Risk of obesity, diabetes, hypertension, and major adverse cardiovascular events after a switch to an integrase inhibitor: a target trial emulation in REPRIEVE

Background Integrase strand-transfer inhibitors (INSTIs) are linked to weight gain, but data on their cardiometabolic effects, particularly major adverse cardiovascular events (MACE), are scarce. We aimed to estimate the risk of obesity, diabetes, hypertension, and MACE after switching to an INSTI in people with HIV at low-to-moderate cardiovascular risk. Methods In this retrospective cohort study, we used data from the global Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) to emulate a series of trials comparing switching to an INSTI versus remaining on a non-INSTI regimen on risk of incident obesity, diabetes, hypertension, and MACE. The REPRIEVE trial collected data across 12 countries from participants aged 40–75 years, on a stable antiretroviral therapy regimen for at least 6 months, with a CD4 count of >100 cells per μL, and with low-to-moderate risk for atherosclerotic cardiovascular disease. From this cohort, we included participants without a previous diagnosis of the outcomes or previous INSTI use and used data for a follow-up period of 5 years, until the outcome event, loss to follow-up, death, or study end. Data from emulated trials were pooled and hazard ratios (HRs) were estimated with weighted Cox proportional hazard models, accounting for competing events. Findings 5114 participants met eligibility criteria for at least one emulated trial, representing 99 357 person-trials (median age 49 years [45–54]; 62 826 [63·2%] of 99 357 were male; 36 531 [36·8%] were female). 2981 (58·3%) of 5114 participants were captured as an INSTI switcher in at least one trial. Most switchers (2412 [80·9%] of 2981) initiated a dolutegravir-based regimen and most (47 263 [67·1%] of 70 458) non-switchers were on an efavirenz-based regimen. The HR of obesity (HR 1·41, 95% CI 1·22–1·59), diabetes (1·50, 1·24–1·81), and hypertension (1·45, 1·26–1·67) was higher in switchers than non-switchers. We did not observe an effect on MACE (1·17, 0·87–1·57). Interpretation The increase in cardiometabolic risk profile suggests long-term observation of people with HIV switching to INSTIs will be crucial to ensure appropriate management of comorbidities and to assess for future development of MACE. Funding National Institutes of Health, Kowa Pharmaceuticals America, Gilead Sciences, and ViiV Healthcare.