Incident diabetes after switching to integrase strand transfer inhibitors in people with HIV in the USA and Canada: a cohort study

Background Integrase strand transfer inhibitor (INSTI) initiation has been associated with diabetes in antiretroviral therapy (ART)-naive people with HIV. We aimed to examine the effect of switching to INSTIs on incident diabetes in ART-experienced people with HIV. Methods In this target trial emulation, we retrospectively used individual-level data from 27 longitudinal cohorts of people with HIV in the USA and Canada. We included participants aged at least 18 years without diabetes who had used non-nucleoside reverse transcriptase inhibitors (NNRTIs) or protease inhibitors for at least 180 days (in 2016–22) but had never used an INSTI. We used data from any clinical encounters in which participants continued an NNRTI or protease inhibitor versus switched to an INSTI, with a follow-up period of up to 5 years. The effect of switching to INSTIs on incident diabetes was estimated with weighted Cox regression with robust variance. We further assessed whether the effect varied by time since the switch and was explained by weight gain in the first year. Findings 13 071 participants were followed up from 2702 encounters in which they switched to an INSTI from an NNRTI, 54 766 encounters in which they continued an NNRTI, 1714 encounters in which they switched to an INSTI from a protease inhibitor, and 26 599 encounters in which they continued a protease inhibitor. Switching from protease inhibitors to INSTIs conferred an adjusted hazard ratio (HR) of 1·38 (95% CI 1·06–1·80) for incident diabetes, whereas switching from NNRTIs to INSTIs conferred an adjusted HR of 1·10 (0·87–1·39). The diabetes risk was higher during the first 2 years after switching from protease inhibitors to INSTIs (HR 1·67, 95% CI 1·21–2·30), but not thereafter (1·08, 0·75–1·57; p_interaction=0·064). The effect of switching from protease inhibitors to INSTIs on diabetes did not appear to be explained by weight gain. In the sensitivity analysis in which weight gain did not exceed 5% in the first year after, the switch from NNRTIs to INSTIs had a HR of 1·03 (95% CI 0·79–1·36) and the switch from protease inhibitors to INSTIs had a HR of 1·37 (1·02–1·84). Interpretation The increased diabetes risk after switching from protease inhibitors to INSTIs highlights a metabolic implication of regimen change and could warrant close monitoring early after switch, regardless of weight gain. Funding US National Institutes of Health.