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REPORTS OF NEURALTUBE DEFECTS FOR 8 ARTS, IN FDA, WHO, EMA, AND UK SAFETY DATABASES
Andrew Hill1, Nikolien S. van de Ven2, Anton Pozniak3, Jacob A. Levi4, Anna Garratt5, Christopher Redd5, Lynne Mofenson6
1Liverpool School of Tropical Medicine, Liverpool, UK,2London School of Hygiene & Tropical Medicine, London, UK,3Chelsea and Westminster Hospital, London, UK,4Chelsea and Westminster NHS Foundation Trust, London, UK,5Imperial College Healthcare NHS Trust, London, UK,6Elizabeth Glaser Pediatric AIDS Foundation, Washington, DC, USA
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.
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
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 from multiple 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
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.