IMPAACT TB SCIENTIFIC COMMITTEE - Treatment Action Groups Childhood TB meeting talk... · IMPAACT...
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IMPAACT TB SCIENTIFIC COMMITTEE Anneke C Hesseling: Chair Sharon Nachman: Interim Vice‐Chair IMPAACT Vice Chair
Transcript of IMPAACT TB SCIENTIFIC COMMITTEE - Treatment Action Groups Childhood TB meeting talk... · IMPAACT...
IMPAACTTBSCIENTIFICCOMMITTEE
AnnekeCHesseling:ChairSharonNachman:InterimVice‐Chair
IMPAACTViceChair
Goal
• Addresscri>caltherapeu>cresearchgapsinthepreven>onandtreatmentoftuberculosisinHIV‐infectedanduninfectedchildren,adolescentsandpregnant/breasFeedingwomen
BURDENOFTBINCHILDREN
• Global:2billionlatentlyinfected,8.8millionnewcases
• >75%in22high‐burdencountries• Es>mated10%among(inaccuratees>mates)• Interna>onalanddomes>cproblem
• Limitedsurveillance:challengesindiagnosis• Limitedprogramma>cemphasis(preven>onanddiagnosis)
• Diagnos>cchallenges• Infec>onanddiseasebothrelevanten>>es
www.who.int
WHO 2011 Global TB report www.who.int
TBINWOMEN• Es>mated3.2million(range:3.0‐3.5million)newTBcasesamongwomenin2010
• Es>mated820,000deathsin2010• 320000deathsamongHIV‐nega>vewomen• 500,000deathsamongHIV‐infectedwomen
• Burdeninpregnancyunknown(1‐2.5%ofHIV+pregnantwomen)Kali JAIDS 2006, Gupta CID 2011, Gounder JAIDS 2011
• Peakincidence:reproduc>veage15‐45years
WHO Global TB report 2011 www.who.int
RELEVANCEOFPEDIATRICTB
• Indica>onofepidemiccontrol(sen>nelsurveillance):failureofhealthsystems
• Recenttransmission:DR,genotypes
• Uniquespectrumandseverityofdisease
• Opportunity:studyofdis>nctphenotypes(TBM)
• Preventable:epidemiccontrol,IPT,vaccines
Exposure
Infec?onLimitedDisease Severe
diseaseDisseminatedDiseaseanddeath
TBINCHILDREN:CONTINUUMOFTBINFECTIONANDDISEASE:WHATDOWEWANTTOPREVENT,DIAGNOSEANDTREAT?
>60%children0‐5withTBdiseasehavehousehold/closeTBexposure
Exposure
Infec?onLimitedDisease Severe
diseaseDisseminateddiseaseanddeath
Age
HIV
Environmentalfactors,strain,nutri?on,gene?cs
RelevanceofTBinPregnant/breasFeedingwomen
• Keyentrypointintohealthcare• DataonTBdrugPK,safety,maternal/fetaloutcomeslimited
• Usuallyexcludedfromdrugtrials– 13trialsofINHpreven>vetherapyinHIV+– allexcludedpregnantwomenatentry
• Womenwillbedevelopingac>veTBinIMPAACTtrials:PROMISE,P1078
SCIENTIFICPRIORITIES
1. Drugs2. Vaccines3. Diagnos>cs4. Otherac>vi>es
PREVIOUS/CURRENTTBACTIVITIES:IMPAACT
• Treatment
– IMPAACTP1041:PrimaryIPTinHIV‐infectedandexposedinfants(completed)
– IMPAACTP1078:SafetyofIPTstrategiesinHIV‐infectedpregnantwomen(2012)
• Vaccines:Areas402,422(2012)• Diagnos?cs:IGRAinHIV‐infectedandexposedinfants(substudies:1041)
• Indevelopment:– pediatricMDRTBPK/safetystudywithTMC207
– IMPAACTco‐endorsementofA5279(INH/rifapen>neshortcourse≥13years
FUTUREPLANS
NEWTBDRUGSDRUG/CLASS ACTG PAEDIATRIC
EVALUATIONWHO?
Quinolones Yes Yes(PK,safety–non‐TB) Bayer
Rifapen>ne Yes Yes(PK,safety‐IPT) TBTC
Bedaquiline(TMC207) Yes Yes(plannedPK,safetyinMDR‐TB)
IMPAACT(indevelopment)
Nitroimidazoprams:PA‐824,Delamanid(OPC‐67683)
Underdiscussion
No(underdiscussion) ?
Diamines(SQ‐109) Underdiscussion
No(underdiscussion) IMPAACT‐CDAsigned
Oxazolidinones(PNU,AZcompounds)
Underdiscussion
No ?
10othernewcompoundsindevelopment Nostudiesincludingpregnantwomen
Diagnos>cs/therapeu>cmonitoringapproaches
SelectedDiagnos?c/monitoringApproaches
Selec>onandOp>miza>onofspecimenyield
GeneXpert
Hainstrips
Urinean>gen
PCR
Hostgeneexpressionprofiling
PETimaging
Which should be considered for clinical trials in children with TB?
