REPORT ON GREEN LIGHT COMMITTEE MONITORING MISSION...
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1 REPORT ON GREEN LIGHT COMMITTEE MONITORING MISSION INDONESIA January 2017 Michael Rich, M.D., M.P.H. Date of mission: 15-27 January 2017 Acknowledgments The monitoring team would like to express gratitude to the National Tuberculosis Control Programme (NTP) Indonesia and the World Health Organization (WHO) Country Office for Indonesia for facilitating this mission. The monitoring team would also like to express gratitude to the patients interviewed, as well as the doctors, nurses and other key personnel from the facilities implementing PMDT. This monitoring mission was embedded in a larger Joint External Monitoring Mission (2017 JEMM) which took place 15-27 January 2017. The 2017 JEMM which had the purpose to make an independent, comprehensive and in-depth analysis of the TB situation, TB control efforts and to provide expert advice and make recommendations for the strengthening of TB control services to reach the endTB strategy targets. Deliverables The principle deliverables of this mission are: 1. rGLC Monitoring Report, 2017 (this report). 2. Participation as member and lead assessor of PMDT in the 2017 JEMM. 3. The chapter for the 2017 JEMM Report of the PMDT focal area. List of references accessed for this report: • National Action Plan for the Programmatic Management of Drug-resistant TB. 2016-2020 (Draft). MoH. • PMDT guidelines (with annexes for short regimen under development) • Monthly monitoring of Xpert scale-up and utilization, Indonesia, December 2016, KNCV/CTB Indonesia • Technical Guide Treatment of Patients with Drug-Resistant TB with New Drug Bedaquiline • Technical Guide Integrated Management of Tuberculosis Control Drug Resistance • Technical Guide Pharmacovigilance Cohort Event-Based Monitoring in PMDT Hospital Referral • Standard Operating Procedure - Submission of Payment to Global Fund - Integrated Management of Drug-Resistant TB • Integrated Management Training for Drug-Resistant TB Control - Facilitator Guidelines in Training with 5 training modules. • Drug-Resistant TB Logistics • Communication, Information, and Education for Drug-Resistant TB • Assuring high quality care for patients with M/XDR TB Scaling up Enhanced Cohort Review for PMDT. Lisa Chen, Baby Djojonegoro, Philip Hopewell Debriefing: 29 October, 2015 • Indonesia TB Patient Pathway Analysis (PPA). January 2017 • Indonesia TB Control Update, December 2016. (A WHO summary document prepared for the 2017 JEMM).
Transcript of REPORT ON GREEN LIGHT COMMITTEE MONITORING MISSION...
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REPORTONGREENLIGHTCOMMITTEEMONITORINGMISSION
INDONESIAJanuary2017
MichaelRich, M.D.,M.P.H.Dateofmission:15-27January2017
AcknowledgmentsThemonitoringteamwouldliketoexpressgratitudetotheNationalTuberculosisControlProgramme
(NTP)IndonesiaandtheWorldHealthOrganization(WHO)CountryOfficeforIndonesiaforfacilitating
thismission.Themonitoringteamwouldalsoliketoexpressgratitudetothepatientsinterviewed,as
wellasthedoctors,nursesandotherkeypersonnelfromthefacilitiesimplementingPMDT.
ThismonitoringmissionwasembeddedinalargerJointExternalMonitoringMission(2017JEMM)
whichtookplace15-27January2017.The2017JEMMwhichhadthepurposetomakeanindependent,
comprehensiveandin-depthanalysisoftheTBsituation,TBcontroleffortsandtoprovideexpertadvice
andmakerecommendationsforthestrengtheningofTBcontrolservicestoreachtheendTBstrategy
targets.
DeliverablesTheprincipledeliverablesofthismissionare:
1. rGLCMonitoringReport,2017(thisreport).
2. ParticipationasmemberandleadassessorofPMDTinthe2017JEMM.
3. Thechapterforthe2017JEMMReportofthePMDTfocalarea.
Listofreferencesaccessedforthisreport:• NationalActionPlanfortheProgrammaticManagementofDrug-resistantTB.2016-2020(Draft).
MoH.
• PMDTguidelines(withannexesforshortregimenunderdevelopment)
• Monthly monitoring of Xpert scale-up and utilization, Indonesia, December 2016, KNCV/CTB
Indonesia
• TechnicalGuideTreatmentofPatientswithDrug-ResistantTBwithNewDrugBedaquiline
• TechnicalGuideIntegratedManagementofTuberculosisControlDrugResistance
• TechnicalGuidePharmacovigilanceCohortEvent-BasedMonitoringinPMDTHospitalReferral
• Standard Operating Procedure - Submission of Payment to Global Fund - Integrated
ManagementofDrug-ResistantTB
• Integrated Management Training for Drug-Resistant TB Control - Facilitator Guidelines in
Trainingwith5trainingmodules.
• Drug-ResistantTBLogistics
• Communication,Information,andEducationforDrug-ResistantTB
• Assuringhighqualitycare forpatientswithM/XDRTBScalingupEnhancedCohortReviewfor
PMDT.LisaChen,BabyDjojonegoro,PhilipHopewellDebriefing:29October,2015
• IndonesiaTBPatientPathwayAnalysis(PPA).January2017
• Indonesia TB ControlUpdate,December 2016. (AWHO summary document prepared for the
2017JEMM).
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TableofContents PAGE Abbreviations and acronyms Anti-tuberculosis drug abbreviations 3 1. Executive summary (and list of references accessed for this report) 5 2. Summary of Recommendations 6 3. Findings, discussions and recommendations 10 A. Background and introduction 10 B. Information on the burden X/MDR-TB in Indonesia 10 C. Government commitment and partnerships 11 D. Organization, management and coordination 12 E. Case finding, diagnosis and definitions 13 F. Laboratory aspects 19 G. Treatment 21 H. Side-effects and monitoring response to treatment 30 I. Treatment delivery and adherence 31 J. Drug Procurement and management 32 K. Infection control 32 L. Information systems and data management 33 ANNEXES Annex A: Progress made on last year’s monitoring mission’s recommendations 34 Annex B: The terms of reference for this visit 37 Annex C: Detailed agenda of mission 39 Annex D: List of People Met During the Mission 43 Annex E: Pediatric drug dosage table for the new shorter MDR Regimen 45
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ABBREVIATIONSANDACRONYMS
AIDS Acquiredimmunodeficiencysyndrome
ART antiretroviraltherapy
CET ClinicalExpertsTeam
DOT Directlyobservedtreatment
DOTS DirectlyObservedTreatmentShort-course
DRS Drugresistancesurvey
DRTB Drug-resistanttuberculosis
DST Drugsusceptibilitytesting
EMR Electronicmedicalrecord
EXPAND-TB ExpandingAccesstoNewDiagnosticsforTB.ProjectfundedbyUNITAIDand
implementedbyGLI,FIND,WHOandGDF
FIND FoundationforInnovativeNewDiagnostics
GDF GlobalTBDrugFacility
GLC GreenLightCommittee
GFATM GlobalFundtoFightAIDS,TuberculosisandMalaria
HIV humanimmunodeficiencyvirus
IUATLD InternationalUnionAgainstTuberculosisandLungDisease
KNCV RoyalNetherlandsTBFoundation
LPA LineProbeAssay
LJ LowensteinJensen
MDG MillenniumDevelopmentGoal
MDR-TB Multidrug-resistanttuberculosis
MOH MinistryofHealth
NGO Nongovernmentalorganization
NTP NationalTuberculosisProgramme
NTRL NationalTBReferenceLaboratory
PMTCT Preventionofmother-to-childtransmission
PPM Public-PrivateorPublic-PublicMix
SEARO SouthEastAsiaRegion
SLD Second-lineanti-tuberculosisdrug
SOP Standardoperatingprocedures
SRL Supranationaltuberculosisreferencelaboratory
TB Tuberculosis
UNAIDS JointUnitedNationsProgrammeonHIV/AIDS
UNICEF UnitedNationsInternationalChildrenFund
Union InternationalUnionAgainstTuberculosisandLungDisease
UNITAID Internationalfacilityforthepurchaseofdrugsandlaboratorycommoditiesfor
HIV/AIDS,malariaandtuberculosis
WHO WorldHealthOrganization
XDR-TB Extensivedrug-resistanttuberculosis
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Anti-tuberculosis drug abbreviations (in the format of the WHO new Grouping of second-line TB drugs)
Group A:
Fluoroquinolones2
Levofloxacin
Moxifloxacin
Gatifloxacin
Lfx
Mfx
Gfx
Group B:
Second-line injectable agents
Amikacin
Capreomycin
Kanamycin
(Streptomycin)3
Am
Cm
Km
(S)
Group C:
Other core second-line agents2
Ethionamide / Prothionamide
Cycloserine / Terizidone
Linezolid��
Clofazimine
Eto / Pto
Cs / Trd
Lzd��
Cfz
Group D:
Add-on agents
(not part of the core MDR-TB
regimen)
D1
Pyrazinamide
Ethambutol
High-dose isoniazid
Z
E
Hh
D2 Bedaquiline
Delamanid
Bdq
Dlm
D3
p-aminosalicylic acid
Imipenem-cilastatin4
Meropenem4
Amoxicillin-
clavulanate4
(Thioacetazone)5
PAS��
Ipm
Mpm
Amx-Clv
(T)
1Thisgroupingisintendedtoguidethedesignofconventionalregimens.�
2MedicinesinGroupsAandCareshownbydecreasingorderofusualpreferenceforuse.
3ForthetreatmentofRR-/MDR-TB,streptomycinisincludedasasubstituteforthesecond-lineinjectableagents
whenaminoglycosidesorcapreomycincannotbeusedandsusceptibilityisconfirmedorhighlylikelyto
streptomycin.Resistancetostreptomycinalonedoesnotqualifyforthedefinitionofextensivelydrug-resistantTB
(XDR-TB).
4Carbapenemsandclavulanatearemeanttobeusedtogether;clavulanateisonlyavailableinformulations
combinedwithamoxicillin
5HIV-statusmustbetestedandconfirmedtobenegativebeforethioacetazoneisstarted
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1.ExecutivesummaryIndonesia has a high number of cases of rifampicin resistant/multidrug resistant TB (RR-/MDR-TB),
rankinghighamongthe20highMDR-TBburdencountriesintheworld.ThepreciseMDR-TBburdenin
IndonesiaisunknownasthereisnonationwiderepresentativedataonRR-/MDR-TBprevalence.Precise
estimatesofXDR-TBarealsounknown.
Inthelastthreeyears,therehasbeenconsiderableprogressmadeinPMDTwithwideruseofXpert,a
steadyincreaseinpatientenrollmentandstrongerpatientsupport.Nonetheless,theprogressinfalling
wellshortofmeetingtheneedswhichincludethousandsofMDR-TBcasesthatnevergetdiagnosedand
apoortreatmentoutcomeswithhighdefaultanddeath.Progressmadeonlastyear’srGLCmonitoring
mission’srecommendations(May2016)canbefoundinAnnexA.
There are ambitious plans in place for the scale up of PMDTwithmany challenges to be overcome.
Thesechallengesinclude:
• Extremely low proportion of eligible groups receive Xpert testing. Eligible groups such asretreatmentafterCategoryIorCategoryI,contactsofDR-TBpatientsandpatientswithTB/HIVare
arenotalwaysscreenedfordrug-resistancewithXpert.Infact,averylowproportionoftheeligible
groupsarescreened.
• ScalinguptheuseofXpert.Xperttestingisverymuchunderutilized.ThenewalgorithmforXpert
thatwasintendedtobeimplementedstartinginMay2016hasnotbeensuccessfullyrolledout.It
was estimated that less than 50,000 Xpert testswere performed2016 and itwill be a significant
challengetoreachthetargetutilizationof1.6milliontestsin2017.
• LimitedaccesstoPMDTservices.The35PMDTreferralhospitalsplus57PMDTtreatmentcenters
arefarfromthenationaltargetof‘AtleastonePMDTReferralHospitalorPMDTTreatmentCentre
inall514districts/municipalities.
• Second-lineDSTforallpatientswithRR-TB/MDR-TB.Second-linephenotypicDSTisbeingdoneonveryfewMDR-TBpatients.Lineprobeassay(LPA),arapidmoleculartest,forsecond-lineDSTisnot
yet operational. The countryplans tohave2 sites operational bymid2017. Two LPA sites could
performtheneedednumberoftestsfor2017;however,thecountrywidespecimentransportwill
provechallenging.LPADSTtosecond-linedrugsisextremelyimportantforidentifyingwhogetsthe
shorterMDRregimenandwhogetsnewTBdrugs.
