DISCUSSION
PWH, TAF, CVD
CVD, EVENTS, EVENT
In this nationwide cohort study of 5362 treatment-naïve PWH and a median follow-up of 5 years, we found no difference in risk for developing CVD events between individuals who started an INSTI-based ART and those who started other ART combinations. These findings are reassuring in the context of increasing INSTI use worldwide and support the prioritization of INSTIs as the preferred agents in current international guidelines [Our main findings contrast with those from RESPOND, who observed a marked increase in CVD risk between 6 and 24 months after the initiation of an INSTI [A previous registry-based study from the United States documented a lower risk for CVD events among 20'000 treatment-naïve PWH who started INSTI-based ART compared with those who started other ART [Our estimates for the impact on CVD events of starting INSTIs compared with other ART combinations differed markedly between unadjusted and adjusted analyses. In part, these differences may be explained by confounding because individuals who started INSTIs were more likely to be men and to receive abacavir, factors that were previously associated with an increased CVD risk [We explored the association between INSTI-based ART and CVD risk using a target trial emulation, a framework that reduces the potential for confounding by indication and selection bias. The study was performed using data from the nationally representative cohort of PWH and showed consistent results across several sensitivity analyses. We relied on long-term follow-up of individuals with and without INSTI-based ART, which allowed us to consider both older and newer generation INSTIs. Furthermore, the SHCS follows a very stringent outcome ascertainment based on prespecified protocols and blinded central validation. However, the relatively low number of CVD events in our study limited the statistical power to detect a difference in CVD risk between groups during each specific time interval and prevented us from performing separate analyses comparing INSTIs with PI or NNRTI starters, as well as evaluating the role of individual INSTI components. In addition, because our study was restricted to treatment-naïve individuals who started ART, our findings cannot be extrapolated to treatment-experienced individuals who switch to an INSTI-based regimen. Dedicated target trial emulations focused on individuals who switch to INSTI-based ART are needed because a simultaneous switch from tenofovir disoproxil fumarate (TDF) to TAF is frequent and may contribute to the CVD risk [In conclusion, we found no evidence of a difference in CVD event risk between treatment-naïve individuals who started INSTI-based ART and those who started other ART combinations. Importantly, the CVD risk was similar between both groups in the short term as well as in the longer term. Similarly designed studies are needed to evaluate the impact of switching to INSTI-based ART among treatment-experienced individuals to further understand the impact of INSTI on cardiometabolic outcomes.