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

Integrase Inhibitors

Cabotegravir (CAB)

Summary

• Pharmacokinetic (PK) data are insufficient to make dosing recommendations for oral cabotegravir (CAB) or long-acting (LA) injectable cabotegravir (CAB-LA) during pregnancy or breastfeeding.
• Clinical data are insufficient to characterize the risk for congenital anomalies associated with in utero exposure to CAB. No reproductive toxicity or teratogenicity concerns were identified in animal studies.
• Long-acting CAB and rilpivirine (RPV) (LA CAB/RPV) is FDA approved for HIV treatment.
• CAB-LA is FDA approved for HIV pre-exposure prophylaxis (PrEP).

Human Studies in Pregnancy

Pharmacokinetics

Prospective CAB PK data during pregnancy and postpartum are limited to preliminary data from the HIV Prevention Trials Network (HPTN) 084 protocol open-label extension (OLE)¹ in which, upon diagnosis of pregnancy, HIV-negative participants were given the choice of continuing the current regimen (either CAB-LA or TDF/FTC) or switching to a self-selected regimen (CAB LA or TDF/FTC) for HIV PrEP. Monthly PK sampling was performed among a subset of 75 participants; preliminary PK data from the first 50 participants, all of whom were continuing on CAB from before pregnancy (median number of CAB-LA intramuscular injections before conception was 6, range 4–7), found that concentrations decreased in pregnancy but were largely maintained above the protocol-defined exposure target of four times the protein-adjusted 90% inhibitory concentration (PA-IC₉₀) of 0.664 µg/mL. No PK data are reported on CAB-LA initiation in pregnancy. 

A case report of a single pregnancy on bi-monthly LA CAB/RPV reported that CAB concentrations were comparable to those in nonpregnant individuals.² No other prospective PK data on LA CAB/RPV for HIV treatment during pregnancy and postpartum exists. Earlier clinical trial PK data are limited to pregnant women who stopped receiving CAB injections for the treatment of HIV once pregnancy was recognized and began an alternative oral antiretroviral (ARV) regimen throughout the remainder of their pregnancies.³

Placental and Breast Milk Passage

Median (interquartile range [IQR] 25–75) CAB maternal-to-fetal concentration ratio assessed using an ex vivo dually perfused human cotyledon model was 10% (IQR 5–16), suggesting low placental transfer.⁴ No data are available describing breast milk passage of CAB in humans.⁵ See Rilpivirine for data about RPV.

Teratogenicity/Adverse Pregnancy Outcomes

The Antiretroviral Pregnancy Registry (APR) provides updated birth defect data for CAB and other ARV drugs twice a year through an interim report released in June and December. The APR has not monitored sufficient numbers of first-trimester exposures to CAB to report on the risk of overall birth defects.

In HPTN 084 OLE,⁶ there were 351 confirmed pregnancies. Pregnancy-related maternal adverse event incidence was 43.7 (95% confidence interval [CI], 30.9–60.0), 52.9 (95% CI, 24.2–100.5), and 40.0 (95% CI, 14.7–87.1) per 100 person-years among those using CAB-LA during pregnancy, using CAB-LA starting before pregnancy, or no CAB LA use, respectively. Adverse pregnancy outcome rates were similar across groups; negative outcomes were reported in 28% (55/194), 35% (24/69), and 26% (11/43) of pregnancies with CAB-LA use during pregnancy, CAB-LA use starting before pregnancy, or no CAB LA use, respectively. One major congenital anomaly was observed in the CAB-LA during pregnancy group and was not considered related to CAB-LA exposure.⁷

In earlier Phase 2b/3/3b trials of CAB and RPV, 25 of 325 women of reproductive potential became pregnant while exposed to CAB and RPV (5 oral, 20 LA injectable), resulting in 8 elective abortions, 6 spontaneous abortions (5 in the first trimester), 1 ectopic pregnancy, and 10 live births (1 oral, 9 LA injectable). Of the 10 live births, 1 case of congenital ptosis was reported in a preterm infant with intrauterine growth restriction, and 1 late preterm birth occurred due to induction of labor.¹ See Rilpivirine for additional information about oral RPV.

Animal Studies

Carcinogenicity

CAB was neither mutagenic nor clastogenic in a series of in vitro and animal in vivo screening tests. Long-term carcinogenicity studies of CAB in mice did not show any carcinogenic potential at systemic exposures that were sevenfold (in females) or eightfold (in males) greater than human exposure at the recommended dose. In rats, no drug-related increases in tumor incidence were observed at CAB exposures up to approximately 26 times higher than those in humans at the recommended dose.⁷

CAB was not genotoxic in the bacterial reverse mutation assay, mouse lymphoma assay, or in vivo rodent micronucleus assay.⁸ See Rilpivirine for data about RPV.

