Population Pharmacokinetic Modeling and Clinical Trial Simulation to optimize HIV Prevention in Pregnancy and Postpartum

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ABSTRACT Pre-exposure prophylaxis (PrEP) with oral tenofovir (TFV) disoproxil fumarate (TDF) and emtricitabine (F or FTC) (F/TDF) is recommended during pregnancy for women at risk for HIV acquisition. F/tenofovir alafenamide fumarate (F/TAF) is not yet approved for PrEP in cisgender women due to lack of efficacy data. Despite the importance of HIV prevention in pregnancy, pregnant women have been excluded from PrEP efficacy studies. PrEP efficacy in pregnancy cannot be extrapolated from non-pregnant populations, as multiple studies indicate that TFV concentrations fall substantially in the 2nd and 3rd trimesters due to increased renal clearance and volume of distribution. Significant declines in FTC concentration are also reported largely due to increased renal excretion. Unlike TDF, TAF has minimal renal clearance, though other changes associated with pregnancy may also reduce its concentration. Given the high TFV blood concentrations required in non-pregnant women to achieve protective concentrations in cervicovaginal tissue, near perfect adherence to F/TDF is required to achieve HIV protection. The decreased TFV and FTC concentrations observed during pregnancy raise concern that a significant proportion of pregnant women on F/TDF for PrEP would not achieve protective concentrations without upward dose adjustment. In anticipation of the eventual approval of F/TAF for HIV prevention in cisgender women, evaluation of pharmacokinetic (PK) parameters and appropriate dosing of both F/TDF and F/TAF for PrEP in pregnancy is critically important to the prevention of both maternal and perinatal transmission. To assist with the future design of clinical trials to correct for this probable underdosing of F/TDF and, possibly, F/TAF, we propose an exploration of F/TAF and F/TDF PK parameters in pregnancy and postpartum. We plan to use F/TDF and F/TAF PK data from completed clinical studies enrolling non-pregnant and pregnant cisgender women in both the treatment and prevention settings, including IMPAACT 1026s, CONRAD 137 and 140, MTN 001, HPTN 066, Partners PrEP, Partners Demonstration Project, and several Gilead PK trials. Our specific aims are to: 1. Build a population PK model of F/TDF and F/TAF related drug analytes with special focus on timing relative to pregnancy in addition to variation in demographic and physiologic variables and building on existing PK models and 2. Simulate two clinical trials, one of F/TAF and one of F/TDF PrEP dosing in pregnancy and postpartum to assist with the future design of clinical trials to validate pregnancy- adjusted doses to maintain non-pregnant levels of HIV protection throughout pregnancy. This population PK research is the critical next step toward a prospective randomized clinical trial to better protect pregnant women and their fetuses against HIV acquisition and is in line with the NICHD Maternal and Pediatric Infectious Disease Branch and Office of AIDS research's stated high priority of “reducing the incidence of HIV” and “adverse pregnancy and infant outcomes related to prevention”.