SUMMARY About 30% of people living with HIV (PLWH) in low- and middle- income countries are overweight/obese, which contributes to substantial morbidity and mortality. Alarmingly, the ADVANCE Trial data in South Africa has shown that in PLWH, initiating a dolutegravir (DTG)- vs. an efavirenz-containing ART regimen is associated with excessive (≥10%) weight gain. While this weight gain may reflect a positive return-to-health effect, it may also increase the risk of cardiometabolic complications. Due to its high potency, low resistance, single daily pill coformulation, and relatively low cost, DTG is expected to play a major role in HIV treatment in Africa. Little is known about the magnitude, clinical significance, and biologic mechanisms of DTG-related weight gain, which disproportionally affects Africans and in particular, African women. Studies investigating weight gain associated with switching from an efavirenz- to a DTG-containing ART regimen are lacking and thus critically needed to provide important and novel insights. We propose, therefore, a 12-month prospective cohort study of African men and women: PLWH who switch to DTG-based ART (N=70) (Group A), PLWH remaining on non-DTG-based ART (N=70) (Group B), and an HIV-uninfected control group (N=70) (Group C, to account for aging effect on weight gain) in Cape Town, South Africa. The specific aims are: 1) To assess the effects of switching to a DTG-based ART regimen on body composition, ectopic fat deposition, and cardiometabolic profile for PLWH; 2) To explore potential mechanisms of DTG-associated weight gain by measuring changes in orexigenic and anorexigenic hormone levels in response to glucose among PLWH who switch to a DTG-based ART regimen; 3) To adapt the South African Diabetes Prevention Package (SA-DPP) for PLWH and assess its acceptability and feasibility. Aim 1 and/or 2: Primary outcome will be absolute weight change (kg) at 12 months from baseline. Secondary outcomes will be measured at baseline, and 6- and 12-months post switch and will include: anthropometry (body mass index [BMI] and waist circumference), total and regional (trunk, limb, and visceral) fat mass and muscle mass (dual energy x-ray absorptiometry [DXA]), and hepatic fat/fibrosis as measured noninvasively by FibroScan®; glucose homeostasis including glucose tolerance, HbA1c, measures of insulin sensitivity (HOMA-IR, Matsuda index), secretion (insulinogenic index), and clearance (C-peptide/insulin molar ratio); subclinical inflammation, blood pressure, and serum lipids; orexigenic and anorexigenic hormone levels. Aim 3: Focus group discussions and in-depth interviews will be conducted to explore the knowledge, barriers, and facilitators to lifestyle modification and weight gain among PLWH as well as mitigating strategies. The overall impact of this study will be to inform appropriate weight gain prevention strategies in preparation for DTG scale-up as the backbone for the next generation of ART in Africa.