HIV-infected participants in SMART were more likely to be male and Black than similar aged participants in CARDIA and MESA. HIV-infected participants were also more likely to smoke cigarettes and take lipid and blood pressure-lowering drugs; they had higher total cholesterol/HDL ratios and lower body mass index than participants in CARDIA and MESA ().
Characteristics of SMART, CARDIA and MESA Participants Used for Biomarker Comparisons
Fifty-one percent of SMART participants aged 33 to 44 and 62 percent aged 45–76 had HIV RNA levels ≤ 400 copies/mL (). The majority of participants in SMART were taking ART. Among these participants on ART, 68 percent for those aged 33 to 44 years and 72 percent for those aged 45 to 76 years had HIV RNA levels ≤ 400 copies/mL. Among those not taking ART, 29 percent were ART-naïve and 32 percent had not used ART for 6 months in the younger age group. Corresponding percents for those 45 to 76 years were 20 percent and 28 percent. CD4+ cell counts averaged over 600 cells/mm3 at study entry.
Unadjusted levels of hsCRP and IL-6 were 42% (p=0.002) and 59% (p<0.001) higher in HIV-infected participants compared to participants in CARDIA (). hsCRP, IL-6, D-dimer and cystatin C were 18% (p=0.003), 118% (p<0.001), 52% (p<0.001) and 25% (p<0.001) higher for HIV-infected participants in SMART compared to participants in MESA (). With adjustment, percent differences increased and all were significant (p<0.001) (, ).
Figure 1a: Percentage Difference (HIV-infected versus General Population for hsCRP and IL-6): Participants Aged 33–44 Years.
Median Levels and Interquartile Range (IQR) of Biomarkers for SMART, CARDIA and MESA Participants
Differences According to Use of ART and HIV RNA Level
With the exception of D-dimer, the biomarkers did not vary for HIV-infected participants according to use of ART. Among HIV-infected participants 33 to 44 years, D-dimer was 62% (95% CI: 27 to 110; p<0.001) higher for participants not taking ART compared to those taking ART. For those aged 45 to 76 years, D-dimer levels were 63% (95% CI: 31 to 101; p<0.001) higher for those not taking ART compared to those on ART. For both those not taking ART and taking ART, D-dimer levels were significantly higher compared to MESA participants by 127% for those not on ART and by 39% for those taking ART (p<0.001 for both).
gives median biomarker levels for those on ART and with HIV RNA ≤ 400 copies/mL. These levels were also higher than in the two general population cohorts (see ). Adjusted percent differences of hsCRP and IL-6 for those aged 33 to 44 in this subgroup of HIV-infected participants were 40% and 39% higher compared to the general population (p<0.001 for both comparisons). For those aged 45 to 76 years, hsCRP, IL-6, D-dimer and cystatin C were 38%, 60%, 49% and 21% higher than the general population, respectively (p<0.001 for all comparisons).
Median Levels and Inter-quartile Range (IQR) of Biomarkers in SMART for Participants on Antiretroviral Treatment and with HIV RNA ≤ 400 copies/mL and Percent Difference from CARDIA and MESA Levels cited in
SMART participants were further subdivided according to use of ART and HIV RNA level (see ). P-values corresponding to adjusted differences between those on ART with HIV RNA ≤ 400 copies/mL and those on ART with HIV RNA > 400 copies/mL for loge transformed levels of hsCRP, IL-6, D-dimer and cystatin-C are 0.27, 0.63, 0.93, and 0.27, respectively.
Biomarker levels by HIV-RNA Level and ART status in SMART at Study Entry
We also explored the correlation of log10 HIV RNA levels and loge biomarker levels for those on ART with HIV RNA levels > 400 copies/mL. A significant positive correlation was found between HIV RNA and D-dimer, but not the other markers. The correlation coefficients (p-values) were −0.03 (0.68), 0.10 (0.18), 0.25 (<0.001) and −0.01 (0.96), for hsCRP, IL-6, D-dimer and cystatin-C, respectively.
Differences According to Type and Duration of ART
Some differences were noted in biomarker levels according to type of ART in SMART. In all cases, however, median levels were higher for SMART participants than participants in MESA and CARDIA. Median levels of hsCRP were greater for those taking an NNRTI (2.81 μg/mL) versus a PI (2.14 μg/mL). In a regression model that adjusted for baseline covariates, hsCRP levels were 48% higher for those on an NNRTI (with or without a PI) versus a PI alone (p<0.001). Levels of IL-6 (p=0.46), D-dimer (p=0.12) and cystatin-C (p=0.13) did not differ significantly between these classes of drugs. Median levels of hsCRP and IL-6 were higher for those taking abacavir (3.07 μg/mL and 2.70 pg/mL) versus other NRTIs besides ddI (2.39 μg/mL and 2.36 pg/mL). After adjustment, hsCRP was 28% higher for those on abacavir compared to other NRTIs besides ddI (p=0.05) and IL-6 was 19% higher (p=0.03). Also, although median levels of D-dimer were similar for those taking abacavir and other NRTIs besides ddI (0.27 and 0.27 μg/mL), the adjusted percent difference was 21% (p=0.054). Cystatin-C levels were similar for those on abacavir and other NRTIs (1% difference, p=0.81).
We also examined whether biomarker levels varied according to total years of ART, years of PI and years of NNRTI use and these associations were not significant (data not shown).
Differences for Smokers and Non-Smokers
Because of the large differences in smoking status between HIV-infected participants and participants in CARDIA/MESA, separate analyses for non-smokers were carried out. Adjusted hsCRP and IL-6 levels were 50% (95% CI: 26 to 79) and 63% (95% CI: 46 to 83) higher in non-smoking HIV-infected participants compared to non-smoking participants in CARDIA. For non-smokers in SMART compared to non-smokers in MESA, levels of hsCRP, IL-6, D-dimer and cystatin C were 60% (95% CI: 41 to 81), 164% (95% CI: 146 to 184), 88% (95% CI: 70 to 108) and 29% (95% CI: 25 to 34) higher, respectively.
Differences According to Gender and Hepatitis C Infection
In all three studies, hsCRP levels were higher in women than men. In SMART, median (IQR) levels were 3.81 μg/mL (1.23–7.50) for women and 2.08 μg/mL (0.92–4.66) for men. There was evidence of an interaction between gender and HIV for hsCRP (p=0.0005 for CARDIA comparison and p=0.01 for MESA comparison) but not for the other biomarkers. Both men and women with HIV-infection had higher adjusted levels of hsCRP than participants of the same gender in CARDIA and MESA, but relative differences were larger for men [77% (p<0.0001) higher than CARDIA and 60% (p<0.0001) higher than MESA] as compared to women [9% (p=0.48) higher than CARDIA and 26% (p=0.02) higher than MESA].
Differences in hsCRP levels between HIV-infected participants and those in the CARDIA and MESA cohorts were greater when participants in SMART with hepatitis C co-infection were excluded (22% of men and 18% of women in SMART) (information to make a similar exclusion was not available for CARDIA and MESA but infection with hepatitis C was assumed to be low). hsCRP levels were 97% higher (p<0.0001) for HIV-infected men in both age groups (SMART versus CARDIA and SMART versus MESA). The corresponding percentage differences for women were 25% (p=0.11) (SMART versus CARDIA) and 62% (p<0.0001) (SMART versus MESA). For both age groups the interaction with gender persisted (p=0.001 for CARDIA comparison and p=0.05 for MESA comparison) after the exclusion of participants in SMART with hepatitis C infection.