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Inflammation Linked to Higher Mortality Even for People with High CD4 Cell Counts

Inflammation was associated with an increased risk of death among HIV positive participants in the FRAM study, according to a report in the November 1, 2012, Journal of Acquired Immunodeficiency Syndromes. People with the highest levels of 2 inflammation biomarkers -- fibrinogen and CRP -- had more than 2.5-fold higher mortality than those with the lowest levels. Inflammation remained a predictor of mortality even among people with CD4 counts above 500 cells/mm3.

A growing body of evidence suggests that chronic inflammation triggered by persistent virus may help explain the higher rates of cardiovascular disease, neurocognitive dysfunction, and other chronic conditions seen in people with HIV -- even those with high CD4 T-cell counts and well-preserved immune function.

To further explore this issue, Phyllis Tien, Carl Grunfeld, and fellow investigators with the FRAM (Fat Redistribution and Metabolic Change in HIV Infection) study looked at the association between levels of 2 inflammatory markers, fibrinogen and C-reactive protein (CRP), and 5-year mortality risk.

Fibrinogen and CRP are acute-phase proteins released as part of the inflammation and clotting cascade that occurs with development of atherosclerosis, or blood vessel narrowing that can lead to heart attack or stroke.

The analysis included 922 HIV positive FRAM participants. A majority (about 70%) were men, the median age was 42 years, and 40% were current smokers. Most (about 90%) had used antiretroviral therapy (ART), about 80% had undetectable viral load, and the average CD4 cell count was about 350 cells/mm3. Participants were followed for 5 years.

Results

  • Participants with fibrinogen levels in the highest tertile or third (> 406 mg/dL) had a 2.6-fold higher risk of death than people with levels in the lowest tertile (< 319 mg/dL).
  • Participants with high CRP (> 3 mg/L) had a 2.7-fold higher risk of death than those with CRP < 1 mg/L.
  • When stratified according to CD4 count, fibrinogen remained independently associated with increased mortality, with the greatest effect seen among people with the lowest counts:
  • < 200 cells/mm3: odds ratio 1.93, or nearly twice the risk of death;200-350 cells/mm3: odds ratio 1.43;
  • 351 to 500 cells/mm3: odds ratio 1.43;
  • > 500 cells/mm3: odds ratio 1.3

Higher CRP remained associated with higher risk of death overall and within each CD4 count subgroup.

Based on these findings, the study authors concluded, "Fibrinogen and CRP are strong and independent predictors of mortality in HIV-infected adults."

"Our findings suggest that even in those with relatively preserved CD4 counts > 500 [cells/mm3], inflammation remains an important risk factor for mortality," they continued. "Further investigation should determine whether interventions to reduce inflammation might decrease mortality risk in HIV-infected individuals."

The researchers noted in their discussion that these findings support the observations from the SMART trial, which found that higher levels of the inflammation biomarkers CRP, interleukin 6 (IL-6), and D-dimer were associated with greater risk of death, progression to AIDS, and non-AIDS conditions such as cardiovascular, kidney, and liver disease.

"The strength of our study was the wide spectrum of CD4 levels in our participants, which allowed us to examine the effect of immunosuppression severity on the association of inflammation with mortality," they wrote. "As expected, we found that the [odds ratio] for mortality associated with fibrinogen and CRP was greatest in magnitude for those with CD4 < 200. However, more important is our finding that higher fibrinogen and CRP levels remained associated with increased mortality risk in participants with CD4 > 500."

Investigator affiliations: Department of Medicine, University of California, San Francisco, San Francisco, CA; Department of Medicine, San Francisco Veterans Affairs Medical Center, San Francisco, CA; Department of Medicine, Stanford University, Stanford, CA; Department of Medicine, University of California, San Diego, San Diego, CA; |Department of Pathology and Biochemistry, University of Vermont, Colchester, VT; Department of Epidemiology and Biostatistics, University of California, San Francisco, CA.

2/25/11

Reference

PC Tien, AI Choi, AR Zolopa, C Grunfeld, and others. Inflammation and Mortality in HIV-infected Adults: Analysis of the FRAM Study Cohort. Journal of Acquired Immune Deficiency Syndromes 55(3): 316-322 (abstract). November 1, 2010.