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

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.