• DecreasingdefaultofpatientsonMDRregimens.Highearlylosttofollowupofrifampicinresistant
TB(RR-TB)positivepatients(approximately25%)isquitecommonatmostsites. Thereasonsvary
from patients refusing treatment because of fear of adverse events, died before treatment, and
simply losttofollowup.Perhapsthemainreason isthatthere isstillvery limitedaccesstoPMDT
services and many patients have to spend considerable time and money to reach these limited
facilities. It is unclear if one cause is the health staff not explaining the treatment properly. An
additional25%getlosttofollowupwhileontreatment.Thesputumandspecimentransportsystem
isweakasisgettingtestresultsbacktothecliniciancaringforthepatient.Resourcesandsystemsto
dohome visits to defaulting patients oftennot available. The financial support of 750,00 IDRper
month is not always enough for theextremepoor and vulnerable. There also canbedelays and
gapsformonthswherethesupportmoneyislategettingtothepatient.
• Transition to the short regimen and use of new TB drugs for those that do not qualify for theshorterregimen.Thetreatmentregimensandthestrategyfordeterminingwhichpatientsgetshort
MDRregimenneedstobewellthoughtout.Thepatientsthathaveacontra-indicationforanewTB
drugwillinmostcasesbenefitformaregimenwithanewTBdrug.Trainingonthetransitionshould
occurnationallyandoverashortperiodoftime.
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• ManagementofcareofthepatientsonMDRRegimensneedsimprovement.EvenwithuseoftheshorterMDRregimens,supportingandmanagingcareofthepatientisachallengeandneedstobe
improved. Adverse effects for patient on MDR-TB treatment are not aggressively managed. The
Puskesmasstaffarenotalwaystrainedwell tomanageMDR-TBpatients.Thereare longdelays in
monitoring culture results getting into the patient’s chart, which are essential for monitoring
effectivenessoftreatment.AtransitiontotheshorterMDRregimenisplannedforJune2017,but
guidelines,trainingmaterialandchangestotheMDR-TBformsarenotyetfinalized.Mostimportant,
in management of care, communications between Clinical Expert Teams (CETs), referral and
treatmentcentres,andsatellitesitesthattreatpatientsissub-optimal.
2.PriorityrecommendationsfrompresentrGLCMission(January2017)(Progressmadeonlastyear’srGLCmonitoringmission’srecommendations(May2016)canbefoundin
AnnexA).SectionARecommendations–Backgroundandintroduction1.Reviewandimplementtherecommendationsthatareinthe2017JEMMtofurtherimproveTB
controlandPMDT.
SectionBRecommandations-InformationonM-/XDR-TB2.CompletethenationalDRStobetterestimatetheprevalenceofDR-TB.ThenationalDRSshould
includedoingSLDresistancetestinginallpatientsfoundtohaveRR-TBinordertodeterminetherateof
fluoroquinoloneandsecond-lineinjectabledrugresistanceinpatientswithRR-/MDR-TB.
SectionCRecommendations–Governmentcommitmentandpartnerships3)FinalizeandimplementtheNationalActionPlanontheProgrammaticManagementofDrug-resistant
TB(PMDT),versionJanuary2017.
• TheactionplanincludesincorporatingallWHOendorsedtoolstofightMDR-TBincluding
modernmoleculardiagnostics,decentralizedtreatment,newshorterMDRregimens,newanti-
TBdrugsbedaquilineanddelamanidforpatientsnotabletoreceivetheshorterMDRregimens,
andarobustsystemofmanagement,supervisionandmonitoring.
• TheActionplanshouldbecomecostedandsupportedbystakeholdersandGoIMoH.
• Thesystemofhumanresourcestoimplementtheplanshouldbereviewedandappropriately
putinplace.
• Increaseengagementoftheprivatesectorandconsiderdesigningrobustpublic-privatemix
managementofPMDT.
SectionDRecommendations-Organization,managementandcoordination(includesrecommendationsonsupervisionandmonitoringoftheprogramme)4.ImprovethesystemoftreatmentdeliveryandmanagementofthepatientsonMDRregimens.
• Establish at least 1 PMDT Referral Hospital or PMDT Treatment Centres in all 514
districts/municipalitiesassoonaspossible,consideracceleratingthePMDTNationalActionPlan
thatonlyreachesthisgoalin2020.
• Provide regular refresher training to theaPMDTReferralHospitalorPMDT treatmentCentre
staffwithanemphasisonrolesandresponsibilities.
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• Re-designthewayasatellitesitegetstrainedandmanagesMDR-TBpatients.
• Considerorganizingacommunity-basedDOToptionforpatients.
• Improve communicationbetween theClinical Expert Teams (CETs), PMDTReferralHospitalor
PMDTtreatmentCentre,andPMDTsatellitesites
SectionERecommendations-Case-findingStrategy5)Improveandscale-upthediagnosisofDR-TBthrough:
• Assure that every patient that belongs to an eligible groups for DR-TB screening (such as
retreatmentafterCategoryIorCategoryI,contactsofDR-TBpatientsandpatientswithTB/HIV
arealwaysscreenedfordrugresistancewithXpert.
• ContinuetoscaleuptheuseofXpertastheinitialtesttodetermineDR-TBandimplementthe
newdiagnosticalgorithmatallXpertsites.
• IncreasenumberofXpertsitesperthePMDTNationalActionPlan(approximately1000Xpert
MTB/RIF machines employed and 2.3 million test performed in 2018; 2000 Xpert MTB/RIF
machinesemployedand4.5milliontestperformedin2020).
• PerformXpertinallhospitalizedpatientswithrespiratorysymptoms(thisrecommendationwill
helpwithinfectioncontrolandcasefindingforbothDS-TBandDR-TB).
• AssurethatprivateclinicianshaveaccesstoXperttesting,freeofchargetothepatient.
• Establish a robust network of sputum/specimen transport to Xpert facilities and referral
laboratorywithasystemofreportingresultsbacktotheorderingfacility.Thisshouldbedone
forXpert,monitoringcultures,andDST.
• Revise the projected number of cartridges need for the new algorithm for TB diagnosis and
number of DR-TB cases to be detected for 2017 to account for slow adaptation of the new
AlgorithmforTBdiagnosis.Keepgoalsfor2018,2019,and2020similarinambition.
• Performasecondalgorithmusinglineprobeassay(LPA)fordiagnosingpreXDRandXDR-TBin
allpatientswithRR-/MDR-TB.
SectionFRecommendations-Laboratoryservices6)Improveandscale-upthediagnosisofDR-TB,monitoringofculturesandDSTtoisoniazidandsecond-
linedrugs.
• ContinuetoscaleuptheuseofXpertastheinitialtesttodetermineDR-TBandimplementthe
newdiagnosticalgorithmatallXpertsites.
• Strengthenthesystemofmonitoringcultures.
• Perform second-line DST in all patientswith RR/MDR-TB, initiallywith LPA to 1st and 2
nd line
drugsandthenphenotypictestingtoisoniazid,kanamycin(oramikacin),capreomycin,andthe
flouroqunolones(ofloxacinandmoxifloxacinat0.5and2.0mg/dLconcentrations).TheWHOis
coming out with new recommendations on critical concentrations for DST of second-line TB
drugsinthelatterhalfof2017,sopleaselookforthemandadaptprotocolsasindicated.
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SectionGRecommendations-Treatmentstrategies7.Modifytreatmentregimenstobeup-to-datewiththe latestWHO2016Guidelinesontreatmentof
DR-TB.
1. UpdateallPMDTguidesfornewshorterMDRregimensandfortheuseofnewTBdrugs,
bedaquilineanddelamanid,whenMDRshorterregimenscannotbeused.
2. ImplementthenewshorterMDRregimeninpatientsthathavenocontraindicationstoitand
implementindividualizedconventionalMDRregimensinpatientswithacontraindicationtothe
shorterMDRregimen.
3. FasttracktheregulatoryapprovalfordelamaniduseinIndonesia.
8.SpecificdesignofregimensarelistedbelowandareconsistantwiththeIndonesianNationalAction
PlanforPMDT2016-2020(seeabovediscussionformoredetails).
SimpleMDR-TB(noSLDresistance):StandardizedregimentobeuseduntilJuly2017:8-12Km-LFX-Eto-Cs-Z-(E)-H/12-14LFX-Eto-Cs-Z-(E)-H
ThesuggestedshorterMDRregimentobestartedafterJuly2017,orsoonerifpossible,is:4-6Km-MfxHD-Pto-Cfz-Z-HHD/5MfxHD-Cfz-Z-ETheuseofPto(orEto)inthecontinuationphaseisuptotheNTPs.Thereisnotclearevidence
onwhetherPtointhecontinuationphaseimprovesoutcomesormakesoutcomesworseas
defaultcouldbehigherdotoaddedadverseeffects.Thisconsultanthasaslightpreferencefor
notusingPto(orEto)throughouttheshorterMDRregimenbutthefinaldecisionislefttothe
NTP.Theobservationalstudyon500patientsfromBangladeshhadexcellentresultsanddid
notusePtointhecontinuationphase.
Pre-XDRTB:Resistanceorseveretoxicitytotheinjectableagent(PreXDRInjectable).ConfidenceinEtoandCs:8-12Bdq(orDlm)-Lfx-Eto-Cs-Z/12-14Lfx-Eto-Cs-Z
Resistanceorseveretoxicitytotheflouroquinolones(FQs)(PreXDR-FQ).ConfidenceinEtoandCs.8-12Km-Bdq(orDlm)-Lzd-(Lfx)-Eto-Cs/12-14Lzd-(Lfx)-Eto-Cs
XDR-TB:NewcaseofXDR-TBorfailuretothestandardconventionalMDRregimen:6Bdq(orDlm)-Lzd-Cfz-Lfx-(Eto)-(Cs)-PAS/14Lzd-Cfz-Lfx-(Eto)-(Cs)-PAS
AcaseofXDR-TBaftertakingtheshorterMDRregimenorfailureoftheshorterMDRregimen(orclosecontactofapersonthatfailedtheshorterMDRregimen):8(Cm)-Dlm-Lzd-(Cfz)-Cs-PAS/16(Dlm)-Lzd-(Cfz)-Cs-PAS
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SectionHRecommendations-Side-effectsandmonitoringresponsetotreatment9.Aggressivelytreatandmanageallside-effectswithaspecialfocusonnauseaandvomiting.
10.ImplementastrongerstrategytohavezerohearinglossfromMDR-TBtreatment.
• BaselineaudiometrytestingforallMDR−TBcasesatinitiationoftreatment.
• Repeataudiogramforanymildsymptomofhearingloss,tinnitus,ordizzinessandroutinelyat
month3and5(ormonthlywhileoninjectableagentsifresourcesareavailable).
• Considertheuseofhandheldaudiometrydevicesthatrunonandroidphonesortablets,suchas
HearScreen®.
• UsenewTBdrugsbedaquilineordelamanidincasesofmoderateorseverehearingloss.In
casesofsuspectedlackofresponsetotheregimenandhearingloss,re-designthewhole
regimenwiththeinclusionofanewTBdrug;
• Inthecaseofmoderateorseverehearinglossonthenewshorterregimen,ifthepatienthas
gottenmorethan3monthsoftreatmentconsidersuspensionoftheinjectableagentand
continuingtherestofthetreatment.Ifthepatienthasgottenlessthan3months,considerre-
designofusingaconventionalregimenandnewTBdrugandnoinjectable.
11.Establisharobustnetworkofsputum/specimentransportwiththereferrallaboratorywithasystem
ofreportingresultsbacktotheorderingfacility.ThisshouldbedoneforXpert,monitoringcultures,and
DSTtofirstandsecond-linedrugs.(SeeSectionsEandFabove).
SectionIRecommendations-TreatmentDeliveryandadherence12.Treatmentdeliveryandadherencecanbeimprovedthrough:
• Re-designinghowasatellitesitegetstrainedandmanagesMDR-TBpatients,withanemphasis
onwaystoimproveadherence.
• Considermoreprovisionsforcommunity-basedDOTs
• Consider increasing the 750,000 IDRmonthly support for all PMDT patients and consider an
additionalsocialsupportpackagefortheextremelypoorandvulnerablepatients.
• Designasystemthatallowsforarobustpublic-privatetreatmentofMDR-TBthatassureshigh
adherenceandpatientsupport.
SectionJRecommendations-Drugmanagement13.Seethe2017GDFreportforallrecommendationsconcerningdrugprocurementofSLDs.
14.FasttracktheregulatoryapprovalfordelamaniduseinIndonesia.
SectionKRecommendations-Infectioncontrol15.See2017JEMMrecommendations.Continuetoemphasizeandfullyfundinfectioncontrolprotocols.
16.ImprovecontacttracingforMDR-TBcases.
