CROI 2019 Abstract eBook

Abstract eBook

Poster Abstracts

compared to males with site as an effect modifier [AOR of 5.9 (95%CI:1.9-17.9), p=0.002]. Conclusion: NTDs are a common congenital malformation affecting births in Kampala. These findings are similar to the current estimates for Africa. ART was not associated with an increased risk for NTDs. With the introduction of new ART regimens during pregnancy, ongoing BD surveillance is critical. 744 NO INCREASE IN BIRTH DEFECTS IN INFANTS EXPOSED TO INTEGRASE INHIBITORS AT CONCEPTION Jeanne Sibiude 1 , Jérôme Le Chenadec 2 , Laurent Mandelbrot 1 , Stephane Blanche 3 , Catherine Dollfus 4 , Nathalie Lelong 5 , Elisa Arezes 6 , Lamya Ait Si Selmi 2 , Sophie Matheron 7 , Christine Rouzioux 8 , Josiane Warszawski 6 , Roland Tubiana 9 , for the ANRS-EPF-CO1/CO11 study groups 1 Hôpital Louis-Mourier, Colombes, France, 2 INSERM, Le Kremlin-Bicetre, France, 3 AP–HP, Paris, France, 4 Hôpital Armand-Trousseau, Paris, France, 5 INSERM, Paris, France, 6 University of Paris-Sud, Orsay, France, 7 AP–HP, Hôpital Bichat- Claude Bernard, Paris, France, 8 Necker Hospital, Paris, France, 9 AP–HP, Hôpitaux Universitaires Pitié Salpêtrière, Paris, France Background: Integrase inhibitors (InSTI) are increasingly used by HIV-infected women during pregnancy. Following an alert on the association of dolutegravir with neural tube defects, we evaluated the risk of birth defects in case of exposure to this antiretroviral class. Methods: The French Perinatal Cohort is a multicenter national cohort including all HIV-infected women in 90 maternities. We studied all mother- infant pairs exposed to InSTI, categorized into 3 groups: (G1) ongoing at conception, (G2) initiated during pregnancy, as first-line regimen, and (G3) initiated during pregnancy, as 2nd-line regimen. Within each group, we matched 1:1 to an InSTI-unexposed infant according to other drugs, ethnicity, center, year of delivery, and gestational age at ART-initiation. InSTI exposed women who did not receive PI or NNRTI were matched to women receiving darunavir, with the same other drugs. We compared birth defect rates between the 3 InSTI-exposed groups and, for each group, with the respective matched group, using chi2 and McNemar tests. Results: Overall, 309 infants were exposed to InSTI at conception (G1): 224 to raltegravir, 41 to dolutegravir, and 44 to elvitegravir. Birth defects rates for InSTI-exposed infants at conception (G1: 5.5% 17/309) did not significantly differ from those of InSTI-exposed infants of the two other groups: 2.7% (5/184) in G2 and 3.0% (10/329) in G3, p=0.18. There was no neural tube defect among infants exposed to InSTI at conception, and only two birth defects among the 41 infants exposed to dolutegravir (a case of Down syndrome, and a persistant ductus arteriosus). When restricting to matched infants, birth defect rates in G1 were not significantly different from the matched InSTI-unexposed group (6,3%, 12/189 vs 3,7%, 7/189, respectively, p=0.26). The EUROCAT types of birth defects were similar for InSTI-exposed at conception and matched infants. There was no difference in stillbirth rates (1.8% vs 0.4%, p=0.37), nor in preterm birth rates (14.3% vs 10.8%, p=0.29) between pregnancies exposed at conception and the matched pregnancies. Among women exposed at conception, 65%were still receiving InSTI at delivery. Similarly, there was no difference in birth defect rates between InSTI-exposed infants in G2 and G3 and the matched unexposed infants. Conclusion: We found no evidence of a higher birth defect rate among 309 infants exposed to InSTI at conception, mostly exposed to raltegravir, however in the current context, surveillance must be pursued for this class of ART. 745 EVALUATION OF NEURAL TUBE DEFECTS AFTER EXPOSURE TO RALTEGRAVIR DURING PREGNANCY Hala H. Shamsuddin , Casey L. Raudenbush, Brittany L. Sciba, Yun-Ping Zhou, T. Christopher Mast, Wayne L. Greaves, George J. Hanna, Ronald Leong, Walter L. Straus Merck Research Labs, North Wales, PA, USA Background: The purpose of this comprehensive review is to evaluate the risk of neural tube defects (NTDs) after exposure to raltegravir during pregnancy. Methods: Exposures to raltegravir during pregnancy reported cumulatively through 31-May-2018 to the company safety database were reviewed. This database includes all reports of pregnancy fromMerck-sponsored clinical trials, spontaneous post-marketing and non-interventional data sources, including the Antiretroviral Pregnancy Registry (APR). Reports were classified as prospective (exposure report prior to knowledge of pregnancy outcome) or retrospective (report after knowledge of pregnancy outcome). Pregnancy