PATHWAYFORPEDIATRICEVALUATION:NOVELAGENTS
Priori?es:• PKincludingdose‐finding• Safety/Toxicity• Appropriateformula>ons• ‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
• Efficacy:lowerpriority,feasibilitybutmayberelevanttopreven>vetrials,pediatricdiseasespectrum(treatmentshortening)whenconsideringnewdrugcombina>ons
1.THERAPEUTICAGENDA:A. DRUG SUSCEPTIBLE TB
• Treatmentshortening:TBdisease(milddisease)
• ShortercourseINHpreven?vetherapy:– IPTplusX
• Unknowns– WheredoHIV+childrenfitin?IPT,Rx– NewagentsalsoforDS‐TB?
• Pregnantwomen,neonatal,infantstudies– HIV+andHIV‐– PK(opportunis>c)andsafety– Breastmilkconcentra>ons?Druginterac>ons?
B. DRUG‐RESISTANT TB
• Newtherapeu>cs– OverallsafetyandPK(Sequella,Pfizer,Tibotec,Otsuka,others)
– TreatmentMDR‐TB(TMC207)• WheredoHIV+popula>onsfitin?
– inclusion, special considera?ons, ART interac?ons • Preven>vetherapy
– INHplusXXXornewXXXalone• Pregnantwomen,neonates/infants
– Opportunis>cPKandsafety– HIV+,HIV‐
2.VACCINES• Aeras402(viralvectored),422(recombinant)• Othercandidates
– Leveragestudiestoinclude:BCGprime,BCGboost,recombinantBCG
– Safety– Immunogenicity
• Difficultissue(correlatesofprotec>on?)
• Popula>ons:– HIVunexposed– HIVexposed– HIV+– Adolescents(withHVTN)– Maternal?
3.DIAGNOSTICS• Diagnos>cchallenges:disease
– standard+novelapproaches• Nestedinotherstudies
– Opportunityforinves>gatorini>atedstudies• Bio‐repositorylinkedtospectrumofinfec>on,diseasestatesandrelevantclinicaloutcomes
• Standardapproaches• R01andothermechanisms
– Hostandorganismbasedapproaches• Diagnos>cmakersofprotec>on/success
– orfailure• Collabora>onacrossnetworksandgroups(FIND,TBTC,ACTG,AERAS,TBALLIANCE,othergroups)
• Labwork:protocol‐driven,collabora>ve
4.OTHERACTIVITIES• LongtermregistryofallsubjectsonTBstudies
• ConsensusstatementonpediatricresearchpathwayfortrialsofnovelTBtherapeu>cs
• SOPs– Labs– Diagnos>cs‐novel– Clinical
• Networkinterac>ons:ACTG,HVTN,other– Currentcross‐cupnginterac>ons:ACTG,TBTC,WHO,IUATLD,TDR,industry,founda>ons
– Co‐endorsementofprotocols• Strongfocusoninves>gator‐ini>atedgrantapplica>ons
ACTIVITIES:2012‐20141. 3‐5clinicaltrials
– 2‐3treatment(CS4101:TMC207,MDR:PKandsafety;opportunis>cPKstudyinpregnant/BFwomen)
– 1vaccine(Aeras402)– 2‐3nesteddiagnos>c/biomarkerstudies
2. Consensusstatementontrialimplementa>onstrategyofnovelTBagentsinchildren
3. SOP:forrepository1. Diagnos>cs2. Clinicaldataincludingepi,endpoints3. Standardiza>onofallimplementa>onaspects
4.Strongindustryandotherpartnerengagement
LABREQUIREMENTS
• Protocol‐driven• Earlyconsulta>on• Labteam:Involvementonprotocolteams
• Biorepositoryfocus• Scopeforlabandclinicalinves>gatorstopropose,implementlab‐relatedcapsules
• Closecollabora>onwithIMPAACTLabcommiree,HANC,SMILEetc
NetworkTBLaboratoryEQA(N=25)ACTG(21)
IMPAACT(13)
HPTN(8)
MTN(4)
HVTN(3)
Other(7)
ACTG 9 9 8 4 3 5
IMPAACT 2 6 4 2 5
HPTN 0 0 1 3
MTN 0 0 1
HVTN 0 1
OTHER 0
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Establishing expanded International TB Laboratory Support
Planned ACTG/IMPAACT RFA to establish an international reference lab and 2-4 regional labs
Corelabs
• ExtensiveuseofPKlabresources• Alsonon‐coreregionalaccreditedlabsforPK(e.g.ACTG‐PK
andother);consul>ngPKandotherexperts
SpecialtyLabs• Xpert/otherassays,genotyping,IGRA,novelbiomarkersofTB
disease,latencyandTBtreatmentresponse,hostgene>cs,micronutrientsetc
• Diagnos>cs:rou>nee.g.culture,Xpertetc:on‐site(real‐>me),HANCaccredita>onprocess
• Greaterflexibility,invi>nglabs/groupstoapplywithscien>ficques>ons,exper>serelevanttospecificIMPAACTTBprotocols.
• Regionaland/orlinkedtoexis>ngIMPAACTsitesanddomes>c
• Addi>onalspecialtylabplaFormssoughtasrelevant(protocol‐driven);representa>ononprotocolteams
OTHERIMPAACTSUPPORT
Sta?s?cal• SDACsupport‐primaryandsecondaryobjec>veanalyses
• Addi>onal/exploratoryanalysis
IMPAACTOpera?onsCenter• Scien>ficCommireeCoordinator• ClinicalManager
THANKYOU
“ A generation of children free of tuberculosis”
