Cabotegravir (CAB) is a long-acting (LA) HIV integrase inhibitor in Phase 3 development for HIV treatment in combination with rilpivirine LA, and as monotherapy for HIV prevention. Injectable CAB LA, given monthly or every 2 months, maintains plasma concentrations that may persist for a year or longer following discontinuation. Nonclinical reproductive toxicology studies of CAB have not identified a birth defect risk at supratherapeutic exposures. We evaluated CAB pharmacokinetics (PK) in HIV-infected women becoming pregnant and neonatal outcomes to date in ViiV-Sponsored trials.
As of December 7, 2018, ≥ 594 HIV-infected or un-infected females of reproductive potential have been exposed to ≥1 dose of CAB (oral/LA) through Phase 3 in ViiV-sponsored clinical trials. Per protocol, CAB troughs were obtained pre-injection with dosing discontinued upon pregnancy detection, however PK sampling continued quarterly for 52 weeks after last injection. Available CAB PK collected pre-pregnancy and during long term follow-up to evaluate the PK tail during pregnancy, delivery, and post-partum were summarized with birth outcomes.
Thirteen pregnancies were reported during CAB dosing (4 oral CAB; 9 CAB LA), 4 resulting in live births (1 in DAIDS HPTN077 study; conception post CAB LA discontinuation), 5 terminated electively, and 4 with miscarriage in first 9 weeks of gestation. No cases of birth defects have been reported. Three HIV-infected women receiving CAB LA 400mg IM monthly injections (range: 16-176 weeks on therapy) became pregnant with subsequent live birth outcomes. All were virologically suppressed with pre-dose CAB concentrations of 2.41-4.63 µg/mL just prior to pregnancy and 2.10-5.04 µg/mL at time of pregnancy confirmation. Following CAB LA discontinuation, residual CAB concentrations remained measurable throughout pregnancy with a predicted concentration of ~0.5 µg/mL(3x PA-IC90 [0.166 µg/mL]) at delivery and remaining detectable post-partum (range: 2-23 weeks) in 2/3 women.These data are consistent with absorption-rate limited PK.
Pre-pregnancy CAB trough concentrations were consistent with population estimates for monthly dosing and declined slowly following drug discontinuation in pregnancy with predicted concentration 3x PA-IC90 at time of delivery in 2 of 3 HIV-infected women with live birth outcomes. CAB PK tail in pregnancy was within the expected range for non-pregnant women. Pregnancy surveillance in the treatment and prevention program continues.