Initial HIV Therapy in Adults Associated With Treatment-Related Weight Gain

A first-line HIV treatment regimen that avoids both an integrase strand transfer inhibitor and tenofovir alafenamide maintained viral suppression while producing less weight gain than a commonly used combination in a randomized clinical trial of 600 adults. The findings suggest that doravirine, lamivudine, and tenofovir disoproxil fumarate may offer an alternative for people beginning antiretroviral therapy who are considered particularly vulnerable to treatment-associated increases in body weight.

The study compared two three-drug regimens. Participants assigned to the experimental group received doravirine, a nonnucleoside reverse transcriptase inhibitor, together with lamivudine and tenofovir disoproxil fumarate. Those in the comparison group received dolutegravir, an integrase strand transfer inhibitor, with emtricitabine and tenofovir alafenamide. Both regimens combine agents that interrupt different stages of HIV replication, limiting the virus’s ability to produce new copies and reducing the risk that resistance will emerge when treatment is taken consistently.

The trial focused on adults with HIV who were at risk of gaining weight after starting treatment. Weight gain has become an important consideration in HIV care as modern antiretroviral therapy has transformed HIV infection into a manageable chronic condition. Although restoring health after the initiation of therapy can itself lead to weight gain, accumulating evidence has also linked some treatment combinations—particularly regimens containing certain integrase inhibitors and tenofovir alafenamide—with greater increases in body weight in some populations.

At 48 weeks, 89.0% of participants receiving doravirine, lamivudine, and tenofovir disoproxil fumarate had achieved viral suppression, defined as an HIV RNA level below 50 copies per milliliter. In the dolutegravir, emtricitabine, and tenofovir alafenamide group, 90.7% reached the same threshold. The difference between the groups met the trial’s prespecified noninferiority margin of minus 10 percentage points, meaning the alternative regimen was considered sufficiently close to the comparator in its ability to suppress HIV.

Noninferiority trials are designed to determine whether a new or alternative treatment performs no worse than an established treatment by more than a clinically acceptable amount. In this case, the analysis did not seek to show that the doravirine-based regimen was superior for viral suppression. Instead, it tested whether any reduction in suppression would remain within a predefined range while allowing researchers to examine potential advantages, including its effect on weight.

The results indicated that participants assigned to the doravirine-based regimen experienced less weight gain than those assigned to the dolutegravir-based regimen containing tenofovir alafenamide. The study summary did not provide numerical differences in weight gain, but the direction of the finding is clinically relevant because body-weight changes can influence metabolic health, cardiovascular risk, quality of life, and long-term treatment decisions.

The pharmacology of the drugs may help explain the observed difference. Dolutegravir blocks HIV integrase, the viral enzyme that inserts HIV genetic material into the DNA of human cells, while bictegravir and other drugs in the same class have also been associated in previous research with treatment-related weight increases. Tenofovir alafenamide is a newer formulation that delivers tenofovir efficiently to cells at a lower circulating dose than tenofovir disoproxil fumarate, improving some aspects of tolerability but potentially contributing to differences in weight outcomes when the two formulations are compared.

Doravirine works through a separate mechanism. As a nonnucleoside reverse transcriptase inhibitor, it binds directly to HIV reverse transcriptase and interferes with the enzyme’s ability to convert viral RNA into DNA. Lamivudine and tenofovir disoproxil fumarate are nucleoside or nucleotide reverse transcriptase inhibitors that act as faulty building blocks during viral DNA synthesis. Used together, the three agents create a combination blockade against replication rather than relying on a single antiviral mechanism.

The findings do not mean that every person taking an integrase inhibitor or tenofovir alafenamide will gain excessive weight, nor do they establish that the doravirine-based regimen is the best option for all adults with HIV. Treatment selection must account for viral resistance, kidney and bone health, coexisting conditions, drug interactions, pregnancy considerations, adherence, access, and national treatment guidelines. The study instead provides evidence that clinicians may be able to consider weight-related priorities without sacrificing short-term virologic efficacy in an appropriate population.

The paper is scheduled for presentation at the International AIDS Society conference. It will be published in JAMA under the DOI 10.1001/jama.2026.14762. The investigators said the full article contains additional information about the study methods, participant characteristics, authorship, funding, and potential conflicts of interest. Longer follow-up will be important to determine whether the difference in weight gain persists beyond 48 weeks and whether it translates into measurable differences in metabolic or cardiovascular outcomes.

Web References: International AIDS Society conference: https://www.iasociety.org/conferences/aids2026

References: JAMA. DOI: 10.1001/jama.2026.14762