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TeratogenicityinrelationtoDolutegravir
Ushma Mehta,Pharm.D,DrPHCentreforInfectiousDiseaseEpidemiologyandResearch(CIDER)
SchoolofPublicHealthandFamilyMedicineUniversityofCapeTown
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Outline
• Terminology•Whatdoesittaketo“make”ateratogen?• IsDTGateratogenyet?....theevidencesofar•HowSouthAfricacancontribute:• Teratovigilance InitiativesinSouthAfrica
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Terminology• TeratogenAnythingthatcausesabnormalitiesinthedevelopmentofthefetus ifthemotherisexposedtoitduringpregnancye.g.chemicals,medicationsandinfections(notallteratogensaremedicines!)• TeratovigilanceTheaspectsofteratology relatingtounderstandingtheepidemiologyofteratogensandtheirimpactonpublichealth
• CongenitalAnomaly/Malformation/DisorderorBirthDefectAnystructuralorfunctionalanomaly(e.g.metabolicdisorder)thatoccursduringintrauterinelife.(notasinglehomogenousoutcome!)
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“Teratogenesis is a unique kind of adverse drug effect, since it
affects an organism (the fetus) other than the one for whom
the drug was intended (the mother)….That “innocent
bystander” status of the fetus raises profound medical, moral
and legal issues.”
AllenA.MitchellinPharmacoepidemiology,Strometal,2005
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FetaleffectsnotjustmalformationsEffect Examplesof causesSpontaneous AbortionandStillbirth Maternaldiabetes
Intrauterine growthretardation AlcoholMajor andminoranomalies Phenytoin,sodiumvalproate,
warfarinDevelopmental problems Sodium valproate,leadAbruptio placenta cocaineCancer Diethylstilboestrol
Socialbehaviour Alcohol
AdaptedfromslidebyProfLewisB.Holmes
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AssessingCausality…
Canthedrugdoit?
?
1. Pharmacology(biologicallyplausible)2. Associationintime(gestationaltiming)andplace(tissueoforigin)betweenexposureandevent3. Consistencyoftheassociation(rechallenge /dose/classeffect?)4. Specificityoftheassociation- caneventoccurinabsenceoftheexposure? Confounding5. Dataquality- malformationclearlydescribed/diagnosed,timingofexposure,otherexposures6. Quantitativestrength– doseanddurationofexposure,effectsize,studydesign,randomerror,bias
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Shepard’s“Criteriaforproofofhumanteratogenicity”
Consistentfindingsbytwoormorehighquality epidemiologicalstudies:a)controlofconfoundingfactors;b)sufficientnumbers;c)exclusionofpositiveandnegativebiasfactors;d)prospectivestudies,ifpossible;e)relativeriskofsixormore(?).
ShepardTH:“Introduction”,CatalogofTeratogenicAgents,EighthEdition,1995,pagexxivTable1.
