DEFINE: A Prospective, Randomized, Phase 4 Trial to Assess a Protease Inhibitor-Based Regimen Switch Strategy to Manage Integrase Inhibitor-Related Weight Gain

Background Integrase strand transfer inhibitor (INSTI)-based antiretroviral (ARV) therapies have been associated with greater weight gain in people living with human immunodeficiency virus (HIV) versus those on protease inhibitor (PI)-based regimens. The DEFINE study investigated whether switching from an INSTI- to a PI-based regimen could mitigate/reverse weight gain. Methods DEFINE (NCT04442737) was a randomized, 48-week, open-label, prospective, phase 4 study in virologically suppressed adults with HIV-1 and >= 10% weight gain on INSTI + tenofovir alafenamide (TAF)/emtricitabine (FTC; <36 months prescreening). Participants either switched immediately to darunavir/cobicistat/FTC/TAF (D/C/F/TAF) or continued INSTI + TAF/FTC during weeks 0-24 then switched to D/C/F/TAF for weeks 24-48. The primary endpoint was least squares (LS) mean (95% confidence interval [CI]) percent weight change from baseline to week 24. Results Overall, 103 adults were randomized (D/C/F/TAF, n = 53; INSTI + TAF/FTC, n = 50); 30% were female, and 61% were Black/African American. No significant difference in weight change was observed at week 24 (LS mean change: D/C/F/TAF, 0.63% [95% CI, -.44% to 1.70%] vs INSTI + TAF/FTC, -0.24% [95% CI, -1.35% to .87%]; P = .24); however, a trend toward weight loss was observed with extended time post-ARV switch to D/C/F/TAF (baseline to week 48, -0.36% [95% CI, -1.77% to 1.06%]), particularly in subgroups at higher weight gain risk (eg, female and Black/African American participants). Metabolic endpoints paralleled weight change over time. D/C/F/TAF was well tolerated, with comparable virologic efficacy between arms. Conclusions While no significant change in body weight was observed at 24 weeks after switching from INSTI + TAF/FTC to D/C/F/TAF among adults with weight gain, a trend toward weight loss emerged with longer time post-ARV switch, supporting further investigation of ARV selection/switch for weight management.