Role of chronic hepatitis C virus (HCV) infection and host genetic variants in risk of myocardial infarction among people living with human immunodeficiency virus (HIV)

With the advent of highly effective antiretroviral therapy in the last 20 years, survival of people living with human immunodeficiency virus (HIV) (PLWH) has improved dramatically. Over the same period, morbidity and mortality from non-AIDS-defining illnesses, including cardiovascular disease (CVD), have increased. PLWH are at higher risk of myocardial infarction (MI) compared to the general population, and more MI events in this group are Type 2 MI (T2MI) rather than Type 1 MI (T1MI). In contrast to classical atheroembolic T1MI, T2MI results from myocardial oxygen demand-supply mismatch, a scenario that occurs secondary to a variety of conditions, including sepsis and stimulant-induced vasospasm. A large body of literature has linked CVD to chronic infection with hepatitis C virus (HCV), a common coinfection in PLWH. However, evidence is not conclusive regarding the association between HCV and MI in PLWH, and no research has addressed whether such an association may differ by MI type. We examined the association between HCV and MI in the Center for AIDS Research (CFAR) Network of Integrated Clinical Systems (CNICS), a multi-center clinical cohort of PLWH, using centrally adjudicated MI ascertainment based on the Universal MI definition. We estimated the association between chronic HCV and time to MI accounting for demographic characteristics, cardiovascular risk factors, clinical characteristics and substance use. We found that, among 23,407 PLWH aged ≥18, HCV was associated with a 68% greater risk of T2MI (adjusted hazard ratio (aHR) 1.68, 95% CI: 1.22, 2.30) but not T1MI (aHR 0.96, 95% CI: 0.63, 1.45). In a cause-specific sensitivity analysis of T2MI, HCV was associated with a 2-fold greater risk of T2MI attributed to sepsis (aHR 2.26, 95% CI: 1.34, 3.81). In a subsequent analysis, we assessed whether variants in the genomic region coding for immune regulators, interferon lambda (IFNL) 3 and IFNL4, were associated with MI events by type. We found that selected variants were not individually associated with T2MI or the subgroup of T2MI attributed to sepsis, but that 3 of 4 selected variants were associated with a 23 to 30% higher odds of atheroembolic T1MI. We leveraged these four variants as instrumental variables, in a Mendelian randomization analysis, to test for evidence of causality in the observed association of HCV with T2MI. Based on these four variants, Mendelian randomization analyses did not provide evidence that chronic HCV causally increases the risk of T2MI (Ratio of odds ratios (ORR) 0.78, 95% CI: 0.33, 1.83) or T2MI attributed to sepsis (ORR 1.13, 95% CI: 0.54, 2.36) in PLWH. Taken together, our findings indicate that, while HCV and T2MI are observationally associated in this cohort of PLWH, this association is unlikely to be causal but instead may result from bias due to unmeasured or misclassified confounding factors. This finding highlights the importance of using the full set of epidemiological methods to explore large and unexpected observational associations to verify their robustness. However, we also found that 3 of 4 selected variants in the IFNL3/4 genomic region were associated with both chronic HCV and T1MI in this cohort. The association of these variants with T1MI has not been previously reported. This raises the question of whether a common genetic background may play a role in observations from numerous sources that HCV is associated with subclinical and clinical CVD and opens a new line of inquiry that may ultimately inform research and clinical care priorities for PLWH who are coinfected with HCV.