1

To:Dr.TedrosAdhanomGhebreyesus,Director-GeneralDr.TerezaKasaeva,GlobalTBProgramDirectorWorldHealthOrganizationAvenueAppia20CH-1211Geneva27,Switzerland

1February2018

RE:WorldHealthOrganizationGuidelinesfortheTreatmentofMultidrug-resistantTuberculosisDearDr.Tedros,Asadvocates,membersandrepresentativesofaffectedcommunities,andmembersofcivilsocietyinvestedinensuringaccesstothebestavailableandevidence-basedtreatmentsfortuberculosis(TB),wearewritingtoexpressourconcernsregardingtheexistingWorldHealthOrganization(WHO)recommendationsforthetreatmentofmultidrug-resistantTB(MDR-TB),andtoshareourpositionforhowtheyshouldberevised.WeencouragetheWHOtoconsolidateitsguidanceregardingthetreatmentforMDR-TB,andintheinterim,asamatterofurgency,torecommendbedaquilineaspartofthepreferredregimenforpatientswithMDR-TBinplaceoftheinjectableagent.TheexistingsituationwhereWHOguidanceissplitacrossmultipledocumentsisuntenable.TherearecurrentlyfivedifferentMDR-TBtreatmentguidancedocumentsincirculation.Theseinclude:(1)WHOtreatmentguidelinesfordrug-resistanttuberculosis:2016update;(2)WHOinterimguidanceontheuseofdelamanidinthetreatmentofMDR-TB;(3)TheuseofdelamanidinthetreatmentofMDR-TBinchildrenandadolescents:Interimpolicyguidance;(4)ReportoftheguidelinedevelopmentgroupmeetingontheuseofbedaquilineinthetreatmentofMDR-TB:Areviewoftheavailableevidence(2016);and(5)WHObest-practicestatementontheoff-labeluseofbedaquilineanddelamanidforthetreatmentofMDR-TB.Additionalguidancedocumentsareanticipatedinearly2018,includingrelatedtophaseIIIandotherobservationaldatafordelamanidandtheshortenedregimen.WerecognizetheimportanceoftheWHO’sresponsetoandinterpretationofevidenceasitemerges,butanynewrecommendationsissuedbytheWHOshouldalwaysbecontextualizedalongsideexistingrecommendationsandevidence,includingforotherinterventions.Torectifythiscurrentdisparity,new,consolidatedguidelinesthatconsiderallavailabledataandprovideclearguidanceforwhendifferentinterventionsareindicatedarenecessary.WhilethereisatremendousneedforclearandconsolidatedWHOguidance,finaldatafortherandomizedclinicaltrialoftheshortenedregimen(STREAMstageI)isnotexpecteduntilmid-2018.Intheinterim,animmediateneedistostoptheunjustifiedsubjectionofMDR-TBpatientstotheriskof,andtheactual,severesideeffectsassociatedwiththeinjectableagents.Theseside-effects,includingpermanenthearingloss,leadtoexactlythe

2

sortofcatastrophiceconomicconsequencesthattheWHO’sENDTBStrategyaimstoeliminate.Inlinewiththeattachedpositionpaperandevidenceandrationaleprovidedtherein,weadvisetheWHOtourgentlyrecommendbedaquilineaspartofthepreferredtreatmentregimenforMDR-TBandtorelegatetheinjectablesforuseonlyinmorecomplicatedDR-TBcases,andwithabsoluterequirementandassuranceofmonitoringforhearingloss.Forchildrenunder12(inwhomsafetyanddosingdataonbedaquilinearenotyetavailable)andotherswhodonotqualifyforbedaquiline,othernewerdrugs(i.e.delamanidorlinezolid)shouldreplacetheinjectableinbedaquiline'sstead.Tofurtherdiscussthisposition—whichhasbeenendorsedbyover21individualsand31organizations—withtheGlobalTBCommunityAdvisoryBoard(TBCAB),pleasedirectcorrespondencetoWimVandeveldeatwim@eatg.org.Respectfullysubmitted,