Reproduction/Fertility

In rats, no effects on fertility were observed at CAB exposures at least 20 times greater than the exposure in humans at recommended doses. See Rilpivirine for data about RPV.

Teratogenicity/Adverse Pregnancy Outcomes

Studies in pregnant rats showed that CAB crosses the placenta and can be detected in fetal tissue. Treatment of rat dams with CAB during pregnancy and postpartum had no effects on fetal viability, although a minor decrease was observed in fetal body weight with exposures 28 times those seen in humans at the recommended dose. No drug-related fetal toxicities were observed with rat dam exposures approximately 13 times those seen in humans at the recommended dose, and no fetal malformations were observed at any rat dam dose. A delay in the onset of parturition and increases in the number of stillbirths and neonatal deaths were seen with exposure of rat dams to CAB at 28 times the human exposure with recommended doses, but not with exposure at 13 times the human exposure with recommended doses.

No drug-related fetal toxicities were observed after CAB exposures of rabbit dams of up to approximately 0.7 times those seen in humans at the recommended dose.⁷

A recent study in mouse models demonstrated decreased human embryonic stem cell counts and pluripotency and induced dysregulation of genes involved in early differentiation at subtherapeutic levels of CAB.⁹ Additionally, a study of zebrafish found that although CAB did not cause gross morphological defects at low doses, pericardial edema, uninflated swim bladder, decreased heartbeats, growth delay, and decreased hatching rate were observed at the highest concentrations. At subtherapeutic doses, decreased locomotion was observed, suggesting alterations of nervous system integrity.¹⁰ Clinical data and clinical trials data in humans are insufficient to refute or corroborate these findings.

See Rilpivirine for data about RPV.

Placental and Breast Milk Passage

Studies in lactating rats and their offspring indicate that CAB is present in rat milk. See Rilpivirine for data about RPV.

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. Marzinke M, Voldal E, Hanscom B, et al. 2024. Evaluation of long-acting cabotegravir (CAB-LA) pharmacokinetics during pregnancy: a sub-study analysis of the HPTN 084 open label extension study. Presented at AIDS 2024, the 25th International AIDS Conference. Available at: https://programme.aids2024.org/Abstract/Abstract/?abstractid=12032.
2. van der Wekken-Pas L, Weiss F, Simon-Zuber C, et al. Long-acting injectible cabotegravir and rilpivirine in a pregnant woman with HIV. Clin Infect Dis. 2024. Available at: https://pubmed.ncbi.nlm.nih.gov/38703388.
3. Patel P, Ford SL, Baker M, et al. Pregnancy outcomes and pharmacokinetics in pregnant women living with HIV exposed to long-acting cabotegravir and rilpivirine in clinical trials. HIV Med. 2023;24(5):568-579. Available at: https://pubmed.ncbi.nlm.nih.gov/36411596.
4. Pencolé L, Lê MP, Bouchet-Crivat F, et al. 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://pubmed.ncbi.nlm.nih.gov/32796211.
5. Eunice Kennedy Shriver National Institute of Child Health and Human Development; 2006. Cabotegravir. Drugs and Lactation Database (LactMed®). 2024 July 15. Available at: https://pubmed.ncbi.nlm.nih.gov/35073031.
6. Delany-Moretlwe S, Voldal E, Saidi F, et al. Initial evaluation of injectable cabotegravir (CAB-LA) safety during pregnancy in the HPTN 084 open-label extension. Presented at: AIDS 2024, the 25th International AIDS Conference. 2024. Available at: https://programme.aids2024.org/Abstract/Abstract/?abstractid=12420.
7. Delany-Moretlwe S, Hughes JP, Guo X, et al. Evaluation of CAB-LA safety and PK in pregnant women in the blinded phase of HPTN 084. Presented at: The Conference on Retroviruses and Opportunistic Infections. 2022. Virtual. Available at: https://www.croiconference.org/abstract/evaluation-of-cab-la-safety-and-pk-in-pregnant-women-in-the-blinded-phase-of-hptn-084.
8. Food and Drug Administration Cabotegravir. Rilpivirine (CABENUVA kit). 2022. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/212888s005s006lbl.pdf.
9. Food and Drug Administration. Edurant (Rilpivirine). 2021. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/202022s014lbl.pdf.
10. Smith MR, Mohan H, Ajaykumar A, et al. Second-generation human immunodeficiency virus integrase inhibitors induce differentiation dysregulation and exert toxic effects in human embryonic stem cell and mouse models. J Infect Dis. 2022;226(11):1992-2001. Available at: https://pubmed.ncbi.nlm.nih.gov/36124861.
11. Zizioli D, Zanella I, Mignani L, et al. Cabotegravir exposure of zebrafish (Danio rerio) embryos impacts on neurodevelopment and behavior. Int J Mol Sci. 2023;24(3). Available at: https://pubmed.ncbi.nlm.nih.gov/36768311.