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. Clinical Trials Registration. NCT04442737.

中文翻译：

---

定义：一项前瞻性、随机、4 期试验，以评估基于蛋白酶抑制剂的方案转换策略来管理整合酶抑制剂相关的体重增加


背景 与接受基于蛋白酶抑制剂 （PI） 的方案相比，基于整合酶链转移抑制剂 （INSTI） 的抗逆转录病毒 （ARV） 疗法与人类免疫缺陷病毒 （HIV） 感染者体重增加增加有关。DEFINE 研究调查了从 INSTI 转换为基于 PI 的方案是否可以减轻/逆转体重增加。方法 DEFINE （NCT04442737） 是一项随机、为期 48 周、开放标签、前瞻性、4 期研究，研究对象为病毒学抑制的 HIV-1 成人≥患者，INSTI + 替诺福韦艾拉酚胺 （TAF）/恩曲他滨 （FTC;<36 个月预筛选）。参与者在第 0-24 周立即改用 darunavir/cobicistat/FTC/TAF （D/C/F/TAF） 或继续 INSTI + TAF/FTC，然后在第 24-48 周改用 D/C/F/TAF。主要终点是从基线到第 24 周的最小二乘 （LS） 平均值 （95% 置信区间 [CI]） 体重百分比变化。结果 总体而言，103 例成人被随机分组 （D/C/F/TAF，n = 53;INSTI + TAF/FTC，n = 50）;30% 是女性，61% 是黑人/非裔美国人。第 24 周时未观察到体重变化的显著差异（LS 平均变化：D/C/F/TAF，0.63% [95% CI，-.44% 至 1.70%] vs INSTI + TAF/FTC，-0.24% [95% CI，-1.35% 至 .87%];P = .24）;然而，随着 ARV 转换为 D/C/F/TAF 后的时间延长（基线至第 48 周，-0.36% [95% CI，-1.77% 至 1.06%]）观察到体重减轻的趋势，特别是在体重增加风险较高的亚组中（例如，女性和黑人/非裔美国人参与者）。代谢终点与体重随时间的变化平行。D/C/F/TAF 耐受性良好，两组之间的病毒学疗效相当。 结论 虽然在体重增加的成年人中，从 INSTI + TAF/FTC 转换为 D/C/F/TAF 后 24 周未观察到体重的显着变化，但随着 ARV 转换后时间的延长，体重减轻的趋势出现，支持进一步研究 ARV 选择/转换体重管理。临床试验注册。NCT04442737。