TeratogenicityinrelationtoDolutegravir

Ushma Mehta,Pharm.D,DrPHCentreforInfectiousDiseaseEpidemiologyandResearch(CIDER)

SchoolofPublicHealthandFamilyMedicineUniversityofCapeTown

Outline

• Terminology•Whatdoesittaketo“make”ateratogen?• IsDTGateratogenyet?....theevidencesofar•HowSouthAfricacancontribute:• Teratovigilance InitiativesinSouthAfrica

Terminology• TeratogenAnythingthatcausesabnormalitiesinthedevelopmentofthefetus ifthemotherisexposedtoitduringpregnancye.g.chemicals,medicationsandinfections(notallteratogensaremedicines!)• TeratovigilanceTheaspectsofteratology relatingtounderstandingtheepidemiologyofteratogensandtheirimpactonpublichealth

• CongenitalAnomaly/Malformation/DisorderorBirthDefectAnystructuralorfunctionalanomaly(e.g.metabolicdisorder)thatoccursduringintrauterinelife.(notasinglehomogenousoutcome!)

“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

FetaleffectsnotjustmalformationsEffect Examplesof causesSpontaneous AbortionandStillbirth Maternaldiabetes

Intrauterine growthretardation AlcoholMajor andminoranomalies Phenytoin,sodiumvalproate,

warfarinDevelopmental problems Sodium valproate,leadAbruptio placenta cocaineCancer Diethylstilboestrol

Socialbehaviour Alcohol

AdaptedfromslidebyProfLewisB.Holmes

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

Shepard’s“Criteriaforproofofhumanteratogenicity”

Consistentfindingsbytwoormorehighquality epidemiologicalstudies:a)controlofconfoundingfactors;b)sufficientnumbers;c)exclusionofpositiveandnegativebiasfactors;d)prospectivestudies,ifpossible;e)relativeriskofsixormore(?).

ShepardTH:“Introduction”,CatalogofTeratogenicAgents,EighthEdition,1995,pagexxivTable1.

SlideAcknowledgement– ProfessorLewisHolmes

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

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

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.

AssociationinTime:GestationalTiming

https://www.cdc.gov/dotw/fasd/index.html

Neuraltubedevelopsandclosesbyday26- 30postfertilisation

Periodofrisk:Earlyfirsttrimester

Exposuresinitiatedafterthisperiodcannotbeimplicated(andhaven’tbeenimplicated)

LMPorgestationaltiming– oftennotknown

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

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

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

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

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/

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

WCPER/BDSChallenges• Dependentonroutineclinicaldata:• Systemstrengthening– clinicalexamination&recordkeeping• Documentingdrughistories• Documentingclinicalexaminations• Examinationofstillborninfants

• Fetalautopsy• Issueofinfantidentifiers(foldernumber)atMOUs&hospitals,esp.stillbirths:linkage• Multiplepatientidentifiers• PHCIS:operationaldatabase• Accuratediagnosisofcongenitaldisorders:photographs

Conclusion

• WearenotyetcertainthatDTGisateratogen• Needconsistencyoffindingsacrossstudies• Biggernumbers– SAisreadytocontribute

• Challengesincommunicatingrisk-benefitinthepresenceofsuchuncertainty

• Howtoimprovepartnershipwithclientsindecision-making?

• Requireinvestmentinrobustpost-marketingsurveillanceforpregnancy

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