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.

项目概要 意义：抗逆转录病毒药物（ARV）可治疗和预防育龄妇女的艾滋病毒感染 是一项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。此外 使用抗逆转录病毒药物作为艾滋病毒治疗方法，孕妇越来越多地使用抗逆转录病毒药物作为暴露前预防 (PrEP) 对抗 HIV 感染。然而，最近的研究表明，妊娠期抗逆转录病毒药物也可能会导致 对发育中的胎盘和胎儿有风险。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 患者相比，服用抗逆转录病毒药物的 WHIV 患者灌注不良更为常见，并且 WHIV 受孕前开始抗逆转录病毒药物（ARV）生下小于胎龄儿的风险比注射 WHIV 的风险高 35% 受孕后开始抗逆转录病毒药物。抗逆转录病毒药物是挽救生命的艾滋病毒治疗和预防，但孕妇的 PrEP 安全性 妇女、她们的胎儿和后代尚不清楚。有关妊娠期 PrEP 安全性的信息是 在这一高风险时期，迫切需要改进作为 PrEP 和 HIV 治疗的抗逆转录病毒药物的选择和管理。 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、 服用抗逆转录病毒药物作为 PrEP 的未感染艾滋病毒的妇女、服用抗逆转录病毒药物的艾滋病毒感染者和艾滋病毒感染者之间的代谢能力 未服用抗逆转录病毒药物的未感染妇女，以确定抗逆转录病毒药物和艾滋病毒对胎盘的独立影响。 我们提出的研究的独特优势包括 1) 同时收集和比较 HIV 暴露者 -未暴露和抗逆转录病毒暴露以及 -未暴露的胎盘，以及 2) 对所有儿童的纵向观察 在生命的前 12 个月内，将胎盘检查结果与出生体重和婴儿生长联系起来。调查员：我们的 具有胎盘病理学和艾滋病毒流行病学专业知识的跨学科团队（PI Bebell，早期职业 NIAID K23 资助的研究员），关于 HIV 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（贡献者 Ngonzi），已做好准备 完成这项工作。方法：我们将利用 PI 正在进行的研究中存储的胎盘和血浆样本 乌干达 NIH 职业发展奖 (K23AI138856) 队列，来自登记女性及其她们的临床数据 儿童，以及 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 胎盘上的抗逆转录病毒药物暴露以及这些变化对儿童早期生长的潜在贡献 这些具体目标： 1) 通过母体 ARV 和 HIV 暴露比较胎盘结构和血管生成 地位。 2) 比较孕产妇抗逆转录病毒药物和艾滋病毒暴露状况的胎盘代谢能力。 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 抗逆转录病毒相关胎盘毒性的研究具有通过优化 PrEP 改善妊娠结局的巨大潜力 和 ART 治疗方案。利用收集到的数据，我们将提交 R01 提案来调查胎盘异常 了解具体的抗逆转录病毒治疗方案，以帮助确定对孕妇最安全的选择。