R01AI157859

Optimizing Prep Regimens for Pregnant Women in Sub-Saharan Africa - Project Summary

Women in Sub-Saharan Africa face an unacceptably high risk of HIV acquisition during pregnancy and breastfeeding. Daily oral pre-exposure prophylaxis (PreP) with emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) is effective in reducing HIV acquisition and is recommended in pregnancy. At standard FTC/TDF doses, however, tenofovir drug concentrations are 23-58% lower during pregnancy, raising concerns about reduced efficacy.

In this study, we seek to identify and evaluate the optimal dose of FTC/TDF for daily oral PreP in pregnancy, focusing on pharmacokinetic (PK) and safety outcomes. To accomplish our aims, we plan several key activities.

Dose Identification (Stage 1): We will randomize 45 pregnant women at 14-24 weeks gestation to three different FTC/TDF doses—standard dose (200mg/300mg), 150% standard dose (300mg/450mg), and 200% standard dose (400mg/600mg). Each participant will undergo three "cycles" comprising 14 days of daily oral PreP, followed by intensive PK sampling over 24 hours. The first two cycles will occur in the second and third trimesters of pregnancy at the assigned FTC/TDF dose; the third will take place at 12 weeks postpartum and use only standard FTC/TDF. We will compare tenofovir diphosphate in peripheral blood mononuclear cells (PBMCs) in each pregnancy trimester to the postpartum control condition, using defined boundaries for bioequivalence. Preliminary safety data will also be obtained.

Independent Review: Findings from this initial stage will be independently reviewed by an expert, multidisciplinary study monitoring committee, which will recommend an increased FTC/TDF dose (150% vs. 200% standard dose) for further study.

Extended Safety Assessment (Stage 2): We will randomize 112 pregnant women at 14-24 weeks gestation to receive either standard vs. increased FTC/TDF doses on a daily basis, under direct observation, until the time of delivery. Safety monitoring will continue through pregnancy, delivery, and the first six months postpartum. We will compare renal function, adverse events, bone mineral density, weight change/growth in women and infants, and pregnancy outcomes. We will evaluate FTC and TFV (and their metabolites) in plasma, PBMCs, red blood cells, urine, and cervicovaginal fluid.

PK Modeling: Using empirical study data, we will develop a PK model that estimates concentrations of FTC and TDF across multiple compartments during pregnancy. Our model will consider key factors that may influence drug concentrations (e.g., body weight, gestational age, renal function) to predict safety outcomes for lengthier exposures in pregnancy.

This study will be led by an experienced team of researchers, with extensive expertise in HIV, clinical trials, pharmacology, and obstetrics. Our proposal leverages the strengths of its partnering institutions, including the robust research infrastructure at the University of Zimbabwe. Over the course of this award, we will provide key insights into the PK and safety of FTC/TDF in pregnancy. Importantly, these findings will help to optimize PreP regimens for an important but often overlooked population: pregnant women in Sub-Saharan Africa.

University Of North Carolina At Chapel Hill

NOT APPLICABLE

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Chapel Hill, North Carolina 27599 United States

Single Zip Code

Research Project Grant (Parent R01 Clinical Trial Required) (PA-20-183)

Amendment Since initial award the End Date has been extended from 03/31/26 to 03/31/27 and the total obligations have increased 381% from $686,617 to $3,304,965.