Pharmacokinetic Enhancement of HIV Antiretroviral Therapy During Pregnancy

Abstract

Pharmacokinetic boosting of antiretroviral (ARV) therapies with either ritonavir or cobicistat is used to achieve target drug exposure, lower pill burden, and provide simplified dosing schedules. Several ARVs require boosting, including the integrase inhibitor elvitegravir as well as protease inhibitors such as darunavir, atazanavir, and lopinavir. The use of boosted regimens in pregnant women living with HIV has been studied for a variety of ARVs; however, a recent recommendation by the US Food and Drug Administration advised against cobicistat-boosted regimens in pregnancy due to substantially lower drug exposures observed in clinical pharmacokinetic studies. The objectives of this article are to review pharmacokinetic enhancement of ARVs with ritonavir and cobicistat during pregnancy and postpartum, describe clinical implications, and provide recommendations for future research.

Keywords: HIV; cobicistat; drug metabolism; pharmacokinetics; pregnancy; ritonavir.

Figure 1.

Mechanisms of ritonavir boosting and cobicistat boosting. (A) Ritonavir inhibits CYP3A in both the liver and gut and demonstrates time-dependent inhibition followed by induction of P-gp in the gut. Ritonavir also inhibits CYP2D6 in the liver while inducing CYP1A2, CYP2C9, CYP2C19, and CYP2B6. (B) Cobicistat boosts TAF plasma exposures by inhibiting efflux transporters (P-gp and BCRP) in gut enterocytes, enhancing oral bioavailability. Cobicistat boosts protease and integrase inhibitors by selectively inhibiting CYP3A metabolism in the liver and intestinal tract and by inhibiting efflux transporters (to a smaller extent). BRCP, breast cancer resistance protein; CYP, cytochrome P450; P-gp, P-glycoprotein; TAF, tenofovir alafenamide.