcome data was collected. A maximum of 13 stars
can be allocated to a cohort study with no relevant issues.
Assessment of the quality of evidence across studies: The quality of the body of evidence will be assessed using the Grading of Recommendations
Assessment, Development and Evaluation approach via the GRADEpro Guideline Development
Tool (GDT).(14) Using this tool, the extent to which one can be confident that the estimate of
effect is close to the truth can be rated as high, moderate, low and very low. With this approach,
observational studies are typically categorised as low quality but can be upgraded if there is a
large effect size, if plausible confounding would reduce the demonstrated effect and if there is a
dose-response gradient.
Reporting: Our findings will be reported according to the Meta-analysis Of Observational Studies in
Epidemiology (MOOSE) guidelines. (15) Moose is a checklist of 35 items that include
recommended elements of background information, search strategy, methodological details,
results, discussion and conclusion. (15) GRADE tables will be constructed for each outcome of
interest. (14)
Potential Limitations: Potential limitations include considerable differences in the studies that used Bedaquiline and
the use of an external control group for the analysis which comes from a different analysis. We
will address these limitations by incorporating the heterogeneity between studies by using
random effects models and also adjusting for study level characteristics.
Ethics and dissemination: The Hamilton Integrated Research Ethics Board (HIREB) has been consulted for ethics
approval. Given that we will be working with anonymized pre-collected data, from studies that
already have ethics approval, a formal application for ethical clearance is not required. The
results will be disseminated as WHO reports and as peer reviewed publications.
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References:
1. World Health Organization. Global tuberculosis report 2015 Geneva: 2015 (WHO/HTM/TB/2015.22 http://www.who.int/tb/publications/global_report/en/, accessed 12 November 2015). 2015. 2. World Health Organization. Guidelines for the programmatic management of drug-resistant tuberculosis - 2008 emergency update (http://whqlibdoc.who.int/publications/2008/9789241547581_eng.pdf, accessed 30 July 2015): World Health Organization; 2008. 3. World Health Organization. Guidelines for the programmatic management of drug-resistant tuberculosis - 2011 update (http://whqlibdoc.who.int/publications/2011/9789241501583_eng.pdf, accessed 15 March 2015). 2011. 4. Ahuja SD, Ashkin D, Avendano M, Banerjee R, Bauer M, Bayona JN, et al. Multidrug resistant pulmonary tuberculosis treatment regimens and patient outcomes: an individual patient data meta-analysis of 9,153 patients. PLoS Med. 2012;9(8):e1001300. PubMed PMID: 22952439. Pubmed Central PMCID: PMC3429397. 5. United States Food and Drug Administration. FDA news release. 31 December 2012 (http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm333695.htm accessed on 15 March 2015). 2012. 6. World Health Organization. The use of bedaquiline in the treatment of multidrug-resistant tuberculosis: interim policy guidance: World Health Organization; 2013 (http://apps.who.int/iris/bitstream/10665/84879/1/9789241505482_eng.pdf, accessed 10 September 2015). 7. Janssen Infectious Diseases-Diagnostics B. A Phase II, open-label trial with TMC207 as part of a multi-drug resistant tuberculosis (MDR-TB) treatment regimen in subjects with sputum smear-positive pulmonary infection with MDR-TB. 2013. 8. Guglielmetti L, Le Du D, Jachym M, Henry B, Martin D, Caumes E, et al. Compassionate use of bedaquiline for the treatment of multidrug-resistant and extensively drug-resistant tuberculosis: interim analysis of a French cohort. Clin Infect Dis. 2015 Jan 15;60(2):188-94. PubMed PMID: 25320286. Epub 2014/10/17. eng. 9. MSF. Compassionate use of bedaquiline: Interim outcomes from the Armenian National Tuberculosis Control Office. 10. Ndjeka N, Conradie F, Schnippel K, Hughes J, Bantubani N, Ferreira H, et al. Treatment of drug-resistant tuberculosis with bedaquiline in a high HIV prevalence setting: an interim cohort analysis. Int J Tuberc Lung Dis. 2015 Aug;19(8):979-85. PubMed PMID: 26162365. Epub 2015/07/15. eng. 11. Ahuja SD, Ashkin D, Avendano M, Banerjee R, Bauer M, Bayona JN, et al. Multidrug resistant pulmonary tuberculosis treatment regimens and patient outcomes: an individual patient data meta-analysis of 9,153 patients. PLoS Med. 2012;9(8):e1001300. PubMed PMID: 22952439. Pubmed Central PMCID: PMC3429397. Epub 2012/09/07. eng. 12. Cegielski JP, Kurbatova E, van der Walt M, Brand J, Ershova J, Tupasi T, et al. Multidrug-Resistant Tuberculosis Treatment Outcomes in Relation to Treatment and Initial Versus Acquired Second-Line Drug Resistance. Clin Infect Dis. 2016 Feb 15;62(4):418-30. PubMed PMID: 26508515. Pubmed Central PMCID: PMC4725381. Epub 2015/10/29. eng. 13. Wells GA, Shea B, O'Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses 2014 [13 January 2014]. Available from: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp.