MarcusLowTechnicalLeadGlobalTBCommunityAdvisoryBoard(TBCAB)Onbehalfof:Organizationendorsements:AIDSandRightsAllianceforSouthernAfrica(ARASA)AIDS-FreeWorld,CanadaAll-UkrainianAssociationofPeopleWhoRecoverfromTBStrongerthanTB,UkraineAmericasTBCoalitionAsiaPacificCoalitionofTBActivists(ACTAP),ThailandBiharNetworkofPeopleLivingwithHIV(BNPPLUS),IndiaDrugResistantTuberculosisScaleUpTreatmentActionTeam(DR-TBSTAT),GlobalTheGlobalTBCommunityAdvisoryBoard(TBCAB)GujratnetworkofpeoplelivingwithHIV(GSNPPLUS),IndiaInternationalTreatmentPreparednessCoalitioninEasternEuropeandCentralAsia(ITPCru)

KenyaAIDSNGOsConsortium(KANCO)KenyaLegal&EthicalIssuesNetworkonHIV(KELIN)KHANA,CambodiaKyrgyzCoalitiontoCombatTuberculosis(CoalitionagainstTuberculosis),KyrgyzstanMadhyaPradeshNetworkofPeopleLivingwithHIV(MPNPPLUS),IndiaNationalCoalitionofPeopleLivingwithHIVinIndia(NCPIplus)NationalEmpowermentNetworkofpeoplelivingwithHIV/AIDSinKenya(NEPHAK)NetworkofMaharashtrabyPeopleLivingwithHIV/AIDS(NMPPLUS),India

3

ONGGLOBE,MauritaniaPamojaTBGroup,KenyaSECTION27,SouthAfricaTheSentinelProjectonDrug-ResistantTuberculosis,UnitedStatesSociosEnSalud(SES),PeruSpiritiaFoundation,IndonesiaStopTBPartnershipKenyaTBPeople,GeorgiaTBProof,SouthAfricaTreatmentActionCampaign,SouthAfricaTreatmentActionGroup(TAG),UnitedStatesTheTunisianCenterforPublicHealth,TunisiaUttarPradeshNetworkofpeoplelivingwithHIV(UPNPPLUS),IndiaIndividualendorsements:Dr.ArnevonDelft,SchoolofPublicHealthandFamilyMedicine,UniversityofCapeTown&TBProof,SouthAfrica

BegimaiTilekKyzy,KNCV,NetherlandsChernyshovAndrey,PublicAssociationforthesupportofpeoplelivingwithHIV(KUAT),Kazakhstan

ChingizRamazanli,TowardsFreeFuture,PublicUnion,AzerbaijanChrisDell,TBsurvivorandmemberofTBPeople,UnitedKingdomDr.DalenevonDelft,TBProof,SouthAfricaDilshatHaitov,TBpeople,KyrgyzstanEdwardoZ.Patac,TBpeople,TDF-(CKAT),PhilippinesElenaShastina,AutonomousNonprofitOrganizationforPreventionofSociallySignificantDiseases(NEWLIFE),RussianFederation

Dr.Helene-MarivanderWesthuizen,TBProof,SouthAfricaIngridSchoeman,TBProof,SouthAfricaDr.JenniferFurin,HarvardMedicalSchool,UnitedStatesKazievaIndira,PublicFoundation,KyrgyzstanMercedesBecerra,HarvardMedicalSchool,UnitedStatesRozaIdrissova,ThePublicFoundationSanatAlemi,KazakhstanDr.RuvandhiNathavitharana,BethIsraelDeaconessMedicalCenterandHarvardMedicalSchool,Boston,andTBProof,SouthAfrica

TatyanaShumikhina,apatientoftheTBregionalhospital,BelarusTimurAbdullaev,TBpeople,UzbekistanVitaliMorosan,NoncommercialPartnership(Medical-Socialprograms),MoldovaDr.VivianCox,MDRClinicalConsultant,UnitedStatesYahyaOuldELEyil,ONGGLOBE,MauritaniaAdditionalendorsements:Dr.EricGoemaere,RegionalHIV/TBtechnicalsupportcoordinator,MSFSouthAfrica,Honoraryseniorlecturer,SchoolofPublicHealth,UniversityofCapeTown

GlobalHealthAdvocates,FranceandIndia

4

HealthandDevelopmentAlliance(HEAD),CambodiaInternationalCoalitionofWomenLivingwithHIV(ICWAP),AsiaPacificDr.JonathanStillo,WayneStateUniversity,UnitedStatesResultsUK,UnitedKingdomTBEuropeCoalition,WesternandEasternEurope,CaucasusandCentralAsia

