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

Integrase Inhibitors

Bictegravir (BIC)

Animal Studies

Carcinogenicity

Bictegravir (BIC) has not been shown to be genotoxic or mutagenic in vitro.¹

Reproduction/Fertility

BIC did not affect fertility, reproductive performance, or embryonic viability in male and female rats at exposures (based on area under the curve [AUC]) that were 29 times higher than those observed in humans who received the recommended dose.¹

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).¹

Placental and Breast Milk Passage

No data are available on placental passage of BIC. 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.¹

Human Studies in Pregnancy

Pharmacokinetics

Limited information about the pharmacokinetics (PKs) of BIC in pregnancy are presented in a case series describing two pregnant individuals of whom one had PK data during pregnancy and postpartum. This patient’s AUC, C_trough, and C_max were 35%, 49%, and 19% lower, respectively, at 33 weeks gestation compared to 6 weeks postpartum. The patient remained virologically suppressed through delivery. The generalizability of these findings is unknown at this time.²

Placental and Breast Milk Passage

Data regarding placental transfer of BIC are limited and provide mixed results. Data from two patients treated with BIC during pregnancy demonstrated high placental transfer; the umbilical cord-to-maternal plasma ratio was 1.49 in one patient 20 hours after BIC dosing and 1.42 in another patient 7 hours after BIC dosing.² However, placental transfer was found to be low in an ex vivo dually perfused human cotyledon model with a median (interquartile range 25–75) maternal-to-fetal ratio of 7% (6% to 9.5%).³ Additional data are needed to refine our understanding of placental passage of BIC. No data are available on breast milk passage of BIC in humans.

Teratogenicity/Adverse Pregnancy Outcomes

The Antiretroviral Pregnancy Registry has prospectively monitored 140 pregnancies in women treated with BIC during periconception or pregnancy, including 91 infants with periconception exposure, 9 infants with later first-trimester exposure, and 40 infants with exposure in the second or third trimester. Three birth defects, including one central nervous system defect that was not a neural tube defect or encephalocele, have been reported to date. However, these data are insufficient to make conclusions regarding the safety of BIC during pregnancy.⁴

Excerpt from Table 11

Note: When using fixed-dose combination (FDC) tablets, refer to other sections in Appendix B and Table 11 in the Perinatal Guidelines for information about the dosing and safety of individual drug components of the FDC tablet during pregnancy.

References

1. Biktarvy (bictegravir, emtricitabine, tenofovir alafenamide fumarate) [package insert]. Food and Drug Administration. 2019. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/210251s006lbl.pdf.
2. 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://www.ncbi.nlm.nih.gov/pubmed/34723856.
3. Pencole L, Le MP, Bouchet-Crivat F, Duro D, Peytavin G, Mandelbrot L. Placental transfer of the integrase strand inhibitors cabotegravir and bictegravir in the ex-vivo human cotyledon perfusion model. AIDS. 2020;34(14):2145-2149. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32796211.
4. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral pregnancy registry international interim report for 1 January 1989–31 January 2020. Wilmington, NC: Registry Coordinating Center. 2020. Available at: http://www.apregistry.com/.