SectionLRecommendations-Recordingandreporting,anddatamanagement17.ContinueeTBManagerforPMDT.
• AssureallsatellitetreatmentsiteshaveaccesstoeTBManager.
• CompleteXPERTMTB/RIFAlertandeTBManagerlinkage.
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• LinkeTBManagerwiththeNationalmedicalinformationsystem(MIS).
3.Findings,discussionsandrecommendationsA.BackgroundandintroductionIndonesia consists of 34 provinces, eachwith a governor and legislature. Provinces are composed of
districts and municipalities (416 + 98), responsible for government services. The Sub-districts or
“Kecamatan” (7,094) are divided into villages or “Desa/ Kelurahan (74,093/ 8,412),which are in turn
dividedintocitizengroups(RW/RT)and,finally,neighborhoods(tenhouseholdgroups).
AlargeJointExternalMonitoringMission(JEMM)tookplacein2017,ledbybothnationaland
internationalreviewers,whichundertookacomprehensiveappraisaloftheNTPandTBcontrolin
Indonesia.Pleaseseethe2017JEMMReportforfurtherdiscussionontheexistingTBcontrolactivities
inIndonesia.
TherehasbeensubstantialprogresssincethelastrGLCvisitofMay2016,especiallyintermsof
establishingaNationalActionPlanforPMDTandanewdiagnosticalgorithmforTBthatusesXpert;still
muchremainstobedone.AnevaluationoftheprogressmadeontherecommendationsfromtheMay
2016rGLCreportisprovidedinAnnexA.ThetermsofreferenceforthisvisitaredescribedinAnnexB,
andthevisitagenda,placesvisited,andpeoplemetaredescribedinAnnexC.
SectionARecommendations–Backgroundandintroduction1.Reviewandimplementtherecommendationsthatareinthe2017JEMMtofurtherimproveTB
controlandPMDT.
B.InformationontheburdenX/MDR-TBinIndonesiaIndonesia has a high number of cases of rifampicin resistant/multidrug resistant TB (RR-/MDR-TB),
rankinghighamongthe20highMDR-TBburdencountriesintheworld.ThepreciseMDR-TBburdenin
IndonesiaisunknownasthereisnonationwiderepresentativedataonRR-/MDR-TBprevalence.Precise
estimatesofXDR-TBarealsounknown. TheNTPandNational InstituteofResearchandDevelopment
(NIHRD)haveinitiatedanationwideresistancesurveyin2016withresultsexpectedin2017.Basedon
datafromthesmallresistancesurveys,theWHOestimatestherecouldbeasmanyas32,000casesof
incidentcasesofTBcorrespondingtoaround10,000casesamongthenotifiedcases(seeTable1and2).
Table1.EpidemiologyofRR-/MDR-TBinIndonesiaIndicador Estimates
DR-TBincidence 12cases/100,000population(32,000cases)
Estimated MDR/RR-TB cases amongnotifiedpulmonaryTBcasesin2015:
10,000cases
Estimated%ofTBcaseswithMDR/RR-TB 2.8%(New)and16%(previouslytreated).
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Table2.EstimatedproportionofMDR-TBcasesamongnotifiedTBcasesinIndonesiain2015 Notifiedcases
2015Drugresistance
estimatesEstimatedDR-TBcases(WHO)
NewpulmonaryTBcases 295,781 2.8% 8,300
Re-treatmentcases 10,325 16% 1,700
Extra-pulmonaryTBcases 24,623 Notknown -
Total 330,729 10,000
SectionBRecommendations-InformationonM-/XDR-TB2.CompletethenationalDRStobetterestimatetheprevalenceofDR-TB.ThenationalDRSshould
includedoingSLDresistancetestinginallpatientsfoundtohaveRR-TBinordertodeterminetherateof
fluoroquinoloneandsecond-lineinjectabledrugresistanceinpatientswithRR-/MDR-TB.
C.GovernmentcommitmentandpartnershipsSeethe2017JEMMforamorethoroughdiscussionongovernmentcommitment,politicalwillandthe
extensivelistofpartnershipsinrespecttoTBcontrolandPMDT.Thereisnownationalhealthinsurance
coveragebeingrolledoutthroughtheBPJS(NationalHealthInsurance).TheBPJSwillcoverthecostof
MDR-TB treatment however, it is not clear if it sufficient and is likely only complimentary to the GF
funding,governmentprogrammaticfunding,andotherfunding(NGOs).Thereislittleinteractionwith
privatesectoronPMDT.
ANationalActionPlanforPMDT2016-2020hasbeenupdatedandexistsindraftform.Highlightsofthe
planaretoscaleupPMDTcareaggressivelywiththefollowing2020goals:
• AtleastonePMDTReferralHospitalorPMDTTreatmentCentreinall514districts/municipalities
• Over2000operatingXpertmachinesthatwillbeperformingover4.5millionXperttestsperyear.
• Acompletedtransitiontotheshortregimen(transitiontostartinfullforcemid-2017)andtheuseof
thenewTBdrugsbedaquilineanddelamanidforcasesthatcannottaketheshortregimen.
• AmorecapableandskilledstaffforthemanagementofMDRregimens.
• MultipleoptionsofmanagingMDR-TBthatincludebetterengagementwithprivatehospitalsand
moreoptionsinthepublicsectorfordecentralizedclinic-basedandcommunity-basedcare.
SectionCRecommendations–Governmentcommitmentandpartnerships3.FinalizeandimplementtheNationalActionPlanontheProgrammaticManagementofDrug-resistant
TB(PMDT),versionJanuary2017.
• TheactionplanincludesincorporatingallWHOendorsedtoolstofightMDR-TBincluding
modernmoleculardiagnostics,decentralizedtreatment,newshorterMDRregimens,newanti-
TBdrugsbedaquilineanddelamanidforpatientsnotabletoreceivetheshorterMDRregimens,
andarobustsystemofmanagement,supervisionandmonitoring.
• TheActionplanshouldbecomecostedandsupportedbystakeholdersandGoIMoH.
• Thesystemofhumanresourcestoimplementtheplanshouldbereviewedandappropriately
putinplace.
• Increaseengagementoftheprivatesectorandconsiderdesigningrobustpublic-privatemix
managementofPMDT.
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D.Organization,managementandcoordinationTheareambitiousplansfortheexpansionofPMDTasdescribedintheNationalActionPlanforPMDT
2016-2020thatincludeadescriptionoftheorganization,managementandorganizationoftheprogram.
TheNationalActionPlanforPMDT2016-2020inrespecttosupervisionandhumanresourcecapacity
buildingshouldbefollowed.
.
PMDTservicesareofferedinafractionofhealthcarefacilitiesincentralizedcentrescalled“PMDT
ReferralHospitals”and“PMDTTreatmentCentres”withDOToftheregimensbeingdecentralizedto
identified“treatmentsatellitesites”.Asofendof2016,thePMDTserviceshaveexpandedto35PMDT
referralhospitals,57PMDTtreatmentcentres(previouslycall“sub-referralcentres”)and1,238
Treatmentsites(treatmentsatellite)in33provinces.Table3describesthePMDTactivitiesperformed
ineachofthedifferentfacilitiesinvolvedinPMDT.
Table3.PMDTactivitybyPMDTtreatmentfacilitytype
AllpatientsarestartedatthePMDTReferralHospitalsorPMDTTreatmentCentresandafterithasbeen
documentedthepatientistoleratingthetreatment,treatmentunderclinic-basedDOTisarrangedata
satellite site,oftenapuskesmasclose to thepatient’s residence. Somepatientsprefer continuecare
PMDTActivity
PMDTtreatmentfacilitytypePMDTReferral
HospitalsPMDTTreatment
CentresTreatment
SatellitesitesClinicalexpertteam + - -
Diagnosing + + +
Establishtreatment + + -
Initiationoftreatment + + +
Continuingtreatment + + +
Inpatient + +/- -
Outpatient + + +
Establishtreatmentoutcome + + -
13
andDOTatthereferralandsub-referrallevelfortheirwholetreatment,andthisoptionisavailableto
patients. Most patients do not require hospitalization for the start of treatment. The satellite site
(usually apuskesmas)does thebulkof theDOT,which is clinic-basedDOT (thepatient travels to the
clinicdailyfortheDOT).Themonthlyfollow-upvisitsandallfollow-upexaminationsandtests(smear,
cultures, blood laboratory tests, hearing tests and specialty consults) and outcome assignments are
done through the PMDT Referral Hospitals and PMDT Treatment Centres. Basic adverse events are
managedbythesatellitesiteswithmorecomplicatedadverseeventsandregimenadjustmentdoneat
the PMDT Referral hospitals and PMDT Treatment Centres. Only the PMDT referral hospitals have
ClinicalExpertTeams(CETs).Thestaffatthesatellitesitesthatsupervisetheoutpatienttreatmentare
generally under-trained in themanagement ofDR-TB. Several grassroots patient support groups help
patients adhere to treatment, but most of these groups are underfunded. The expansion of PMDT
facilitiesisdescribedinTable4.
Table4.ExpansionofPMDTFacilities.
2016
(actual)2017 2018 2019 2020
ProvincesthathaveatleastoneDR-TBreferralsite
Developmentof
DR-TBtreatmentreferralsites
33 34 34 34 34
Regency/Citythathaveatleast1DR-TBtreatmentsite
DevelopmentofDR-TBtreatment
sites
57
(12%)
205
(40%)
308
(60%)
411
(80%)
514
(100%)
Primaryhealthcare(PHC)
DevelopmentofthesatelliteDR-
TBtreatmentsites
1238
(13%)
2439
(25%)
5500
(50%)
7900
(75%)
9754
(100%)
SectionDRecommendations-Organization,managementandcoordination(includesrecommendationsonsupervisionandmonitoringoftheprogramme)4.ImprovethesystemoftreatmentdeliveryandmanagementofthepatientsonMDRregimens.
• Establish at least 1 PMDT Referral Hospital or PMDT Treatment Centres in all 514
districts/municipalitiesassoonaspossible,consideracceleratingthePMDTNationalActionPlan
thatonlyreachesthisgoalin2020.
• Provide regular refresher training to theaPMDTReferralHospitalorPMDT treatmentCentre
staffwithanemphasisonrolesandresponsibilities.
• Re-designthewayasatellitesitegetstrainedandmanagesMDR-TBpatients.
• Considerorganizingacommunity-basedDOToptionforpatients.
• Improve communicationbetween theClinical Expert Teams (CETs), PMDTReferralHospitalor
14
PMDTtreatmentCentre,andPMDTsatellitesites
E.Casefinding,diagnosisanddefinitions Diagnostic capacity for drug-resistant TB (DR-TB) is steadily increasing, up to November 2016, there
were83XpertMTB/RIFmachinesoperationalin33provinces.Currently330machinesareintheprocess
ofplacementusingtheGlobalFundgrant,withtheGovernmentofIndonesiaalsoprocuringXPERT201
machines in 2016 andmore to come in near future. There are 16 labs for culturewhere 8 labs are
certifiedforfirst-lineDSTand5labsarecertifiedforfirst-andsecond-lineDST.
A“newalgorithmforTBdiagnosis”thatincludestheuseofXpertasaprimarydiagnosticforTBforall
patientswithsymptomssuggestiveofTBwasdesignedanddisseminatedtotheprovincesinMay2016.
An interim letter fromtheDirectorGeneral forms thebasis for implementationof thisnewalgorithm
with a newministerial decree that is to be signed soon. Xpert will also continue to be used as the
primary and initial diagnostic for DR-TB. The addition of it being used as a diagnostic tool for drug-
susceptibleTB(DS-TB)willincreasethenumberofcasesofDR-TBfound.Therewasnodataonaverage
turn-roundtimeofrequestofXperttestingtoreturnofresultstotheorderingfacility;however,all2017
JEMMteamsreportedthesystemspecimentransportandreportingpoorfunctioningandwithdelays.
Inaddition,inmostcasespatientsarerequestedtotraveltotheXperttestingsiteratherthansendinga
specimen.Furthermore,allteamsreportedlowtonoupdateofthenewXpertalgorithm.
AccordingtoNTPdata(fromeTBManager)averageturn-aroundtimeofDSTis81days(median77days);
however,thisisbasedonthetimethespecimenspentinthelaboratoryanddoesnotincludespecimen
transittimesortimetakentoreturnresultsbacktothetreatmentcentresorentryintoeTBManager.
ThereferralnetworkingforcultureandDSTtestingareupdatedannuallybasedonupdatedcapacityof
culture and DST laboratories. The NTP has conducted the piloting of specimen transportation in 9
provincesusingcouriermechanism.Theguidelineforspecimentransportationhasbeenfinalized.
