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

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Abstract

IMPORTANCE: 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. OBJECTIVE: 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. DESIGN, SETTING, AND PARTICIPANTS: 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. INTERVENTIONS: 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). MAIN OUTCOMES AND MEASURES: 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. RESULTS: 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. CONCLUSIONS AND RELEVANCE: 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. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05924438.

Abstract as published, via PubMed.