5

TheWorldHealthOrganization(WHO)mustrecommendbedaquilineaspartofthepreferredregimenformultidrug-resistanttuberculosis(MDR-TB):ApositionstatementfromtheGlobalTBCommunityAdvisoryBoard(TBCAB)TheGlobalTuberculosisCommunityAdvisoryBoard(TBCAB)isagroupofresearch-literatetreatmentactivistsfromaroundtheworldwhoworkinanadvisorycapacitytoresearchersandproductdevelopersconductingtrialsofnewandrepurposedtuberculosis(TB)drugs,regimens,anddiagnostictechnologies,andprovideinputonstudydesigns,earlyaccess,regulatory,postmarketing,implementation,andaccessstrategies.Inrecentmonths,theTBCABhashadin-depthdiscussionsontheappropriatenessofthecurrentdrugsfrequentlyusedtotreatmultidrug-resistantTB(MDR-TB).TheurgencyofthesediscussionsisdrivenbytheexperiencesofpatientsandcliniciansandtheaccumulatingevidenceonthesafetyandefficacyofthenewerTBdrugs–especiallybedaquiline–andwhetheranevidentiarythresholdhasbeencrossedwheretheuseofnewerTBdrugsshouldbeexpandedandplacedaheadofcertainolderdrugswithwell-knowntoxicities.RecentlyannouncedfindingsfromstageIoftheSTREAMtrial(aphaseIIIstudyconductedbytheUnioncomparinga9-12monthstandardizedregimento18-24monthsofindividualizedtreatmentforMDR-TB,bothofwhicharerecommendedbytheWHOundercertainconditions)havealsocreateduncertaintyregardingtheoptimaltreatmentforMDR-TBbasedonexistingevidence.TheSTREAMtrialdidnotshowthatthenewshorterregimenisnon-inferiortotheprevious18–24monthstandardofcareforMDR-TB.1Undertheconditionsofarandomized,controlledclinicaltrial(RCT),bothregimensachievedaround80percenttreatmentsuccess.WhiletheshorterregimenperformedsimilarlyintheRCT(78percenttreatmentsuccess)topreviouslyconductedcohortstudies,2thecontrol(the18-24monthregimen)performedbetterintheRCTthancommonlyreportedinprogramsettings(80.6vs.54percenttreatmentsuccess).34Still,weconsiderunfavourableoutcomesinoneofeveryfivepatientstobeunacceptable,especiallygiventhatratesoftreatmentsuccessarelowerinnon-trialsettings.Furthermore,theshorterregimenofferednoadvantageintermsofadverseeffectsormortalitycomparedto18-24monthsoftreatment.5TheTBCABbelievesacasecanbemadeformovingbeyondthefalsedichotomyofchoosingbetweentwosub-optimallyperformingregimenstoathirdpossibility:aregimenthatincludesoneofthenewerTBdrugs.ThecurrentWHOguidelinesforthetreatmentofMDR-TBplacepatientsatsubstantialriskofsevereside-effectsanddrug-relatedtoxicities,includingdangerouskidneytoxicity,electrolyteabnormalities,andhearingloss.Thegroupofdrugsthatcausehearinglossinasmanyas50percentofpatientsarecalledaminoglycosidesorinjectableagents.67Theyincludeamikacin,capreomycin,andkanamycin.Apartfromhearingloss,patientsalsoreportthattheinjectionsareoftenverypainful.AccordingtocurrentWHOguidelines,peoplewithMDR-TBmustreceiveaninjectableunlesstheyaretestedforandshowresistanceorsignsofhearingloss—inotherwords,onlyoncesomehearinglossisacquiredarepatientsofferedanotherdruginplaceoftheinjectable.Basedonanecdotalevidence,inmostresource-limited,highTBburdensettings,audiometrytestingtomonitorforhearing