Enrollmentnumbersarelow(Figure1)andoutcomesaresub-optimalwithasuccessrateinthelow50
percentagerangeformostyears(Table3).Theprogramisenrollingonly1848casesoutofthe10,000
notifiedcases(18.5%),estimatedtobe6%ofthe32,000prevalentRR-.MDR-TBcases.
Figure1.TotalnumberofDR-TBpatientsinIndonesia2009-2016
15
TheplannedincreaseinXpertfacilitiesandnumberofcartridgesneededisprojectedinTable6,note
thenumbersfor2016inTable6areprojectionsandwerenotmet.BecausethenewalgorithmforTB
diagnosiswithXperthasnotyetbeenimplementedwidely,thenumberofXperttestsperformedin
IndonesiaweremostlydonetodiagnoseDR-TB,withapproximately27,000testsperformedin2016.
Thisismanytimeslowerthantheprojectedgoalof1millionXperttestsfor2016.Itisexpectedin2017
thenumberofXperttestswillgreatlyincreaseandhencegreatlyimprovecasefindingofRR-TB.Table7
illustratestheprojectednumberofDR-TBtobefoundifthenewalgorithmforTBdiagnosisisused.
16
Table5.ExpectednumberofXpertmachinesandcartridgesneedfornewalgorithmforTBdiagnosis
Baseline 2016 2017 2018 2019 2020
Target TB case finding
335,000 411.380 515.556 677.265 648.464
Probable TB targets 10: 1 3,350,000 4,113,800 5,155,560 6,772,650 6,484,640
1. Plans for diagnostic examinations
a. Microscopic 99.8% 68% 60% 55% 45% 30%
b. Xpert 0.2% 32% 40% 45% 55% 70%
2. Load diagnostic tests
a. Microscopic
2,278,000 2,468,280 2,835,558 3,047,693 1,945,392
b. Xpert cartridges 10% 1,072,000 1,645,520 2,320,002 3,724,958 4,539,248
3. DR-TB diagnostic facilities Number of Xpert machines
63 504 786 1,108 1.778 2,167
Scope Province 33 34 34 34 34 34 District / City 56 315 514 518 518 518
Laboratory cultures 16 20 30 40 46 46
DST laboratory 12 13 14 15 17 17
LPA laboratory – 1st and 2nd Line. 2 (1st line) 2 (1st line) 3 4 5 6
17
Table7-ProjectednumberofDR-TBtobefoundifthenewalgorithmforTBdiagnosisisused
% 2015 2016 2017 2018 2019 2020
CaseDiscovery
NumberofTBcasefinding
targets(allforms) 330,729 335,000 396,976 530,493 599,338 605,291
1. PulmonaryTB
306,106 311,550 369,188 493,358 557,384 562,
-Newtreatment 95 295,781 295,973 350,728 468,691 529,515 534,775
-Re-treatment 5 10,325 16,750 18,459 468,691 529,515 534,775
1. Extra-pulmonaryTB
24,623 21,809 27,788 37,135 41,954 42,370
EstimatedMDR-TB/RR-TBamongnotifiedpulmonaryTBcases
Newtreatments 2.8 8,282 8,287 9,820 13,123 14,826 14,974
Re-treatment 16 1,652 2,680 2,954 3,947 4,459 4,503
TOTAL
9,934 10,967 12,774 17,070 19,285 19,477
TargetMDR-TB/RR-TBcasestobetreated
%AnnualTarget
40% 60% 70% 80% 80% 80%
Numberofpatients
3,974 6,580 8,942 13,656 15,428 15,582
Actualnumberofpatients
1,589 1,757 N/A N/A N/A N/A
%achievements
16% 16% N/A N/A N/A N/A
%revisedtarget,National
ActionPlanforPMDT,2016-
2020
16% 16% 40% 60% 70% 80%
RevisedtargetnumberofRR-/MDR-TBpatients
5,110 10.242 13,500 15.582
TheNTPshouldanticipatethatamassiveandrobustsystemofspecimentransportandinformation
systemofreturninglaboratoryresultswillbeneeded.Figure2illustratestheanticipatedsystem,with
theprojected2020numbersoflaboratoriesandfacilitiesaspertheNationalActionPlanforPMDT
2016-2020.
18
Figure2. Illustrationof the flowof specimensand informationasperNationalActionPlan forPMDT2016-2020withapproximateprojectionnumbersoftreatmentandlaboratoryfacilitiesforyear2020.
Adescriptionoftheflowofspecimensandinformationisasfollows:FromthePHC,sendspecimensto
anXperttesting/labwithinformationgoingbacktoPHC.ifRifampicinresistanceisfound,thePHC
referspatientstoPMDTreferral/treatmentsite.ThePMDTreferral/treatmentsitethensends1
specimentoanLPAfordirectsecondlineDST(ifthespecimenissmearpositive)andsends2specimens
toalaboratoryforcultureandfirst-lineDST.Ifmycobacteriumgrowsonculture,thenrefertheisolate
toalaboratoryforSLDDST(ifLPAforSLDnotyetperformed,dobothSLDphenotypictestingandLPA
fromculture).AllLPA,cultureandphenotypicDSTlaboratoryresultsarereportedbacktoPMDT
referral/treatmentsitesinatimelymanner.
SectionERecommendations-Case-findingStrategy5)Improveandscale-upthediagnosisofDR-TBthrough:
• Assure that every patient that belongs to an eligible groups for DR-TB screening (such as
retreatmentafterCategoryIorCategoryI,contactsofDR-TBpatientsandpatientswithTB/HIV
arealwaysscreenedfordrugresistancewithXpert.
• ContinuetoscaleuptheuseofXpertastheinitialtesttodetermineDR-TBandimplementthe
newdiagnosticalgorithmatallXpertsites.
• IncreasenumberofXpertsitesperthePMDTNationalActionPlan(approximately1000Xpert
MTB/RIF machines employed and 2.3 million test performed in 2018; 2000 Xpert MTB/RIF
machinesemployedand4.5milliontestperformedin2020).
19
• PerformXpertinallhospitalizedpatientswithrespiratorysymptoms(thisrecommendationwill
helpwithinfectioncontrolandcasefindingforbothDS-TBandDR-TB).
• AssurethatprivateclinicianshaveaccesstoXperttesting,freeofchargetothepatient.
• Establish a robust network of sputum/specimen transport to Xpert facilities and referral
laboratorywithasystemofreportingresultsbacktotheorderingfacility.Thisshouldbedone
forXpert,monitoringcultures,andDST.
• Revise the projected number of cartridges need for the new algorithm for TB diagnosis and
number of DR-TB cases to be detected for 2017 to account for slow adaptation of the new
AlgorithmforTBdiagnosis.Keepgoalsfor2018,2019,and2020similarinambition.
• Performasecondalgorithmusinglineprobeassay(LPA)fordiagnosingpreXDRandXDR-TBin
allpatientswithRR-/MDR-TB.
20
F.LaboratoryaspectsReviewofthelaboratorynetworktookplaceaspartofthe2018JEMM,fromwhichFigure2and3are
takenanddescribesthepresentsituationforcultureandDST.
Figure2.CultureandDSTlaboratories2006-2016
Figure3.Mapofcertifiedculturelaboratories,2016
21
Table6abovedescribestheNTPS’sambitiousplantoscaleuprapidmoleculartestingforTBdiagnosis
and support forMDR-TB treatmentwith culture and additional phenotypic and genotypic (LPA) DST.
Furtherlaboratoryrecommendationscanbefoundinthe2017JEMMreport.
PhenotypicDSTshouldnolongerbedonetoOfloxacin.TheWHOiscomingoutwithnewguidanceon
criticalconcentrationsandclinicalbreakpointsfortheFQs,soanticipatethatthelabshouldstarttobe
prepared for this.FuadMirzayevat theWHOGenevacanbecontacted for suggestedconcentrations,
andforwhichFQsshouldhaveDST. The laboratoryshouldstartthetransitionassoonaspossible,so
thatafulltransitioncanbemadebytheendoftheyear.
SectionFrecommendations-Laboratoryservices6)Improveandscale-upthediagnosisofDR-TB,monitoringofculturesandDSTtoisoniazidand
second-linedrugs.
• Continue to scale up the use of Xpert as the initial test to determine DR-TB and
implementthenewdiagnosticalgorithmatallXpertsites.
• Strengthenthesystemofmonitoringcultures.
• Performsecond-lineDSTinallpatientswithRR/MDR-TB,initiallywithLPAto1stand2
nd
line drugs and then phenotypic testing to isoniazid, kanamycin (or amikacin),
capreomycin, and the flouroqunolones (levofloxacin and moxifloxacin at 0.5 and 2.0
mg/dLconcentrations).
G.TreatmentThepresenttreatmentregimenusedinIndonesiaisastandardizedconventionalregimen:
8-12Km-LFX-Eto-Cs-Z-(E)-H/12-14LFX-Eto-Cs-Z-(E)-H
Theregimencanbemodifiedslightlyforseriousadverseeventsorresistancepatterns(i.e.withCM,or
PAS),butthisisnotcommonlydone.Theprogramhassub-optimalresultsfromtheuseofthepresent
regimen(Table8)andhasdecidedtotransitiontothenewshorterMDRregimenandtoindividualized
conventionalregimensforthosethatdonotqualifyforthenewshorterMDRregimen
Table8.OutcomesofDR-TBTreatment,2009-2016
source:MDRTB08eTBManageraccessedJanuary11,2017.
2009 2010 2011 2012 2013 2014 2015 2016
Numberofcases: 19 140 255 432 820 1,301 1,590 1,848
OOutcom
esutcomes
Cured(%) 52.6% 62.9% 56.5% 53.5% 48.8% 43.4% 6.9% 0%
Complete(%) 5.3% 5% 1.6% 1.2% 1.3% 2.4% 0.2% 0%
Defaulted(%) 10.5% 10.7% 25.1% 26.9% 28.7% 27.1% 24.7% 9.5%
Failed(%) 5.3% 4.3% 1.2% 3.2% 3% 2.2% 2.3% 0.3%
Deaths(%) 10.5% 12.9% 15.3% 15.3% 16.7% 17.3% 14.2% 8.7%
Notevaluated/other 15.8% 4.3% 0.4% 0% 0% 1% 2% 1.2%
Stillintreatment 0% 0% 0% 0% 0% 6.5% 49.7% 80.2%
22
ThereisaplannedtransitiontothenewshortMDRregimen.Thenewregimenisnotfinalizedinfine
detail(i.e.intermsofthedoseofmoxifloxacinorwhetherethionamideorprothionamidewillbeused).
OnJanuary21stoftheJEMManadhocmeeting“Partnersmeetingoncountrypreparednessfor
introductionoftheshorttreatmentregimen(STR)”tookplace.Thisconsultanthasreviewedtheshort
regimenplanandthetransitionisplannedtostartinJuly2017andisasolidplan.
Onlypatientsthatmeettheinclusioncriteriawillbegiventheshortregimen.Theprogramisusingthe
recommendedWHOcriteriaforwhogetstheshortMDRregimen,whichisreproducedinFigure2.The
planforthe“individualized”conventionalregimensarenotfinalizedandrecommendationsofthe
individualizedregimenswillcomeattheendofthissection.
Figure4.WHOrecommendedalgorithmforidentifyingwhichpatientsreceivethenewshorterMDRregimenandwhichpatientsreceiveandindividualizedconventionalregimen.
Inadditiontothetransitiontotheshortregimen,thecountryhashadthreepilotsitesfortheuseof
bedaquilineandhasenrolled50patientsin2016.ThereisalsooneUNITAIDendTBProjectsiteat
CempakaPutihIslamicHospital,whereonepatientwasenrolledonbedaquilineinlate2016andmore
areplannedfor2017.
Todate,nopatientshavebeenenrolledondelamanidandthedrughasnotbeenimportedtoIndonesia.
23
DETAILEDRECOMMENDATIONSONREGIMENDESIGNFORINDONESIA:Thefollowingisadetailedsummaryoftheregimenstobeusedunderthetransitionincluding
recommendationsinareasofwhereexistingguidanceintheIndonesianprogramislackinginrespectto
theshorterMDRregimenandforthedesignoftheindividualizedconventionalregimens.
Patientwillcontinuetobeplacedonthestandardizedconventionalregimenuntilthetransitiondate,
whichshouldbeassoonasdrugsareincountryandpersonnelaretrained,expectednolaterthanJuly
2017,butcanbesoonerinareas.
SimpleMDR-TB(noSLDresistance):StandardizedregimentobeuseduntilJuly2017:8-12Km-LFX-Eto-Cs-Z-(E)-H/12-14LFX-Eto-Cs-Z-(E)-H
• NewTBdrugsmaybeusedifthereisseveretoxicitytoanyofthesecond-lineTBdrugs.
