Rasi, Virginia; (2021) Use and safety of antiretrovirals in pregnancy: filling the gap between regulatory recommendation and clinical practice. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Antiretroviral therapy (ART) contributed enormously to the reduction of HIV vertical transmission rate whilst treating maternal disease. Nowadays the proportion of women living with HIV (WLWH) knowing their HIV status and conceiving whilst being on effective combination of antiretroviral agents (ARVs) has stabilized at high level. However, early treatment initiation means prolonged infants in utero exposure to ARVs and consequent potential toxic effect to the developing embryo (i.e. congenital anomalies) and adverse pregnancy outcomes (including stillbirths and preterm delivery). Aim of this thesis was to evaluate safe and effective use of ARVs in pregnant WLWH, to evaluate pregnancy outcomes - with a main focus on detection of congenital anomalies (CAs), and to assess whether early exposure to combinations of ARV was associated with increased risk for CAs. Furthermore, a gap-analysis evaluating real-world use of ARVs and regulatory recommendation for the safe and effective use of ARV agents was conducted. I used data from the National Surveillance of HIV in Pregnancy and Childhood (NSHPC), an ongoing surveillance study of all pregnancies in WLWH and their infants across the UK/Ireland. The analysis included data on pregnancies reported to the NSHPC from 2008 to 2018. For the gap-analysis, I have assessed publicly available data from the European Medicines Agency through their website as source for regulatory recommendations, while the NSHPC was the data source for the real-world use of ARV agents. This thesis identified three main findings: an increased earlier use in pregnancy and from before conception of combinations of ARV (34.5%, 412/1,194 of pregnancies in 2008 started ART prior conception vs 80.6%, 478/593 in 2018) and a wider range of available ARV combinations for pregnant WLWH in the UK between 2008-2018. A gap between real-world use of ART and regulatory/clinical recommendations for pregnant WLWH, with regulatory recommendation “catching up” with real-world use of ARVs and only in recent years timely amended their guidelines whenever a safety signal from the real-world evidence has been detected. No evidence of increased risk of CAs in infants with in utero exposure to ART with an overall CA prevalence of 2.03% (95%CI 1.77-2.31, 227 CA/111,197 liveborn infants) nor of any particular patterns of CAs affecting the same organs/systems by the rule of three.

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