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

Protease Inhibitors

Darunavir (Prezista, DRV)

Summary

• Darunavir (DRV) trough concentrations (C_trough) are reduced during pregnancy by approximately 10% with use of DRV boosted with ritonavir (DRV/r) 600 mg/100 mg twice daily and by approximately 50% with use of DRV/r 800 mg/100 mg once daily.
• DRV C_trough are reduced during pregnancy by approximately 90% with use of DRV boosted with cobicistat (DRV/c) 800 mg/150 mg once daily.
• The Panel on Treatment of HIV During Pregnancy and Interventions to Reduce Perinatal HIV Transmission (the Panel) recommends the use of twice-daily dosing with DRV/r 600mg/100 mg during pregnancy and does not recommend use during pregnancy of once-daily dosing with DRV/r 800 mg/100 mg or the use of DRV/c 800 mg/150 mg.
• First-trimester exposures to DRV have not been associated with increased risk of congenital anomalies.

Human Studies in Pregnancy

Pharmacokinetics

Several studies of the pharmacokinetics (PK) of DRV/r during pregnancy have been completed.^1-4 During the third trimester, DRV plasma area under the curve (AUC) was reduced by 17% to 26% with DRV/r 600-mg/100-mg twice-daily dosing and by 33% to 39% with DRV/r 800-mg/100-mg once-daily dosing, compared with postpartum.^1-5 During the third trimester, DRV C_trough was reduced by 8% to 12% with DRV/r 600-mg/100-mg twice-daily dosing and by 42% to 58% with DRV/r 800-mg/100-mg once-daily dosing, compared with postpartum.^2-4

Three studies measured DRV protein binding during pregnancy. One study found no change in DRV protein binding during the third trimester. The other two studies reported decreased unbound DRV concentrations during pregnancy that were not considered clinically significant.^1,3,4 Because of the low DRV trough levels that occur with once-daily dosing, twice-daily dosing of DRV is recommended during pregnancy, especially for antiretroviral-experienced patients.^2,6 The U.S. Food and Drug Administration recommends the use of once-daily DRV/r 800-mg/100-mg dosing only for pregnant people who were virally suppressed on a stable, once-daily DRV/r regimen before pregnancy and whose adherence or ability to tolerate a regimen may be compromised by a switch to twice-daily DRV/r.⁷ After reviewing the available evidence, the Panel does not recommend once-daily dosing of DRV/r in pregnancy. Because use of 800-mg DRV doses administered twice daily did not increase DRV exposure in pregnant women, the Panel recommends the use of twice-daily 600-mg DRV dosing during pregnancy.⁵

Data are available from two studies describing the PK and safety of cobicistat (COBI) boosting of DRV during pregnancy. In both studies, darunavir/cobicistat (DRV/c) 800 mg/150 mg was administered during pregnancy.^8,9 In a study of seven pregnant women with HIV who were treated with DRV/c, no drug-related adverse events were observed. When PK parameters during the second and third trimesters were compared with postpartum PK parameters, total DRV AUC was reduced by 56% and 50%, and C_trough was reduced by 92% and 89%, respectively. Unbound DRV concentrations decreased during the second and third trimesters of pregnancy compared to postpartum, with AUC 45% and 40% lower and C_trough 92% and 88% lower, respectively. COBI exposures were lower during pregnancy, with reductions during the second and third trimesters of 63% and 49% for AUC and 83% and 83% for trough concentration, compared with postpartum. Six of seven participants remained virally suppressed during pregnancy. One woman who was not virally suppressed was found to be nonadherent to treatment, based on pill count. No infants born to study mothers contracted HIV.⁹ On the basis of these data, the package insert for the fixed-dose combination of DRV/c was edited to include a statement saying that this product is not recommended for use in pregnant women because of substantially lower exposures of DRV and COBI during pregnancy.¹⁰ These findings are consistent with the larger PK study, which included data from 29 pregnant women who received DRV/c as part of clinical care and showed that when PK parameters during the second and third trimesters were compared with postpartum PK parameters in these women, total DRV AUC was reduced by 33% and 48%, respectively, and DRV C_trough were reduced by 71% and 75%, respectively.⁸

Placental and Breast Milk Passage

In an ex vivo human cotyledon perfusion model, the mean fetal transfer rate of DRV was 15%.¹¹ In five studies that reported data from between 6 and 14 subjects each, the median ratio of DRV concentration in cord blood–to–DRV concentration in maternal delivery plasma ranged from 13% to 24%.^1-3,9,12

Breast milk transfer of DRV was low in two mother–infant pairs where the mother was receiving DRV/r while breastfeeding, with a median DRV breast milk–to–maternal plasma concentration ratio of 0.12, median estimated infant DRV dose of 0.05 mg/kg, and no detectable DRV in infant plasma.¹³

Teratogenicity/Adverse Pregnancy Outcomes

The Antiretroviral Pregnancy Registry has monitored sufficient numbers of first-trimester exposures to DRV to allow detection of 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 DRV. Among cases of first-trimester DRV exposure that have been reported to the Antiretroviral Pregnancy Registry, the prevalence of birth defects was 3.7% (27 of 737 live births; 95% confidence interval, 2.4% to 5.3%) compared with a 2.7% total prevalence in the U.S. population, based on Centers for Disease Control and Prevention surveillance.¹⁴