SlideAcknowledgement– ProfessorLewisHolmes
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SpecialCharacteristicsofTeratovigilance
• Mostpregnanciesareunplanned– inadvertentexposures– womenofchild-bearingage(WOCBA)areatrisk• TeratogensdonotuniformlyincreaseratesofALLcongenitalanomalies,butratherselectedones.• Teratogenicriskisunknownforvastmajorityofmedicines(poordataonbiologicalplausibility)includingOTCmedicines• Mostteratogensdonotcauseauniqueanomalybutrathercauseincreaseinrateofknownanomalies(e.g.neuraltubedefects(folicacid,otherdrugs).Cleftlip/palate,etc.)• Someanomaliescannotbeinfluencedbyenvironmentalexposures(e.g.chromosomalanomalies)• Terminationofpregnancy/abortion/stillbirthcanavoidtheoutcomeofinterestiftheoutcomeisonlyassessedinlive-births
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LargeSampleSizesNeededSamplesizeestimationbasedonbackgroundincidence
IncidenceinComparatorGroup
1exposed/1 unexposed 1exposed/4unexposed
RRtobedetected:2
RRtobedetected:10
RRtobedetected:2
RRtobedetected:10
Exposed Unexposed Exposed Unexposed Exposed Unexposed Exposed Unexposed
5% 474 474 19 19 274 1096 10 40
1% 2515 2515 121 121 1445 5780 61 244
0.1% 25471 25471 1272 1272 14621 58484 628 2512
MehtaUetal,BMCPregnancyandChildbirth,2012
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Dolutegravir: BiologicalPlausibility&ConsistencyofAssociation• Animaldata(FDAPI)• Crossesplacentaandexcretedintobreastmilk• Doesnotaffectfertilityinmaleorfemalerats/rabbitsat27xhumandose• Noevidenceofdevelopmentaltoxicity,teratogenicityoreffectonreproductivefunctioninratsandrabbits
• Clinicaltrials• 4anomaliesreportedin1pharmacokinetictrialIMPAACT1026s– laterconsideredunrelatedtoDTG
• AntiretroviralPregnancyRegistry*• - 0CNSeffectsreportedasat1Jan2018- 3anomaliesreportedfrom133preconceptionexposures(2.3%)
• Otherintegraseinhibitors– raltegravir – increaseinsupranuerary ribsinrat/rabbitat3xhumandose
*TheAntiretroviralPregnancyRegistryfindsnoapparentincreasesinfrequencyofdefectswithfirsttrimesterexposurescomparedtoexposuresstartinglaterinpregnancyandnopatterntosuggestacommoncause;however,potentiallimitationsofregistriesshouldberecognized.ProvidersarestronglyencouragedtoreporteligiblepatientstoSM_APR@INCResearch.com orvisitwww.APRegistry.com.
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AssociationinTime:GestationalTiming
https://www.cdc.gov/dotw/fasd/index.html
Neuraltubedevelopsandclosesbyday26- 30postfertilisation
Periodofrisk:Earlyfirsttrimester
Exposuresinitiatedafterthisperiodcannotbeimplicated(andhaven’tbeenimplicated)
LMPorgestationaltiming– oftennotknown
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Datacollectionfrom8facilitiesacrossBotswana(45%ofnationalbirthcohort)
Since2014
Datacollectedatdeliveryfromobstetricrecordincludingsurfaceexam
Incaseofanomaly– studystaffcontactedtophotographanomalyafterconsentobtained
Photographsreviewedremotelybyclinicalgeneticist-blindedtoexposure
• TDF/FTC/DTGinitiatedasfirstlinetreatmentinBotswanain2016• Noincreasedriskofadversebirthoutcomesamongwomeninitiatedduringpregnancycomparedto
TDF/FTC/EFVandnoincreasedriskamong280initiatedduringfirsttrimester(Zash R,LancetGH,2018)
• PerformedunplannedanalysisinMay2018forWHOGuidelinescommittee• SignalofNTDs…..
Tsepamo Study:Botswana
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89,064birthsincludedinsurveillance
88,755births(99.7%)examined(liveandstillbirths)
86neuraltubedefects(0.1%0ofbirths;95%confidenceinterval[CI],0.08to
0.12)
49(57%)withphotos
37(43%)Confirmedbydescription(nophotos)
42 meningocele or myelomeningocele, 30 anencephaly, 13 encephalocele, 1 iniencephaly.
