Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions to Reduce Perinatal HIV Transmission in the United States

Integrase Inhibitors

Bictegravir (BIC)

Summary

• No dose adjustment for bictegravir (BIC) is recommended in pregnancy.
• First-trimester exposure to BIC has not been associated with an increased risk of congenital anomalies.

Human Studies in Pregnancy

Pharmacokinetics

BIC pharmacokinetics (PK) during pregnancy have been reported in two clinical studies,^1,2 a case series,^3,4 and one case report.⁵ 

IMPAACT 2026⁶ evaluated the PK of BIC among 27 pregnant women, which showed that total BIC area under the curve (AUC) was decreased by 46% to 52%; the concentrations at 24 hours postdose (C_24h) were 62% to 68% lower during pregnancy compared to postpartum.¹ Seven of 12 (58%) participants during the second trimester and 13 of 21 (62%) during the third trimester fell below the 10th percentile AUC for nonpregnant adults, but none of these women had a detectable viral load. All C_24h values across the second and third trimesters were above the BIC protein-adjusted 95% maximal effective concentration (EC₉₅) of 0.162 ug/mL, with median values approximately sevenfold and 5.9-fold above the EC₉₅.¹ Because BIC is highly protein bound and pregnancy can be associated with decreased plasma protein binding, unbound drug concentrations were also assessed.  Compared with postpartum, the percent unbound was 45% and 42% higher in the second and third trimesters, respectively. However, median unbound BIC concentrations remained lower during pregnancy (3.83 ng/mL and 3.01 ng/mL for the second and third trimesters, respectively, compared to 5.83 ng/mL during postpartum). Virologic suppression (<40 copies/mL) was maintained in 88% to 92% of participants across pregnancy, birth, and postpartum, and no confirmed infant HIV infections occurred among the 26 for whom data are available.

A separate study² in 33 pregnant women showed that total BIC AUC was approximately 56% to 59% lower, and BIC trough concentrations (C_trough) were approximately 70% to 74% lower during the second or third trimester compared to 6 or 12 weeks postpartum. Total BIC AUC in the pregnant women was 41% lower during the third trimester compared with historical data in nonpregnant adults with HIV. The AUC for unbound BIC was approximately 38% to 41% lower during pregnancy than postpartum. The mean unbound fractions were higher during pregnancy than postpartum (0.351% and 0.365% during the second and third trimester, respectively, compared with 0.261% and 0.252% at 6 and 12 weeks postpartum, respectively). Mean C_trough values during the second and third trimesters were about 6.5-fold above the BIC protein-adjusted EC₉₅, and all but one individual C_trough value was above this threshold. All women maintained virologic suppression (<50 copies/mL) through Week 18 postpartum, including at birth, and no infant HIV infections occurred.

Collectively, these findings demonstrate that despite lower AUC and C_24h or C_trough values during pregnancy, drug exposures were still above those needed to maintain virologic suppression when using standard BIC doses, and thus no dose adjustment is recommended. Separate large cohort studies have also demonstrated rates of virologic suppression (<50 copies/mL) of approximately 82% to 91% through birth with BIC/tenofovir alafenamide/emtricitabine.⁷

Placental and Breast Milk Passage

Placental transfer of BIC is high, with a mean/median umbilical cord blood–to–maternal plasma ratio of approximately 1.4 at birth.^1,2 The estimated median half-life in neonates based on washout data is prolonged in comparison to adults, with one study estimating 43 hours (interquartile range 38–58; n = 10)² and another estimating 33 hours (interquartile range 26–46; n = 25).¹ These umbilical cord blood–to–maternal plasma ratios are comparable to a previous case series in which ratios of 1.49 were measured in one patient 20 hours after BIC dosing and 1.42 in another patient 7 hours after BIC dosing.³ A separate case report conveyed an umbilical cord blood–to–maternal plasma ratio of 0.68 approximately 16 hours after BIC dosing.⁴ The concentration of BIC was 2,826 ng/mL in cord blood at birth, 2,097 ng/mL in the infant on Day 3 after birth, and undetectable (<5 ng/mL) in the infant by Day 22.

Data on the passage of BIC in human breast milk are very limited. BIC milk-to-plasma ratios have only been reported in one woman, which revealed a ratio of 0.01 and subsequent estimated infant daily dose of 0.01 mg/kg.⁸ Additional data are needed to refine our understanding of the breast milk passage of BIC.

Teratogenicity/Adverse Pregnancy Outcomes

The Antiretroviral Pregnancy Registry (APR) provides updated birth defect data for BIC and other antiretroviral (ARV) drugs twice a year through an interim report released in June and December. The APR has monitored sufficient numbers of first-trimester exposures to BIC to detect at least a twofold increase in the risk of overall birth defects. No such increase in the risk of birth defects has been observed with BIC. Figure 1. Summary of Birth Defects Among First Trimester Exposures in the APR interim report provides a summary of the number and prevalence of birth defects per live births among cases of first-trimester exposure to BIC and other ARV drugs reported to the APR where there are sufficient data to determine 95% confidence intervals. The data in Figure 1 can be compared with the prevalence of birth defects in the U.S. population (2.72 birth defects per 100 live births) based on the Centers for Disease Control and Prevention surveillance system (The Metropolitan Atlanta Congenital Defects Program [MACDP]) and with the Texas Birth Defects Registry ([TBDR] 4.17 per 100 live births).

