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

Non-Nucleoside Reverse Transcriptase Inhibitors

Rilpivirine (Edurant, RPV)

Summary

• Rilpivirine (RPV) plasma concentrations after oral dosing are decreased by approximately 20% to 50% during pregnancy.
• Higher-than-standard oral doses have not been studied, and not enough data are available to recommend a dosing change during pregnancy. When standard oral dosing of RPV is received during pregnancy, viral loads should be monitored more frequently.
• Pharmacokinetic data are insufficient to make dosing recommendations for long-acting injectable RPV during pregnancy or breastfeeding.
• First-trimester exposure to RPV is not associated with an increased risk of congenital anomalies.

Human Studies in Pregnancy

Pharmacokinetics

RPV exposure after oral dosing is decreased by 20% to 50% during pregnancy. The International Maternal Pediatric Adolescent AIDS Clinical Trials P1026s (IMPAACT P1026) study evaluated pharmacokinetic (PK) and safety data from 32 pregnant women with HIV found that median RPV area under the curve concentration (AUC) and trough concentration (C_trough) after oral dosing were approximately 20% to 30% lower in the second and third trimesters than in the postpartum period. Median RPV C_trough were significantly lower at 14 visits where the women had detectable HIV RNA (30 ng/mL) than at 62 visits where they had undetectable HIV RNA (63 ng/mL). Ninety percent of women had C_trough above the protein-adjusted 90% maximal effective concentration for RPV. PK parameters between participants were highly variable in this study.¹ A subsequent study among 16 pregnant women with HIV similarly found that exposure after oral dosing was approximately 50% lower in the third trimester than in the postpartum period, with 4 of the 16 women having C_trough below the target levels during pregnancy.² Based on these findings, the authors recommended therapeutic drug monitoring during the third trimester and oral RPV dosing with meals. A third study among 15 women during pregnancy reported that total RPV exposure after oral dosing decreased by approximately 30%, and unbound RPV levels decreased by 22% to 25% compared to their postpartum concentrations.³

Cervicovaginal fluid RPV concentrations were described in a study of 24 women who took RPV orally daily during pregnancy and postpartum. RPV steady-state concentrations in the cervicovaginal fluid of these women were similar to the concentrations seen in their plasma. The RPV cervicovaginal fluid–to-plasma AUC ratio was higher during pregnancy than postpartum.⁴ Although RPV plasma concentration is reduced during pregnancy, higher-than-standard doses of RPV have not been studied, and not enough data are available to recommend a dosing change during pregnancy. In the ANRS-EPF French Perinatal Cohort, 184 virologically suppressed women who switched to RPV‑free regimens during pregnancy had a higher risk of viral rebound compared with 63 women who continued RPV during pregnancy (20% vs. 0%, P = 0.046). Birth outcomes were similar between these groups.⁵ For considerations regarding switching antiretroviral (ARV) drugs during pregnancy, see Antiretroviral Therapy Use During Prepregnancy and Early Pregnancy. When the standard oral dose of RPV is received during pregnancy, viral loads should be monitored more frequently (see Initial Evaluation and Continued Monitoring of HIV During Pregnancy).

No studies have been conducted on the PKs of ongoing intramuscular injections of long-acting cabotegravir (CAB) and RPV (LA CAB/RPV) during pregnancy. Clinical trial data reported to date are limited to pregnant women who stopped receiving the long-acting injectable formulations for the treatment or prevention of HIV once pregnancies were recognized and began alternative oral ARV regimens throughout the remainder of their pregnancies. From the Phase 2b/3/3b clinical trials of LA CAB/RPV for the treatment of HIV, PK data are available for seven of the nine participants with live-birth outcomes. Plasma concentrations were within the range of observed concentrations of nonpregnant women who discontinued LA CAB/RPV.⁶ A physiologically-based pharmacokinetics (PBPK) model of LA CAB/RPV initiation during pregnancy early in the second trimester predicted a reduction in RPV plasma concentrations of 23.0 at the first trough (C_trough) after the first injection. After the sixth injection in the second and third trimesters, plasma RPV concentrations were 29.2% lower. These reductions are attributable to the predicted induction of uridine diphosphate glucuronosyltransferase 1A1 and cytochrome P450 3A4 during the second and third trimesters.⁷ An additional PBPK model predicted that the RPV C_trough at Week 12 for monthly and bimonthly long-acting RPV would be below 50 ng/mL in at least 40% and more than 90% of the pregnant population.⁸ A single case report of bimonthly LA CAB/RPV found that RPV concentrations were 70% to 75% lower⁹ than historical nonpregnant levels; viral suppression was maintained.

See Cabotegravir for data about CAB.