• AsPASisnowgroupednowin“GroupD-3”,thelowestgroupinthehierarchyofTBdrugs.Most
programsuseBdqorDlmasthefirstchoiceofdrugifthereisatoxicitytoanyofthesecond-line
drugs.Ifthepatientisrespondingwelltotheregimen(clinicalandcultureevidenceofimproving)
thenasimplesubstitutioncanbemadereplacingthedrugcausingthetoxicitywithanewTB
drug.Ifitisunclearifthepatientwithadrugtoxicityisrespondingtotheregimen,itisbestto
replacethedrugcausingthedrugtoxicitywithanewTBdrugplusanother“GroupC”drugor
completelyredesigntheregimen.Thisistoavoidaddingasingledrugtoafailingregimen.This
consultantrecommendstheuseofanewTBdrug(BdqorDlm)pluslinezolidwhentwodrugs
areneeded.ThispreservestheuseofCfzfortheshorterMDRregimen.Ifthepatientisfailinga
regimenandhastoxicity,itisbesttodesignawholenewregimen.
• IftheinhAmutationisdetectedbyLPA,thereisnoneedtouseEtoorPtointheregimen;the
drugswillhavenoefficacyandwillonlyaddtoxicity.Itissuggestedbythisconsultanttouse
Dlm,orBdq,orLzd,orPAS(thedrugsareintheorderofpreferenceofthisconsultant).Again,if
makingasubstitution,neveraddasingledrugtoafailingregimen.IfEtoorPtoisresultingin
recalcitrantvomiting.
• IfLPAforsecond-linedrugshastherrsmutation,usenoinjectable(substituteanewTBdrug);if
theeispromotormutationispresentuseCm.
ThesuggestedshorterMDRregimentobestartedasofJuly2017,orsoonerifpossible,is:4-6Km-MfxHD-Pto-Cfz-Z-HHD/5MfxHD-Cfz-Z-E
• OnlypatientsthatmeetthecriteriaforthenewshorterMDRregimenshouldreceiveit.
• Thisconsultantstronglyprefershigh-dosemoxifloxacn(MfxHD)).
• SLDDSTwithLPAtotheinjectableagentsandfluoroquinolonesshouldbedoneinallRR-TB
patientstodetermineifthepatientmeetsthecriteriaforthenewshorterMDRregimen.Asthe
widespreadavailabilityofSLDDSTwithLPAisnotpresentlyavailable,itshouldbeallowableto
atthestartoftheprogramtostartapatientonthenewshorterMDRregimeniftheyhaveno
historyoffailinganMDRregimenandarenotacontactofsomeonethatfailedanMDRregimen
orhasSLDresistance(especiallyifthecontacthadpreXDRorXDRTB).
• BecausethereisalargestockEtoincountry(andmorecomingintransit)thecountryshoulduse
Etoatthestartofthetransition.NonewordersforEtoaresuggestedasPtoisconsideredto
havefewersideeffects.
• TheuseofPto(orEto)inthecontinuationphaseisuptotheNTPs.Thereisnoclearevidence
onwhetherPtointhecontinuationphaseimprovesoutcomesormakesoutcomesworseas
defaultcouldbehigherdotoaddedadverseeffects.Thisconsultanthasaslightpreferencefor
notusingPto(orEto)inthelaterphaseintheshorterMDRregimen;butthefinaldecisionisleft
24
totheNTP.Theobservationalstudyon500patientsfromBangladeshhadexcellentresultsand
didnotusePtointhecontinuationphase.
• Pyridoxineatadoseof25mg/daywillbeaddedtotheregimenasprophylaxisforperipheral
neuropathy(increasedriskinHIVco-infectedpatients,malnourished,diabetic,alcoholics,and
pregnantwomen)withtheuseofhighdoseIsoniazid.Ifneuropathyappearsitshouldbetreated
withhigherdoseofpyridoxine(from100-200mg/day).
• IftheinhAmutationisdetectedbyLPA,thereisnoneedtouseEtoorPtointheregimen;the
drugswillhavenoefficacyandwillonlyaddtoxicity.Also,thehigh-doseHintheshortregimenb
willbehighlyeffective.
• Moxifloxacinmustbeadministeredseparatelyfromantacids,iron,magnesium,andvitamins(by
4hours).
• Useweight-basedhigh-doseMfxandTable9isthesuggesteddosing(AnnexEisasuggested
dosingofthenewshorterMDRregimenforchildren).
25
Table9.Weight-baseddosingofanti-TBdrugsinthe9-monthMDRRegimen
Month of treatment
Drug Weight in KG*
24-32 kg 33-50 kg >50** kg
Taken daily for months 1-4; may be prolonged if not responding to therapy
Moxifloxacin (Mfx) (400 mg)
400 mg 600 mg 800 mg
Pyrazinamide (Z) (500 mg)
1000 mg 1200 mg 1600 mg
Ethambutol (E) (400 mg)
600 mg 800 mg 1200 mg
Isoniazid (H) (300 mg)
300 mg 450 mg (>55 kg)** 600 mg
Ethionamide (Eto)# (250 mg)
250 mg 500 mg (>55 kg)** 750 mg
Clofazimine (Cfz) (100 mg)
50 mg 100 mg 100 mg
Kanamycin (Km) (1 g vial)$
500 mg 750 mg–1000 mg 1000 mg
Taken daily for months 5-9
Moxifloxacin (Mfx) (400 mg)
400 mg 600 mg 800 mg
Pyrazinamide (Z) (500 mg)
1000 mg 1200 mg 1600 mg
Ethambutol (E) (400 mg)
600 mg 800 mg 1200 mg
Ethionamide (Eto)# (250 mg)
250 mg 500 mg (>55 kg)** 750 mg
Clofazimine (Cfz) (100 mg)
50 mg 100 mg 100 mg
*Forweight less than24kg, theregimenwillbe individuallydesignedbasedonthepediatricdoses in thePIHGuide for the
MedicalManagementforMDR-TB,2013.
**Pto/EtoandHhighestdosesaregivenabove55kg,ratherthanabove50kgliketheotherdrugs.#Pto/EtocanbegiventwiceadayintheintensivephaseifmaximumdosesareusedandthepatienthasmajorGIsideeffects
notresponsivetoanti-emetics.$IfresistanttoKanamycinandsusceptibletoCapreomycin,CapreomycincanbeusedatthesamedoseasKanamycin.
26
Table10isasuggestedmonitoringschedule.
Table10.Monitoringschedule
Monitoring&Evaluation
9to11monthshorterMDRRegimen
EvaluationbyaclinicianspecializedinPMDT
Atbaseline,thenmonthlyclinicalfollowupsatfollowupfacilityandquarterlyat
atthePMDTReferralHospitalsorPMDTTreatmentCentres.
ScreeningbyDOTprovider
AteveryDOTencounter.OftendoneatthePuskesmasasclinic-basedDOT.
Sputumsmearandculture
Monthlyforthefulltreatment.
Weight Atbaselineandthenmonthly(adjustdosesifweightchanges)
Drugsusceptibilitytest(DST)
Atbaseline,theminimumrequiredDSTisrifampicinbyXpertMTB/RIF.Additional
DSTisrecommendedatbaselineforH,Lfx,Km,andCminallRR-TBpatientsif
possible.DSTtoH,Lfx,Km,andCmisrecommendedforallpatientsthatremain
orbecomeculturepositivedespitetreatmentfor>3months.
Chestradiograph Atbaseline,andthenrepeatifonlyclinicallyindicated.
SerumcreatinineandSerumpotassium
Atbaseline,thenmonthlywhilereceivinginjectabledrugs.
Every1to3weeksinHIVinfectedpatients,diabeticsandotherhighriskpatients
orwhenindicated.
ThyroidstimulatingHormone(TSH)
Monitormonthlyforsigns/symptomsofhypothyroidism,obtainaTSHifsignsare
present.RoutinescreeningTSHatmonth3and6isrecommended.
Liverserumenzymes Inpatientsatriskfororwithsymptomsofhepatitis.
MonthlyforHIV-infected.
HIVscreening Atbaseline,andrepeatifclinicallyindicated
Pregnancytests Atbaselineforwomenofchildbearingage,andrepeatwhenindicated
Hemoglobinandwhitebloodcount
ForHIV-infectedpatientsonAZTmonitormonthlyinitiallyandthenasneeded
basedonsymptomsforanemia
Patientsthatdonotconvertby6monthsorwhoaredeterminedtobeclinicallydeterioratingatany
timewillbeswitchedofftheregimenandplacedonanindividuallydesignedMDR-TBregimenthatwill
includetheoptionofusingthenewTBdrugs(bedaquilineordelamanid).
Table11describesasuggestedstrategytodeterminethedurationoftreatmentforthenewshorter
MDRregimen,whichlasts9to11monthslongdependingonsmearmicroscopy.
27
Table11.Lengthoftreatmentofthe9-monthMDRRegimen
IntensivePhase(injectablephase) ContinuationPhase(alloral)Duration Atleast4months.Ifsmearpositiveat
month4,continuetheintensivephase
foranother2months(total6months).
5months(afterstoppingtheinjectableagent).
Description Sevendrugs,includinganinjectableand
highdoseisoniazid.
Fivedrugs.
Thetreatmentoutcomewillbeconsideredtohavefailedwhenthereisanabsenceofbacteriological
responsethatwillbedefinedasfollows:
• Patientfailstohavenegativeculturesbytheendofmonth5;
• Patientisculturepositiveduringthecontinuationphase(eithertwopositiveculturesduringthe
continuationphaseoronepositivecultureduringthelast3monthsoftreatment);
• Treatmentwillalsobeconsideredtohavefailedifaclinicaldecisionhasbeenmadetoterminate
treatmentearlybecauseofpoorclinicalorradiologicalresponseoradverseevents.
AllfailureswithadocumentedpositivecultureshouldhaveLPASLDDSTandconventionalDSTfortoLfx
(and/orMfx),Km,andCm.Anewindividualizedconventionalregimenshouldbestartedwhilewaiting
theDSTresultsforthesecond-linedrugsifonlyphenotypicDSTisbeingused.Ifitisnotpossibleto
obtainDSTforsecond-linedrugs,theindividualregimenshouldcoverthepossibilitythepatientmay
haveXDR-TB.
Patientsthatdonotconvertby6monthsorwhoaredeterminedtobeclinicallydeterioratingatany
timewillbeswitchedoffthenewshorterMDRregimenandplacedonanindividuallydesigned
conventionalMDR-TBregimenthatwillincludetheoptionofusingthenewTBdrugs(bedaquilineor
delamanid).AlsopregnantwomenwithMDR-TBwillhaveindividuallydesignedregimens.
Thefollowingsectioncontainssuggestedrecommendedregimensforpatientsthatneedan
individualizedconventionalregimen.
PreXDR-TB:Resistanceorseveretoxicitytotheinjectableagent(Pre-XDRInjectable).ConfidenceinEtoandCs:8-12Bdq(orDlm)-Lfx-Eto-Cs-Z/12-14Lfx-Eto-Cs-Z
• AlsoaddLzdifunsurethattherearefiveeffectivedrugsorifthereisanyquestionthepatientis
notrespondingtotheregimen.Alwaysavoidaddingasingledrugtoafailingregimen.
• Re-designtheregimencompletelyincaseofsuspectedfailure.
Resistanceorseveretoxicitytotheflouroquinolones(FQs)(Pre-XDR-FQ).ConfidenceinEtoandCs.8-12Km-Bdq(orDlm)-Lzd-(Lfx)-Eto-Cs/12-14Lzd-(Lfx)-Eto-Cs
• IfnoconfidenceinEtoand/orCs,addorreplacewithCfzand/orPAS.
• IfseveretoxicitytoeitherEtoorCssubstitutewithCfzorPAS:
28
• UseofLfxisoptionalasitmaystillbeeffectiveinsomestrainsidentifiedtoberesistantto
fluoroquinolonesonLPAortoconventionalofloxacinDST.
• UseMfxonlyindocumentedsusceptiblecasestohigherconcentrationsofMfxonphenotypic
DST.WhenusingMfx,DlmispreferredoverBdqtominimizeQTprolongation.
• IfLzdhassideeffectssupstitutewithPAS.
• Iflowconfidenceintheinjectableortoxicitytoinjectabledevelops,useanXDR-TBregimen.
• PtocanbeusedinsteadofEto.
