Doravirine-based ART cuts weight gain without sacrificing viral control

Clinical takeaway: When selecting initial antiretroviral therapy for adults concerned about treatment-associated weight gain or cardiometabolic risk, doravirine/lamivudine/tenofovir disoproxil fumarate may offer similar virologic efficacy with less weight gain than dolutegravir/emtricitabine/tenofovir alafenamide, although potential tradeoffs—including bone health and resistance if virologic failure occurs—should be considered.

Weight gain after starting antiretroviral therapy has become an increasingly important clinical issue, particularly with regimens containing an integrase strand transfer inhibitor (INSTI) plus tenofovir alafenamide. Because this weight gain may increase long-term cardiometabolic risk and is often difficult to reverse, strategies to prevent it are gaining attention.

In the randomized Opti-DOR trial, investigators enrolled 600 treatment-naive adults with HIV in South Africa and compared once-daily doravirine/lamivudine/tenofovir disoproxil fumarate with dolutegravir/emtricitabine/tenofovir alafenamide. At 48 weeks, viral suppression (HIV RNA <50 copies/mL) was achieved in 89.0% and 90.7% of participants, respectively, meeting the prespecified criterion for noninferiority.

The doravirine-based regimen was associated with significantly less weight gain. Median weight increased by 3.0 kg versus 5.0 kg with the dolutegravir-based regimen, a between-group difference of 2.0 kg. Fewer patients receiving doravirine experienced clinically meaningful weight gain of at least 5% (41.1% vs 56.8%) or at least 10% (16.4% vs 26.2%). Participants in the doravirine group also had smaller increases in body fat and more favorable lipid changes.

The findings also highlight important tradeoffs. Bone mineral density declined more with the tenofovir disoproxil fumarate-containing regimen, while high-level doravirine resistance emerged in 7 participants with virologic failure. Most of these individuals subsequently achieved viral suppression after switching to dolutegravir-based therapy. Serious adverse events were uncommon and were not considered treatment related.

These results suggest that regimen selection may play a meaningful role in reducing treatment-associated weight gain at the start of HIV therapy. For patients at elevated risk of obesity or cardiometabolic disease, clinicians may increasingly weigh metabolic benefits against considerations such as bone health, renal risk, and the need for prompt detection of virologic failure.

“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,” the study authors concluded.

Source: Woods J, et al. (2026 Jul 31) JAMA. Initial HIV therapy for adults and treatment-associated weight gain