6

lossisnotimplemented.Asaresult,patientsareallowedtogodeaf,eventhoughalternativetreatmentoptionsexist.Theevidencefortheeffectivenessofinjectablesisunclear—onereviewrecentlypublishedinTheInternationalJournalofTuberculosisandLungDiseasestated“eventhoughinjectableagentshavebeenrecommendedascoreagentsfortreatingMDR-TBforalmost20years,theevidencebasefortheuseofinjectableagentsisweakatbest.”8ThatreviewalsopointsoutthecompletelackofRCTsevaluatingtheinjectablesforthetreatmentofMDR-TB.Whileevidencedemonstratingtheefficacyoftheinjectableagentsislacking,theevidenceofhearinglossisundisputed.Inrecentyears,evidenceofthesafetyandefficacyofbedaquilinehasbeenaccumulating.Whileahard-to-explainimbalanceindeathsinanearlierphaseIIbtrialofthedrugraisedconcern,9wideuseofthedrugsincethensuggeststhatthedrugactuallyprovidesamortalitybenefit.10AccumulatingevidencealsostronglysuggeststhatthedrugiseffectiveagainstMDR-TB,includingasasubstitutefortheinjectableagent.11,12,13,14,15Whenthesafetyprofileofbedaquilineiscomparedtothatofthemostwidelyusedinjectables,bedaquilineismuchsaferandbettertolerated,posingnoriskofhearinglossandnotrequiringanyinjections.Themainconcernregardingbedaquilineisthedrug’seffectontheheart’srhythm(alsoknownasQT-prolongingeffects),althoughthiseffecthasnotappearedtohaveclinicalsignificancetodate.16ItisalsoimportanttoacknowledgethatotherTBdrugsalsohaveQT-prolongingeffects,includingtwousedintheshorterregimen,moxifloxacinandclofazimine.17Regardingefficacy,thereismorerigorousrandomizedtrialevidenceofactivityagainstTBavailableforbedaquilinethanforanyoftheinjectableagents.WhileweacknowledgethatwiththephaseIIItrialunderway,thereisstillsomeuncertaintyabouthowbedaquiline’sefficacywillfareinaclinicaltrialwithlong-termoutcomes,thereisagrowingbodyofevidencefromtheuseofthedruginover8,000patientswithDR-TB.18Abalancedconsiderationofalltheevidenceleavesuswithnoreasontoprefertheuseofinjectables.Theefficacyofbedaquilineismuchclearerthanthatoftheinjectableagents,anditstoxicityappearstobelesscommonandlessseriousthanthatoftheinjectableagents.WeareawarethatseveralimportanttrialsarecurrentlyunderwaythatwillmoreclearlyaddresstheQTcprolongationissuewhileusingmultiplenewerdrugs,andevaluatewhethernewdrugscanreplacetheinjectableagentsinregimenstoshortentreatmentforMDR-TB(e.g.NEXT-TB,TB-Practecal,endTB,STREAMstageII,MDR-END,etc.).19Thesetrialswillbecriticallyimportanttoprovidingastrongerevidence-basenecessarytoinformfuturedecision-making.However,evenbasedonthecurrent,admittedlyincompleteevidence,thecasetoreplacetheinjectableswithbedaquilineiscompellingandinourviewscientificallysound.Weareinnodoubtthateachofus,giventhechoice,wouldpreferaregimenwithbedaquilinetoaregimencontaininganinjectable.WearealsoconfidentthatmostexpertsinthefieldwouldhavethesamepreferenceshouldtheybediagnosedwithMDR-TB.Wethusseeno

