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: 10175397
• 负责人: ELAINE Janine ABRAMS
• 金额: $ 238.29万
• 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/10175397
• 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; 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 南非 (SA) 有超过 800 万人感染艾滋病毒，其中包括超过 250,000 名女性 每年怀孕，并且超过 50% 的南澳女性超重/肥胖。1 在南澳和全球范围内，多替拉韦 (DTG)- 基于抗逆转录病毒治疗 (ART) 的规模正在扩大，作为首选一线 ART 方案的一部分。然而， 最近，DTG 被认为是一种与体重和脂肪组织增加有关的致肥胖物质 与其他抗逆转录病毒药物相比有所增益。2,3 妊娠期肥胖与不良健康结果相关 对于母亲和儿童4-9，因为怀孕是一个关键时期，在此期间接触会导致身体状况发生变化 代谢健康不仅可能影响长期孕产妇健康，还可能影响胎儿、新生儿，最终影响儿童 健康。对于感染艾滋病毒的妇女 (WLHIV) 及其子女来说，这些暴露是无数的，包括艾滋病毒/抗逆转录病毒治疗、 体重增加和肥胖。我们研究的总体目标是调查 DTG 对妊娠的影响 及其对 HIV 感染女性 (WLHIV) 及其代谢健康的致肥胖影响 儿童，与未感染艾滋病毒的妇女及其孩子相比。为了实现这一目标，我们将利用： (i) 南澳现有 NIH 资助的研究基础设施和 (ii) NIH 大型 R01 机制招募 1900 名研究人员 妊娠第 1 个月的孕妇（633 WLHIV 在怀孕期间开始 DTG，633 WLHIV 继续使用 DTG） 对 633 名未感染艾滋病毒的妇女及其子女进行了为期两年的跟踪调查。在此范围内 队列中，我们将首先研究 HIV 和/或 DTG 的使用 (HIV/DTG) 如何影响体重和体重的纵向变化 使用排气体积描记法测量妊娠期脂肪组织量。我们将进一步调查 通过评估以下因素来评估妊娠期体重过度增加和脂肪生成的途径：a) 热量之间的平衡 摄入量和静息能量消耗，b) 全身性和脂肪炎症、肠道完整性的标志物，以及 饱腹感/饥饿感，以及 c) 皮下脂肪组织 (SAT) 功能和体内平衡。接下来，我们将前往 研究妊娠期和产后使用 HIV/DTG 如何影响产后产妇代谢健康 （产后体重滞留、肥胖、血糖异常、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）。要了解是否 代谢物和脂质亚种的特征簇与孕产妇和儿童代谢健康相关， 我们将应用广泛有针对性的代谢组学技术来测量母体（怀孕期间）和脐带血 代谢物、脂质亚种和类二十烷酸。为了解决不同的具体目标，我们将使用一系列 嵌套子研究，包括主要队列中较小的嵌套队列和有效的病例队列设计。 这项研究将在定义 DTG 的致肥机制和临床后果方面发挥关键作用 在 WLHIV 及其子女怀孕期间使用。我们的研究结果将为代谢提供见解 在艾滋病毒/抗逆转录病毒治疗背景下降低疾病风险，确定干预措施的潜在目标，并告知公众 减少 WLHIV 及其子女一生中慢性合并症的健康方法。