Separate, smaller retrospective studies with sample sizes of approximately 50 to 150 participants have also reported pregnancy outcomes with BIC and have not identified higher rates of congenital anomalies with exposure occurring during the first trimester^7,9 or at any time during pregnancy.¹⁰

Animal Studies

Carcinogenicity

BIC has not been shown to be genotoxic or mutagenic in vitro.¹¹

Reproduction/Fertility

BIC did not affect fertility, reproductive performance, or embryonic viability in male or female rats at exposures (based on AUC) that were 29 times higher than those observed in humans who received the recommended dose.¹¹

Teratogenicity/Adverse Pregnancy Outcomes

No adverse embryo-fetal effects were observed in rats and rabbits at BIC exposures (based on AUC) of up to about 36 times (in rats) and 0.6 times (in rabbits) the exposures observed in humans who received the recommended dose. Spontaneous abortion, increased clinical signs (e.g., fecal changes, thin body, cold to touch), and decreased body weight were observed in rabbits at a maternally toxic dose (i.e., 1,000 mg/kg per day, which produced an exposure approximately 1.4 times higher than the exposure observed in humans who received the recommended dose).¹¹

Placental and Breast Milk Passage

No data are available on placental passage of BIC in animals. In a prenatal and postnatal development study conducted in rats, BIC was detected in the plasma of nursing rat pups on postnatal Day 10, likely due to the presence of BIC in milk.¹¹

Excerpt from Table 14

Note: When using fixed-dose combination (FDC) tablets, refer to other sections in Appendix B and Table 14 in the Perinatal Guidelines for information about the dosing and safety of individual drug components of the FDC tablet during pregnancy.

References

1. Powis KM, Pinilla M, Bergam L, et al. Pharmacokinetics and virologic outcomes of bictegravir in pregnancy and postpartum. Presented at: Conference on Retroviruses and Opportunistic Infections. Seattle, WA. Available at: https://www.croiconference.org/wp-content/uploads/sites/2/posters/2023/IMPAACT_PHARMACOKINETICS_AND_VIROLOGIC_15Feb23-133209845782009090.pdf.
2. Zhang H, Hindman JT, Lin L, et al. A study of the pharmacokinetics, safety, and efficacy of bictegravir/emtricitabine/tenofovir alafenamide in virologically suppressed pregnant women with HIV. AIDS. 2023. Available at: https://pubmed.ncbi.nlm.nih.gov/37939141.
3. Bukkems VE, Hidalgo-Tenorio C, Garcia C, et al. First pharmacokinetic data of bictegravir in pregnant women living with HIV. AIDS. 2021;35(14):2405-2406. Available at: https://pubmed.ncbi.nlm.nih.gov/34723856.
4. Le MP, Ferre VM, Mazy F, et al. Bictegravir pharmacokinetics in a late-presenting HIV-1-infected pregnant woman: a case report. J Antimicrob Chemother. 2022;77(3):851-853. Available at: https://pubmed.ncbi.nlm.nih.gov/34792155.
5. Miller C, Giguere P, McGuinty M, Angel JB. Breakthrough HIV viraemia on bictegravir/emtricitabine/tenofovir alafenamide in the third trimester of pregnancy. J Antimicrob Chemother. 2024;79(9):2390-2391. Available at: https://pubmed.ncbi.nlm.nih.gov/38984452.
6. Powis K, Mauricio P, McMorrow F, et al. Pharmacokinetics and safety of bictegravir in pregnant and postpartum persons with HIV and their infants. J Acquir Immune Defic Syndr. 2024. Available at: https://journals.lww.com/jaids/abstract/9900/pharmacokinetics_and_safety_of_bictegravir_in.545.aspx.
7. Holt LM, Short WR, Momplaisir F, et al. Bictegravir use during pregnancy: a multi-center retrospective analysis evaluating HIV viral suppression and perinatal outcomes. Clin Infect Dis. 2024. Available at: https://pubmed.ncbi.nlm.nih.gov/38666408.
8. Aebi-Popp K, Kahlert CR, Crisinel PA, et al. Transfer of antiretroviral drugs into breastmilk: a prospective study from the Swiss Mother and Child HIV Cohort Study. J Antimicrob Chemother. 2022;77(12):3436-3442. Available at: https://pubmed.ncbi.nlm.nih.gov/36177836.
9. Fung K, Hernandez-Diaz S, Zash R, et al. First-trimester exposure to newer antiretroviral agents and congenital anomalies in a US cohort. AIDS. 2024;38(11):1686-1695. Available at: https://pubmed.ncbi.nlm.nih.gov/38864586.
10. Olivero RM, Williams PL, Sawyer G, et al. Birth outcomes following bictegravir use during pregnancy. Presented at: Conference on Retroviruses and Opportunistic Infections 2024. Denver, Colorado. Available at: https://www.croiconference.org/abstract/birth-outcomes-following-bictegravir-use-during-pregnancy.
11. Biktarvy (bictegravir/emtricitabine/tenofovir alafenamide) [package insert]. Food and Drug Administration. 2022. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/210251s015lbl.pdf.