7

justificationwhatsoeverastowhyanyonewithMDR-TBshouldstillbesubjectedtotheriskof,andtheactual,severesideeffectsassociatedwiththeinjectableagents.Thus,asamatterofurgency,weurgetheWHOtorecommendbedaquilineaspartofthepreferredregimenforMDR-TBandtorelegatetheinjectablesforuseonlyinmorecomplicatedcases,andwithabsoluterequirementandassuranceofmonitoringforhearingloss.Forchildrenunder12(inwhomsafetyanddosingdataonbedaquilinearenotyetavailable)andotherswhodonotqualifyforbedaquiline,othernewerdrugs(i.e.delamanidorlinezolid)shouldreplacetheinjectableinbedaquiline'sstead.1RusenID,NunnA,PhillipsP,BertelSquireS.STREAMtrial(EvaluationofaStandardisedTreatmentRegimenofAnti-tuberculosisDrugsforPatientswithMultidrug-resistantTuberculosis):preliminarystage1results.Satellitesessionat:48thUnionWorldConferenceonLungHealth,Guadalajara,Mexico;12October2017.2TrébucqA,SchwoebelV,KashongweZ,etal.Treatmentoutcomewithashortmultidrug-resistanttuberculosisregimeninnineAfricancountries.IJTD2017;22(1):17–25.3RusenID,NunnA,PhillipsP,BertelSquireS.STREAMtrial(EvaluationofaStandardisedTreatmentRegimenofAnti-tuberculosisDrugsforPatientswithMultidrug-resistantTuberculosis):preliminarystage1results.Satellitesessionat:48thUnionWorldConferenceonLungHealth,Guadalajara,Mexico;12October2017.4GlobalTuberculosisReport2017.Geneva:WorldHealthOrganization:2017.Availablefrom:http://www.who.int/tb/publications/global_report/en/.5RusenID,NunnA,PhillipsP,BertelSquireS.STREAMtrial(EvaluationofaStandardisedTreatmentRegimenofAnti-tuberculosisDrugsforPatientswithMultidrug-resistantTuberculosis):preliminarystage1results.Satellitesessionat:48thUnionWorldConferenceonLungHealth,Guadalajara,Mexico;12October2017.6ShinSS,PasechnikovAD,GelmanovaIY,etal.AdversereactionsamongpatientsbeingtreatedforMDR-TBinTomsk,Russia.IJTLD2007;11:1314–1320.7TorunT,GungorG,OzmenI,etal.Sideeffectsassociatedwiththetreatmentofmultidrug-resistanttuberculosis.IJTLD2005;9:1373–1377.8ReuterA,TisileP,vonDelftD,etal.Thedevilweknow:istheuseofinjectableagentsforthetreatmentofMDR-TBjustified?IJTLD2017;21(11):1114–1126.9FoodandDrugAdministration(U.S).Anti-infectivedrugsadvisorycommitteemeetingbriefingdocumentTMC207(bedaquiline).TreatmentofpatientswithMDR-TB.NDA204-384.2012November28.10A2016reviewofavailableevidenceontheuseofbedaquilineinthetreatmentofmultidrug-resistanttuberculosis.Geneva:WorldHealthOrganization:2017.Availablefrom:http://www.who.int/tb/publications/2017/GDGreport_Bedaquiline/en/11Reportoftheguidelinedevelopmentgroupmeetingontheuseofbedaquilineinthetreatmentofmultidrug-resistanttuberculosis.Geneva:WorldHealthOrganization:2016.Availablefrom:http://www.who.int/tb/publications/2017/GDGreport_Bedaquiline/en/.12A2016reviewofavailableevidenceontheuseofbedaquilineinthetreatmentofmultidrug-resistanttuberculosis.Geneva:WorldHealthOrganization:2017.Availablefrom:http://www.who.int/tb/publications/2017/GDGreport_Bedaquiline/en/13GugliemettiL,JaspardM,LeDuD,etal.Long-termoutcomeandsafetyofprolongedbedaquilinetreatmentformultidrug-resistanttuberculosis.EurRespirJ2017;49:1601799.14NdjekaN,ConradieF,SchnippelK,etal.Treatmentofdrug-resistanttuberculosiswithbedaquilineinahighHIVprevalencesetting:aninterimcohortanalysis.IJTLD2015;19:979–985.15BorisovSE,DhedaK,EnweremM,etal.Effectivenessandsafetyofbedaquiline-containingregimensinthetreatmentofMDR-andXDR-TB:amulticentrestudy.EurRespirJ2017;49:1700387.16YoonH-Y,JoK-W,NamGB,ShimTS.ClinicalsignificanceofQT-prolongingdruguseinpatientswithMDR-TBorNTMdisease.IJTLD2017;21(1):996–1001.17HarauszE,CoxH,RichM,etal.QTcprolongationandtreatmentofmultidrug-resistanttuberculosis.IJTLD2015;19(4):385–391.18PaiM,FurinJ.Tuberculosisinnovationsmeanlittleiftheycannotsavelives.eLife2017;6:e25956.

8

19LowM.Thetuberculosistreatmentpipeline:AbreakthroughyearforthetreatmentofXDR-TB.In:2017pipelinereport.NewYork:TreatmentActionGroup;2017.