IMPAACT TB SCIENTIFIC COMMITTEE - Treatment Action Groups Childhood TB meeting talk... · IMPAACT TB SCIENTIFIC COMMITTEE Anneke ... therapeuc research gaps in the prevenon and treatment

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

11/4/11 25

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”