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

项目摘要 南非有超过800万艾滋病毒携带者，其中包括25万名女性 每年怀孕，50%的SA妇女超重/肥胖。1在SA和全球范围内，多洛替格列韦(DTG)- 基于抗逆转录病毒疗法(ART)的规模正在扩大，作为首选的一线ART方案的一部分。然而， DTG最近被认为是一种肥胖因素，与体重和脂肪组织的增加有关 与其他抗逆转录病毒药物相比，体重增加。2，3孕期肥胖与不良健康结局相关 对于母亲和孩子来说，4-9因为怀孕是一个关键时期，在此期间暴露会导致 新陈代谢健康不仅可能影响长期的产妇健康，还可能影响胎儿、新生儿，并最终影响儿童 健康。对于艾滋病毒携带者(WLHIV)妇女及其子女来说，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。本研究的总体目标是研究糖尿病糖原对妊娠的影响。 及其对HIV感染者(WLHIV)代谢健康的肥胖效应 儿童，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)南卡罗来纳州由NIH资助的现有研究基础设施和(Ii)NIH大型R01机制，以招收1900人 妊娠前三个月的孕妇(633名WLHIV在孕期开始服用DTG，633名WLHIV继续使用DTG 从怀孕前到未感染艾滋病毒的633名妇女)及其子女，随访至两年。在这个范围内 首先，我们将检查HIV和/或DTG的使用(HIV/DTG)如何影响体重和 空气置换体积描记法测定妊娠期脂肪组织质量。我们将进一步调查 通过评估：A)热量平衡来评估妊娠超重增加和脂肪增加的途径 摄入和静息能量消耗，b)全身和脂肪炎症的标志物，肠道完整性，以及 饱腹感/饥饿感，以及c)皮下脂肪组织(SAT)功能和动态平衡。在此之后，我们将前往 探讨孕期和产后使用HIV/DTG对产后母体代谢健康的影响 (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 代谢物和脂肪亚种的标志性簇与母婴代谢健康有关， 我们将广泛应用有针对性的代谢组学技术来测量孕妇(孕期)和脐带血。 代谢物、类脂亚种和二十烷类化合物。为了解决不同的具体目标，我们将使用一系列 主要队列内的嵌套子研究，包括较小的嵌套队列和有效的病例队列设计。 这项研究将在明确DTG的肥胖致病机制和临床后果方面发挥关键作用 在WLHIV及其子女孕期使用。我们的研究结果将提供对新陈代谢的洞察 在艾滋病毒/抗逆转录病毒疗法的背景下减少疾病风险，确定潜在的干预目标，并告知公众 卫生方法，以减少WLHIV及其子女在一生中的慢性并存。

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.