Obesogenic origins of maternal and child metabolic health involving dolutegravir (ORCHID)

涉及多替拉韦 (ORCHID) 的孕产妇和儿童代谢健康的肥胖起源

• 批准号: 10268257
• 负责人: ELAINE Janine ABRAMS
• 金额: $ 229.44万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-25 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10268257
• 关键词: Address; Adipocytes; Adipose tissue; Affect; Air; Anti-Inflammatory Agents; Anti-Retroviral Agents; Arachidonic Acids; C-Peptide; Child; Child Health; Chronic; Clinical; Complex; Data; Docosahexaenoic Acid n-3; Dyslipidemias; Eicosanoids; Eicosapentaenoic Acid; Energy Intake; Energy Metabolism; Enrollment; Equilibrium; Exposure to; Fibrosis; First Pregnancy Trimester; Functional disorder; Funding; Goals; HIV; HIV Infections; HIV antiretroviral; Health; Homeostasis; Human Milk; Hunger; Hypertrophy; Hypoxia; Inflammation; Inflammatory; Insulin; Insulin Resistance; Integrase Inhibitors; Interleukin-6; Intervention; Leptin; Life; Life Cycle Stages; Link; Lipids; Lysophosphatidylcholines; Maternal Health; Measures; Metabolic; Metabolic Diseases; Mitochondria; Mothers; N-3 polyunsaturated fatty acid; Neonatal; Obesity; Omega-3 Fatty Acids; Omega-6 Fatty Acids; Outcome; Overweight; Pathway interactions; Pharmaceutical Preparations; Phospholipids; Play; Plethysmography; Polyunsaturated Fatty Acids; Population; Postpartum Period; Pregnancy; Pregnant Women; Public Health; Regimen; Research Infrastructure; Research Project Grants; Research Support; Respiration; Rest; Risk Reduction; Role; Satiation; Series; Shapes; South Africa; Techniques; Time; Triglycerides; Umbilical Cord Blood; United States National Institutes of Health; Weight; Weight Gain; Woman; Women' s Health; adiponectin; alpha-Melanocyte stimulating hormone; antiretroviral therapy; base; cohort; comorbidity; critical period; design; excessive weight gain; fetal; gestational weight gain; ghrelin; in utero; insight; intestinal fatty acid binding protein; metabolomics; obesogen; obesogenic; postpartum health; postpartum weight; pregnant; prenatal exposure; prepregnancy; recruit; scale up; subcutaneous

PROJECT ABSTRACT More than 8 million people are living with HIV in South Africa (SA), including >250,000 women who become pregnant annually, and >50% of SA women are overweight/obese.1 In SA and globally, Dolutegravir (DTG)- based antiretroviral therapy (ART) is being scaled up as part of the preferred 1st-line ART regimen. However, DTG has recently been implicated as an obesogen that is associated with increased weight and adipose tissue gain compared to other antiretroviral agents.2,3 Obesity in pregnancy is associated with poor health outcomes for both mother and child4-9 as pregnancy is a critical period during which exposures leading to alterations in metabolic health may influence not only long-term maternal health but also fetal, neonatal, and ultimately child health. For women living with HIV (WLHIV) and their children, these exposures are myriad, including HIV/ART, weight gain, & obesity. The overall goal of our study is to investigate the impact of DTG in pregnancy and its obesogenic effects on the metabolic health of women living with HIV (WLHIV) and their children, compared to women without HIV and their children. To address this goal, we will leverage: (i) existing NIH-funded research infrastructure in SA and (ii) the NIH large R01 mechanism to enroll 1900 pregnant women in the 1st trimester (633 WLHIV initiating DTG in pregnancy, 633 WLHIV continuing DTG use from pre-pregnancy, and 633 women without HIV) and their children, following them to two years. Within this cohort, we will first examine how HIV and/or DTG use (HIV/DTG) impacts longitudinal changes in weight and adipose tissue mass in pregnancy using air displacement plethysmography. We will further investigate pathways of excess gestational weight gain and adipose accrual by evaluating: a) the balance between caloric intake and resting energy expenditure, b) markers of systemic and adipose inflammation, gut integrity, and satiety/hunger, and c) subcutaneous adipose tissue (SAT) function and homeostasis. Following this, we will go on to examine how HIV/DTG use in pregnancy and postpartum affects maternal metabolic health postpartum (postpartum weight retention, adiposity, dysglycemia, insulin resistance, and dyslipidemia) as well as neonatal and child metabolic health (weight, adiposity, insulin resistance and dyslipidemia). To understand whether signature clusters of metabolites and lipid subspecies are associated with maternal and child metabolic health, we will apply widely targeted metabolomics techniques to measure maternal (in pregnancy) and cord blood metabolites, lipid subspecies, and eicosanoids. To address the different specific aims we will use a series of nested substudies, including smaller nested cohorts and efficient case-cohort designs, within the main cohort. This study will play a pivotal role in defining the obesogenic mechanisms and clinical consequences of DTG use in pregnancy in WLHIV and their children. The results of our study will provide insights into metabolic disease risk reduction in the context of HIV/ART, identify potential targets for interventions, and inform public health approaches to diminish chronic co-morbidities over the life course for WLHIV and their children.

