Incident Diabetes after Switching to Integrase Strand Transfer Inhibitors among People with HIV in the United States and Canada: A Cohort Study

SUMMARY Background: Integrase strand transfer inhibitor (INSTI) initiation has been associated with diabetes among antiretroviral therapy (ART)-naïve people with HIV (PWH). We examined the effect of switching to INSTIs on incident diabetes among ART-experienced PWH. Methods: We emulated a target trial within longitudinal cohorts of PWH in the US and Canada. Participants without diabetes who had used non-nucleoside reverse transcriptase inhibitors (NNRTIs) or protease inhibitor (PIs) for ≥180 days (2016–2022) were followed from encounters where they continued an NNRTI or PI vs switched to an INSTI, for up to 5 years. The effect of switching on incident diabetes was estimated using weighted Cox regression with robust variance. We further assessed whether the effect (i) varied by time since switch and (ii) was explained by weight gain in the first year. Findings: 13,071 participants were followed from 2,702 encounters where they switched to an INSTI from an NNRTI, 54,766 encounters where they continued an NNRTI, 1,714 encounters where they switched to an INSTI from a PI, and 26,599 encounters where they continued a PI. Switching from PIs to INSTIs conferred an adjusted hazard ratio (HR) of 1.38 (95% confidence interval [CI], 1.06–1.80) for incident diabetes, whereas switching from NNRTIs to INSTIs conferred an HR of 1.10 (95% CI, 0.87–1.39). The diabetes risk was higher during the first two years after switching from PIs to INSTIs (HR, 1.67; 95% CI, 1.21–2.30), but not thereafter (HR, 1.08; 95% CI, 0.75–1.57; interaction P = 0.06). The effect of switching from PIs to INSTIs on diabetes did not appear to be explained by weight gain. Interpretation: The increased diabetes risk after switching from PIs to INSTIs highlights a metabolic implication of regimen change and may warrant close monitoring early after switch, regardless of weight gain.