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14. Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, et al. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. J Clin Epidemiol. 2011 Apr;64(4):383-94. PubMed PMID: 21195583. Epub 2011/01/05. eng. 15. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA. 2000 Apr 19;283(15):2008-12. PubMed PMID: 10789670. Epub 2000/05/02. eng.
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Annex 1: Search strategies for studies retrieval
PubMed Search ("Tuberculosis"[Mesh] AND "Tuberculosis, Multidrug-Resistant"[Mesh]) AND "Drug Resistance,
Bacterial"[Mesh] AND ("bedaquiline"[Supplementary Concept] OR "bedaquiline"[All Fields]) OR
diarylquinoline[All Fields] OR sirturo[All Fields] OR ("bedaquiline"[Supplementary Concept] OR
"bedaquiline"[All Fields] OR "tmc207"[All Fields]) OR ("bedaquiline"[Supplementary Concept] OR
"bedaquiline"[All Fields] OR "r207910"[All Fields]) AND ("safety"[MeSH Terms] OR "safety"[All Fields])
AND ("2011/01/05"[PDat] : "2016/01/03"[PDat] AND "humans"[MeSH Terms])
New PubMed Search "Tuberculosis"[Mesh] OR tuberculosis [TW] OR “ Lupus Vulgaris ”[TIAB] OR “ koch s disease ” [TW]
OR tubercul*[TW] OR tuberculoma [TW] OR Silicotuberculosis [TW] OR "Tuberculosis Vaccines"[Mesh] OR "BCG
Vaccine"[Mesh] OR ( calmette*[TW] AND vaccin*[TW]) OR "Tuberculin Test"[Mesh] OR Tuberculin [TW] OR
"Mycobacterium tuberculosis"[Mesh] OR TB [Ti]
EMBASE Search (http://www.embase.com) bedaquiline'/exp OR '1 (6 bromo 2 methoxy 3 quinolinyl) 4 dimethylamino 2 (1 naphthyl) 1 phenyl 2
butanol':de,ab,ti OR '1 (6 bromo 2 methoxyquinolin 3 yl) 4 (dimethylamino) 2 (naphthalen 1 yl) 1
phenylbutan 2 ol':de,ab,ti OR '6 bromo alpha [2 (dimethylamino) ethyl] 2 methoxy alpha (1 naphthalenyl)
beta phenyl 3 quinolineethanol':de,ab,ti OR '6 bromo alpha [2 (dimethylamino) ethyl] 2 methoxy alpha (1
naphthyl) beta phenyl 3 quinolineethanol':de,ab,ti OR 'bedaquiline fumarate':de,ab,ti OR 'r
207910':de,ab,ti OR 'r 403323':de,ab,ti OR 'r207910':de,ab,ti OR 'r403323':de,ab,ti OR
'sirturo':de,ab,ti OR 'tmc 207':de,ab,ti OR 'tmc207':de,ab,ti OR bedaquiline
Cochrane Central Register of Controlled Trials multidrug resistant OR drug-resistant AND tuberculosis OR TB AND bedaquiline OR sirturo OR TMC207 AND
treatment in Title, Abstract, Keywords Publication Year from 2000 to 2016, in Cochrane Reviews (Reviews
only) and Trials (Word variations have been searched)