An important step in linking HIV-associated immunologic perturbations to cardiovascular disease is demonstrating that specific markers of these pathways predict subsequent cardiovascular disease events. As might be expected, hsCRP (a nonspecific acute-phase reactant) has generally been associated with cardiovascular disease in HIV-infected adults [23
], although whether the prognostic role of hsCRP in HIV-infected adults differs from that in uninfected adults is not clear [24
A unique role of inflammation in HIV disease first became evident in the SMART study. As reviewed by Triant et al in this supplement, SMART was a study comparing individuals who were randomly assigned to receive continuous antiretroviral therapy with those who were randomized to receive intermittent therapy that was based on a strategy of maintaining CD4+ T-cell counts >250 cells/mm3
. Those who received continuous treatment had a lower risk of developing cardiovascular disease [26
]. Across the entire study population, elevated levels of interleukin 6 (IL-6) and D-dimers at baseline were strongly associated with a higher risk of mortality [25
]. These trends were observed in the antiretroviral-treated subset. Although the number of deaths attributed to cardiovascular disease was low and hence not fully analyzed, the findings were similar to those for all-cause mortality, suggesting a potential role of these biomarkers in predicting HIV-associated cardiovascular events. Importantly, while plasma IL-6 and D-dimer levels in treated HIV-infected individuals are only marginally higher than those in HIV-uninfected individuals [27
], their impact on the subsequent risk of mortality and cardiovascular disease appears to be much greater in the HIV-infected population [25
]. This observation may suggest that inflammation plays a greater role in the pathogenesis of cardiovascular disease in the HIV-infected population than in the general population. Other observational studies in HIV-infected individuals have reported similar findings. For example, in the FRAM study, elevations in hsCRP and fibrinogen levels were associated with all-cause mortality (this effect was evident even in those with high CD4+ T-cell counts) [28
]. A case-control study from the National Institute of Allergy and Infectious Diseases (NIAID) cohort demonstrated an association between D-dimers and vascular cell adhesion molecule 1 levels to cardiovascular disease events, but the low prevalence of cardiovascular events and heterogeneity in the study population prevented a definitive assessment of all pathways, particularly in the antiretroviral-treated population [29
]. Collectively, these studies indicate that a number of inflammatory plasma biomarkers known to predict cardiovascular events in the uninfected population are elevated in treated HIV disease and also predict cardiovascular events in this setting.
To determine whether HIV infection is associated with disease independent of high-level viremia, advanced immunodeficiency, and treatment toxicity, we compared carotid intima-media thickness (IMT) in HIV-infected individuals who were able to control viral load in the absence of therapy (ie, “elite controllers”) with that in HIV-uninfected controls. Surprisingly, the elite controllers in our cohort had a higher median carotid IMT than that observed in HIV-uninfected subjects, even after adjustment for traditional cardiovascular risk factors [30
]. Interestingly, we previously found in this cohort that certain measures of inflammation and immune dysfunction, including T-cell activation and hsCRP levels, were higher in elite controllers, compared with uninfected individuals [31
]. These data provide additional evidence for some HIV-associated factor (which we hypothesize to be chronic inflammation) as a causal factor in early heart disease, although it is certainly possible that some unmeasured risk factors may have explained the differences in carotid IMT.