Pregnancy outcomes and pharmacokinetics in pregnant women living with HIV exposed to long‐acting cabotegravir and rilpivirine in clinical trials

Abstract

Background Limited data exist on pregnant women living with HIV exposed to cabotegravir + rilpivirine (CAB + RPV). Outcomes in pregnant participants exposed to CAB + RPV, and pharmacokinetic washout data in those exposed to CAB + RPV long‐acting (LA) with live births, are presented. Methods Women exposed to one or more doses of CAB + RPV (oral/LA) from ViiV Healthcare‐sponsored phase 2b/3/3b clinical trials and the compassionate use programme who became pregnant were included. Upon pregnancy in the trial programme, CAB + RPV was discontinued, an alternative antiretroviral regimen was initiated, and quarterly pharmacokinetic sampling for 52 weeks post‐last injection was obtained. CAB + RPV continuation or alternative antiretroviral regimen initiation was decided by pregnant compassionate use programme participants and their treating physicians. Results As of 31 March 2021, 25 pregnancies following CAB + RPV exposure at conception were reported (five oral, 20 LA), including four who conceived during pharmacokinetic washout following treatment discontinuation. There were eight elective abortions, six miscarriages (five in first trimester), one ectopic pregnancy, and 10 live births (one oral, nine LA), including one infant born with congenital ptosis. Among participants exposed to CAB + RPV LA at conception with live births, plasma CAB and RPV washout concentrations during pregnancy were within the range of those observed in non‐pregnant women. Conclusion In this first analysis of pregnancy outcomes following CAB + RPV exposure at conception, 10 live births, including one with congenital anomaly, were reported. Plasma CAB and RPV washout concentrations during pregnancy were within the range of those in non‐pregnant women. Pregnancy surveillance within ViiV Healthcare‐sponsored clinical trials is ongoing, with dedicated pregnancy studies planned.

Cabotegravir Exposure of Zebrafish (Danio rerio) Embryos Impacts on Neurodevelopment and Behavior

“…Previous data from studies on embryo-fetal CAB safety performed in rats and rabbits did not disclose any alterations, except for a decrease in the offspring weight [13]. More recently, a first analysis evaluating pregnancy outcomes in 25 women exposed to CAB at the time of conception found a rate of spontaneous abortions of 24%; however, this may be explained considering that CAB-treated women were more frequently tested for pregnancy in order to discontinue the treatment and switch to an alternative antiviral therapy and, as a consequence, very early pregnancies (then with a higher risk of abortion) were identified [17]. Typically, pregnant women are excluded from enrollments in drug clinical trials and women of childbearing potential are required to use effective method of contraception.…”

Clinical trial simulation to evaluate tenofovir disoproxil fumarate/emtricitabine HIV pre-exposure prophylaxis dosing during pregnancy

“…Although there are safety and PK data for HIV treatment in cisgender women, including during pregnancy, tenofovir alafenamide (TAF)/FTC is not yet recommended in cisgender women for PrEP given the lack of efficacy data. There are only limited safety and PK data for long-acting Cabotegravir in pregnancy ( 38 , 39 ) and although there are reassuring safety data on the use of the Dapivirine ring in pregnancy ( 40 , 41 ), its approval is limited globally. Decreased protective efficacy of TDF/FTC PrEP during pregnancy due to lower TFV and FTC exposures, as indicated in the clinical trial simulation, is cause for considerable concern, especially as the baseline HIV incidence among pregnant and postpartum women is two to four times that of non-pregnant women ( 42 , 43 ).…”

Clinical Trials That Have Changed Clinical Practice and Care of Pregnant People With HIV

“…Pregnant PWH may face the same challenges in addition to the added pregnancy-specific challenges of early pregnancy nausea and vomiting or hyperemesis gravidarum that can affect oral ART adherence. However, the long-acting CAB/RPV formulation is categorized as not recommended for use as an initial regimen in pregnancy by the Panel due to insufficient data on PK, toxicity, and efficacy during pregnancy 21,66 . Highlighted by the preceding findings from the IMPAACT 2010/VESTED trial and with several newer INSTIs now available, PWH need safe and effective treatment during pregnancy, and further clinical trials are imperative to evaluate novel ART agents.…”