AbstractIntroductionAlthough dolutegravir (DTG) is deemed stable, safe, cost‐effective, and clinically beneficial, it also carries the risk of side effects, including observed weight gain among patients on DTG‐based antiretroviral therapy (ART) regimens. We compared weight changes among adults (≥18 years) initiating tenofovir disoproxil fumarate, lamivudine, and dolutegravir (TLD) or tenofovir disoproxil fumarate, emtricitabine, and efavirenz (TEE) regimens and those switching from TEE to TLD (TEE‐to‐TLD switchers) in three large primary care facilities in South AfricaMethodsWe conducted a retrospective longitudinal record review using patient medical records, extracting relevant demographic and clinical data from October 2018 to June 2021 from randomly selected adults who initiated TLD or TEE (initiators) and adult TEE‐to‐TLD switchers. We assessed weight, body mass index (BMI), and percentage weight changes for both groups and fitted linear regression and generalized linear models to determine factors associated with weight and BMI change and percentage weight change ≥10%, respectively, among treatment initiators. We fitted linear mixed‐effect models among TEE‐to‐TLD switchers to consider repeated measures.ResultsOf 860 initiators, 450 (52.3%) initiated on TEE and 410 (47.7%) on TLD, with median follow‐up of 1.4 years and 1.0 year, respectively. At initiation, 43.3% on TEE and 40.8% on TLD were overweight or obese. TLD initiators had an adjusted higher mean weight gain of 1.6 kg (p < 0.001) and mean BMI gain of 0.51 kg/m² (p < 0.001) than TEE initiators. Independent risk factors for higher mean weight and BMI included age ≥50 years, male, on ART for >12 months, initial BMI of <18.5 kg/m², and CD4 counts <200 cells/μL.Of 298 TEE‐to‐TLD switchers, 36.6% were overweight or obese at TEE initiation. Comparing before and after TLD switch, TEE‐to‐TLD switchers had an adjusted mean weight of 1.2 kg less while on TLD (p = 0.026). Being overweight and CD4 counts >350 cells/μL were independent risk factors for lower weight gain after TLD switch.ConclusionsWe report more weight gain among TLD than among TEE initiators, although to a lesser extent than previously reported. TEE‐to‐TLD switchers experienced less weight gain after TLD switch; return to health before receiving TLD may be a contributory factor. The current findings are reassuring for those switching to a DTG‐based regimen