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

HIV、抗逆转录病毒治疗和 PrEP 对胎盘结构和代谢功能的影响

• 批准号: 10453670
• 负责人: Lisa M Bebell
• 金额: $ 16.5万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-19 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10453670
• 关键词: AIDS prevention; Address; Affect; Amino Acids; Angiogenic Factor; Anti-Retroviral Agents; Benefits and Risks; Biometry; Birth; Birth Weight; Blood Vessels; Breast Feeding; Child; Child Health; Clinical; Clinical Data; Cohort Studies; Collection; Combination Medication; Conceptions; Country; Data; Enrollment; Epidemiology; FRAP1 gene; Fetal Growth; Fetus; Fumarates; Funding; Glucose Transporter; Goals; Growth; HIV; HIV Infections; HIV antiretroviral; HIV therapy; Individual; Infant; Infrastructure; K-Series Research Career Programs; Knowledge; Laboratories; Life; Low Birth Weight Infant; Maternal Health; Metabolic; Metabolism; National Institute of Allergy and Infectious Disease; Oral; Outcome; Pathology; Pathway interactions; Persons; Pharmaceutical Preparations; Placenta; Placental Insufficiency; Placental Toxicity; Placentation; Plasma; Positioning Attribute; Pregnancy; Pregnancy Outcome; Pregnant Women; Prevention; Protocols documentation; Public Health; Publishing; Regimen; Research; Research Infrastructure; Research Personnel; Risk; Safety; Sampling; Savings; Small for Gestational Age Infant; Somatomedins; Structure; Tenofovir; Testing; Time; Toxic effect; Uganda; United States National Institutes of Health; Weight; Woman; Women' s Group; Work; World Health Organization; aged; angiogenesis; antiretroviral therapy; career; cohort; comorbidity; fetal; high risk; improved; innovation; maternal outcome; offspring; pediatric human immunodeficiency virus infection; pre-exposure prophylaxis; prevent; reproductive; success; systematic review

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.

项目摘要 意义：抗逆转录病毒药物（ARV）治疗和预防生殖妇女的HIV感染 已经是具有里程碑意义的公共卫生成功，避免了数百万个小儿艾滋病毒感染。此外 将ARV作为HIV治疗，孕妇越来越多地将ARV作为预防前的预防 （准备）针对HIV感染。但是，最近的研究表明，怀孕中的ARV也可能会授予 胎盘和胎儿的风险。胎盘重量低，胎盘不足和母体血管 与不服用ARV相比，在服用ARV的WHIV中更为常见，WHIV 启动ARV前召开前的孕期婴儿的风险比WHIV高35％ 启动ARV概念后。 ARV是挽救生命的艾滋病毒疗法和预防，但在怀孕的准备安全性 妇女，胎儿和后代尚不清楚。有关怀孕准备安全性的信息是 在这种高度的情况下，迫切需要改善ARV的选择和管理为PREP和HIV治疗 风险时间。创新：我们提出了第一项研究，以同时比较胎盘结构，血管生成， 与艾滋病毒未感染的妇女一起服用ARV作为PREP，服用ARV和HIV-之间的代谢能力 未感染的妇女不服用ARV来确定ARV和HIV对胎盘的独立影响。 我们提出的研究的不同优势包括1）同时收集和比较HIV暴露 以及 - 无暴露和ARV暴露且无暴露的胎盘，以及2）所有儿童的纵向观察 在生命的前12个月中，将胎盘发现与出生体重和婴儿生长联系起来。调查人员：我们的 跨学科团队具有胎盘病理学和艾滋病毒流行病学专业知识（Pi Bebell，早期职业生涯 NIAID K23资助的研究者），关于HIV和抗逆转录病毒的胎盘作用的转化实验室工作 （Co-i Serghides），生物统计学（Co-I Rabideau）和孕产妇健康（贡献者Ngonzi），已妥善化为 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品 NIH职业发展奖（K23AI138856）在乌干达，来自注册妇女及其的临床数据 儿童和Serghides博士建立的实验室基础设施，以阐明HIV的独立影响 通过胎盘的ARV暴露以及这些变化对早期儿童成长的潜在贡献 这些具体目的：1）比较母体ARV和HIV暴露的胎盘结构和血管生成 地位。 2）通过母体ARV和HIV暴露状况比较胎盘代谢能力。 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 与ARV相关的胎盘毒性的巨大潜力可以通过优化的PREP提高妊娠结局 和艺术方案。使用收集的数据，我们将提交R01提案以调查胎盘异常 用于特定的ARV方案，以帮助确定孕妇最安全的选择。