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Markers of Inflammation, Coagulation,
and Renal Function Are Elevated in Adults with HIV Infection
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The Journal of Infectious Diseases May 6 2010
"The elevation of these biomarker levels among HIV-infected persons receiving effective ART as well as among those not receiving ART may reflect ongoing immune activation even with successful suppression of HIV replication [25]. Given the magnitude of the elevations and their association with cardiovascular disease, renal disease, and all-cause mortality in the general population, as well as with all-cause mortality in the SMART study, treatments that target inflammatory and coagulation pathways and decrease hsCRP, IL-6, and D-dimer levels may warrant investigation among patients with HIV infection....In the largest study, the Fat Redistribution and Metabolic Change in HIV Infection (FRAM) study, hsCRP levels were elevated in HIV-infected men but not women, compared with HIV-uninfected participants in the CARDIA study, and the differences between HIV-infected and HIV-negative participants varied according to coinfection with hepatitis C virus....We recently showed that cystatin C levels increased rapidly after ART interruption and that cystatin C levels were correlated with inflammatory and coagulation markers"
Jacqueline Neuhaus,1 David R. Jacobs, Jr,1 Jason V. Baker,1,2 Alexandra Calmy,7 Daniel Duprez,1 Alberto La Rosa,8 Lewis H. Kuller,3 Sarah L. Pett,9 Matti Ristola,10 Michael J. Ross,4 Michael G. Shlipak,5 Russell Tracy,6 and James D. Neaton,1 for the
International Network for Strategic Initiatives in Global HIV Trials (INSIGHT) Strategies for Management of Anti-Retroviral Therapy (SMART), Multi-Ethnic Study of Atherosclerosis (MESA), and Coronary Artery Development in Young Adults (CARDIA) Research Groupsa
1University of Minnesota and 2Hennepin County Medical Center, Minneapolis, Minnesota; 3University of Pittsburgh, Pittsburgh, Pennsylvania; 4Mount Sinai School of Medicine, New York, New York; 5University of California, San Francisco; 6University of Vermont, Burlington; 7Geneva University Hospital, Geneva, Switzerland; 8Asociacion Civil Impacta Salud y Educacion, Lima, Peru; 9University of New South Wales, Sydney, Australia; 10Helsinki University Central Hospital, Helsinki, Finland
ABSTRACT
Background. Human immunodeficiency virus (HIV) replication and immune activation may increase inflammation and coagulation biomarkers. Limited data exist comparing such biomarkers in persons with and without HIV infection.
Methods. For persons 45-76 years of age, levels of high-sensitivity C-reactive protein (hsCRP), interleukin (IL)-6, D-dimer, and cystatin C were compared in 494 HIV-infected individuals in the Strategies for Management of Anti-Retroviral Therapy (SMART) study and 5386 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) study. For persons 33-44 years of age, hsCRP and IL-6 levels were compared in 287 participants in the SMART study and 3231 participants in the Coronary Artery Development in Young Adults (CARDIA) study.
Results. hsCRP and IL-6 levels were 55% (p<.001) and 62% (p<.001) higher among HIV-infected participants than among CARDIA study participants. Compared with levels noted in MESA study participants, hsCRP, IL-6, D-dimer, and cystatin C levels were 50%, 152%, 94%, and 27% higher, respectively (p<.001, for each), among HIV-infected participants. HIV-infected participants receiving antiretroviral therapy who had HIV RNA levels <400 copies/mL had levels higher (by 21% to 60%) (p<.001) than those in the general population, for all biomarkers.
Conclusions. hsCRP, IL-6, D-dimer, and cystatin C levels are elevated in persons with HIV infection and remain so even after HIV RNA levels are suppressed with antiretroviral therapy. Additional research is needed on the pathophysiology of HIV-induced activation of inflammatory and coagulation pathways, to guide potential interventions.
There is a growing body of data indicating that the risk of serious non-AIDS conditions, such as cardiovascular disease, kidney disease, liver disease, and non-AIDS-defining malignancies, is increased in individuals with human immunodeficiency virus (HIV) infection, compared with the general population [1]. The reasons for this increase are not clear. HIV-induced activation of inflammatory and coagulation pathways could explain the increased risk.
