Abstract and Introduction
Background: Tenofovir alafenamide (TAF) is a key component of HIV treatment, but pharmacokinetic data supporting the use of TAF during pregnancy are limited. In this study, we report pharmacokinetic, safety, and birth outcomes for TAF 25 mg with a boosted protease inhibitor in pregnant women living with HIV.
Methods: IMPAACT P1026s was a multicenter, nonrandomized, open-label, phase IV prospective study. Pregnant women living with HIV receiving TAF 25 mg with a boosted protease inhibitor were eligible. Intensive pharmacokinetic assessments were performed during the second and third trimesters and 6–12 weeks postpartum. Maternal and cord blood samples were collected at delivery. Infant washout samples were collected through 5–9 days postbirth. Comparisons of paired pharmacokinetic data between pregnancy and postpartum were made using geometric mean ratios (GMR) [90% confidence intervals (CIs)] and Wilcoxon signed-rank tests with P < 0.10 considered significant.
Results: Twenty-nine women were enrolled from the United States (median age 31 years and weight 84.5 kg during the third trimester; 48% Black, 45% Hispanic/Latina). TAF AUCtau did not significantly differ in the second [GMR 0.62 (90% CI: 0.29 to 1.34); P = 0.46] or third trimester [GMR 0.94 (90% CI: 0.63 to 1.39); P = 0.50] vs. postpartum and were comparable with historical data in nonpregnant adults. TAF was only quantifiable in 2/25 maternal delivery samples and below the limit of quantification in all cord blood and infant washout samples, likely because of the short half-life of TAF.
Conclusion: TAF AUCtau did not significantly differ between pregnancy and postpartum. These findings provide reassurance as TAF use during pregnancy continues to expand.
Tenofovir is a key component of several recommended HIV regimens.[1–5] Tenofovir is available as 2 different prodrugs: tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF). Both prodrugs yield the same active moiety, tenofovir diphosphate, within cells, but the pharmacology and safety profiles of the 2 drugs differ markedly.[6–10] TDF is administered at a 300-mg dose in adults and adolescents with HIV. TAF dosing varies depending on the concomitant antiretroviral medications and region of use: In the United States, it is administered as either a 10-mg dose in cobicistat-containing fixed-dose combinations[12,13] or a 25-mg dose with all other antiretroviral combinations in adults, and in Europe, TAF is administered as a 10-mg dose with all cobicistat-containing or ritonavir-containing regimens and 25 mg without a pharmacoenhancer. TAF yields ~75%–90% lower plasma tenofovir area under the concentration–time curve over the dosing interval (AUCtau) and ~2-fold–10-fold higher tenofovir-diphosphate concentrations in peripheral blood mononuclear cells.[7,8,10] In recent years, patterns of clinical use have shifted toward TAF-containing regimens in the United States, and this will likely increase globally as access expands.[3,17] However, data supporting TAF use during pregnancy have lagged behind nonpregnant adults, with guidelines only recently conditionally recommending its use.[1,5]
One of the primary concerns with using antiretroviral drugs in pregnant women living with HIV (PWLH) is that drug exposures may differ and be too low to adequately suppress viral replication, leading to virologic failure and/or resistance in the PWLH and an increased risk of perinatal HIV transmission. The safety of newer medications in PWLH and infants are also critical to assess. We previously showed that TAF AUCtau did not significantly differ between pregnancy and postpartum when administered as a 10-mg dose with cobicistat but were higher postpartum in comparison with pregnancy when administered at a 25-mg dose without boosters. The PANNA network reported a similar magnitude of difference between pregnancy and postpartum with pooled pharmacokinetic results from these same dose combinations. TAF AUCtau during pregnancy and postpartum in both arms of the IMPAACT P1026s study were comparable or higher than historical AUCtau in nonpregnant adults. Separately, the International Maternal Pediatric Adolescent AIDS Clinical Trial Network (IMPAACT) 2010/VESTED study showed the combination of dolutegravir with TAF/emtricitabine was associated with lower rates of adverse pregnancy outcomes vs. TDF-containing comparator regimens and was also associated with higher rates of virologic suppression in comparison with efavirenz/TDF/emtricitabine. Collectively, these findings provide reassurance that plasma TAF AUCtau during pregnancy is likely adequate and that TAF-containing regimens will become additional safe and effective treatment options in PWLH.
Although available data for TAF 10 mg with cobicistat and TAF 25 mg without boosting suggests that TAF AUCtau is likely adequate in pregnancy,[18,19] TAF is also licensed for administration at a 25-mg dose in combination with emtricitabine when given as a separate product along with a protease inhibitor (PI) boosted with either ritonavir or cobicistat in the United States. There are currently no pharmacokinetic data with this combination during pregnancy and postpartum. In nonpregnant adults, coadministration of TAF 25 mg with a boosted PI may increase plasma TAF exposure by up to 135% depending on the specific concomitant booster and PI. Ritonavir-boosted atazanavir and darunavir are preferred PI regimens during pregnancy; thus, it is critical to understand the pharmacokinetics (PK) of TAF 25 mg when coadministered with boosted PIs. The primary objective of this study was to characterize the PK of TAF when administered at a 25-mg dose in combination with boosted PIs during pregnancy and postpartum. Primary outcomes included comparisons of TAF PK between pregnancy and postpartum and with historical data in nonpregnant adults living with HIV. Secondary objectives were to examine transplacental TAF transfer and describe maternal and infant safety and clinical outcomes.
J Acquir Immune Defic Syndr. 2022;90(3):343-350. © 2022 Lippincott Williams & Wilkins