Elevated Inflammation Biomarkers Linked to Increased Mortality in People with HIV

		SUMMARY: Increased levels of 2 biomarkers of inflammation and coagulation -- C-reactive protein and fibrinogen -- are "strong and independent predictors" of increased risk of death for people with HIV, even among individuals with relatively high CD4 T-cell counts, according to findings from the FRAM study reported in the June 25, 2010 advance online edition of the Journal of Acquired Immune Deficiency Syndromes.

By Liz Highleyman

Inflammation has become a growing focus of HIV research in the years since the SMART study showed that people who interrupted antiretroviral therapy (ART) were more likely than those on continuous treatment to develop non-AIDS conditions including cardiovascular, kidney, and liver disease, and that these conditions were linked to elevated levels of biomarkers of inflammation, coagulation (blood clotting), and endothelial (blood vessel) dysfunction.

In the present analysis, Phyllis Tien from the University of California at San Francisco and colleagues with the Fat Redistribution and Metabolic Change in HIV Infection (FRAM) study looked at the correlation between 5-year mortality risk and levels of C-reactive protein (CRP; a biomarker of inflammation) and fibrinogen (a coagulation by-product).

The investigators evaluated data from 922 HIV positive participants in FRAM, which focused on body composition changes associated with HIV infection and ART; most participants were on combination therapy.

Participants were stratified according to baseline fibrinogen level (< 319 mg/dL, 319-406 mg/dL, or < 406 mg/dL) and CD4 cell count. About one-third had either elevated fibrinogen or elevated CRP; higher levels were correlated with higher viral load and lower CD4 counts overall, but even some people with well-preserved CD4 counts had elevated biomarkers.

People with the highest fibrinogen levels were on average older, more likely to be black, and were more likely to have cardiovascular risk factors including higher total cholesterol, low HDL "good" cholesterol, more use of medication for high blood pressure, and higher CRP.

Results

	Looking at fibrinogen alone, the 5-year risk of death for participants with levels in the highest third (> 406 mg/dL) was 24.7%, compared with 7.4% for those with levels in the lowest third (< 319 mg/dL)
	Looking at CRP alone, the 5-year mortality risk for participants with high levels (> 3 mg/L) was 19.3%, compared with 7.3% for those with low levels (< 1 mg/L).
	After adjusting for cardiovascular risk and HIV-related factors, people with the lowest fibrinogen levels had a 3.4-fold higher risk of death than those with the lowest levels.
	Similarly, people with the highest CRP levels had a 3.7-fold higher risk of death than those with the lowest levels.
	In a multivariate model considering the 2 biomarkers together, participants with fibrinogen levels in the highest third had a 2.6-fold higher risk of death over 5 years than those in the lowest third.
	People with high CRP levels had a 2.7-fold higher risk of death than those with low CRP.
	Fibrinogen remained independently associated with increased mortality at all CD4 cell levels:
	< 200 cells/mm3: odds ratio (OR) 1.93 per 100 mg/dL increase; 200-350 cells/mm3: OR 1.43; 350 to 500 cells/mm3: OR 1.43; > 500 cells/mm3: OR 1.30.
	Higher CRP also remained associated with higher risk of death at each CD4 count level.

These findings led the researchers to conclude, "Fibrinogen and CRP are strong and independent predictors of mortality in HIV-infected adults."

"As expected, we found that the OR for mortality associated with fibrinogen and CRP was greatest in magnitude for those with CD4 < 200," they continued in their discussion. "However, more important is our finding that higher fibrinogen and CRP levels remained associated with increased mortality risk in participants with CD4 > 500."

"Our findings suggest that even in those with relatively preserved CD4 counts > 500 [cells/mm3], inflammation remains an important risk factor for mortality," they wrote. "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 the HAART era."

These results add to the growing body of evidence that starting ART even earlier than the current U.S. antiretroviral treatment guidelines threshold of 500 cells/mm3 might be beneficial for some people.

The authors recommended that, "Further investigation should determine whether interventions to reduce inflammation might decrease mortality risk in HIV-infected individuals."

Investigator affiliations: Department of Medicine, 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; Department of Epidemiology and Biostatistics, University of California, San Francisco, CA.

7/13/10

Reference
PC Tien, AI Choi, AR Zolopa, and others (FRAM study team). Inflammation and Mortality in HIV-Infected Adults: Analysis of the FRAM Study Cohort. Journal of Acquired Immune Deficiency Syndromes (Abstract). June 25, 2010 (Epub ahead of print)