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Teratogenicity in relation to Dolutegravir Ushma Mehta, Pharm.D, DrPH Centre for Infectious Disease Epidemiology and Research (CIDER) School of Public Health and Family Medicine University of Cape Town

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Page 1: Teratogenicity in relation to Dolutegravir · Teratogenicity in relation to Dolutegravir UshmaMehta, Pharm.D, DrPH Centre for Infectious Disease Epidemiology and Research (CIDER)

TeratogenicityinrelationtoDolutegravir

Ushma Mehta,Pharm.D,DrPHCentreforInfectiousDiseaseEpidemiologyandResearch(CIDER)

SchoolofPublicHealthandFamilyMedicineUniversityofCapeTown

Page 2: Teratogenicity in relation to Dolutegravir · Teratogenicity in relation to Dolutegravir UshmaMehta, Pharm.D, DrPH Centre for Infectious Disease Epidemiology and Research (CIDER)

Outline

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

Page 3: Teratogenicity in relation to Dolutegravir · Teratogenicity in relation to Dolutegravir UshmaMehta, Pharm.D, DrPH Centre for Infectious Disease Epidemiology and Research (CIDER)

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

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

Page 4: Teratogenicity in relation to Dolutegravir · Teratogenicity in relation to Dolutegravir UshmaMehta, Pharm.D, DrPH Centre for Infectious Disease Epidemiology and Research (CIDER)

“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

Page 5: Teratogenicity in relation to Dolutegravir · Teratogenicity in relation to Dolutegravir UshmaMehta, Pharm.D, DrPH Centre for Infectious Disease Epidemiology and Research (CIDER)

FetaleffectsnotjustmalformationsEffect Examplesof causesSpontaneous AbortionandStillbirth Maternaldiabetes

Intrauterine growthretardation AlcoholMajor andminoranomalies Phenytoin,sodiumvalproate,

warfarinDevelopmental problems Sodium valproate,leadAbruptio placenta cocaineCancer Diethylstilboestrol

Socialbehaviour Alcohol

AdaptedfromslidebyProfLewisB.Holmes

Page 6: Teratogenicity in relation to Dolutegravir · Teratogenicity in relation to Dolutegravir UshmaMehta, Pharm.D, DrPH Centre for Infectious Disease Epidemiology and Research (CIDER)

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

Page 7: Teratogenicity in relation to Dolutegravir · Teratogenicity in relation to Dolutegravir UshmaMehta, Pharm.D, DrPH Centre for Infectious Disease Epidemiology and Research (CIDER)

Shepard’s“Criteriaforproofofhumanteratogenicity”

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

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

SlideAcknowledgement– ProfessorLewisHolmes

Page 8: Teratogenicity in relation to Dolutegravir · Teratogenicity in relation to Dolutegravir UshmaMehta, Pharm.D, DrPH Centre for Infectious Disease Epidemiology and Research (CIDER)

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

Page 9: Teratogenicity in relation to Dolutegravir · Teratogenicity in relation to Dolutegravir UshmaMehta, Pharm.D, DrPH Centre for Infectious Disease Epidemiology and Research (CIDER)

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

Page 10: Teratogenicity in relation to Dolutegravir · Teratogenicity in relation to Dolutegravir UshmaMehta, Pharm.D, DrPH Centre for Infectious Disease Epidemiology and Research (CIDER)

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.

Page 11: Teratogenicity in relation to Dolutegravir · Teratogenicity in relation to Dolutegravir UshmaMehta, Pharm.D, DrPH Centre for Infectious Disease Epidemiology and Research (CIDER)

AssociationinTime:GestationalTiming

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

Neuraltubedevelopsandclosesbyday26- 30postfertilisation

Periodofrisk:Earlyfirsttrimester

Exposuresinitiatedafterthisperiodcannotbeimplicated(andhaven’tbeenimplicated)

LMPorgestationaltiming– oftennotknown

Page 12: Teratogenicity in relation to Dolutegravir · Teratogenicity in relation to Dolutegravir UshmaMehta, Pharm.D, DrPH Centre for Infectious Disease Epidemiology and Research (CIDER)

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

Page 13: Teratogenicity in relation to Dolutegravir · Teratogenicity in relation to Dolutegravir UshmaMehta, Pharm.D, DrPH Centre for Infectious Disease Epidemiology and Research (CIDER)

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

Page 14: Teratogenicity in relation to Dolutegravir · Teratogenicity in relation to Dolutegravir UshmaMehta, Pharm.D, DrPH Centre for Infectious Disease Epidemiology and Research (CIDER)

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

Page 15: Teratogenicity in relation to Dolutegravir · Teratogenicity in relation to Dolutegravir UshmaMehta, Pharm.D, DrPH Centre for Infectious Disease Epidemiology and Research (CIDER)

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

Page 16: Teratogenicity in relation to Dolutegravir · Teratogenicity in relation to Dolutegravir UshmaMehta, Pharm.D, DrPH Centre for Infectious Disease Epidemiology and Research (CIDER)

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/

Page 17: Teratogenicity in relation to Dolutegravir · Teratogenicity in relation to Dolutegravir UshmaMehta, Pharm.D, DrPH Centre for Infectious Disease Epidemiology and Research (CIDER)

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

Page 18: Teratogenicity in relation to Dolutegravir · Teratogenicity in relation to Dolutegravir UshmaMehta, Pharm.D, DrPH Centre for Infectious Disease Epidemiology and Research (CIDER)

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

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

Page 19: Teratogenicity in relation to Dolutegravir · Teratogenicity in relation to Dolutegravir UshmaMehta, Pharm.D, DrPH Centre for Infectious Disease Epidemiology and Research (CIDER)

Conclusion

• WearenotyetcertainthatDTGisateratogen• Needconsistencyoffindingsacrossstudies• Biggernumbers– SAisreadytocontribute

• Challengesincommunicatingrisk-benefitinthepresenceofsuchuncertainty

• Howtoimprovepartnershipwithclientsindecision-making?

• Requireinvestmentinrobustpost-marketingsurveillanceforpregnancy

Page 20: Teratogenicity in relation to Dolutegravir · Teratogenicity in relation to Dolutegravir UshmaMehta, Pharm.D, DrPH Centre for Infectious Disease Epidemiology and Research (CIDER)

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

Page 21: Teratogenicity in relation to Dolutegravir · Teratogenicity in relation to Dolutegravir UshmaMehta, Pharm.D, DrPH Centre for Infectious Disease Epidemiology and Research (CIDER)