Reduced exposure to darunavir and cobicistat in HIV-1-infected pregnant women receiving a darunavir/cobicistat-based regimen

Abstract

Objectives: The aim of the study was to evaluate darunavir and cobicistat pharmacokinetics in pregnant women with HIV-1 infection. Methods: This phase 3b, open-label study enrolled HIV-1-infected pregnant women (18–26 weeks of gestation) receiving combination antiretroviral therapy with once-daily darunavir/cobicistat 800/150 mg. The plasma pharmacokinetics of darunavir (total and unbound) and cobicistat were assessed over 24 h during the second and third trimesters (24–28 and 34–38 weeks of gestation, respectively) and 6–12 weeks postpartum. Pharmacokinetic parameters [area under the plasma concentration–time curve over 24 h (AUC 24 h ), maximum plasma concentration (C max ) and minimum plasma concentration (C min )] were derived using noncompartmental analysis and compared using linear mixed effects modelling (pregnancy versus postpartum). Antiviral activity and safety were evaluated. Results: Seven women were enrolled in the study; six completed it. Total darunavir exposure was lower during pregnancy than postpartum (AUC 24 h , 50–56% lower; C max , 37–49% lower; C min , 89–92% lower); unbound darunavir exposure was also reduced (AUC 24 h , 40–45% lower; C max , 32–41% lower; C min , 88–92% lower). Cobicistat exposure was also lower during pregnancy than postpartum (AUC 24 h , 49–63% lower; C max , 27–50% lower; C min , 83% lower). At study completion, five of six (83%) women were virologically suppressed (HIV-1 RNA < 50 copies/mL). There was one virological failure (the patient was nonadherent; no emerging genotypic resistance was observed and susceptibility to antiretrovirals was maintained). No mother-to-child transmission was detected among six infants born to the six women who completed the study. Overall, darunavir/cobicistat was well tolerated in women and infants. Conclusions: In view of markedly reduced darunavir and cobicistat exposures during pregnancy, this combination is not recommended in HIV-1-infected pregnant women.