Doravirine-based HIV regimen shows less weight gain than dolutegravir combination, trial finds

A once-daily HIV regimen built around doravirine resulted in less weight gain over 48 weeks than a widely used dolutegravir-based combination, while matching it for viral suppression, according to a randomized clinical trial published in JAMA.

Trial design

‘Initial HIV Therapy for Adults and Treatment-Associated Weight Gain’ was led by a group of researchers including Joana Woods, MBChB, MPH, from the University of the Witwatersrand in Johannesburg, South Africa.

Woods and her team randomized 600 adults with HIV starting antiretroviral therapy for the first time to once-daily doravirine, lamivudine and tenofovir disoproxil fumarate or to dolutegravir, emtricitabine and tenofovir alafenamide. Enrollment ran at two South African sites — an urban clinic in Johannesburg and a rural site in Somkhele — between October 2023 and March 2025, with final follow-up visits completed in early 2026. The study population was 99.5% Black African and nearly 69% female, the demographic groups that earlier research has linked to the highest risk of antiretroviral-related weight gain. It is, according to the study's authors, the first head-to-head randomized trial comparing a doravirine-based regimen with a contemporary integrase-inhibitor regimen containing tenofovir alafenamide at ART initiation.

Second-generation integrase strand transfer inhibitor (InSTI) regimens — chiefly those pairing dolutegravir or bictegravir with tenofovir alafenamide — are the global standard for first-line HIV treatment because of their potency and high barrier to resistance; more than 23 million people in low- and middle-income countries take dolutegravir-based regimens. But these regimens, especially when combined with tenofovir alafenamide, have been linked in prior research to substantial weight gain that hits hardest in the first one to two years of treatment, disproportionately affects women, Black patients and people with more advanced HIV disease, and has been tied to elevated risk of diabetes, hypertension and cardiovascular disease.

Viral suppression results similar between regimens

At 48 weeks, 89.0% of participants on the doravirine-based regimen had achieved viral suppression (HIV RNA below 50 copies/mL), compared with 90.7% on the dolutegravir-based regimen, a gap that fell well within the trial's prespecified noninferiority margin. Doravirine resistance emerged in seven participants who experienced virologic failure, most of whom had more advanced HIV disease at enrollment; of six who switched to the dolutegravir-based regimen after resistance was detected, five went on to achieve viral suppression. No participants in the dolutegravir group developed drug-class resistance.

Doravirine regimen linked to less weight gain

Weight outcomes diverged more sharply between the two groups. Median weight gain at 48 weeks was 3.0 kg with the doravirine-based regimen versus 5.0 kg with the dolutegravir-based regimen, and participants on doravirine were substantially less likely to gain 5% or more of their body weight. Dual-energy X-ray absorptiometry scans showed the doravirine group also gained less total body fat and trunk fat, though it saw a slightly larger decline in hip and spine bone mineral density than the dolutegravir group. Serious adverse events were low and similar between arms, and doravirine was linked to fewer clinically significant declines in kidney function.

What it means for HIV treatment and payers

The findings land as clinicians and payers weigh newer tenofovir alafenamide-containing regimens against older tenofovir disoproxil fumarate formulations. Tenofovir alafenamide was adopted widely for kidney- and bone-density advantages documented in patients with preexisting risk factors, but this trial adds to a growing body of research finding it comes with greater weight gain and less favorable lipid profiles than tenofovir disoproxil fumarate, particularly when combined with an InSTI.

“Critically, once established, this weight gain appears largely irreversible,” Woods and her time write in the study. “Studies of therapy switches to protease inhibitor–based or doravirine-based regimens have not demonstrated meaningful weight loss, indicating prevention of weight gain after initiation of ART may be more achievable than weight loss later in treatment. To our knowledge, no head-to-head randomized clinical trial has evaluated regimen selection specifically to mitigate treatment-associated weight gain after initiation of ART.”

On cost, the authors noted that voluntary licenses already allow generic manufacturers to produce doravirine and the fixed-dose combination in 86 countries, including all sub-Saharan Africa, though cost-effectiveness for other health systems has not yet been evaluated.