reports were further reviewed to identify cases of NTDs. We also reviewed data from two ongoing pregnancy cohorts. Results: A total of 2426 pregnancies with reported outcomes were identified among women exposed to raltegravir: 1238 from the Merck safety database and 1188 from United Kingdom/Ireland and French pregnancy cohorts. Among all 2426 pregnancy reports, 1991 were prospective. No cases of NTDs were identified among the prospective pregnancy reports, of which 767 were first trimester, including 456 in the periconception period (at or within 28 days after conception). Among the 435 retrospective reports, four NTD cases per APR criteria were identified, of which only one (myelomeningocele) was among exposures in the periconception period. Given the inherent limitations and bias of retrospective reports, it is not appropriate to calculate an incidence rate. Conclusion: Prospectively collected pregnancy outcome data do not suggest an association between raltegravir exposure in the periconception period and NTDs. 746 REPORTS OF NEURALTUBE DEFECTS FOR 8 ARTS, IN FDA, WHO, EMA, AND UK SAFETY DATABASES Andrew Hill 1 , Nikolien S. van de Ven 2 , Anton Pozniak 3 , Jacob A. Levi 4 , Anna Garratt 5 , Christopher Redd 5 , Lynne Mofenson 6 1 Liverpool School of Tropical Medicine, Liverpool, UK, 2 London School of Hygiene & Tropical Medicine, London, UK, 3 Chelsea and Westminster Hospital, London, UK, 4 Chelsea and Westminster NHS Foundation Trust, London, UK, 5 Imperial College Healthcare NHS Trust, London, UK, 6 Elizabeth Glaser Pediatric AIDS Foundation, Washington, DC, USA Background: The Botswana TSEPAMO study reported neural tube birth defects (NTDs) in 4/596 (0.67%) infants of women receiving dolutegravir (DTG) antiretroviral therapy (ART) preconception vs 14/11,300 (0.12%) receiving preconception non-DTG ART. Further data are required to confirm or refute this potential safety signal. Pregnant women were excluded from Phase 3 randomised DTG trials and data from other observational studies of DTG in pregnancy are currently limited. Clinicians, patients and pharmaceutical companies can report adverse drug reactions (ADRs) to pharmacovigilance (PV) databases, which could be used to assess potential safety signals. Methods: 4 PV databases with online data availability were analysed for NTD reports for 4 integrase inhibitors (DTG, raltegravir, elvitegravir, bictegravir), two protease inhibitors (darunavir, atazanavir) and two non-nucleosides (nevirapine, efavirenz): 1. Food and Drug Administration FAERS database (USA) 2. World Health Organisation VigiAccess (WHO) 3. European EudraVigilance (EU), 4. UK Medicines Health Regulatory Authority (MHRA). ADR reports in the System Organ Class (SOC) “Congenital or Familial Disorders” were searched for NTDs using the search terms Neural Tube Defect, spina bifida, meningocele, meningomyelocele, anencephaly, iniencephaly, and encephalocele Results: NTDs were reported for all drugs except bictegravir. The number of reported NTD cases with DTG exposure were similar in the FDA and WHO databases, but no cases were reported to EU and UK MHRA (Table 1). Since ART consists of multiple drugs, NTDs could be reported for multiple drugs and frommultiple sources for the same patient; for example, for one patient in the FDA database, there were 91 NTD reports for the same patient who received 7 different drugs Conclusion: PV databases included reports of NTDs for pregnant women taking a wide range of ARVs. These databases have many limitations – there is no denominator for patient exposure to the drug, reporting is not systematic, there is overlap in reports for multiple drugs given combination ART, duplicate cases are difficult to identify, and results differ between the databases. Given widespread use of multiple new ARVs worldwide, and anticipated use of new drugs (e.g. TAF, bictegravir cabotegravir), prospective follow up of pregnant women and birth surveillance studies such as Tsepamo are critically needed for a wide range of ARVs. In addition, pregnant women should be enrolled in Phase 3 trials where regulations allow.

Poster Abstracts

CROI 2019 287