Optimizing PrEP regimens for pregnant women in sub-Saharan Africa

项目摘要 撒哈拉以南非洲妇女在怀孕期间感染艾滋病毒的风险高得令人无法接受， 母乳喂养。恩曲他滨/富马酸替诺福韦酯每日口服暴露前预防（PrEP） (FTC/TDF）可有效减少艾滋病毒感染，并建议在怀孕期间使用。按标准FTC/TDF 然而，在怀孕期间，替诺福韦的药物浓度降低了23-58%，这引起了人们对 降低功效。在这项研究中，我们试图确定和评估每日口服PrEP的最佳剂量FTC/TDF 妊娠期，重点关注药代动力学（PK）和安全性结局。为了实现我们的目标，我们计划了几个 关键活动。剂量确定（第1阶段）：我们将对45名妊娠14-24周的孕妇进行随机分组 三种不同的FTC/TDF剂量-标准剂量（200 mg/300 mg）、150%标准剂量（300 mg/450 mg）和 200%标准剂量（400 mg/600 mg）。每个参与者将经历三个“周期”，包括14天的每日 口服PrEP，随后在24小时内进行密集PK采样。前两个周期将发生在第二个周期， 在指定的FTC/TDF剂量下的妊娠第三个三个月;第三个将在产后12周进行 并仅使用标准FTC/TDF。我们将比较替诺福韦二磷酸在外周血单核细胞 （PBMC）在每个妊娠三个月至产后对照条件，使用定义的边界， 生物等效性还将获得初步的安全性数据。独立审查：初步调查结果 阶段将由一个专家、多学科研究监测委员会独立审查， 建议增加FTC/TDF剂量（150% vs. 200%标准剂量）进行进一步研究。扩展安全 评估（第2阶段）：我们将112名妊娠14-24周的孕妇随机分为两组， 在直接观察下，每天给予标准剂量与增加FTC/TDF剂量，直至分娩。安全 监测将持续到怀孕、分娩和产后头六个月。我们将比较肾脏 功能、不良事件、骨矿物质密度、女性和婴儿的体重变化/生长以及妊娠 结果。我们将评估血浆、PBMC、红细胞、尿液和血浆中的FTC和TFV（及其代谢产物）， 宫颈阴道液PK建模：使用经验研究数据，我们将开发一个PK模型来估计 妊娠期间多个隔室的FTC和TDF浓度。我们的模型将考虑 可能影响药物浓度的因素（例如，体重、胎龄、肾功能）来预测 妊娠期更高暴露的安全性结局。这项研究将由一个经验丰富的团队领导， 研究人员，在艾滋病毒，临床试验，药理学和产科方面具有广泛的专业知识。我们的提案利用了 其合作机构的优势，包括大学强大的研究基础设施， 辛巴威.在这个奖项的过程中，我们将提供关键的见解，PK和安全性的FTC/TDF在 怀孕重要的是，这些发现将有助于优化PrEP方案，以实现一个重要但经常被忽视的目标。 人口：撒哈拉以南非洲的孕妇。

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 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 empiric 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.