Background:  In the Strategies for Management of ART (SMART) trial, elevated study entry levels of interleukin-6 (IL-6) and D-dimer were strongly related to all-cause mortality and to cardiovascular disease (CVD). These markers, as well as high-sensitivity C-reactive protein (hsCRP) and cystatin-C, are associated with CVD and mortality in the general population. Understanding the magnitude by which these and other biomarkers are elevated as a consequence of HIV infection or ART could guide the development of interventions.

Methods:  IL-6, hsCRP, D-dimer, and cystatin-C were measured by the same laboratory for SMART, the Coronary Artery Development in Young Adults (CARDIA) Study, and the Multi-Ethnic Study of Atherosclerosis (MESA). The latter 2 studies were population based and HIV infection was not ascertained, but was assumed to be rare and AIDS death was <1%. Comparisons between 33- to 44-year-old black and white participants enrolled by US sites in SMART and CARDIA and between 45 and 76 year old black, Hispanic, and white participants in SMART and MESA were made. Using log (natural) transformed values, analysis of covariance was carried out with the following co-variates:  age, race, gender, body mass index, smoking, total/HDL cholesterol, diabetes, and blood pressure or lipid lowering treatment. 

Results:  At study entry median CD4⁺ counts were 557 and 584 in the 33- to 44-year-old and the 45- to 76-year old SMART age groups, respectively. More than 70% of SMART participants were on ART. Unadjusted medians of the biomarkers at study entry in SMART (assessed in 2002 to 2006) and MESA (2000 to 2002) and at year 15 in CARDIA (2000 to 2001) and percentage differences between the studies adjusted for the co-variates above (derived from natural log transformed values) are below. For SMART participants, median D-dimer was higher for those not taking ART at entry compared to those taking ART (0.49 vs 0.29 μg/mL). D-dimer levels for those on and off ART in SMART were higher than in MESA (p <0.001 for both). Other markers did not vary in a consistent manner by use of ART

Conclusions:   Since levels of hsCRP, IL-6, D-dimer ,and cystatin-C are associated with risk of CVD or mortality in the general population, the higher levels of these markers in HIV-infected participants would predict adverse clinical outcomes.