In the Strategies for Management of Anti-Retroviral Therapy (SMART) trial, episodic use of antiretroviral treatment (ART) guided by the CD4+ cell count was compared with the current practice of continuous ART. The episodic ART strategy was also associated with an 84% (p<.007) increased risk of all-cause mortality. Most of the deaths were attributed to serious non-AIDS diseases [2]. A study using stored plasma specimens for SMART study participants was undertaken to explore the reasons for the greater risk of death from non-AIDS diseases in the episodic ART group. Interleukin (IL)-6 and D-dimer levels were found to increase significantly in the first month after the interruption of ART. Furthermore, levels of high-sensitivity C-reactive protein (hsCRP), IL-6, and D-dimer measured at study entry were strongly associated with mortality, and the association with mortality was evident in participants who were assigned to both the episodic and continuous ART groups [3]. Taken together, the findings from these 3 reports support the hypothesis that HIV induces activation of inflammatory and coagulation pathways, and they suggest that ART might dampen the effects.
To further understand these findings, we compared the levels of hsCRP, IL-6, D-dimer, and cystatin C in SMART study participants with levels for participants of similar age in 2 large population-based studies: the Multi-Ethnic Study of Atherosclerosis (MESA) study [4] and The Coronary Artery Risk Development in Young Adults (CARDIA) study [5]. Our hypothesis was that SMART study participants, all of whom were HIV infected, would have higher values of each of these markers than either the CARDIA or MESA study participants, who were recruited from the general population and were unlikely to be HIV infected.
Results
HIV-infected participants in the SMART study were more likely to be male and black than were participants of similar age in the CARDIA and MESA studies. 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 a lower body mass index than participants in the CARDIA and MESA studies (Table 1).
Fifty-one percent of SMART participants 33-44 years of age and 62% of those 45-76 years of age had HIV RNA levels 400 copies/mL (Table 1). The majority of participants in the SMART study were receiving ART. Of these participants receiving ART, 68% of those 33-44 years of age and 72% of those 45-76 years of age had HIV RNA levels 400 copies/mL. Of those not receiving ART in the younger group, 29% were ART naive, and 32% had not used ART for 6 months. Corresponding percentages for those 45-76 years of age were 20% and 28%, respectively. CD4+ cell counts averaged >600 cells/mm3 at study entry.
Unadjusted levels of hsCRP and IL-6 were 42% (p=.002) and 59% (p<.001) higher in HIV-infected participants than in participants in the CARDIA study (Figure 1A). hsCRP, IL-6, D-dimer, and cystatin C levels were 18% (p=.003), 118% (p<.001), 52% (p<.001), and 25% (p<.001) higher for HIV-infected participants in the SMART study than for participants in the MESA study (Figure 1B). With adjustment, the percentage differences increased, and all were significant (p<.001) (Table 2 and Figure 1A and 1B).
Differences according to the use of ART and the 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 33-44 years of age, D-dimer was 62% (95% CI, 27%-110%) (p<.001) higher for participants not receiving ART, compared with those receiving ART. For those 45-76 years of age, D-dimer levels were 63% (95% CI, 31%-101%) (p<.001) higher for those not receiving ART than for those receiving ART. For both groups, study participants not receiving ART and those receiving ART, D-dimer levels were significantly higher, compared with levels noted in MESA study participants; these levels were 127% higher for those not receiving ART and 39% higher for those receiving ART (p<.001, for both).
Table 3 presents median biomarker levels for study participants receiving ART who had an HIV RNA level 400 copies/mL. These levels were also higher than those in the 2 general population cohorts (Table 2). For HIV-infected participants 33-44 years of age, the adjusted percentage differences in hsCRP and IL-6 levels were 40% and 39% higher than those in the general population (p<.001, for both comparisons). For those 45-76 years of age, hsCRP, IL-6, D-dimer, and cystatin C levels were 38%, 60%, 49%, and 21% higher, respectively, than in the general population (p<.001, for all comparisons).
Table 3. Biomarkers Levels in SMART Study Participants Receiving Antiretroviral Therapy (ART) Who Had an HIV RNA Level <400 Copies/mL and Percentage Differences in Levels Versus CARDIA and MESA Study Participants, as Cited in Table 2
SMART study participants were further subdivided according to use of ART and the HIV RNA level (see Table A1 in the appendix, which does not appear in the print version of the Journal). P values corresponding to adjusted differences between those receiving ART who had an HIV RNA level 400 copies/mL and those receiving ART who had an HIV RNA level >400 copies/mL for loge-transformed levels of hsCRP, IL-6, D-dimer, and cystatin-C are p=.27 ,p=.63 ,p=.93 , and p=.27, respectively.
