Pharmacogenetics of efavirenz exposure in cervicovaginal fluid during pregnancy and postpartum

Abstract

AbstractObjectivesAdequate antiretroviral drug distribution into the female genital tract (FGT) could play an important role in reducing the risk of heterosexual and mother-to-child transmission of HIV. In this study, we investigated the combined influence of pregnancy and genetic polymorphisms on efavirenz pharmacokinetics in cervicovaginal fluid (CVF) of women receiving antiretroviral therapy.MethodsA total of 159 women (147 pregnant and 12 postpartum) living with HIV and receiving efavirenz-containing antiretroviral therapy were recruited across two sites in Nigeria (Federal Medical Centre, and Bishop Murray Medical Centre, Makurdi) between 2017-2020. In stage 1, sparse CVF and dried blood spot (DBS) samples were obtained from each participant during pregnancy to assess possible association between drug concentration andCYP2B6polymorphisms (516G>T and 983 T>C). In the second stage, participants were stratified into three genotype groups (extensive, intermediate and low metabolisers) and re-enrolled for intensive pharmacokinetic sampling.ResultsIn stage 1 (88 CVF, 81 plasma and 73 paired samples),CYP2B6 516G>Twas independently associated with both CVF (β = 997 ng/mL (90% CI: 598, 1357),p =5.7 x 10-5) and plasma (β = 1400 ng/mL (90% CI: 1051, 1748),p =5.7 x 10-9) efavirenz concentration during pregnancy. In the second stage (12 pregnant, 12 postpartum), median (IQR) efavirenz Cminin CVF during pregnancy versus postpartum was 243 ng/ml (168-402) vs 447 ng/ml (159-974), Cmaxwas 1031 ng/ml (595-1771) vs 1618 ng/ml (675-2695), and AUC0-24was 16465 ng.h/ml (9356-30417) vs 30715 ng.h/ml (10980-43714). Overall, median CVF-to-plasma AUC ratio was 0.34 during pregnancy and 0.46 postpartum. When patients were stratified usingCYP2B6 516G>T, efavirenz median clearance increased by 57.9% during pregnancy compared with postpartum control (p= 0.232) in patients with theCYP2B6516GT genotype. The AUC0-24h, Cmaxand Cminreduced by 33.8% ((p=0.182), 8.6% (0.175) and 59.5% (0.171) during pregnancy, with values of 20671 ng.h/ml (15993-28712), 1550 ng/ml (1090-2090) and 330 ng/ml (250-440), respectively, compared with 31229 ng.h/ml (27660-41873), 1695 ng/ml (1540-3003) and 814 ng/ml (486-981) during postpartum in this genotype.Median efavirenz Cminin CVF was 1.93 and 3.55 times higher than the PBIC90of 126 ng/ml in the pregnant and postpartum cohorts, respectively.ConclusionsEfavirenz is well distributed into the CVF, and both pregnancy and polymorphisms in its disposition genes affect CVF exposure.