Optimizing PrEP regimens for pregnant women in sub-Saharan Africa

项目总结 撒哈拉以南非洲的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/富马酸替诺福韦每日口服暴露前预防(PrEP) (FTC/TDF)在减少艾滋病毒感染方面是有效的，建议在怀孕期间使用。在标准FTC/TDF上 然而，在怀孕期间，替诺福韦的药物浓度降低了23%-58%，这引发了人们对 降低了药效。在这项研究中，我们试图确定和评估每日口服PrEP的FTC/TDF的最佳剂量 在怀孕期间，重点关注药代动力学(PK)和安全结局。为了实现我们的目标，我们计划了几个 关键活动。剂量鉴定(阶段1)：我们将随机选择45名怀孕14-24周的孕妇 对于三种不同的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”，包括每天14天 口服PrEP，然后在24小时内进行密集的PK采样。前两个周期将发生在第二个周期和 妊娠晚期，给予FTC/TDF剂量；第三次将在产后12周进行 并且只使用标准的FTC/TDF。我们将比较外周血单核细胞中的替诺福韦二磷酸 (PBMCs)在每个妊娠三个月到产后控制条件，使用定义的边界 生物等效性。还将获得初步的安全数据。独立审查：初步审查结果 阶段将由多学科研究监测委员会这一专家独立审查，该委员会将 建议增加FTC/TDF剂量(150%对200%标准剂量)以供进一步研究。扩展的安全性 评估(阶段2)：我们将随机选择112名怀孕14-24周的孕妇接受 在直接观察下，每天的标准剂量与增加的FTC/TDF剂量，直到交付时间。安全问题 监测将持续到怀孕、分娩和产后前六个月。我们会比较肾脏 妇女和婴儿的功能、不良事件、骨密度、体重变化/生长，以及怀孕 结果。我们将评估血浆、PBMC、红细胞、尿液和尿液中的FTC和TFV(及其代谢物)。 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，以估计 妊娠期间多个隔室的FTC和TDF浓度。我们的模型将考虑关键 可能影响药物浓度预测的因素(如体重、胎龄、肾功能) 孕期较长时间暴露的安全后果。这项研究将由一支经验丰富的 在艾滋病毒、临床试验、药理学和产科方面拥有广泛专业知识的研究人员。我们的提案充分利用了 其合作机构的优势，包括加州大学强大的研究基础设施 津巴布韦。在获奖过程中，我们将提供对FTC/TDF的PK和安全性的关键见解 怀孕了。重要的是，这些发现将有助于优化PrEP方案，以治疗重要但经常被忽视的 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.