Evaluating Infant PrEP Exposure During Pregnancy and Breastfeeding

在艾滋病毒高流行地区，妇女在怀孕和哺乳期间感染艾滋病毒的风险很高。去保护 世界卫生组织妇女和消除母婴艾滋病毒传播目标 建议向艾滋病毒阴性的孕妇/产后提供口服暴露前预防(PrEP) 高负担设置。到目前为止，还没有对产前使用PrEP的大规模纵向安全性评估 进行了调查，没有超过12个月的长期数据。这项拟议的研究旨在量化婴儿出生前的 和出生后PrEP暴露，并评估PrEP后的出生、骨骼、生长和神经认知结果 通过孩子5岁生日的曝光。我们的总体目标是定义一个全面的安全概况 产前/产后PrEP在一个独特的持续集群中的应用--肯尼亚比较PrEP分娩方法的随机对照试验 在4500名孕妇中(PRIMA研究，R01AI125498，MPI：John-Stewart/Baeten)。通过利用现有的 Prima基础设施，将随访期从9个月延长到60个月，并在此收集新的成果数据 史无前例的队列，我们在评估婴儿PrEP暴露和结果方面具有独特的地位。我们的目标是： 目标1-通过母婴配对分析，量化婴儿在宫内和母乳中的PrEP暴露 头发样本。头发样本将从参加PRIMA的母婴对中收集，以评估PrEP 通过停止母乳喂养在子宫内暴露。头发中的预备物浓度将使用 验证了LC-MS/MS方法。PrEP的婴儿和母亲毛发浓度的比率(代表 将对母婴转移)进行评估。我们还将确定PrEP的使用时间、妊娠期 PrEP开始时的年龄、产妇年龄和婴儿性别与毛发水平和比例有关。 假设：在分娩时，婴儿头发中可以检测到PREP，并与母亲头发中的水平相关。 婴儿出生时PrEP水平将达到峰值，当接触母乳有限时，PrEP水平会下降。 目的2-确定产前暴露于PrEP是否与不良分娩和婴儿结局有关。我们会 比较流产、死产、早产、低出生体重和小于胎龄儿的发生率， 任何产前暴露、暴露三个月和测量的暴露量对婴儿生长的影响 由产妇的PrEP药物水平决定。假设：产前使用PrEP与不良结局无关。 目的3-评估孕期和哺乳期PrEP暴露是否与婴儿和 儿童骨骼发育、神经认知或生长发育结果长达60个月。我们将测量骨矿物质 密度使用双能x射线吸收测量仪，进行神经认知评估，并测量生长 PRIMA中母婴配对的扩展队列，以检测PrEP暴露的差异(二进制和层级 PrEP药物水平)。假设：母亲的PrEP不会导致儿童早期结局的改变。 这些高度创新的研究将提供全面的、长期的结果数据，并提供准确的暴露 迄今为止妊娠评估中最大的PrEP的量化。

In high HIV prevalence regions, women are at high risk for HIV during pregnancy and breastfeeding. To protect women and reach elimination of mother-to-child HIV transmissions targets, the World Health Organization recommends offering oral pre-exposure prophylaxis (PrEP) to HIV-negative pregnant/postpartum women in high-burden settings. To date, no large-scale longitudinal safety evaluation of prenatal PrEP use has been conducted and there are no long-term data beyond 12 months. The proposed study aims to quantify infant pre- and postnatal PrEP exposure and evaluate birth, bone, growth, and neurocognitive outcomes following PrEP exposure through the child’s 5th birthday. Our overall goal is to define a comprehensive safety profile of prenatal/postpartum PrEP in a unique ongoing cluster-RCT in Kenya that compares PrEP delivery approaches in >4500 pregnant women (PrIMA Study, R01AI125498, MPI: John-Stewart/Baeten). By leveraging existing PrIMA infrastructure, extending follow up from 9 to 60 months, and collecting new outcome data in this unprecedented cohort, we are uniquely positioned to assess infant PrEP exposure and outcomes. Our aims: Aim 1-Quantify infant PrEP exposure in utero and via breastmilk through a paired analysis of mother-infant hair samples. Hair samples will be collected from mother-infant pairs enrolled in PrIMA to assess PrEP exposure in utero through breastfeeding cessation. PrEP concentrations in hair will be quantified using validated LC-MS/MS methods. Ratios of infant-to-maternal hair concentrations of PrEP (representing degree of maternal-to-infant transfer) will be assessed. We will also determine whether duration of PrEP use, gestational age at PrEP initiation, maternal age, and infant sex are associated with hair levels and ratios. Hypothesis: PrEP will be detectable in infant hair at delivery and will correlate with levels in maternal hair. Infant PrEP levels will peak at birth and decrease when exposure is limited to breastmilk. Aim 2–Determine whether prenatal PrEP exposure is associated adverse birth and infant outcomes. We will compare frequency of miscarriage, stillbirth, preterm birth, low birth birthweight, and small-for-gestational age, and infant growth by any prenatal PrEP exposure, trimester of exposure, and quantity of exposure measured by maternal PrEP drug levels. Hypothesis: Prenatal PrEP use will not be associated with adverse outcomes. Aim 3–Evaluate whether PrEP exposure during pregnancy and breastfeeding is associated with infant and child bone development, neurocognitive, or growth outcomes up to 60 months. We will measure bone mineral density using dual energy x-ray absorptiometry, conduct neurocognitive assessments, and measure growth in an extension cohort of mother-infant pairs in PrIMA to detect differences by PrEP exposure (binary and strata of PrEP drug levels). Hypothesis: Maternal PrEP will not result in changes in early childhood outcomes. These highly innovative studies will provide comprehensive, long-term outcome data, with precise exposure quantification in the largest PrEP in pregnancy evaluation to date.