Obesity is endemic across the globe, with the World Health Organization (WHO) reporting that one in eight people on the planet is obese. A bump in weight is commonly experienced after people start ART, especially when CD4 cell counts are low and/or plasma HIV RNA levels are high. Because differential trajectories in weight gain have been observed in people initiating different ARV regimens, there is concern that some agents or combinations are weight-promoting and may contribute to adverse health outcomes associated with being overweight or obese.
Numerous clinical trials that have followed people starting or switching ARVs have linked the newer integrase inhibitors, particularly bictegravir and dolutegravir, in combination with tenofovir alafenamide (TAF), to greater increases in weight when compared to regimens that do not contain these ARVs. Complicating this is the known weight-attenuating effect of TDF.
To date, most of the data regarding weight change during HIV therapy are derived from studies that tracked weight after the start or switch of antiretrovirals. In contrast, the DO-IT trial was the first to focusing on those experiencing significant weight gain during HIV treatment and testing whether switching from an integrase inhibitor and/or TAF caused a reduction in weight. DO-IT enrolled 145 people with controlled viremia on bictegravir, dolutegravir, or raltegravir in combination with TAF and emtricitabine (FTC) and a BMI of 30 kg/m2. Participants were then randomized to continue their pre-trial regimen or switch to either doravirine plus TAF/FTC (or lamivudine [3TC]) or doravirine plus TDF/FTC (or 3TC). Weight was assessed carefully over time. Almost half the participants were female and over 50% were Black.
After 48 weeks there was no significant difference in weight change by study arm. In fact, each group tended to lose a bit of weight during follow-up. These results persisted in the analyses of subgroups including those based on sex, gender, race, age, entry regimen, and history of weight gain on an integrase inhibitor.
Clinicians understandably contemplate modifying HIV therapy in patients who experience substantial weight gain after starting or switching antiretrovirals. This important ACTG trial demonstrates that this is unlikely an effective strategy – a finding that joins observations from other studies that have looked more generally at people with HIV who changed from integrase inhibitors and TAF with similarly negative results. Weight change during HIV treatment is complicated and influenced by multiple factors, including HIV therapy, other medications, substance use, diet, physical activity, environment, food security, genetics, among others – all interacting. While it may be tempting to consider changing antiretrovirals to try to shed pounds, the evidence from this ACTG trial is clear, just don’t do it.
Koethe J, et al. A Randomized Multicenter 3-arm Controlled Trial for People with Obesity on Integrase Inhibitors and Tenofovir Alafenamide switching to Doravirine, with or without Tenofovir Disoproxil Fumarate (The DO-IT Trial). International AIDS Conference, Kigali, Rwanda, 2025