INSTI switching linked to higher metabolic risk in people with HIV

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The lancet. HIV Published May 2, 2026 Medically reviewed May 8, 2026 Study authors: Kileel Emma M, Malvestutto Carlos D, Zanni Markella V, Davies-Smith Emma, Fichtenbaum Carl J, Lake J… PubMed ↗ DOI ↗ By Dr. Amelia Tan, PhD · Internal Medicine & Chronic Disease

Key Takeaway

Switching to integrase inhibitors in people with HIV raises metabolic risks but not MACE over five years.

This retrospective cohort study, emulating a target trial, analyzed data from 5,114 people with HIV at low-to-moderate cardiovascular risk across 12 countries. The primary exposure was switching to an integrase strand-transfer inhibitor (INSTI) regimen, with the comparator being remaining on a non-INSTI regimen. The study followed participants for five years to assess the risk of incident obesity, diabetes, hypertension, and major adverse cardiovascular events (MACE).

The main findings indicated that switching to an INSTI was associated with a significantly higher risk of developing obesity, diabetes, and hypertension compared to staying on a non-INSTI regimen. For obesity, the hazard ratio (HR) was 1.41 (95% CI 1.22-1.59). For diabetes, the HR was 1.50 (95% CI 1.24-1.81). For hypertension, the HR was 1.45 (95% CI 1.26-1.67). These results suggest a consistent pattern of increased metabolic risk following a switch to INSTI therapy.

In contrast, the study found no significant effect on the risk of MACE, with an HR of 1.17 (95% CI 0.87-1.57). This indicates that while metabolic comorbidities may be elevated, the immediate cardiovascular event risk did not differ meaningfully between the groups over the five-year follow-up period.

The study's global setting and large sample size enhance the generalizability of these findings to diverse populations of people with HIV. However, the retrospective design and lack of reported absolute risk numbers are important limitations. The analysis did not account for all potential confounding factors, and the causality of the observed associations cannot be definitively established.

Funding was provided by several entities, including the National Institutes of Health and pharmaceutical companies such as Kowa Pharmaceuticals America, Gilead Sciences, and ViiV Healthcare. These relationships warrant consideration when interpreting the results, though the study's design and execution were independent.

From a clinical practice perspective, these findings underscore the need for long-term monitoring of metabolic parameters in patients who switch to INSTI regimens. Clinicians should be vigilant for the development of obesity, diabetes, and hypertension, and consider proactive management strategies to mitigate these risks.

The study did not report on safety outcomes, such as adverse events or discontinuations, which limits a comprehensive assessment of the overall risk-benefit profile of INSTI switching. Future prospective studies are needed to confirm these observations and to explore the underlying mechanisms driving the increased metabolic risk.

In summary, this research highlights a trade-off in HIV management: while INSTIs are effective for viral suppression, their use may be associated with a higher burden of metabolic comorbidities. Careful patient selection and ongoing surveillance are essential to optimize long-term health outcomes.

Study Details

Study typeRct

Sample sizen = 5,114

EvidenceLevel 2

Follow-up900.0 mo

PublishedMay 2026

PMID41911941

View Original Abstract ↓

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.