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Metabolic syndrome and cardiovascular risk on INSTIs, Comment
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Download the PDF here
Download the PDF here
Download the PDF here
Download the PDF here
May 2026
See attached pdf for full comment.
Treatment regimens containing integrase strand-transfer inhibitors (INSTIs) are taken lifelong by most people with HIV. The potency, tolerability, and high resistance barrier of INSTIs make them the treatment of choice. Widespread long-term use requires vigilance for rare or delayed adverse effects. Within real-world evidence frameworks, inferring causality requires considerably more than a statistically significant association. Apparent effects might merely reflect who receives which treatment. In the RESPOND cohort1 for example, people with HIV on antiretroviral therapy (ART) with a moderate D:A:D 5-year cardiovascular risk score had higher odds of being switched to an INSTI (odds ratio 1•26, 95% CI 1•20-1•33; p<0•001), rising to an odds ratio of 1•51 (95% CI 1•40-1•63; p<0•001) with high or very high risk, compared with those at low risk. Such non-trivial differences that precede INSTI exposure illustrate why stringent adjustment for confounding, together with biological plausibility and consistency across datasets, are essential before inferring causality.
These results raise a key question: do the early metabolic disturbances observed with INSTI exposure ultimately lead to higher rates of major adverse cardiovascular events (MACE)? In this context, RESPOND1 reported increased cardiovascular events in the first 2 years of INSTI exposure. We found this early timing difficult to reconcile with a pathway mediated by incidental diabetes, hypertension, or obesity, which would affect outcomes over longer timeframes.
Taken together, these findings begin to elucidate what we perceive as the INSTI metabolic syndrome but cardiac reprieve paradox. Just as test and treat transformed HIV care through early therapy and prevention benefits, screening early and proactively managing modifiable cardiovascular risk factors could avert long-term harm.
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