Effects of HIV, antiretroviral therapy, and PrEP on placental structure and metabolic function

项目摘要 意义：抗逆转录病毒药物（ARV）用于治疗和预防育龄妇女的艾滋病毒感染 这是一个具有里程碑意义的公共卫生成功，避免了数百万儿童艾滋病毒感染。除了 越来越多的孕妇服用抗逆转录病毒药物作为艾滋病毒治疗，越来越多的孕妇服用抗逆转录病毒药物作为接触前预防 （PrEP）预防艾滋病毒感染。然而，最近的研究表明，怀孕期间的抗逆转录病毒药物也可能使 对胎盘和胎儿发育的风险。胎盘重量低、胎盘功能不全和母体血管 与未服用抗逆转录病毒药物的WHIV相比，服用抗逆转录病毒药物的WHIV中灌注不良更为常见， 受孕前使用抗逆转录病毒药物生下小于胎龄婴儿的风险比WHIV高35% 怀孕后开始抗逆转录病毒治疗抗逆转录病毒药物是挽救生命的艾滋病毒治疗和预防，但PrEP在孕妇中的安全性 他们的儿女，他们的儿女。关于PrEP在妊娠期的安全性信息 迫切需要改善抗逆转录病毒药物作为PrEP和艾滋病毒治疗的选择和管理， 风险时间创新：我们提出了第一项同时比较胎盘结构，血管生成， 和代谢能力之间的艾滋病毒未感染的妇女服用抗逆转录病毒药物作为PrEP，WHIV服用抗逆转录病毒药物，和艾滋病毒- 未感染的女性未服用抗逆转录病毒药物，以确定抗逆转录病毒药物和艾滋病毒对胎盘的独立影响。 我们提出的研究的明显优势包括1）同时收集和比较艾滋病毒暴露 和-未暴露和抗逆转录病毒药物暴露和-未暴露胎盘，和2）所有儿童的纵向观察 在出生后的头12个月，将胎盘检查结果与出生体重和婴儿生长联系起来。研究人员：我们的 拥有胎盘病理学和HIV流行病学专业知识的跨学科团队（PI Bebell，早期职业生涯 NIAID K23资助的研究者），关于艾滋病毒和抗逆转录病毒药物对胎盘影响的转化实验室工作 (Co-I Serghides）、生物统计学（Co-I Rabideau）和孕产妇保健（撰稿人Ngonzi），已做好准备， 完成这项工作。方法：我们将利用PI正在进行的储存胎盘和血浆样本 在乌干达的NIH职业发展奖（K23 AI 138856）队列中，来自入组妇女及其 和Serghides博士建立的实验室基础设施，以阐明艾滋病毒的独立影响 和抗逆转录病毒药物在胎盘上的暴露，以及这些变化对儿童早期生长的潜在作用， 这些特定的目的：1）通过母体ARV和HIV暴露来比较胎盘结构和血管生成 status. 2)比较孕妇抗逆转录病毒和艾滋病病毒暴露状况对胎盘代谢能力的影响。3)确定 胎盘结构和代谢能力对出生体重和婴儿生长的影响。识别机制 抗逆转录病毒相关的胎盘毒性具有很大的潜力，通过优化的PrEP改善妊娠结局 和ART疗法。利用收集的数据，我们将提交R 01提案，以研究胎盘异常 为特定的抗逆转录病毒治疗方案，以帮助确定最安全的选择孕妇。

PROJECT SUMMARY Significance: Antiretroviral medications (ARVs) to treat and prevent HIV infection in reproductive-aged women have been a landmark public health success, having averted millions of pediatric HIV infections. In addition to taking ARVs as HIV treatment, pregnant women are increasingly taking ARVs as pre-exposure prophylaxis (PrEP) against HIV infection. However, recent studies have shown that ARVs in pregnancy may also confer risks to the developing placenta and fetus. Low placenta weight, placental insufficiency, and maternal vascular malperfusion are more common among WHIV taking ARVs compared to WHIV not taking ARVs, and WHIV initiating ARVs pre-conception have a 35% higher risk of having a small-for-gestational-age baby than WHIV initiating ARVs post-conception. ARVs are life-saving HIV therapy and prevention, but PrEP safety in pregnant women, their fetuses, and their offspring is unknown. Information about the safety of PrEP in pregnancy is urgently needed to improve selection and management of ARVs as PrEP and HIV treatment during this high- risk time. Innovation: We propose the first study to simultaneously compare placenta structure, angiogenesis, and metabolic capacity between HIV-uninfected women taking ARVs as PrEP, WHIV taking ARVs, and HIV- uninfected women taking no ARVs to determine the independent effects of ARVs and HIV on the placenta. Distinct advantages of our proposed research include 1) simultaneous collection and comparison HIV-exposed and -unexposed and ARV-exposed and -unexposed placentas, and 2) longitudinal observation of all children over the first 12 months of life to relate placental findings to birth weight and infant growth. Investigators: Our interdisciplinary team with expertise in placental pathology and HIV epidemiology (PI Bebell, an early career NIAID K23-funded investigator), translational laboratory work on the placental effects of HIV and antiretrovirals (Co-I Serghides), biostatistics (Co-I Rabideau) and maternal health (contributor Ngonzi), is well-poised to complete this work. Approach: We will leverage stored placental and plasma samples from the PI's ongoing NIH Career Development Award (K23AI138856) cohort in Uganda, clinical data from enrolled women and their children, and Dr. Serghides' established laboratory infrastructure to elucidate the independent effects of HIV and ARV exposure on the placenta and potential contribution of these changes to early child growth through these specific aims: 1) Compare placental structure and angiogenesis by maternal ARV and HIV exposure status. 2) Compare placental metabolic capacity by maternal ARV and HIV exposure status. 3) Determine the effects of placental structure and metabolic capacity on birth weight and infant growth. Identifying mechanisms of ARV-related placental toxicities has great potential to improve pregnancy outcomes through optimized PrEP and ART regimens. Using data gathered we will submit an R01 proposal to investigate placental abnormalities for specific ARV regimens to help determine the safest options for pregnant women.