In a contemporary cohort of HIV-infected ART-naive individuals without advanced HIV disease, ultrasonographic measures of CVD risk were more strongly associated with traditional risk factors such as aging, body size, and lipoprotein measurements, rather than CD4 cell count, viral replication, inflammatory markers, and cytokines. Several aspects of this study and findings are notable and important for understanding CVD risk in contemporary patients with HIV infection. This is the first large study to evaluate CVD risk among HIV-infected, but treatment-naïve individuals ready to initiate ART. Given the complex interplay between HIV infection and treatment on CVD risk factors and CVD risk, understanding the associations with arterial disease prior to ART initiation is important for understanding why patients with HIV infection appear to be at increased CVD risk compared to HIV-negative individuals. This is the only study of its kind to simultaneously evaluate CIMT and FMD along with multiple, putative markers of CVD risk including advanced lipoprotein testing, inflammatory markers, immune activation, HIV disease activity. Its multicenter nature with strict quality control enhanced the reliability of the data and our ability to identify associations. A medium or high 10-year predicted CVD risk was associated with increased CIMT in the common and bifurcation carotid artery segments, more carotid artery lesions, lower brachial artery FMD and larger brachial artery diameter – each of the ultrasound measures of increased CVD risk, demonstrating the internal validity of our findings.
By demonstrating that modifiable risk factors such as increased body size and lipoprotein measures are the major associates of increased CIMT, carotid artery lesions, and impaired FMD, these parameters can be targeted for early preventive lifestyle and if necessary, pharmacological interventions to reduce future CVD risk in patients initiating ART. Indeed, a recent randomized clinical trial demonstrated that a focused dietary intervention significantly reduced LDL cholesterol in HIV-infected patients beginning their first ART regimen [22
], the magnitude of which would be expected to significantly reduce long-term CVD risk. AIDS Clinical Trials Group Study A5078, a longitudinal, observational investigation showed that in cross-section, traditional risk factors overshadowed the impact of HIV protease inhibitor exposure, and that progression of CCA CIMT was similar among age- and risk-factor matched individuals with and without HIV infection [23
]. Our results confirm and extend these findings, showing that traditional CVD risk factors, but not markers of inflammation and HIV disease activity are strongly associated with bifurcation CIMT, carotid artery lesions, and brachial artery FMD in a low CVD risk population.
Despite a wide range of CD4 cell counts among our participants, CD4 cell counts were not independently associated with any ultrasonographic marker of CVD risk. This may be due to the relatively small sample size since within the larger sample sizes of the Multicenter AIDS Cohort Study and the Women’s Interagency HIV Study, a CD4 cell count <200 cells/mm3
was independently associated with increased carotid artery lesion prevalence and with increased carotid arterial stiffness in HIV-infected vs. HIV-uninfected individuals [17
]. However, these individuals were older than those in our study and most were ART-experienced. It has been hypothesized that starting ART in subjects with higher cell counts would reduce CVD risk [26
The effects of HIV viral load on arterial function and disease are less clear. Lower HIV loads were weakly associated with carotid artery lesions but neither CIMT measure; and higher viral loads were associated with smaller brachial artery diameters, but not worse FMD. Active infection may invalidate the observational association between smaller arteries and lower CVD risk, perhaps because of sympathetic activation and attendant vasoconstriction [8
]. Indeed, higher viral loads were associated with higher heart rates. In ACTG Study A5152 s, a randomized clinical trial of 3 ART regimens in treatment-naïve patients, effective ART improved FMD, reduced heart rates, and increased brachial artery diameters [20
]. Improvement in FMD was related to the reduction in HIV load, indicating that treating HIV infection improves endothelial function and relieves vasoconstriction that accompanies untreated HIV infection [20
]. In the Study to Understand the Natural History of HIV/AIDS in the ERA of Effective Therapy, suppression of plasma HIV-1 RNA viral load to <400 copies/ml was associated with decreased progression of CCA CIMT over a 2-year period [27
]. The possibility of increased CVD risk with treatment interruption was observed in the SMART study [28
]. Therefore, treatment of HIV infection may reduce CVD risk, as does treatment of CVD risk factors.
Limitations of this study include the absence of an HIV-negative or HIV treatment-experienced control group and the young age of the participants, who on average, were at low CVD risk. Although this is the largest report, to date, describing CVD risk among treatment-naïve HIV-infected individuals, it still is relatively small and underpowered for detecting modest risk factor associations with our CVD risk markers, especially considering the high intra-individual and/or measurement variability of some of the markers we studied. Also, this was a cross-sectional analysis; longitudinal follow-up, which is in progress, may be even more informative.
Given these limitations, the absence of significant associations between inflammation and the arterial measurements in this study does not exclude a role for inflammation and immune activation as contributors to CVD risk in patients with HIV. The association between increasing interleukin-6 levels and the prevalence of carotid artery lesions was the only independent association between any inflammatory marker or adipocytokine with a vascular marker that we evaluated. The meaning of this finding is unclear; however, higher interleukin-6 levels have been linked to increased mortality in individuals with HIV. It is possible that other unmeasured markers of inflammation or immune activation may be more strongly associated with vascular disease. In recent studies, CD4 and CD8 T-cell activation and CD8 T-cell senescence were associated with increased carotid artery lesion prevalence and increased carotid arterial stiffness in HIV-infected individuals [18
Finally, this study sheds insight into the interaction between brachial artery size and FMD. FMD is lower in individuals with larger arteries; however, it is unclear if this is merely a mathematical function of brachial artery size being in the denominator of the formula for calculating FMD, or if it represents pathophysiology related to larger patients having risk factors associated with increasing body size and adiposity. Contemporaneous measurement of body composition helped us show that lean body mass was associated much more strongly with brachial artery size than any fat depot or adiposity measure. Lean body mass was associated with height and weight, indicating that the association between increased brachial artery size and CVD risk is not due to adiposity; arteries are larger in bigger people with greater muscle mass.
Subjects in this study reflect contemporary patients with HIV initiating their first ART regimen. They have notably less advanced HIV disease than in historical cohorts, even more recent ART-naïve cohorts such as in ACTG Study A5224 s [30
]. Contemporary patients starting ART have higher CD4 cell counts and a shorter duration of HIV infection, but also have a different burden of traditional risk factors than historical cohorts. They tend to be younger, have lower (albeit still excessive) rates of smoking, and lower triglycerides, but they are heavier and have higher BMIs. The changing demographics and CVD risk burden of HIV-infected patients initiating ART further complicates efforts to understand predictors of CVD risk in patients with HIV.