Pharmacokinetics, safety and efficacy study in pregnancy and existing cumulative data/evidence to support clinical use and labelling of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in pregnant women with HIV

Abstract

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Pharmacokinetics, safety and efficacy study in pregnancy and existing cumulative data/evidence to support clinical use and labelling of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in pregnant women with HIV

Dhananjay Marathe, Priyanka Arora, Haeyoung Zhang, Jason Hindman, Hui Liu, Sandhya Girish, Casey Davis and Ramesh Palaparthy

Gilead Sciences, Inc

Background: Safe, effective and convenient treatment options are needed for pregnant women with HIV. Bictegravir is metabolized by uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) and cytochrome P450 3A4 (CYP3A4). Pregnancy is associated with physiological changes, including increased CYP3A4 and UGT1A1 activities; however, limited data exist on the pharmacokinetics, safety and efficacy of B/F/TAF during pregnancy.

Material and methods: An open-label study (NCT03960645) was conducted in virologically suppressed pregnant women with HIV-1 (n = 33). Steady-state plasma pharmacokinetic samples were collected over 24 h following once-daily oral B/F/TAF dosing during second/third trimesters of pregnancy and postpartum. Bictegravir exposure parameters during pregnancy and postpartum were compared and contextualized with prior pooled phase 3 data in non-pregnant participants. Plasma HIV-1 RNA/DNA was measured in mothers and their neonates. Efficacy response was calculated as the proportion of mothers with HIV-1 RNA < 50 copies/mL (missing = excluded) at delivery. Exposure-efficacy response (E-R) relationships were visualized and contextualized using pooled phase 3 data. Literature evidence from contemporary studies of B/F/TAF in different populations was collated for additional comparisons.

Results: While plasma bictegravir AUC_tau was lower (~59%) during pregnancy than postpartum, the difference was less pronounced when compared to non-pregnant adults with HIV (~40%). Bictegravir AUC_tau was similar during second and third trimesters. Mean bictegravir Ctrough was >6 × inhibitory quotient (IQ)1 during pregnancy. All pregnant women maintained virologic suppression (VS), with HIV-1 RNA < 50 copies/mL at delivery (n = 32 [100%]) and no observed virologic failure or treatment-emergent resistance. B/F/TAF was well tolerated, with no adverse events (AEs) leading to premature discontinuation; AEs were consistent with those expected in this pregnant population. No cases of perinatal HIV transmission in neonates (n = 29) occurred. E-R relationship visualizations for once-daily B/F/TAF showed robustly high and plateaued responses over a large exposure range. Current literature is supportive of these data. In IMPAACT 2026 [1], similar efficacy/safety and bictegravir exposure changes during pregnancy were described in a different demographic population. In the INSIGHT trial [2], co-administration of twice-daily B/F/TAF with a rifampicin-based tuberculosis regimen in adults with HIV and tuberculosis showed continued robust efficacy (~97%) at week 24 despite much lower mean trough bictegravir exposures (~2.5 × IQ1).

Conclusions: Despite lower bictegravir exposures during pregnancy, all mothers maintained VS, and B/F/TAF was generally well tolerated, which suggests appropriateness of B/F/TAF use during pregnancy with no need for dose adjustments. E-R analysis and existing literature evidence further support the likelihood of robust efficacy at the bictegravir exposures observed in pregnancy. Based on our pregnancy study data [3], the US Department of Health and Human Services perinatal guidelines were updated (31 January 2024) to include bictegravir as an alternative integrase strand transfer inhibitor in certain groups of pregnant people and non-pregnant people who are trying to conceive. Furthermore, these data and the evidence from IMPAACT 2026 and INSIGHT supported the recent (2024) FDA approval and labelling of B/F/TAF for pregnant subpopulation.

References:

[1] Powis, KM, et al. CROI 2023. Poster 783.

[2] Naidoo, A. CROI 2024, Oral 211.

[3] Zhang, H, Hindman, J.T., Lin, L., Davis, M., Shang, J., Xiao, D., Avihingsanon, A., Arora, P., Palaparthy, R., Girish, S., Marathe, D.D. Aids 2024; 38(1): F1–9, A study of the pharmacokinetics, safety, and efficacy of bictegravir/emtricitabine/tenofovir alafenamide in virologically suppressed pregnant women with HIV, DOI: 10.1097/QAD.0000000000003783.