Tsepamo Study:Botswana Zash Retal,NEJMSept62018
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0.94%
0.05%0.12%0.00%
0.09%0"
0.5"
1"
1.5"
2"
2.5"
DTG,CONCEPTION% ANY%NON,DTG%ART,CONCEPTION%
EFV,CONCEPTION% DTG%STARTED%DURING%
PREGNANCY%
HIV,NEG%
PERC
ENTA
GE%(9
5%%CI)%WITH%NE
URAL
%TUB
E%DE
FECT
%
NTDs/Exposures 4/426 14/11,300 3/5,787 0/2.812 61/66,057
%withNTD(95%CI)
0.94%(0.37%,2.4%)
0.12%(0.07%,0.21%)
0.05%(0.02%,0.15%)
0.00%(0.00%, 0.13%)
0.09%(0.07%,0.12%)
PrevalenceDifference(95%CI)
ref -0.82%(-0.24%,-2.3%)
-0.89%(-0.31%,- 2.3%)
-0.94%(-0.35%, -2.4%)
-0.85%(-0.27%,-2.3%)
NTDPrevalenceDifferencebyExposure
Zash R,AIDS2018NEJMSept6,2018
1)Encephalocele2)Anencephaly(nophoto)3)Myelomeningocele4)Iniencephaly
NeuralTubeCases
Tsepamo Study
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Tsepamo:SensitivityAnalysis&Update• Sensitivity• Noclusteringintime(restrictedanalysistoratesafterDTGintroduction)• Noclusteringbyfacility• Nochangeincaseascertainment(usingpostaxialpolydactylydetectionasmarker)• Nofolatesupplementation,epilepsyordiabetespriortopregnancyinanycases
• Updateanalysis• July2018- nonewcasesinT1exposedDTG4/596(0.67%,95%CI0.26%-1.7%)• Nextformalanalysis– March2019– anticipate1226T1exposuresexpandingto18facilities• “Ifonly1moreNTDcaseintotalof1226– thenlowerCIwilloverlapwithupperCIforotherARTatconception”
Zash R,AIDS2018
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InitiativesinSouthAfrica• SAHPRA- riskmanagementplans• AcknowledgementofriskformforWOCBA• CompaniesrequiredtosupportreportingtoAPRbyclinicianswhowishtocontributedataonexposures.
• PregnancyExposureRegistry/BirthDefectSurveillance(PER/BDS)• KZN–DurbanSouthdistrict- >45000womentodate– initiatedOct2013• WesternCape– GMOU-MMH-GSHreferralchain– initiatedSept2016
• Conference:BuildingTeratovigilance CapacityinAfrica- Nov2017• https://globalpharmacovigilance.tghn.org/resources/building-teratovigilance-capacity-africa/
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P
GugulethuMOU
MowbrayMaternityHospital
TygerbergHospital
WorcesterHospital
WorcesterMOU
GrooteSchuurHospital
ValidatingExposuresPregnancyEvidenceValidating
PregnancyOutcomes
Clinicom
NHLS
MomConnect
PHCIS
ValidationofdatacollectedfromMaternityCaseRecord
CDU
ETR
JAC
PaedsSurgery
PHCIS
PPIP
FetalMedicine
Genetics
NHLShistologyandfetalautopsy
WCProvincialPublicHealthDataCentre
Datacaptureatsitesbyclericalstaffembeddedinfacilities
WesternCapePregnancyExposureRegistry/BirthDefectSurveillanceMethodology
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WCPER/BDSChallenges• Dependentonroutineclinicaldata:• Systemstrengthening– clinicalexamination&recordkeeping• Documentingdrughistories• Documentingclinicalexaminations• Examinationofstillborninfants
• Fetalautopsy• Issueofinfantidentifiers(foldernumber)atMOUs&hospitals,esp.stillbirths:linkage• Multiplepatientidentifiers• PHCIS:operationaldatabase• Accuratediagnosisofcongenitaldisorders:photographs
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Conclusion
• WearenotyetcertainthatDTGisateratogen• Needconsistencyoffindingsacrossstudies• Biggernumbers– SAisreadytocontribute
• Challengesincommunicatingrisk-benefitinthepresenceofsuchuncertainty
• Howtoimprovepartnershipwithclientsindecision-making?
• Requireinvestmentinrobustpost-marketingsurveillanceforpregnancy
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Acknowledgements• UCT/CIDER/SOPHFM• EmmaKalk• AndrewBoulle• NishaJacob• LandonMyer• Mary-AnnDavies• KarenFieggen
• StellenboschUniversity• AmySlogrove• AlexWelte• Cari vanSchalkwyk• MikeUrban
• SAHPRA• HelenRees• MarcBlockman• Shabir Banoo• PortiaNkambule• FloraMatlala
• NationalDepartmentofHealth• Mukesh Dheda• Yogan Pillay
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