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Background The nature and burden of weight gain associated with antiretroviral treatment (ART) using a combination of Tenofovir disoproxil fumarate, lamivudine and dolutegravir (TLD) among people living with HIV (PLWH) has not been thoroughly investigated in Ethiopia. Therefore, this study aimed to evaluate changes in body weight and body mass index (BMI) in adults who initiated TLD or switched to TLD compared to those who received a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based therapies. Methods A retrospective cohort study was conducted among adult PLWH who had been receiving ART between February 2017 and October 2022 in Hawassa city administration, Sidama region. Linear mixed-effects model was used to examine BMI and body weight trends over time, while a binary logistic regression was performed to identify factors associated with a ≥ 10% weight gain. Results A total of 524 adult PLWH with a median age of 35 (interquartile range: 30–41) years were included. TLD-initiated arm experienced significantly greater mean weight (8.6 kg vs. 4.95 kg, p < 0.0001) and BMI (3.11 kg/m 2 vs. 1.84 kg/m 2 , p < 0.0001) increase than the NNRTI-based arm at two years. However, the switched arm showed no significant difference in weight (5.6 kg) and BMI (2.13 kg/m 2 ) compared to the NNRTI-based arm ( p > 0.05). There was a significant interaction effect between ART regimens and time in predicting weight and BMI gain ( p < 0.01). Initiating ART with TLD had higher odds of ≥10% body weight gain at two years (adjusted odds ratio [AOR]: 1.9; 95% CI: 1.19–3.04). Other baseline factors such as age ≥40 years (AOR: 2.02; 95% CI: 1.35–3.02), weight <50kg (AOR: 3.0; 95% CI: 1.86–4.84), advanced disease stages (AOR: 1.78; 95% CI: 1.1–2.86) and ambulatory-bedridden functional status (AOR: 2.0; 95% CI: 1.05–3.8) were also associated with ≥10% weight gain. Conclusion Initiating ART with TLD was significantly associated with greater weight and BMI gain than the NNRTI-based regimens. Therefore, the cardio-metabolic implications of weight gain after the TLD initiation in this population should be monitored and thoroughly investigated.

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