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

项目摘要 南非有800多万人感染艾滋病毒，其中包括25万多名妇女， 每年怀孕，并且>50%的南澳女性超重/肥胖。1在南澳和全球范围内，度鲁特韦（DTG）- 基于抗逆转录病毒疗法（ART）的治疗正在扩大规模，作为首选的一线ART方案的一部分。然而，在这方面， DTG最近被认为是一种与体重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，2，3妊娠期肥胖与不良健康结果相关 4 -9，因为怀孕是一个关键时期，在此期间， 代谢健康不仅会影响产妇的长期健康，还会影响胎儿、新生儿，最终影响儿童的健康。 健康对于感染艾滋病毒的妇女及其子女来说，这些风险是无数的，包括艾滋病毒/抗逆转录病毒疗法， 体重增加和肥胖。我们研究的总体目标是调查DTG在妊娠中的影响 及其对艾滋病毒感染者（WLHIV）的代谢健康的致肥胖作用， 与未感染艾滋病毒的妇女及其子女相比，为了实现这一目标，我们将利用： (i)现有的NIH资助的研究基础设施在SA和（ii）NIH大型R 01机制，以招募1900 妊娠早期孕妇（633例WLHIV在妊娠期开始DTG，633例WLHIV继续DTG使用 从怀孕前，和633名妇女没有艾滋病毒）和他们的孩子，跟踪他们到两年。在这 队列中，我们将首先检查HIV和/或DTG使用（HIV/DTG）如何影响体重和 使用空气置换体积描记法测量妊娠期脂肪组织质量。我们将进一步调查 通过评估：a）热量和热量之间的平衡， 摄入和静息能量消耗，B）全身性和脂肪炎症、肠道完整性的标志物，和 饱腹感/饥饿感，和c）皮下脂肪组织（SAT）功能和稳态。接下来，我们将前往 研究如何艾滋病毒/DTG使用在怀孕和产后影响产妇代谢健康产后 （产后体重保持、肥胖、发育不良、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特征簇与母亲和儿童代谢健康相关， 我们将广泛应用代谢组学技术来测量孕妇和脐带血， 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，包括主队列内的较小嵌套队列和有效病例队列设计。 这项研究将在确定DTG的致肥胖机制和临床后果方面发挥关键作用 在WLHIV及其子女的妊娠期使用。我们的研究结果将为代谢 在艾滋病毒/抗逆转录病毒治疗的背景下减少疾病风险，确定干预的潜在目标，并向公众宣传 健康方法，以减少WLHIV及其子女在生命过程中的慢性合并症。

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.