Table S1. Biomarker Levels, According to Human Immunodeficiency Virus (HIV) RNA Level and Antiretroviral Therapy (ART) Status of SMART Study Participants at Study Entry
We also explored the correlation of log10 HIV RNA levels and loge biomarker levels for those receiving ART who had an HIV RNA level >400 copies/mL. A significant positive correlation was found between the HIV RNA level and the D-dimer level, but not the other markers. The correlation coefficients (P values) were -0.03 (p=.68), 0.10 (p=.18), 0.25 (p<.001), and -0.01 (p=.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 received in SMART participants. In all cases, however, median levels were higher for SMART participants than for participants in the MESA and CARDIA studies. The median levels of hsCRP were greater for those receiving an NNRTI (2.81 µg/mL) versus those receiving a PI (2.14 µg/mL). In a regression model that adjusted for baseline covariates, hsCRP levels were 48% higher for those receiving an NNRTI (with or without a PI) versus a PI alone ( ). Levels of IL-6 ( ), D-dimer ( ), and cystatin C ( ) did not differ significantly between these classes of drugs. Median levels of hsCRP and IL-6 were higher for those receiving abacavir (3.07 µg/mL and 2.70 pg/mL, respectively) versus those receiving other NRTIs other than ddI (2.39 µg/mL and 2.36 pg/mL, respectively). After adjustment, the hsCRP level was 28% higher for those receiving abacavir, compared with those receiving other NRTIs other than ddI ( ), and the IL-6 level was 19% higher ( ). Also, although median levels of D-dimer were similar for those taking abacavir and other NRTIs other than ddI (0.27 µg/mL and 0.27 µg/mL, respectively), the adjusted percentage difference was 21% ( ). Cystatin C levels were similar for those receiving abacavir and other NRTIs (1% difference, ).
We also examined whether biomarker levels varied according to the total number of years of ART use, the number of years of PI use, and the number of years of NNRTI use, and these associations were not significant (data not shown).
Differences for smokers and nonsmokers.
Because of the large differences in smoking status between HIV-infected participants and participants in the CARDIA and MESA studies, separate analyses were conducted for nonsmokers. Adjusted hsCRP and IL-6 levels were 50% (95% CI, 26%-79%) and 63% (95% CI, 46%-83%) higher in nonsmoking HIV-infected participants than in nonsmoking participants in the CARDIA study. For nonsmokers in the SMART study, compared with nonsmokers in the MESA study, levels of hsCRP, IL-6, D-dimer, and cystatin C were 60% (95% CI, 41%-81%), 164% (95% CI, 146%-184%), 88% (95% CI, 70%-108%), and 29% (95% CI, 25%-34%) higher, respectively.
Differences according to sex and hepatitis C virus infection.
In all 3 studies, hsCRP levels were higher in women than men. In the SMART study, median (IQR) levels were 3.81 µg/mL (1.23-7.50 µg/mL) for women and 2.08 µg/mL (0.92-4.66 µg/mL) for men. There was evidence of an interaction between sex and HIV for hsCRP (P<.001, for comparison with the CARDIA study; p=.01, for comparison with the MESA study) but not for the other biomarkers. Both men and women with HIV infection had higher adjusted levels of hsCRP than participants of the same sex in the CARDIA and MESA studies, but relative differences were larger for men (77% [p<.001] higher than in the CARDIA study and 60% [p<.001] higher than in the MESA study) than for women (9% [p=.48] higher than in the CARDIA study and 26% [p=.02] higher than in the MESA study).
Differences in hsCRP levels between HIV-infected study participants
and those in the CARDIA and MESA study cohorts were greater when SMART study participants with hepatitis C virus coinfection were excluded (22% of men and 18% of women in the SMART study) (information to make a similar exclusion was not available for the CARDIA and MESA studies, but the prevalence of hepatitis C virus infection was assumed to be low). hsCRP levels were 97% higher (p<.001) for HIV-infected men in both age groups (the SMART study vs. the CARDIA study and the SMART study vs. the MESA study). The corresponding percentage differences for women were 25% (p=.11) (the SMART study vs. the CARDIA study) and 62% (p<.001) (the SMART study vs. the MESA study). For both age groups, the interaction with sex persisted (p=.001, for comparison with the CARDIA study; , for comparison with the MESA study) after the exclusion of participants in the SMART study who had hepatitis C virus infection.
