Optimizing PrEP regimens for pregnant women in sub-Saharan Africa

优化撒哈拉以南非洲孕妇的 PrEP 方案

• 批准号: 10395611
• 负责人: PETER L. ANDERSON
• 金额: $ 69.16万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-13 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10395611
• 关键词: AIDS prevention; Adherence; Adverse event; Africa South of the Sahara; Area; Award; Benchmarking; Birth; Body Weight; Body Weight Changes; Bone Density; Breast Feeding; Clinical; Clinical Trials; Creatinine clearance measurement; Data; Diphosphates; Discipline of obstetrics; Dose; Drug Kinetics; Effectiveness; Erythrocytes; Evaluation; Event; Face; Fumarates; Future; Gestational Age; Goals; Growth; HIV; HIV Infections; Hematology; Hepatitis B Therapy; Hour; Infant; Institution; International Maternal Pediatric Adolescent AIDS Clinical Trials; Intervention; Kidney; Life; Liquid substance; Measures; Modeling; Monitor; Oral; Outcome; Participant; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacology; Phase; Plasma; Population; Postpartum Period; Pregnancy; Pregnancy Outcome; Pregnancy Trimesters; Pregnant Women; Prophylactic treatment; Randomized; Regimen; Renal function; Reporting; Research Infrastructure; Research Personnel; Safety; Sampling; Second Pregnancy Trimester; Tenofovir; Therapeutic Equivalency; Third Pregnancy Trimester; Time; Universities; Urine; Woman; Zimbabwe; adverse pregnancy outcome; base; bone; cervicovaginal; design; emtricitabine; experience; follow-up; high risk; high risk population; infant outcome; insight; multidisciplinary; oral HIV; pharmacokinetic model; pre-exposure prophylaxis; predictive modeling; pregnant; primary outcome; safety assessment; safety outcomes

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.

项目摘要 撒哈拉以南非洲的妇女面临怀孕期间艾滋病毒康复的高风险 哺乳。每日口服预防预防（PREP），用富甲甲苯性甲己酸酯毒素毒素 （FTC/TDF）可有效减少艾滋病毒的获取，建议在怀孕中进行。在标准FTC/TDF处 但是，剂量在怀孕期间替诺福韦药物浓度降低了23-58％，引起了人们对 效率降低。在这项研究中，我们试图识别和评估每日口服准备的FTC/TDF的最佳剂量 在怀孕中，专注于药代动力学（PK）和安全结果。为了实现我们的目标，我们计划了几个 关键活动。剂量识别（第1阶段）：我们将在14-24周妊娠45名孕妇随机分配 到三种不同的FTC/TDF剂量 - 标准剂量（200mg/300mg），150％的标准剂量（300mg/450mg）和 200％标准剂量（400mg/600mg）。每个参与者将经历三个“周期”，每天完成14天 口服准备，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， 指定的FTC/TDF剂量时怀孕的第三个三个孕期；第三个将在产后12周举行 并仅使用标准FTC/TDF。我们将比较外周血单核细胞中的替诺福韦二磷酸 （PBMC）在每个怀孕三个月到产后控制状况，使用定义的边界 生物等效性。还将获得初步安全数据。独立评论：最初的发现 阶段将由专家，多学科研究监测委员会独立审查，该委员会将 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）：我们将在14-24周妊娠14-24周将112名孕妇随机分配 标准与增加的FTC/TDF剂量每天在直接观察下，直到交付时间为止。安全 监测将持续到怀孕，分娩和产后六个月。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/生长以及怀孕 结果。我们将在血浆，PBMC，红细胞，尿液和 宫颈阴道流体。 PK建模：使用经验研究数据，我们将开发一个估计的PK模型 怀孕期间，FTC和TDF的浓度跨多个隔间。我们的模型将考虑关键 可能影响药物浓度（例如体重，胎龄，肾功能）的因素以预测 在怀孕中暴露更长的安全结果。这项研究将由经验丰富的团队领导 研究人员，具有广泛的艾滋病毒，临床试验，药理学和妇产科专业知识。我们的建议利用 其合作机构的优势，包括大学的强大研究基础设施 津巴布韦。在此奖项的整个过程中，我们将对FTC/TDF的PK和安全性提供关键见解 孕。重要的是，这些发现将有助于优化重要但经常被忽视的准备方案 人口：撒哈拉以南非洲的孕妇。