XDR-TB:NewcaseofXDR-TBorfailuretothestandardconventionalMDRregimen:6Bdq(orDlm)-Lzd-Cfz-Lfx-(Eto)-(Cs)-PAS/14Lzd-Cfz-Lfx-(Eto)-(Cs)-PAS
• EitherBdqorDlmcanbeusedintheXDRregimen.• Ifthereisnotahighconfidenceofleast3drugsinthecontinuationphase,theconsiderationfor
BdqorDlmextensionbeyond6monthsisindicated.ManyprojectsusingthenewTBdrugsare
findingasignificantpercentageneedextensionbeyond6months.ConsiderhavingtheExpert
ClinicalatthePMDTReferralHospitalsrevieweverypatientforwhethertheyneedextenstionor
not.• Inrarecaseswhenthereisonlyconfidencethat3orfeweranti-TBareeffectiveatthestartof
treatment,BdqandDlmcanbeusedconcomitantlywithverycloseECGmonitoring–every2
weeksisrecommended.CriteriafortheExpertClinicalTeamstofollowatthePMDTReferral
HospitalsshouldbeestablishbytheNTP.
AcaseofXDR-TBaftertakingtheshorterMDRregimenorfailureoftheshorterMDRregimen(orclosecontactofapersonthatfailedtheshorterMDRregimen):8(Cm)-Dlm-Lzd-(Cfz)-Cs-PAS/16(Dlm)-Lzd-(Cfz)-Cs-PAS
• BecausetherecouldbecrossresistancewithBdqandCfz,itispreferredthatXDRregimensused
totreatfailuresfromtheshorterMDRregimencontainDlmasthenewTBdrug,insteadofBdq.
• OftenEto(orPto)isnotaddedtopatientswithXDR-TBregimensasmanyXDRstrainsarealso
resistanttoEto(orPto);thisimprovestolerabilityoftheregimen.IfthereisevidencethatEto
(orPto)maystillbeeffective,addittotheregimen.
• UseofLfxisoptionalasitmaystillbeeffectiveinsomestrainsidentifiedtoberesistantto
fluoroquinolonesonLPAorwithconventionalofloxacinDST.
• UseMfxonlyindocumentedsusceptiblecasestohigherconcentrationsofMfxonphenotypic
DST.WhenusingMfx,DlmispreferredoverBdqtominimizeQTprolongation.
• IfCmistestingsusceptibleconsideraddingittotheregimen.XDRregimensshouldonlycontain
aninjectableagentifoneisstillconsideredtobeeffective.IfLPAforsecond-linedrugshasthe
rrsmutation,usenoinjectable;iftheeispromotormutationispresentuseCm.
• ExtensionofDlmbeyond6monthsmaybeneededasdescribeabovefortheXDRregimenafter
failuretoastandardconventionalregimen.
• Inrarecaseswhenthereisonlyconfidencethat3orfeweranti-TBareeffectiveatthestartof
treatment,BdqandDlmcanbeusedconcomitantlywithverycloseECGmonitoring–every2
weeksisrecommended.CriteriafortheExpertClinicalTeamstofollowatthePMDTReferral
HospitalsshouldbeestablishbytheNTP.
TheWHOhasnotyetofferedguidanceontheuseofBdqandDlmforlongerthan6monthsorincases
wherethedrugsneedtobeconcomitantlyusedtogetherinthesameregimen.TheWHOisawarethat
UNITAID’sendTBProjectoftendoesthisinextremecasesunderstrongoperationalresearchconditions.
SinceendTBisoperatinginIndonesia,theNTPmayconsiderusingtheendTB’sMedicalCommitteefor
29
adviceforindividualcasesorforgeneralguidelines.
SectionGrecommendations-Treatmentstrategies7. Modify treatment regimens to be up-to-date with the latest WHO 2016 Guidelines on
treatmentofDR-TB.
• UpdateallPMDTguidesfornewshorterMDRregimensandfortheuseofnewTBdrugs,
bedaquilineanddelamanid,whenMDRshorterregimenscannotbeused.
• ImplementthenewshorterMDRregimeninpatientsthathavenocontraindicationsto
itandimplementindividualizedconventionalMDRregimensinpatientswitha
contraindicationtotheshorterMDRregimen.
• FasttracktheregulatoryapprovalfordelamaniduseinIndonesia.
8.SpecificdesignofregimensarelistedbelowandareconsistantwiththeIndonesianNational
ActionPlanforPMDT2016-2020(seeabovediscussionformoredetails).
SimpleMDR-TB(noSLDresistance):StandardizedregimentobeuseduntilJuly2017:8-12Km-LFX-Eto-Cs-Z-(E)-H/12-14LFX-Eto-Cs-Z-(E)-H
ThesuggestedshorterMDRregimentobestartedafterJuly2017,orsoonerifpossible,is:4-6Km-MfxHD-Pto-Cfz-Z-HHD/5MfxHD-Cfz-Z-E*TheuseofPto(orEto)inthecontinuationphaseisuptotheNTPs.Thereisnotclear
evidenceonwhetherPtointhecontinuationphaseimprovesoutcomesormakes
outcomesworseasdefaultcouldbehigherdotoaddedadverseeffects.Thisconsultant
hasaslightpreferenceforkeepingPto(orEto)throughouttheshorterMDRregimen
butthefinaldecisionislefttotheNTP.Theobservationalstudyon500patientsfrom
BangladeshhadexcellentresultsanddidnotusePtointhecontinuationphase.
Pre-XDRTB:Resistanceorseveretoxicitytotheinjectableagent(PreXDRInjectable).ConfidenceinEtoandCs:8-12Bdq(orDlm)-Lfx-Eto-Cs-Z/12-14Lfx-Eto-Cs-Z
Resistanceorseveretoxicitytotheflouroquinolones(FQs)(PreXDR-FQ).ConfidenceinEtoandCs.8-12Km-Bdq(orDlm)-Lzd-(Lfx)-Eto-Cs/12-14Lzd-(Lfx)-Eto-Cs
XDR-TB:NewcaseofXDR-TBorfailuretothestandardconventionalMDRregimen:6Bdq(orDlm)-Lzd-Cfz-Lfx-(Eto)-(Cs)-PAS/14Lzd-Cfz-Lfx-(Eto)-(Cs)-PAS
AcaseofXDR-TBaftertakingtheshorterMDRregimenorfailureoftheshorterMDRregimen(orclosecontactofapersonthatfailedtheshorterMDRregimen):8(Cm)-Dlm-Lzd-(Cfz)-Cs-PAS/16(Dlm)-Lzd-(Cfz)-Cs-PAS
30
H.Side-effectsandmonitoringresponsetotreatmentAdverseeffectsforpatientonMDR-TBtreatmentarenotaggressivelymanaged.ThePuskesmasstaff
arenotalwaystrainedwelltomanageMDR-TBpatients.Therearelongdelaysinmonitoringculture
resultsgettingintothepatient’schart,whichareessentialformonitoringeffectivenessoftreatment.
Themostcommonadverseeffecttotheconventionalregimenisnauseaandvomiting.Somepatients
aretakingtheirmedicinesandthenvomitingshortlyaftertomakethemselvesfeelbetter.Thiscanbe
verydangerousandthebehaviormustbechanged.Patientswhodothiscanhavelowbloodlevelsof
drugintheirbodyandrelapsewithworseresistancepatterns,includingXDR-TB.Itisnotcleartowhat
extentthisishappening.Implementingtheshorterregimenshouldhelpthis,aslessnauseaand
vomitingisassociatedwithit.NewTBdrugs(bedaquilineordelamanid)canalsobeusedtosubstitute
forethionamideincasesofirretraceablenauseaandvomiting.Insum,nauseaandvomitingmustbe
aggressivelytreatedinallpatientsonMDRRegimens,regardlessifitistheconventionalornewshorter
regimen.
Ototoxicityisacommonside-effectofinjectabletherapyinIndonesia.CliniciansatthePMDTtreatment
centersareawareofthisadverseeventbuttheuseofaudiometryandearlyinterventiontoprevent
hearinglosscouldimprove.NewTBdrugscanbeusedtosubstitutefortheinjectableagentifthe
patientisrespondingtotheregimenandhasototoxicity.Alwaysavoidaddingasingledrugtoafailing
regimen,soiffailureissuspectedeitheraddtwodrugs(usuallylinezolidisaddedtoanewTBdrug)or
re-designtheregimencompletelyincaseofsuspectedfailure.
Therearelongdelaysingettingresultsinthechartforthemonthlymonitoringsmearsandcultures.
SectionHRecommendations-Side-effectsandmonitoringresponsetotreatment9.Aggressivelytreatandmanageallside-effectswithaspecialfocusonnauseaandvomiting.
10.ImplementastrongerstrategytohavezerohearinglossfromMDR-TBtreatment.
• BaselineaudiometrytestingforallMDR−TBcasesatinitiationoftreatment.
• Repeataudiogramforanymildsymptomofhearingloss,tinnitus,ordizzinessandroutinelyat
month3and5(ormonthlywhileoninjectableagentsifresourcesareavailable).
• Considertheuseofhandheldaudiometrydevicesthatrunonandroidphonesortablets,suchas
HearScreen®.
• UsenewTBdrugsbedaquilineordelamanidincasesofmoderateorseverehearingloss.In
casesofsuspectedlackofresponsetotheregimenandhearingloss,re-designthewhole
regimenwiththeinclusionofanewTBdrug;
• Inthecaseofmoderateorseverehearinglossonthenewshorterregimen,ifthepatienthas
gottenmorethan3monthsoftreatmentconsidersuspensionoftheinjectableagentand
continuingtherestofthetreatment.Ifthepatienthasgottenlessthan3months,considerre-
designofusingaconventionalregimenandnewTBdrugandnoinjectable.
11.Establisharobustnetworkofsputum/specimentransportwiththereferrallaboratorywithasystem
ofreportingresultsbacktotheorderingfacility.ThisshouldbedoneforXpert,monitoringcultures,and
DSTtofirstandsecond-linedrugs.(SeeSectionsEandFabove).
31
I.TreatmentdeliveryandadherenceSeeSectionDOrganization,ManagementandCoordinationforadescriptionofthehowtreatment
deliverisorganized.
HighearlylosttofollowupofrifampicinresistantTB(RR-TB)positivepatients(approximately25%)is
quitecommonatmostsites.Thereasonsvaryfrompatientsrefusingtreatmentbecauseoffearof
adverseevents,diedbeforetreatment,andsimplylosttofollowup.Perhapsthemainreasonisthat
thereisstillverylimitedaccesstoPMDTservicesandmanypatientshavetospendconsiderabletime
andmoneytoreachtheselimitedfacilities.Itisunclearifonecauseisthehealthstaffnotexplaining
thetreatmentproperly.Anadditional25%getlosttofollowupwhileontreatment.Thesputumand
specimentransportsystemisweakasisgettingtestresultsbacktothecliniciancaringforthepatient.
AtransitiontotheshorterMDRregimenisplannedforJune2017,butguidelines,trainingmaterialand
changestotheMDR-TBformsarenotyetfinalized.Mostimportant,inmanagementofcare,
communicationsbetweenClinicalExpertTeams(CETs),referralandtreatmentcentres,andsatellite
sitesthattreatpatientsissub-optimal.
Allpatientscanqualifyforthesocio-economicsupport,750,000IDRpermonth;however,itdoesnot
alwaysstartthefirstmonthanddelaysresultinsomegapslongerthan1monthbetweenpayments.
ThefactthatthemoneyiscollectedatthemonthlyvisitatthePMDTHospitalortreatmentcenterisa
strongincentiveforthepatienttocomefortheirmonthlyfollowup.
Resourcesandsystemstodohomevisitstodefaultingpatientsoftennotavailable.
Satellitesitesarenotadequatelytrainedontechniquestoimproveadherence.Thereisnoprovisionsfor
community-basedDOT.
SectionIRecommendations-TreatmentDeliveryandadherence12.Treatmentdeliveryandadherencecanbeimprovedthrough:
• Re-designing how a satellite site gets trained andmanagesMDR-TB patients,with an
emphasisonwaystoimproveadherence.
• Considermoreprovisionsforcommunity-basedDOTs
• Considerincreasingthe750,000IDRmonthlysupportforallPMDTpatientsandconsider
anadditionalsocialsupportpackagefortheextremelypoorandvulnerablepatients.
• Design a system that allows for a robust public-private treatment of MDR-TB that
assureshighadherenceandpatientsupport.
32
J.DrugProcurementandmanagement The2017JEMMincludedafullevaluationofallTBdrugsneedsandevalauaitonofthesupplychain
systembytheGDF.ThetransitiontothenewshorterMDRregimenwillproveachallengetodrug
ordersandsomelosesmaybeunavoidable,butoverallaquickertransitionwillsavethecountrymoney.
TheWHOhasendorsedtheuseofbedaquiline,delamanid,clofazimineandlinezolidunderavarietyof
conditions.Thesedrugswillneedtobeorderedinsufficientquantitiesbasedthefinalregimensusedin
Indonesia.SuggestedregimenstobeusedareprovidedinSectionG.Treatment.