Animal Studies

Carcinogenicity

DRV was neither mutagenic nor clastogenic in a series of in vitro and animal in vivo screening tests. A dose-related increase in the incidence of hepatocellular adenomas and carcinomas was observed in both male and female mice and rats, as was an increase in thyroid follicular cell adenomas in male rats. The observed hepatocellular findings in rodents are considered to be of limited relevance to humans. Repeated administration of DRV to rats caused hepatic microsomal enzyme induction and increased thyroid hormone elimination; this predisposed rats, but not humans, to thyroid neoplasms. At the highest tested doses, the systemic exposures to DRV (based on AUC) were between 0.4-fold and 0.7-fold higher in mice and 0.7-fold and onefold higher in rats than the exposures observed in humans who received the recommended therapeutic doses of DRV/r 600 mg/100 mg twice daily or DRV/r 800 mg/100 mg once daily.⁷

Reproduction/Fertility

No effects on fertility or early embryonic development were seen in rats that received DRV.⁷

Teratogenicity/Adverse Pregnancy Outcomes

No embryotoxicity or teratogenicity was seen in rats that experienced DRV exposures (based on AUC) that were threefold higher than those seen in humans who received recommended DRV/r doses; likewise, no embryotoxicity or teratogenicity was seen in mice and rabbits that experienced DRV exposures that were less than onefold those seen in humans who received the recommended DRV/r doses. Administering DRV alone or with ritonavir to female rats during lactation resulted in a reduction in pup weight gain during a rat prenatal and postnatal development study. DRV/r is not recommended for pediatric patients aged <3 years because of the toxicity and mortality observed in juvenile rats dosed with DRV up to 23 to 26 days of life.⁷

Placental and Breast Milk Passage

No animal studies of placental passage of DRV have been reported. Passage of DRV into breast milk has been noted in rats.⁷

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. Zorrilla CD, Wright R, Osiyemi OO, et al. Total and unbound darunavir pharmacokinetics in pregnant women infected with HIV-1: results of a study of darunavir/ritonavir 600/100 mg administered twice daily. HIV Med. 2014;15(1):50-56. Available at: https://pubmed.ncbi.nlm.nih.gov/23731450.
2. Stek A, Best BM, Wang J, et al. Pharmacokinetics of once versus twice daily darunavir In pregnant HIV-infected women. J Acquir Immune Defic Syndr. 2015;70(1):33-41. Available at: https://pubmed.ncbi.nlm.nih.gov/25950206.
3. Colbers A, Molto J, Ivanovic J, et al. Pharmacokinetics of total and unbound darunavir in HIV-1-infected pregnant women. J Antimicrob Chemother. 2015;70(2):534-542. Available at: https://pubmed.ncbi.nlm.nih.gov/25326090.
4. Crauwels HM, Kakuda TN, Ryan B, et al. Pharmacokinetics of once-daily darunavir/ritonavir in HIV-1-infected pregnant women. HIV Med. 2016;17(9):643-652. Available at: https://pubmed.ncbi.nlm.nih.gov/27187894.
5. Eke AC, Stek AM, Wang J, et al. Darunavir pharmacokinetics with an increased dose during pregnancy. J Acquir Immune Defic Syndr. 2020;83(4):373-380. Available at: https://pubmed.ncbi.nlm.nih.gov/31923087.
6. Schalkwijk S, Ter Heine R, Colbers A, et al. Evaluating darunavir/ritonavir dosing regimens for HIV-positive pregnant women using semi-mechanistic pharmacokinetic modelling. J Antimicrob Chemother. 2019;74(5):1348-1356. Available at: https://pubmed.ncbi.nlm.nih.gov/30715324.
7. Darunavir (Prezista) [package insert]. Food and Drug Administration. 2022. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/021976s067,202895s035lbl.pdf.
8. Momper JD, Wang J, Stek A, et al. Pharmacokinetics of darunavir and cobicistat in pregnant and postpartum women with HIV. AIDS. 2021;35(8):1191-1199. Available at: https://pubmed.ncbi.nlm.nih.gov/34076612.
9. Crauwels HM, Osiyemi O, Zorrilla C, et al. Reduced exposure to darunavir and cobicistat in HIV-1-infected pregnant women receiving a darunavir/cobicistat-based regimen. HIV Med. 2019;20(5):337-343. Available at: https://pubmed.ncbi.nlm.nih.gov/30873741.
10. Prezcobix (darunavir/cobicistat) [package insert]. Food and Drug Administration. 2022. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/205395s024lbl.pdf.
11. Mandelbrot L, Duro D, Belissa E, Peytavin G. Placental transfer of darunavir in an ex vivo human cotyledon perfusion model. Antimicrob Agents Chemother. 2014;58(9):5617-5620. Available at: https://pubmed.ncbi.nlm.nih.gov/24982090.
12. Courbon E, Matheron S, et al. Safety, efficacy, and pharmacokinetic of darunavir/ritonavir-containing regimen in pregnant HIV-infected women. Presented at: 19th Conference on Retroviruses and Opportunistic Infections; 2012. Seattle, WA. Available at: https://natap.org/2013/HIV/011613_04.htm.
13. 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.
14. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry international interim report for 1 January 1989–31 January Morrisville, NC: Registry Coordinating Center; 2023. Available at: https://www.apregistry.com