Metabolic impact of ART on women living with HIV and their infants

Project Summary People living with HIV in Sub-Saharan Africa and elsewhere have weight gain with integrase strand transfer inhibitor (INSTI)-based treatment regimens. Weight gain with Dolutegravir (DTG), an INSTI, has also been observed in postpartum women although how DTG-regimens affects postpartum weight is not known. Understanding the impact of maternal DTG-regimens on the physiology of postpartum body weight regulation has clinical significance as postpartum weight retention is known to increase future maternal risk of overweight, obesity and non-communicable diseases (NCD). With the ongoing scale-up of DTG in Sub-Saharan Africa for HIV management, our understanding of how DTG regimens affect the physiology of postpartum body weight regulation could help identify potential interventions to reduce future overweight and NCD risk in this population. To address this research gap, in aim 1 of this study, we propose to initiate a prospective cohort study in Uganda of postpartum women with HIV on DTG and non-DTG based regimens, as well as a control group without HIV. In this cohort, we will study how DTG-regimens, as compared to non-DTG regimens or women without HIV, affects the macro-phenotype (i.e. energy intake and expenditure) and micro-phenotype (i.e. metabolic profile) of the physiology of body weight regulation in postpartum women. Metabolic profile includes assessment of orexigenic and anti-orexigenic peptides and hormones, short-chain fatty acids, and unbiased `omics' approaches. Aim 2 of this study will leverage the postpartum cohort to also follow their breastfeeding infants for similar investigations of how maternal DTG-regimens affects infant energy intake, expenditure and metabolic profile. Further, by comparing to infants born to mothers without HIV, our study will help us understand the physiology of growth deficits observed in infants born to mothers with HIV (and on non-DTG regimens), one of the most clinically significant outcomes in this population; and to understand whether DTG impacts are similar to other ARTs. Our overall hypothesis is that maternal DTG-based ART regimens will result in increased maternal and infant energy intake, with increased appetite and a dysregulated metabolic profile. Through these two aims, we address an urgent need to understand how maternal HIV and DTG impacts the physiology of body weight regulation in postpartum women and their HIV-exposed uninfected (HEU) infants. These maternal-infant populations have a unique physiological profile with increased energy demands on the lactating mother and breastfeeding infant to sustain growth. In addition to improving our understanding of the physiology, our detailed metabolic assessments will further help identify potential therapeutics (e.g. related to intake/appetite, expenditure, or metabolic pathways) for management of postpartum weight and infant growth in maternal-infant populations with HIV.