In this cohort of long-term effectively-treated HIV-infected men, a low nadir CD4+ T-cell count was the strongest clinical predictor of endothelial dysfunction as assessed by brachial artery FMD. Specifically, a nadir CD4+ T-cell count < 350 cells/μl was associated with a 1.2% decrease in FMD. When compared with previous studies in non-infected individuals, this reduction in FMD represents a greater impairment than is observed in the presence of diabetes, smoking, or prevalent cardiovascular disease [20
]. These findings suggest that delaying the initiation of antiretroviral therapy until late in the disease process (as defined by nadir CD4+ T-cell counts) may be associated with adverse cardiovascular consequences. Although most guidelines now recommend starting therapy before this threshold is reached, a substantial proportion of individuals enter care with more advanced disease, and many if not most treated individuals have a low nadir CD4+ T-cell count.
Endothelial dysfunction plays a central role in the development and progression of atherosclerosis, and predicts future cardiovascular events in non-HIV infected patients [21
]. HIV-infected patients have impaired endothelial function when compared with non-infected controls [23
]. The mechanism of endothelial dysfunction in HIV disease is unclear. Previous studies have shown worse endothelial dysfunction with higher viral load [23
], and others have demonstrated improved endothelial function with HAART treatment [25
]. One study demonstrated significant improvement in endothelial function in antiretroviral-naïve individuals within 4 weeks of HAART initiation [27
]. Our study extends these findings to a cohort of effectively-treated adults on stable HAART, and suggests that the degree of immunological compromise prior to initiation of HAART is associated with endothelial dysfunction. Our results also suggest that immunological recovery as assessed by proximal CD4+ T-cell does not abrogate the cardiovascular risk linked to low nadir CD4+ T-cell counts.
The role of HIV disease in the pathogenesis of early atherosclerosis is supported by the consistent observation that both CD4+ count and viral load influence this disease. The CD4+ count nadir predicts subclinical carotid atherosclerosis and vascular stiffness in our investigations [5
], and a low CD4+ count on HAART has been associated with cardiovascular risk [28
]. The association of low CD4+ T-cell count with cardiovascular disease is not well understood, and may be due to chronic inflammation [31
] or direct viral effects [32
]. Inflammatory markers have also been associated with subclinical atherosclerosis [33
], mortality, and cardiovascular disease in HIV-infected individuals [34
]. In secondary analyses, the association of low nadir CD4+ T-cell count and endothelial dysfunction was not mediated by inflammation as measured by CRP in our study.
Several limitations deserve mention. Potential confounding factors are a challenge in our observational study design, and only a randomized controlled clinical trial of early versus late initiation of HAART can address the issue definitively. In the absence of such a study, observational cohorts provide the best available evidence to address the question. Although we adjusted for differences in identifiable cardiovascular risk and HIV associated factors, unmeasured factors remain a possible explanation for the observed greater endothelial dysfunction in subjects with lower nadir CD4+ counts. Therefore, our results must be interpreted with caution, as the cross-sectional nature of the study precludes any causal inferences. Clearly, prospective longitudinal studies are needed to evaluate the effect of early HAART initiation on cardiovascular outcomes. Our study is of modest size, which limits complex analyses examining mediators of the observed association of nadir CD4+ T-cell count and vascular function. It is also unclear whether the association of endothelial dysfunction and nadir CD4+ T-cell count extends beyond a threshold of 500 cells/μl, as few participants met these criteria. Despite these limitations, the strengths of the study were a contemporary sample of treated HIV-infected individuals with HAART initiation both early and late in the course of HIV infection, and rigorous assessment of endothelial function.
In conclusion, a nadir CD4+ T-cell count < 350 cells/μl was associated with worse endothelial function in HIV-infected men on stable HAART. The association of nadir CD4+ T-cell count and vascular function was greater than that of traditional cardiovascular risk factors. Although causal inferences cannot be drawn from this cross-sectional study, our study provides compelling evidence that earlier initiation of HAART at higher nadir CD4+ T-cell counts may have a favorable impact on cardiovascular risk. Future prospective studies examining early HAART initiation with respect to cardiovascular outcomes are needed.