New data from a large-scale HIV clinical trial reveals that switching to integrase inhibitor-based antiretroviral therapy significantly increases the risk of weight gain and cardiometabolic complications, though without raising the immediate risk of major cardiovascular events.
The AIDS Clinical Trials Group (ACTG) presented these findings from the REPRIEVE study at the 2025 Conference on Retroviruses and Opportunistic Infections (CROI) in San Francisco on March 8. The late-breaking presentation detailed how patients who switched to integrase inhibitor-containing regimens faced higher risks of developing obesity, diabetes, hypertension, and metabolic syndrome compared to those who remained on non-integrase inhibitor treatments.
Increased Metabolic Risks Identified
The analysis included 2,708 study participants who switched to integrase inhibitor-containing regimens, with 82 percent receiving dolutegravir-based treatments. Researchers found statistically significant increased risks across multiple cardiometabolic parameters:
- Obesity: 32% increased risk (HR: 1.32, 95% CI: 1.07-1.47)
- Diabetes: 38% increased risk (HR: 1.38, 95% CI: 1.10-1.69)
- Hypertension: 38% increased risk (HR: 1.38, 95% CI: 1.13, 1.61)
- Metabolic syndrome: 15% increased risk (HR: 1.15, 95% CI: 1.00-1.31)
Notably, the study did not detect an increased risk of major adverse cardiovascular events (MACE) such as heart attacks or strokes (HR: 1.03, 95% CI: 0.63, 1.52) during the follow-up period.
"This analysis from REPRIEVE provides an in-depth evaluation of the metabolic effects of switching to an integrase inhibitor," said ACTG Chair Joseph J. Eron, M.D., from the University of North Carolina. "While a number of prior studies have reported disproportionate weight gain among people living with HIV who initiated treatment with an integrase inhibitor, this is one of the few that has evaluated people who were taking other HIV treatments and followed them for more than two years after switching to an integrase inhibitor."
REPRIEVE Study Context
REPRIEVE stands as the first large-scale clinical trial to test a primary prevention strategy for reducing cardiovascular disease risk in people living with HIV. The main study found that pitavastatin calcium (a daily statin) reduced the risk of major adverse cardiovascular events by 36 percent compared to placebo over a median five-year follow-up period.
The current analysis specifically examined the cardiometabolic consequences of switching to integrase inhibitor-based regimens, which have become increasingly common in HIV treatment due to their efficacy and tolerability profile.
Clinical Implications
Senior Author and Study Chair Steven Grinspoon, M.D., of Harvard Medical School, noted that while the absolute risk increase was relatively small, the findings warrant attention.
"The risk of cardiometabolic complications associated with integrase inhibitors was small in this study," Dr. Grinspoon said. "However, given that rates of obesity, diabetes, hypertension, and metabolic syndrome increased following a switch to an integrase inhibitor-based regimen, and that these are all important contributors to cardiovascular disease risk, individuals on integrase inhibitor-containing regimens should be closely monitored for cardiometabolic complications over the long term."
The researchers emphasized the need for future studies to determine whether long-term use of integrase inhibitors eventually leads to increased cardiovascular disease events and to investigate the underlying cardiometabolic mechanisms.
Study Methodology and Collaboration
REPRIEVE began in 2015 as a collaborative effort between the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Diseases (NIAID), with additional funding from the NIH Office of AIDS Research, Kowa Pharmaceuticals America, Inc., Gilead Sciences, Inc., and ViiV Healthcare.
The study was led by Dr. Grinspoon and Pamela S. Douglas, M.D., of Duke University School of Medicine, with Heather Ribaudo, Ph.D., from Harvard School of Public Health serving as Lead Statistician and Michael Lu, M.D., M.P.H., from Harvard Medical School and Massachusetts General Hospital leading the Data Coordinating Center.
Balancing Treatment Decisions
These findings add important nuance to treatment decisions for people living with HIV. Integrase inhibitors remain highly effective antiretroviral medications, but the metabolic risks identified suggest the need for personalized treatment approaches and vigilant monitoring.
For patients with pre-existing metabolic conditions or cardiovascular risk factors, clinicians may need to weigh these newly identified risks against the benefits of integrase inhibitor-based regimens. Regular monitoring of weight, blood pressure, and metabolic parameters appears particularly important for patients switching to or maintaining these treatments.
The ACTG network, which conducted this research, is the world's largest and longest-running clinical trials network focused on HIV and other infectious diseases, comprising thousands of researchers across 65 locations on four continents.
