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Diverse Disease Markers Up in SMART Patients Regardless of Antiretroviral Therapy: inflammation markers linked to death, ART interruption, HIV, aging, & ART
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16th Conference on Retroviruses and Opportunistic Infections, February 8-11, 2009, Montreal
Mark Mascolini
Compared with two general-population cohorts, SMART study participants had higher levels of inflammatory markers, a coagulation and fibrinolysis marker, and a renal function marker [1]. Levels of most markers analyzed were elevated in HIV-infected people regardless of whether they were taking antiretrovirals.
"The magnitude of the differences in these markers" between people with and without HIV is clinically relevant, the SMART investigators argued, "considering the prognostic importance of these markers in the general population."
The comparison involved three groups--participants in the SMART trial, which established the superiority of steady antiretroviral therapy over CD4 count-guided interruptions, members of the Multi-Ethnic Study of Atherosclerosis (MESA), and members of the Coronary Artery Risk Development in Young Adults (CARDIA) study. Neither CARDIA nor MESA tested people for HIV, but HIV infection is assumed to be rare in both cohorts.
Specifically, this analysis compared 287 SMART participants from 33 to 44 years old with 3231 CARDIA members of the same age. These 287 SMART group had high-sensitivity C-reactive protein (hsCRP), interleukin 6 (IL-6), and D-dimer measured at study entry, and 172 of them had cystatin-C measurements. Another 494 SMART participants from 45 to 76 years old were compared with 5386 MESA members of the same age. These SMART enrollees all had hsCRP, IL-6, and D-dimer measured at study entry, and 231 had cystatin-C measures. hsCRP and IL-6 are inflammation markers, D-dimer is a marker of coagulation and fibrinolysis, and cystatin-C is a kidney function marker.
Compared with MESA and CARDIA members, SMART participants were more likely to be male and black, to smoke cigarettes and take lipid-lowering drugs, to have a higher ratio of total cholesterol to high-density lipoprotein (HDL) cholesterol, and to have a lower body mass index. Most SMART participants were taking antiretrovirals and had a viral load below 400 copies. Levels of hsCRP and D-dimer were 50% to more than 100% higher in SMART enrollees than in CARDIA or MESA members. Cystatin-C concentrations were 27% higher in SMART than in MESA.
After statistical adjustment for cardiovascular risk factors, levels of these markers were even higher in SMART participants than in the two control groups. Among people who did not smoke, hsCRP and IL-6 were 50% and 63% higher in SMART than in CARDIA. Comparing nonsmokers in SMART and MESA, the investigators recorded 60% higher levels of hsCRP, 164% higher levels of IL-6, 88% higher levels of D-dimer, and 29% higher levels of cystatin-C.
Levels of hsCRP, IL-6, and cystatin-C did not differ significantly between SMART members taking versus not taking antiretrovirals. Among 33-to-44-year-old SMART participants, D-dimer concentrations were 62% higher in SMART patients not taking antiretrovirals (P < 0.001). mong 45-to-76-year-old SMART patients, D-dimer levels were 63% higher among untreated people (P < 0.001). Both men and women in SMART had higher adjusted hsCRP concentrations than people of the same gender in CARDIA and MESA, but the differences were larger for men than for women. hsCRP level differences between SMART and the two control cohorts were even greater when the analysis excluded people with hepatitis C virus (HCV).
Multiple regression analysis for all SMART participants in this analysis linked higher AhsCRPA levels to:
• Older age
• Female gender
• Smoking
• Higher body mass index
• Higher total-to-HDL cholesterol ratio
• Absence of HCV infection
This analysis tied higher IL-6 concentrations to:
• Older age
• Higher body mass index
• Smoking
Higher AD-dimerA levels correlated with:
• Older age
• Higher body mass index
• Black race
• Female gender
• Diabetes
• Smoking
• Absence of lipid-lowering therapy
• Lower CD4 count
ACystatin-CA was higher with:
• Older age
• Male gender
• Higher total-to-HDL cholesterol ratio
• Antihypertensive therapy
• HCV coinfection
Earlier work linked elevated hsCRP, IL-6, and D-dimer to all-cause mortality in SMART [2]. In that analysis, interrupting antiretrovirals led to increases in all three markers.
References
1. Neuhaus J, Jacobs D, INSIGHT SMART, MESA and CARDIA study groups. Markers of inflammation, coagulation, and renal function in HIV-infected adults in the Strategies for Management of ART study and in 2 large population-based studies, Coronary Artery Risk Development in Young Adults and Multi-ethnic Study of Atherosclerosis. 16th Conference on Retroviruses and Opportunistic Infections. February 8-11, 2009. Montreal. Abstract 740.
(Poster is online at http://www.retroconference.org/2009/PDFs/740.pdf.)
2. Kuller LH, Tracey R, Belloso W, et al. Activation of inflammatory and coagulation pathways is associated with mortality in patients with HIV infection. PLoS Med. 2008;5(10):e203.
(Article online at http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pmed.0050203.)
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