Placental and Breast Milk Passage

RPV has moderate-to-high placental transfer compared to other ARV drugs. IMPAACT P1026 included data on RPV concentration at birth for 21 mother–infant pairs, with a median cord blood RPV plasma concentration of 29.2 ng/mL (range <10.0 to 101.5 ng/mL), a median maternal delivery RPV plasma concentration of 55.2 ng/mL (range <10.0 to 233.8 ng/mL), and a median cord blood–to–maternal plasma ratio of 0.55 (range 0.3–0.8).¹ Osiyemi et al. found that the median ratio of cord blood–to–maternal plasma concentration of total RPV in eight women was 0.55 (range 0.43–0.98).³ Similarly, Schalkwijk et al. found a median cord blood–to–maternal plasma ratio of 0.5 (range 0.35–0.81) in five women.^2,10 No data exist on whether RPV is excreted in breast milk in humans.

Teratogenicity/Adverse Pregnancy Outcomes

The Antiretroviral Pregnancy Registry (APR) provides updated birth defect data for ATV and other 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 oral RPV 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 RPV. 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 ATV 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) according to the Centers for Disease Control and Prevention’s surveillance system (The Metropolitan Atlanta Congenital Defects Program or MACDP) and with the Texas Birth Defects Registry ([TBDR] 4.17 per 100 live births).

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

Animal Studies

Carcinogenicity

RPV was neither mutagenic nor clastogenic in a series of in vitro and in vivo screening tests. RPV was neither carcinogenic nor genotoxic in animal studies.¹¹

Reproduction/Fertility

RPV had no effect on fertility in animal studies.¹¹

Teratogenicity/Adverse Pregnancy Outcomes

No significant toxicological effects were seen in RPV animal studies.¹¹

Placental and Breast Milk Passage

Studies in lactating rats and their offspring indicate that RPV is present in rat 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. Tran AH, Best BM, Stek A, et al. Pharmacokinetics of rilpivirine in HIV-infected pregnant women. J Acquir Immune Defic Syndr. 2016;72(3):289-296. Available at: https://pubmed.ncbi.nlm.nih.gov/26918544.
2. Schalkwijk S, Colbers A, Konopnicki D, et al. Lowered rilpivirine exposure during third trimester of pregnancy in HIV-1-positive women. Clin Infect Dis. 2017;65(8):1335-1341. Available at: https://pubmed.ncbi.nlm.nih.gov/28595298.
3. Osiyemi O, Yasin S, Zorrilla C, et al. Pharmacokinetics, antiviral activity, and safety of rilpivirine in pregnant women with HIV-1 infection: results of a phase 3b, multicenter, Open-label study. Infect Dis Ther. 2018;7(1):147-159. Available at: https://pubmed.ncbi.nlm.nih.gov/29335895.
4. Eke AC, Chakhtoura N, Kashuba A, et al. Rilpivirine plasma and cervicovaginal concentrations in women during pregnancy and postpartum. J Acquir Immune Defic Syndr. 2018;78(3):308-313. Available at: https://pubmed.ncbi.nlm.nih.gov/29528944.
5. Frange P, Tubiana R, Sibiude J, et al. Rilpivirine in HIV-1-positive women initiating pregnancy: to switch or not to switch? J Antimicrob Chemother. 2020;75(5):1324-1331. Available at: https://pubmed.ncbi.nlm.nih.gov/32157283.
6. 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.
7. Yu Y, Bekker A, Li X, et al. PBPK model prediction of long-acting cabotegravir and rilpivirine concentrations In pregnancy. Presented at: CROI; 2023. Seattle, Washington. Available at: https://www.croiconference.org/abstract/pbpk-model-prediction-of-long-acting-cab-and-rpv-concentrations-in-pregnancy.
8. Atoyebi S, Bunglawala F, Cottura N, et al. Physiologically-based pharmacokinetic modelling of long-acting injectable cabotegravir and rilpivirine in pregnancy. Br J Clin Pharmacol. 2024. Available at: https://pubmed.ncbi.nlm.nih.gov/38340019.
9. van der Wekken-Pas L, Weiss F, Simon-Zuber C, et al. Long-acting cabotegravir and rilpivirine in a pregnant woman with HIV. Clin Infect Dis. 2024. Available at: https://pubmed.ncbi.nlm.nih.gov/38703388.
10. Mandelbrot L, Duro D, Belissa E, Peytavin G. Erratum for mandelbrot et al., placental transfer of rilpivirine in an ex vivo human cotyledon perfusion model. Antimicrob Agents Chemother. 2015;59(9):5869. Available at: https://pubmed.ncbi.nlm.nih.gov/26276897.
11. Rilpivirine (Edurant) [package insert]. Food and Drug Administration. 2022. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/202022s016lbl.pdf.