Koethe JR, Lake JE, Kantor A, et al. A 48-week, Randomized Controlled Trial of Doravirine for Individuals with HIV and Obesity on Integrase Inhibitors and Tenofovir Alafenamide: The Do IT Study (ACTG A5391). Clin Infect Dis. 2026 March 18:ciag196. doi:10.1093/cid/ciag196.

ACTG A5391 is an open-label, multi-center trial designed to assess whether a switch from INSTI-based combinations to a DOR-containing regimen, as well as from TAF- to TDF-, leads to weight reduction and improved metabolic health parameters among U.S. adults with HIV and obesity.  People on TAF/FTC plus either bictegravir, dolutegravir, or raltegravir for over a year with virologic suppression were eligible for randomization to: DOR plus TAF/FTC; DOR plus TDF/FTC; or no change in therapy.  145 participants initiated study treatment (47 in the DOR plus TAF/FTC group; 49 in the DOR plus TDF/FTC group; and 49 in the INSTI plus TAF/FTC group).  Median BMI at entry was 34.9 kg/m², waist circumference 111 cm, 49% were female, 53% Black, and 18% Hispanic/Latine.  65% had experienced an unintentional ≥ 10% weight gain in the first 1-3 years of INSTI use.  The primary efficacy analysis population included 127 participants who completed 48 weeks of follow-up.  Although over half of participants in all groups lost some weight (estimated mean change in weight was -0.47% for DOR plus TAF/FTC, -2.73% for DOR plus TDF/FTC, and -1.84% for INSTI plus TAF/FTC), CI limits for the treatment difference in weight change did not exceed the pre-specified 5% threshold.  Estimated mean treatment differences in waist circumference changes were not significant; similarly, there were no significant changes in total fat, trunk fat, or total lean mass as measured by DEXA.

For people with HIV and obesity who had been taking INSTI-based regimens for over a year, switching to a DOR-based combination (with or without TDF) did not lead to significant weight reductions over 48 weeks.  Subgroup analyses examining changes according to sex at birth, gender, race/ethnicity, age, and historical ART-related weight gain also did not reveal any significant treatment differences.  Comprehensive strategies and interventions outside of ART-related modifications will be necessary to effectively prevent and manage unintentional weight gain for people with HIV.