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Inflammation Biomarkers Linked to Increased Risk of Death in People with HIV

HIV positive people with elevated levels of C-reactive protein (CRP) and fibrinogen, 2 biomarkers associated with inflammation and blood clotting, had a significantly higher risk of death over 5 years, according to a report in the November 1, 2010 Journal of Acquired Immune Deficiency Syndromes. These findings suggest that inflammation remains an important risk factor for mortality even among individuals with relatively high CD4 cell counts, the researchers concluded.

A growing body of evidence indicates that chronic immune activation and persistent inflammation contribute to increased rates of non-AIDS conditions such as cardiovascular disease in people with HIV, well before they experienced severely impaired immune function.


Phyllis Tien, Carl Grunfeld, and fellow investigators with the Fat Redistribution and Metabolic Change in HIV Infection (FRAM) study looked at the relationship between mortality and blood levels of the inflammation biomarker C-reactive protein and the coagulation (clotting) biomarker fibrinogen among HIV positive individuals over the course of 5 years.

CRP and fibrinogen are released as part of the inflammatory and clotting cascades that occur with development of atherosclerosis, a build-up of cholesterol, immune cells, scar tissue, and other material in the arteries. Atherosclerosis plaques and blood clots can block arteries, leading to a heart attack or stroke can result.

The present analysis included 922 HIV positive FRAM participants. The majority (about 70%) were men, the median age was just over 40 years, and about 40% were smokers. About 90% were on antiretroviral therapy (ART) and about 80% had undetectable viral load. The average CD4 count was approximately 350 cells/mm3 -- the level at which HIV positive people should definitely start treatment, according to current U.S. ART guidelines.

Participants with baseline fibrinogen levels in the highest tertile, or third, were on average older, more likely to be black, and had higher total cholesterol, lower HDL ("good cholesterol"), higher HIV viral load, and lower CD4 cell counts.

Results

  • Over a 5-year period, baseline levels of both CRP and fibrinogen were significantly associated with increased risk of death due to any cause, after adjusting for traditional cardiovascular risk factors.
  • Participants with high CRP levels (> 3 mg/L) had a 2.7-fold higher likelihood of death than those with low levels (< 1 mg/L).
  • Patients with fibrinogen levels in the highest tertile (> 406 mg/dL) had a 2.6-fold higher likelihood of death compared with those in the lowest tertile (< 319 mg/dL).
  • When stratified according to CD4 cell count, fibrinogen remained independently associated with elevated mortality for all categories:
  • CD4 < 200 cells/mm3: odd ratio (OR) 1.93 per 100 mg/dL increase in fibrinogen;
  • 200-350 cells/mm3: OR 1.43;
  • 350-500 cells/mm3: OR 1.43;
  • CD4 > 500 cells mm3: OR 1.30.

Based on these results, the investigators 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 lack of a substantial interaction of fibrinogen and CRP with CD4 also strengthened our hypothesis that the association of inflammation with mortality is independent of the absolute CD4 count," they elaborated in their discussion. "These findings could suggest that the CD4 cells remain immunologically activated despite CD4 cell restoration. The subsequent persistent inflammatory state could contribute to non-HIV-related comorbidities such as liver and cardiovascular disease, which have been reported as the leading causes of non-HIV-related death in theHAART era."

Investigator affiliations: Department of Medicine and Department of Epidemiology & Biostatistics, University of California at 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 at San Diego, San Diego, CA; Department of Pathology and Biochemistry, University of Vermont, Colchester, VT.

10/29/10

Reference

PC Tien, AI Choi, AR Zolopa, 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.