SectionJRecommendations-DrugManagement13.Seethe2017GDFreportforallrecommendationsconcerningdrugprocurementofsecond-line
drugs.
14.FasttracktheregulatoryapprovalfordelamaniduseinIndonesia.
K.InfectioncontrolTheachievements,challengesandrecommendationsregardinginfectioncontrolarediscussedatlength
inthe2017JEMMandwillnotberepeatedhere.
ContacttracingforMDR-TBcasescouldgreatlybeimproved.
Stricterinfectioncontrolinopenwardsandinwaitingareascan
SectionkRecommendations-Infectioncontrol15.See2017JEMMrecommendations.Continuetoemphasizeandfullyfundinfectioncontrolprotocols.
16.Improvecontact tracing for MDR-TB cases.
33
L.InformationsystemsanddatamanagementStandardizedrecordingandreportingdataformsareconsistentlyutilizedthroughoutthePMDTsystem.
Anelectronicmedicalrecord(EMR),eTBManager,isbeingusedtomonitorandevaluatethepatients.
Inaddition,itisbeingusedasaclinicalchart.ItisfunctioningwellbuttheJEMMteamsobserved
limitedaccesstoitbysatellitetreatmentsites.LinkingXPERTMTB/RIFAlertandeTBManagerisin
progress,thislinkwillbridgeautomaticnotificationfromXpertMTB/RIFmachinesequippedwithXPERT
MTB/RIFAlertSystemtoeTBManager.PlansarealsounderwaytolinkeTBManagerwiththeNational
medicalinformationsystem(MIS).
e-TBManagerisnotusedfortheregularDOTSprogram.
SectionLRecommendations-Recordingandreporting,anddatamanagement17.ContinueeTBManagerforPMDT.
• AssureallsatellitetreatmentsiteshaveaccesstoeTBManager.
• CompleteXPERTMTB/RIFAlertandeTBManagerlinkage.
• LinkeTBManagerwiththeNationalmedicalinformationsystem(MIS).
34
AnnexA.ProgressmadeontherecommendationsfromthepreviousrGLCMission(May2016)
Recommendation
Responsiblepersons/agency
Status Comment
CaseFindings
Alignthediagnosticalgorithmto
useGenXupfrontforall
presumptiveTBpatients
NTP,technical
partners
Done Anewalgorithmwas
designedanddisseminated
totheprovincesinMay2016
DecentralizeGenXandensureits
efficientuseandmaintenanceNTP,PHO,DHO
InProgress Significantexpansionand
decentralizationofXpertis
underway.
IncreaseLPA(1stand2ndLine)and
MIGITcapacitytomeetthe
expansionrequirements
NTP
InProgress PlanforLPAsecond-line
drugsisnotyetoperational.
EnhanceCasedetectioninchildren
NTP,PHO,DHO,
technical
partners
InProgress Coveredinnewdiagnostic
algorithmandXpert
expansion.
StrengthenTB–HIVlinkage(cross
referral)
NTP,PHO,DHO,
InProgress Progressismoderate.The
newrecommendations
comingoutofthe2017
JEMMshouldbefollowed.
Intensifiedcasedetectionin
specificgroupsandactive
screeninginkeyaffected
populations
NTP,PHO,DHO,
technical
partners
InProgress Coveredinnewdiagnostic
algorithmandXpert
expansion.
Treatment Decentralizetreatmentbeyond
Hospital,Puskasmastosubdistrict
andlinkingittodecentralized
diagnosis
NTP,PHO,DHO,
InProgress Stillneedsstrengthening.
Treatmajorityofpatientsas
ambulatoryandhospitalization
onlyforsevereADR/complications
NTP,PHO,DHO
Done Onlytheseverelyillor
complicatedpatientsare
startedinhospital.
StrengthInfectioncontrolin
hospitals
NTP,PHO,DHO
InProgress N-95masksarereadily
availableandinfection
controlprotocolsfollowedin
TBhospitals.Muchworkstill
neededsoallhospitalshave
goodinfectioncontrol
Strengthenmechanismforretrieval
oflosstofollowuppatients
NTP,PHO,DHO
InProgress Variesfromonesettingto
another.Ingeneralstill
needsstrengthening.
ConsiderdailytreatmentforDSTB NTP,technical InProgress Willbechangedtodaily
35
asperinternationalstandardofTB
care
partners,CWG
treatment(insteadofthree
timesaweek)asaresultof
theJEMM2018
ConsidershorterWHOapproved
regimensforDRTBinaccordance
withWHOGuidelinesforthesame
NTP,technical
partners,CWG
Done Decisionhasbeenmadeto
transitiontotheshorter
regimen.
Others
ThecountryneedstostartDRS
Surveyattheearliestinaccordance
withthelatestrecommendations
forsuchsurveys
NTP,Partners
(Nationaland
International)
Done DRSstarted.Resultspending
inlaterpartof2017.
StrengthenMonitoringand
supervisionatalllevels.Thiswould
alsorequireincreasingthenumber
ofstafffornotificationmonitoring
andsupportivesuperivsion
NTP,PHO,DHO
InProgress Ongoing.TheNational
ActionPlanforPMDT,
versionJanuary2017
describesthesystemof
humanresourcesneededand
shouldbefollowed.
Patientsupportmechanismbe
mademoreefficientwithtimely
disbursementoftravelcostsetc.
andlinkageswithpatientsupport
groups
NTP,PHO,DHO,
Done Stillsomedelayand
inconsistenciesbutforthe
mostpartworkingmuch
better.
Enhanceprivatesector
involvementandmandatory
notification
NTP,PHO,DHO,
technical
partnersand
doctor
associations
Inprogress Inprogress,butverylittlehas
beendonetodate.Anumber
ofrecommendationsinthis
areawillbemadeinthe2017
JEMMandshouldbe
followed.
Reducestigmaamonghealth
workersandcommunity
NTP,PHO,DHO,
technical
partnersand
NGOs
Inprogress Moreneedstobedone.
Severalrecommendationsin
the2017JEMMhavebeen
madeinthisarea.
StrengthenlinkageswithNGOsand
othersupportorganizationsto
increasecasedetectionand
treatmentadherenceat
communitylevel
NTP,PHO,DHO,
technical
partners
Inprogress Anumberof
recommendationsinthis
areawillbemadeinthe2017
JEMMandshouldbe
followed.
36
AnnexB.ThetermsofreferenceforthisvisitAlsoseeTorfor2017JEMM
TermsofReferenceforDrMichaelL.Rich:
Scopeofwork:
AsaDrug-ResistantTBLeadExpert,MichaelL.Richwillcarryoutthefollowingtasks:
• ParticipateintheJointExternalTBMonitoringMission(JEMM)inIndonesia,16-27January
2017andbealeadassessorforDR-TBcomponents;� • BeresponsibleforoverallreviewandpreparationofrecommendationsandreportfortheDR-TB
componentoftheprogrammeduringtheJEMMandrGLCannualmission2017;� • EnsuretheDR-TBsub-teamachievesitsobjectivesandconductedinawell-organizedandtimely
manner;� • Ensurein-depthreviewoftheDR-TBsituation,policies,strategy,guidelinesandpractices;� • BeresponsibletoguideandadviseallJEMMmembersforreviewofDR-TBcomponent;� • Collectandcollatekeyfindings,recommendationsandreportsonDR-TBcomponentfromall
fiveteamsandsubmittoJEMMMissionLeaderforsubmissiontohighlevelmissionandMoHby
24January2017;� • PreparedebriefingmaterialonDR-TBcomponentandsubmittoJEMMTeamLeaderfor
presentationtotheMOHattheendofthemission;� • BeresponsibleforpreparationofthefinalDR-TBchapteroftheJEMMreport;� • FinalizeandsubmitDR-TBchapteroftheJEMMreportwithintwoweeksofthemission
conclusiontothemissionleader.Keyissuestobeevaluatedandreviewed�
1.AssesscountryPMDTprogramstructureandimplementationstatusandevaluatecurrent
achievement: • AssessmentofprogressonachievingtargetsincludedintheNSPandGlobalFundgrantand
providesrelevantrecommendations. 2.ReviewandassesstheprogressofPMDTexpansioninpublicandprivatesectors:.
• AssessmentofthecurrentmodelofPPManddefineframeworkstostartPPM-PMDTmodelsin
country; • Providingrecommendationsonoptionstoexpandengagementofprivatecareproviders
includingdiagnosticandtreatmentservicesforpatientswithDR-TB. 3.Reviewcasefinding,treatmentstrategies,administrationandfollowup:
• AssessmentoftheoverallcasefindingstrategyandproviderecommendationstoimproveDR-TB
casedetection; • AssessmentandrecommendationonintroductionsandscaleupofambulatorytreatmentofDR-
TBcasesatdistricthospitalandorprimarycare;
37
• Assessmentandrecommendationonintroductionandscaleupofuseof“shortregimens”and
newdrugsforDR-TB; • AssessmentofqualityofPMDTservicesincludingimprovingtreatmentoutcomeofpatients
receivingSLD; • ReviewcurrentcapacityforclinicalmonitoringofpatientsisinlinewiththePMDTroll-outplan;
4.Reviewthestatusoflaboratoryservices,includingpossibilityforfurtherdecentralizationofnew
diagnostic: • UrgentandaggressivescaleupofGeneXpertdeploymenttoallowtestingsymptomaticTBcases
(retreatmentandnewcases)toimproveTBdiagnosisanddetectDR-TBcases; • AssessmentandproviderecommendationsonoptionstoscaleupcultureandDSTandsample
transportation; 5.Reviewandassesstheengagementofcommunityandcivilsocietyorganizationtodeliveramodelof
communitybasedDrugsResistantTBservicedelivery. 6.AssessthestatusofnewTBdrugsintroduction(Bedaquiline)andrecommendationforothernew
drugsonthepipelineasperWHOrecommendation. 7.MakerecommendationonpriorityareasandactionsfortheNTPforthenextfiveyearperiod(2017-
2022). AsaDrugResistantTBLeadExpert,youwilldeliverthefollowingdeliverablesasperagreedtimelines: § LeadtheDrugsResistantTBcomponentofJEMMinanefficientandtimelymanner;� § Inconsultationwiththemissionleaderpreparedatacollection,reportingtemplatesand
toolsas�perJEMMandrGLCrequirements;� § FinalizationofcomprehensivechapteroftheJEMMreportontheDrugsResistantTB
programmaticarea;� § TheJEMMdebriefingmaterialsonDrugsResistantTBcomponentincludingkeyfindingsand
recommendations;� § CompleterGLCannualmissionreport.�
38
AnnexC:AgendaforrGLC.Thisexpertconsultantparticipatedinthefull2017JEMMandvisitedCentralJavafordetailed
programmaticevaluation.
Joint External TB Monitoring Mission Indonesia, 16 - 27 January 2017
Agenda
DATE/TIME ACTIVITIES VENUE/Remarks Saturday, 14 January 2017 Arrival team members in Jakarta The Ritz-Carlton, Jakarta, Mega
Kuningan Sunday, 15 January 2017 12.00 – 13.00 13.00-14.00 14.00 - 15.00 15.00-16.00
Briefing on current country situation to external experts by WHO MO TB and team Lunch Break Discussion on organization, tools and methods and preparation by Team Leader and Sub Team Leaders Briefing with WR
The Ritz-Carlton, Jakarta, Mega Kuningan
Monday, 16 January 2017 08.30 – 09.00 09.00 – 10.00 10.00 – 10.30 10.30 – 12.00 12.00 – 13.00 13.00 – 15.00
Registration Welcome and Introduction: – Welcome and Opening Remarks by DG of Prevention and
Disease Control (Dr HM. Subuh) – Welcome and Opening Remarks by WHO Representative for
Indonesia (Dr Jihane Tawilah) – Introductions – Group Photo Tea/ Coffee break Progress report NTP and NAP and discussions:
- National TB and HIV Strategic Plan-key approaches and targets DG Prevention and DC - Director of CDC (Dr Wiendra Waworuntu);
- NTP Situation, GF Grant Performance and TB Progress in Indonesia - NTP Manager (Dr Asik Surya);
- NAP Situation, GF Grant Performance and HIV Progress in Indonesia - NAP Manager (Dr Endang Budi Hastuti);
- Discussion. Lunch break Review JEMM objectives, methods and tools -- Mission Leader Mission Schedule – WHO MO TB Epidemiology and results of EPI review -- WHO HQ NTP Progress presentation on TB Care and Prevention areas – NTP Deputy Manager
- Surveilance, Information System, M&E - Diagnostics and Treatment - Laboratory and TB Infection Control - PMDT
The Ritz-Carlton, Jakarta, Mega Kuningan Joint TB and HIV JEMM experts and invitees participants. TB and HIV meeting participants will be splitted after lunch break Moderator: Paul Nunn
39
15.00 – 15.30 15.30 – 17.00 17.00-17.30 17.30-17.45
- TB HIV - Childhood TB
Tea/ Coffee break NTP Progress presentation on TB Care and Prevention areas – NTP Deputy Manager (continue)
- Political Commitment and Leaderships - PPM - HRD TB - Community Engagement - TB Financing and Role of Health Insurance - Procurement and Suplay Chain Management - TB Research
Preparation for field visits: - Discussion on program and tools for field visits – by Team
Leader - Roles of external and national experts
Security briefing – UNDSS Note: JEMM team will be divided into 5 groups. Each group will visit 1 province/multiple districts. Depending on agreement of Provincial authority and logistical feasibility provincial team may be divided to 2 sub-groups. Provinces to be visited are; West Sumatera, DKI Jakarta, Central Java, South Kalimantan, South East Sulawesi.
