Cardiovascular Disease Risk with Integrase Inhibitor-based Antiretroviral Therapy: A Causal Inference Analysis in RESPOND

Background: A previous RESPOND analysis suggested that integrase inhibitors (INSTIs) increase cardiovascular disease (CVD) risk compared with other antiretroviral therapy (ART). We reanalyzed the data using target trial emulations examining the impact of methodological choices. Methods: Treatment-naïve analyses included ART-naïve adults with detectable HIV viraemia and recent CD4 and HIV-RNA measurements. Treatment-experienced analyses included adults with suppressed HIV-RNA receiving INSTI-free ART. We estimated adjusted risk differences (RDs) and risk ratios (RRs) for CVD events comparing INSTI initiation or switching versus other ART using inverse-probability weighting and pooled logistic regression. Results: Among 7111 treatment-naïve individuals, 95 CVD events occurred over a median of 62 months. Risk ratios comparing INSTI initiation with starting other ART were 1.07 (95% confidence interval .29-4.93) at 1 year, 1.21 (.41-3.91) at 2 years, and 1.87 (1.06-3.26) at 6 years. Corresponding RDs were 0.02% (-.32-.29), 0.09% (-.43-.53), and 1.03% (0.08-2.07). Among 22 921 treatment-experienced individuals, 800 CVD events occurred over a median of 37 months. Risk ratios were 1.55 (1.16-2.00) at 1 year, 1.30 (1.07-1.62) at 2 years, and 0.93 (.78-1.09) at 6 years. Corresponding RDs were 0.26% (.08-.47), 0.29% (.03-.58), and -0.22 (-.66-.25). Conclusions: Switching to INSTIs was associated with a transient increase in CVD risk during the first 2 years among treatment-experienced individuals, whereas starting INSTIs in ART-naïve individuals was associated with a gradual increase over time, albeit based on few events. Absolute RDs remained small, but the findings suggest a potential impact of INSTIs on the development of CVD.