Initial HIV Therapy for Adults and Treatment-Associated Weight Gain: The Opti-DOR Randomized Clinical Trial.

Antiretroviral therapy (ART), particularly regimens containing tenofovir alafenamide with dolutegravir or bictegravir, is associated with substantial weight gain, potentially exacerbating cardiometabolic risk in people with HIV. To determine whether a regimen with doravirine, lamivudine, and tenofovir disoproxil fumarate results in less weight gain than a regimen with dolutegravir, emtricitabine, and tenofovir alafenamide while maintaining noninferior viral suppression. Open-label, noninferiority randomized clinical trial including ART-naive adults (≥18 years of age) with an HIV RNA level greater than 500 copies/mL and no detectable baseline, high-level doravirine resistance. The study was conducted at 2 South African sites and individuals were recruited between October 2023 and March 2025. The final participant visit occurred in February 2026. A once-daily regimen with 100 mg of doravirine, 300 mg of lamivudine, and 300 mg of tenofovir disoproxil fumarate (n = 299) or 50 mg of dolutegravir, 200 mg of emtricitabine, and 25 mg of tenofovir alafenamide (n = 301). The primary outcome was viral suppression (HIV RNA level <50 copies/mL) at week 48 (prespecified noninferiority margin of -10 percentage points). The key secondary outcomes included changes in body weight, treatment-associated effects on body composition, and safety and adverse events. Among 600 participants, 597 (99.5%) were Black African, 413 (68.8%) were assigned female at birth, and the median age was 34 years (IQR, 28-41). At week 48, 266 participants (89.0%) in the doravirine, lamivudine, and tenofovir disoproxil fumarate group achieved viral suppression (HIV RNA level <50 copies/mL) vs 273 participants (90.7%) in the dolutegravir, emtricitabine, and tenofovir alafenamide group (between-group difference, -1.7 percentage points [95% CI, -6.6 to 3.1], meeting the prespecified noninferiority margin of -10 percentage points). The median weight gain was 3.0 kg in the doravirine, lamivudine, and tenofovir disoproxil fumarate group vs 5.0 kg in the dolutegravir, emtricitabine, and tenofovir alafenamide group (between-group difference, -2.0 kg [95% CI, -3.0 to -1.0 kg]; P < .001). Among participants in the doravirine, lamivudine, and tenofovir disoproxil fumarate group, the median change in hip bone mineral density (BMD) was -2.1% (IQR, -4.1% to -0.5%) and was -3.2% (IQR, -5.4% to -0.8%) for spine BMD vs -0.5% (IQR, -1.9% to 1.2%) for hip BMD and -1.3% (IQR, -3.2% to 0.8%) for spine BMD with dolutegravir, emtricitabine, and tenofovir alafenamide (P < .001 for each between-group comparison). Resistance to doravirine emerged among 7 of 9 participants experiencing virologic failure in the doravirine, lamivudine, and tenofovir disoproxil fumarate group. Of these 7 participants, 5 of 6 achieved viral suppression after switching to dolutegravir-based therapy and 1 was lost to follow-up. Serious adverse events and deaths (n = 2) were infrequent and not considered treatment-related. Among predominantly Black African adults initiating ART, a regimen with doravirine, lamivudine, and tenofovir disoproxil fumarate was noninferior to a regimen with dolutegravir, emtricitabine, and tenofovir alafenamide for 48-week viral suppression and was associated with less weight gain. ClinicalTrials.gov Identifier: NCT05924438.