Moderator: Maarten van Cleeff
Tuesday, 17 January 2017
- Travel to provinces. See the details tentative agenda for each province.
- Briefing meeting with provinces (depends on time arrival)
Province
Wednesday, 18 January 2017 Field visit District Thursday, 19 January 2017 Field visit District Friday, 20 January 2017 Field visit and Briefing to Province
Return to Jakarta (West Sumatera and Central Java Team) District and Province
Saturday, 21 January 2017
15.00-16.00
Return to Jakarta (South East Sulawesi and South Kalimantan Team) Group work (external and national experts) Preparation of team finding/key finding and recommendation report. Side meeting for Short Treatment Regimen (NTP and GF)
The Ritz-Carlton, Jakarta, Mega Kuningan On NTP invitation – The Ritz-Carlton, Jakarta, Mega Kuningan
Sunday, 22 January 2017 Group work (external experts)
Preparation of team finding/key finding and recommendation report. The Ritz-Carlton, Jakarta, Mega Kuningan
Monday, 23 January 2017 08.30 – 12.30
Meetings with partners, departments, agencies, Ministries, Parliamentarian, Professionals, and CSOs (facilitated by NTP):
- National planning Bureau (BAPPENAS) and Inter-ministerial (Ministry of Internal Affairs, Ministry of Finance,
BAPPENAS Office
DPR Building IDI Office
40
Ministry of Law and Human Right, Ministry of Social Welfare, Ministry of Education, Ministry of Village Development);
- National Parliament (DPR); - Professional Societies: Indonesian Medical Association,
Pharmacist Association, Laboratory Association, Pulmonologist Society, Internist Society & Pediatric Society;
- MOH Inter-Sector: Health Facility, Quality and Accreditation Directorate, Food & Drug Administrator (Badan POM)& DG of Pharmaceutical and Health Equipment (Binfaralkes), NAP and Health Human Resource Board, MoH (BPPSDM);
- Health Insurance and Health Financing (P2JK) and National Health Insurance Board (BPJS);
- Indonesia Stop TB Partnership Forum, CSOs, Partners and Development Partners;
- KOMLI (Expert Committee), TWGs (PMDT, Childhood, Lab) and National Institute for Health Research and Development.
MoH Office MoH Office PPTI Office NIHRD Office
13.00 – 14.00 Lunch break The Ritz-Carlton, Jakarta, Mega Kuningan
14.00 – 17.00 Field Visit Team debriefing (Jakarta, Central Java, South Kalimantan) - 60 min for each team - Discussion - Tea/coffee break
The Ritz Carlton, Jakarta, Mega Kuningan
17.00 -18.30 Side meeting: TB-HIV collaboration meeting On invitation by NTP and NAP Tuesday, 24 January 2017 09.00 – 11.00 Field Visit Team debriefing (West Sumatera, SE
Sulawesi) - 60 min for each team - Discussion - Tea/coffee break
11.00 – 12.30
Discussion of key technical areas findings and recommendations (external and national consultants grouping into technical areas)
13.00 – 14.00 Lunch at hotel 14.00 – 17.00 Discussion of key technical areas findings and recommendations
(external and national consultants grouping into technical areas) The Ritz Carlton, Jakarta, Mega Kuningan
Wednesday, 25 January 2017 08.30 – 10.30 Debriefing on key technical areas findings and recommendation to
NTP: - PillarI:7keyareas(15mineach)
The Ritz Carlton, Jakarta, Mega Kuningan
10.30-10.45 Tea/coffee break 10.45-13.00 Debriefing on key technical areas findings and recommendation to
NTP: - PillarII:7keyareas(15mineach)- PillarIII(15min)
The Ritz Carlton, Jakarta, Mega Kuningan
13.00 – 14.00 Lunch at Hotel 14.00 – 17.00 Wrap up on key technical areas findings and recommendation to NTP
led by Team Leader The Ritz Carlton, Jakarta, Mega Kuningan
17.00 – 18.30 High Level Mission (HLM) briefing by JEMM Mission Leader and Sub Team Leaders on key finding and recommendations
HLM participants and Team Leader and Sub Team Leaders The Ritz-Carlton, Jakarta, Mega Kuningan
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Thursday, 26 January 2017 HIGH LEVEL MISSION and JEMM Team 09.30 –11.00 11.00 – 11.30 11.30 – 12.30 13.00-onwards 13.00 – 15.00 19.00-21.00
Debriefing with Minister of Health Press Conference by Minister of Health Lunch at MoH JEMM Team: Completion of individual/ review component report writing HLM : Meeting with Ministry of Internal Affairs (Kemendagri) high officials to increase sub-national level funding for TB control Dinner hosted by Ministry of Health
MoH Building MoH Building No room arrangement Ministry of Internal Affair (TBC), NTP and HLM Penang Bistro Restaurant
Friday, 27 January 2017 09.00 – 11.00 HLM: Audience meeting to Vice President or Coordinating Minister
of Human Development tbc by MoH
13.30 – 15.30 HLM : Meeting with Ministry of Village Development (Kemendes) high officials to increase funding for community/ family TB control initiatives
Ministry of Village Development (tbc), HLM and NTP
JEMM Team: Completion of individual/review component report writing
No room arrangement
Saturday, 28 January 2017 Departure Mission members.
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AnnexD:MainListofPeopleMetDuringtheMissionSee2017 JEMMfor listofpersonsmeton theMission. Amaincontact for this rGLCmssionwasDr.
EndangLukitosari(Dr.Luki)FocalpersonforPMDTNTP,[email protected]
A list of key people and emails is provide below:
Name Email
PaulNunn [email protected]
MichaelRich [email protected]
FarhanaAmanullah [email protected]
BlessinaKumar [email protected]
CharalamposSismanidis [email protected]
MukundUplekar [email protected]
AnnemiekeBrands [email protected]
AvinashKanchar [email protected]
NebiatGebreselassie [email protected]
LauraAnderson [email protected]
KhurshidA.Hyder [email protected]
BernardCouttolenc [email protected]
AsikSurya [email protected]
YullitaEvariniYuzwar [email protected]
Nurjannah [email protected]
BawaWuryaningtyas [email protected]
BudiartiSetiyaningsih [email protected]
AgnesGebhard [email protected]
JhonSugiharto [email protected]
CatharinaS.B.vanWeezenbeek [email protected]
MichaelE.Kimerling [email protected]
EdineW.Tiemersma [email protected]
MaartenvanCleeff [email protected]
KarinBergstrom [email protected]
PetradeHaas [email protected]
NettyKamp [email protected]
MerrySamsuri [email protected]
AmyPiatek [email protected]
RichardLumb [email protected]
MarziaCalvi [email protected]
WilliamWells [email protected]
JonathanRoss [email protected]
AliaHartanti [email protected]
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PhilipWegner [email protected]
SandeepMeharwal [email protected]
BezaSeyoum [email protected]
RajeevPatel [email protected]
SuvanandSahu [email protected]
ZazaMunez [email protected]
CarmeliaBasri [email protected]
GailSteckley [email protected]
DiWu [email protected]
M.Farag [email protected]
M.Yasin [email protected]
LieslPageShipp [email protected]
UzmaKhan [email protected]
AmyCollins [email protected]
PhillipHowell [email protected]
FranDuMelle [email protected]
EkpenoAkpanowo [email protected]
AndreZagorsky [email protected]
M.Akhtar [email protected]
SetiawanJatiLaksono [email protected]
MariaReginaChristian [email protected]
BenyaminSihombing [email protected]
MikyalFaralina [email protected]
YoanaAnandita [email protected]
NelsySiahaan [email protected]
NuniekPujiLestari [email protected]
DadangSupriyadi [email protected]
GuyStallworthy [email protected]
MiladiKurniasari [email protected]
RiniPalupi [email protected]
BettyNababan [email protected]
BeySonata [email protected]
LucieBlok [email protected]
NastitiKaswandhani [email protected]
UmmuSalamah [email protected]
Purwantyastuti [email protected]
SitiKunarisasi [email protected]
SilviaDini [email protected]
NurulBadriyah [email protected]
FainalWirawan [email protected]
DavidPapworth [email protected]
TiaraVerdinawati [email protected]
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YusiePermata [email protected]
HariadiWibisono [email protected]
ArifinNawas [email protected]
Yahya [email protected]
NovayantiTangirerung [email protected]
RizkaNurFadilla [email protected]
RoniChandra [email protected]
EndahRamadhinie [email protected]
OceBoymau [email protected]
SudijantoKamso [email protected]
ErlinaBurhan [email protected]
Munziarti [email protected]
RudyHutagalung [email protected]
SyarifahKhodijah [email protected]
DikkiPramulya [email protected]
HariniJaniar [email protected]
EndangLukitosari [email protected]
AmeliaYuri [email protected]
TiarSalman [email protected]
RitaKusriastuti [email protected]
RetnoKusumaDewi [email protected]
TotokHaryanto [email protected]
RinaHandayani [email protected]
FirzaAsnelyP [email protected]
ErmanVarella [email protected]
MichaelRich [email protected]
Samijono [email protected]
HIVProgramme
EndangBudiHastuti [email protected]
TriyaNovitaDinihari [email protected]
FabioDeMesquita [email protected]
TiaraM.Nisa [email protected]
BagusRahmat [email protected]
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AnnexE–PediatricdrugdosagetableforthenewshorterMDRRegimen
Weightinkg Capreomycin/Kanamycin Amikacin Isoniazid
highdose Moxifloxacin PtoorEto Clofazimine Pyrazinamide Ethambutol
Dose 15-30mg/kg 15-30mg/kg 15-20mg/kg 7.5-10mg/kg 15-20mg/kg 2-3mg/kg 30-40mg/kg 15-25mg
Formulation
1gin4mldilution 2mlvial tablet tablet tablet Suspml tablet Pharmacologicalpreparation tablet tablet tablet
250mg/ml 250mg/ml
100mg
300mg
400mg
20mg/ml 250mg mg 400mg 100m
g400mg
Eitherofthedosage--Notadditional!
Eitherofthedosages--Notadditional!
Eitherofthedosages--Notadditional!
unit Ml ml Tab Tab Tab ml Tab mg Tab Tab Tab5 0.5 0.5 1 2 0.5 10-15mg 0.5 1 6 0.5 0.5 1 3 0.5 15mg 0.5 1 7 0.75 0.75 1 3 0.5 15-20mg 0.5 1 8 0.75 0.75 1.5 0.5 3 0.5 20mg 0.75 2 0.59 1 1 1.5 0.5 4 0.5 20-25mg 0.75 2 0.510 1 1 1.5 0.5 0.25 4 0.5 25mg 1 2 0.511 1 1 2 0.5 0.25 5 1 25-30mg 1 2 0.512 1 1 2 0.5 0.25 5 1 30mg 1 2 0.513 1 1 2 0.5 0.25 6 1 30-35mg 1 3 0.514 1.5 1.5 2 0.5 0.5 6 1 35mg 1 3 0.515 1.5 1.5 3 1 0.5 6 1 35-40mg 1.5 3 116 1.5 1.5 3 1 0.5 7 1 40mg 1.5 3 117 2 2 3 1 0.5 7 1 40-45mg 1.5 3 118 2 2 3 1 0.5 7 1.5 45mg 1.5 4 119 2 2 3 1 0.5 8 1.5 45-50mg 1.5 4 120 2 2 3 1 0.5 8 1.5 50mg 1.5 4 121 2 2 3 1 0.5 8 1.5 50-75mg 2 4 122 2 2 3 1 0.5 9 1.5 50-75mg 2 4 123 2 2 3 1 0.5 9 1.5 50-75mg 2 5 124 2 2 3 1 0.5 10 1.5 50-75mg 2 5 125 2.5 2.5 3 1 0.5 10 1.5 50-75mg 2 5 1
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