项目摘要 超过800万人在南非（SA）感染了艾滋病毒，其中包括25万名妇女 每年怀孕，> 50％的SA女性超重/肥胖。1在SA和全球，DoluteGravir（DTG） - 基于抗逆转录病毒疗法（ART）正在作为首选一线艺术方案的一部分进行缩放。然而， DTG最近被认为是与体重增加和脂肪组织增加有关的肥胖原 与其他抗逆转录病毒药物相比，增益。2,3怀孕的肥胖与健康状况不佳有关 对于母亲和儿童4-9作为怀孕是关键时期，在此期间暴露导致改变 代谢健康不仅可能影响长期的孕产妇健康，还会影响胎儿，新生儿和最终儿童 健康。对于患有艾滋病毒（WLHIV）及其子女的妇女，这些暴露是无数的，包括艾滋病毒/艺术 体重增加和肥胖。我们研究的总体目标是研究DTG在怀孕中的影响 及其对艾滋病毒（WLHIV）妇女代谢健康的肥胖作用及其 与没有艾滋病毒的妇女及其子女相比。为了解决这个目标，我们将利用： （i）SA中现有的NIH资助研究基础设施和（ii）NIH大R01机制1900 孕妇在第一个三个月（633 WLHIV在怀孕中启动DTG，633 WLHIV继续使用DTG 从怀孕前和633名没有艾滋病毒的妇女及其子女，跟随她们两年。在此 队列，我们​​将首先研究HIV和/或DTG使用（HIV/DTG）如何影响体重的纵向变化和 脂肪组织质量在妊娠中使用空气位移。我们将进一步调查 通过评估妊娠体重增加和脂肪量过剩的途径：a）热量之间的平衡 摄入和静止的能量消耗，b）系统性和脂肪炎症的标记，肠道完整性以及 饱腹感/饥饿，c）皮下脂肪组织（SAT）功能和稳态。之后，我们将去 继续检查艾滋病毒/DTG在怀孕和产后的使用如何影响孕产后的产后孕产后 （产后保留，肥胖，血糖，胰岛素抵抗和血脂异常）以及新生儿 和儿童代谢健康（体重，肥胖，胰岛素抵抗和血脂异常）。了解是否 代谢物和脂质亚种的签名簇与母亲和儿童代谢健康有关， 我们将应用广泛靶向的代谢组学技术来测量母体（怀孕）和脐带血 代谢产物，脂质亚种和类花生素。为了解决不同的特定目标，我们将使用一系列 主队列内的嵌套下属，包括较小的嵌套队列和有效的案例 - 可容纳设计。 这项研究将在定义DTG的肥胖机制和临床后果方面发挥关键作用 在WLHIV及其子女中使用怀孕。我们的研究结果将为代谢提供见解 艾滋病毒/艺术背景下的疾病风险降低，确定干预措施的潜在目标，并告知公众 健康方法是减少WLHIV及其子女生活课程的慢性合并症。