Discussion
We compared the levels of 4 biomarkers between HIV-infected study participants and participants in 2 large population-based studies. Each of the biomarkers has been associated with cardiovascular disease in the general population [17-24], and 3 of the biomarkers (hsCRP, IL-6, and D-dimer) have recently been associated with all-cause mortality in the SMART study [3]. Compared with participants in the general population cohorts, CARDIA and MESA HIV-infected individuals in the SMART study had higher levels of inflammatory markers, as measured by hsCRP and IL-6; coagulation and fibrinolysis activity, as measured by D-dimer; and impaired renal function, as measured by cystatin C. Higher levels of these markers were evident even among HIV-infected study participants who were receiving ART and had HIV RNA levels <400 copies/mL.
The elevation of these biomarker levels among HIV-infected persons receiving effective ART as well as among those not receiving ART may reflect ongoing immune activation even with successful suppression of HIV replication [25]. Given the magnitude of the elevations and their association with cardiovascular disease, renal disease, and all-cause mortality in the general population, as well as with all-cause mortality in the SMART study, treatments that target inflammatory and coagulation pathways and decrease hsCRP, IL-6, and D-dimer levels may warrant investigation among patients with HIV infection [26, 27]. Among SMART study participants, some differences were noted in biomarker levels according to NNRTI and PI use and according to NRTI type. For the latter, we found higher levels of hsCRP and IL-6 among participants taking abacavir, compared with those taking other NRTIs other than ddI. This finding is consistent with a previous report on the SMART study cohort [14]. Differences among ART drugs are best explored in randomized studies, and these findings indicate that these markers should be considered in future trials of ART regimens.
Only a few studies have compared these biomarkers between participants with HIV infection and uninfected controls. hsCRP has been the focus of several reports [16, 28, 29]. In the largest study, the Fat Redistribution and Metabolic Change in HIV Infection (FRAM) study, hsCRP levels were elevated in HIV-infected men but not women, compared with HIV-uninfected participants in the CARDIA study, and the differences between HIV-infected and HIV-negative participants varied according to coinfection with hepatitis C virus [16]. Like the FRAM study, our study found that HIV infection was associated with greater differences in hsCRP levels for men, compared with women. The reasons for this finding are unclear. We also found that differences in hsCRP levels between those with HIV infection and those in the general population were smaller for those with hepatitis C virus coinfection, compared with those without hepatitis C virus coinfection. Reasons for differences in hsCRP levels according to hepatitis C status are likely multifactorial, although hsCRP is primarily synthesized by hepatocytes, and differences in hepatic function among patients coinfected with HIV and hepatitis C virus, compared with patients with hepatitis C virus monoinfection, may be a contributing factor to the hsCRP difference between coinfected and monoinfected participants [30].
In the FRAM study, cystatin C levels were also compared with those in participants in the CARDIA study [8]. Levels were higher in HIV-infected participants, compared with participants in the CARDIA study, after adjustment for demographic and clinical factors. Cystatin C may reflect, in part, ongoing inflammation as well as loss of kidney function. We recently showed that cystatin C levels increased rapidly after ART interruption and that cystatin C levels were correlated with inflammatory and coagulation markers [7].
The strengths of this investigation include the use of a single laboratory for the measurement of biomarkers in the SMART, CARDIA, and MESA studies. The age range and sex-ethnic distribution of SMART permitted comparisons across a broad spectrum of people with HIV infection. A weakness is that the SMART study did not exclude participants with more advanced HIV infection and included few ART-naive participants. Furthermore, there were many differences between the participants in the SMART study and those in the CARDIA and MESA studies. Although many factors were considered in the multivariate analyses and they did not have a substantial effect on the results, and although several subgroup analyses were considered, it is possible that there are other differences that explain our findings. Finally, because these were cross-sectional comparisons, the temporal relationship between the biomarkers and some of the predictors considered is uncertain. In summary, we found that markers of inflammation, coagulation, and renal function were elevated in HIV-infected study participants receiving or not receiving ART, compared with participants in 2 large population-based studies. Additional research on the reasons for these elevations and the interventions required to lower them is needed.
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