Clonal hematopoiesis and risk of mortality and cardiovascular disease in older adults with and without HIV

Background Despite viral suppression, people with HIV (PWH) experience residual cardiovascular and mortality risk not explained by traditional risk factors. Age-related clonal hematopoiesis of indeterminate potential (CHIP) is an independent predictor of mortality and cardiovascular disease (CVD) in people without HIV (PWoH) and is reportedly more prevalent among PWH, suggesting its possible role in residual risk. Purpose To assess baseline CHIP prevalence and its association with incident clinical events in US veterans with and without HIV in the Veterans Aging Cohort Study Biomarker Cohort. Methods We assayed baseline CHIP driver mutations using high-coverage targeted sequencing, defining presence of CHIP as variant allele frequency (VAF) >2%. Multivariable models adjusted for age, sex, race, and smoking status were used to assess cross-sectional associations of HIV with CHIP (logistic regression) and individual and interactive effects of CHIP and HIV on mortality and incident CVD events, including acute myocardial infarction, unstable angina, revascularization, heart failure, or ischemic stroke (Cox models). We report odds ratios (OR), hazard ratios (HR), and 95% confidence intervals (CI). Results Among 1524 PWH and 852 PWoH, 66% of participants were Black. At baseline, 316 (13%) had CHIP, with no difference by HIV status (191 [14.7%] PWH, 125 [12.5%] PWoH). PWH and PWoH with CHIP were older than those without CHIP, and 57% of those with CHIP reported current smoking (Table 1). DNMT3A was the most common driver mutation among PWH and PWoH, followed by TET2 and PPMD1 (Figure 1A). In multivariable-adjusted models, older age (OR 1.08 [95% CI 1.06-1.10]; p <0.001) and current smoking (OR 1.51 [1.11-2.08]; p <0.01) were associated with CHIP, whereas HIV was not (OR 0.99 [0.77-1.29]). Over a median follow-up of 17.5 years, baseline CHIP showed a nonsignificant trend toward higher mortality risk (adjusted HR 1.15 [0.99-1.35]; p = 0.073), whereas HIV was significantly associated with mortality (HR 1.26 [1.11-1.43]; p <0.001). The concomitant presence of CHIP and HIV was associated with nearly 50% higher incident mortality compared with absence of both (HR 1.48 [1.20-1.83]; p< 0.001; Figure 1B). Among participants free of baseline CVD, CHIP was not associated with incident CVD overall but was associated with lower risk among PWoH (HR 0.55 [0.35-0.86], p = 0.009) over 12.5 years of median follow-up, which was robust in stratified analyses. CHIP did not modify the association between HIV and mortality; however, a significant CHIP-HIV interaction was observed for incident CVD, with more than twofold higher risk among PWH than PWoH (pinteraction = 0.006). Conclusions In contrast to prior reports, HIV was not associated with the presence of CHIP in this older cohort of US veterans. The observed interaction between CHIP and HIV warrants further investigation to clarify potential synergistic effects on cardiovascular risk.