A new study suggests that people with HIV who have high blood levels of two inflammatory proteins—fibrinogen and C-reactive protein (CRP)—might have an increased risk of premature death. The study, published online June 25 in the Journal of Acquired Immune Deficiency Syndromes, found that the increased mortality risk was present even in people with high CD4 counts.

Researchers have previously found that people with HIV—including those on antiretroviral (ARV) thereapy—might be at a three-fold higher risk of premature death than their HIV-negative counterparts, even after controlling for traditional health risk factors. The most likely culprit for the increased disease and death risk, say researchers, is a process known as inflammation. Inflammation is a natural—and usually desirable—immune response to infection and cancerous cells. Chronic inflammation, however, has been strongly associated with cardiovascular disease, liver disease and diabetes.

To determine the effect of two inflammatory proteins on survival, Phyllis Tien, MD, from the University of California in San Francisco, and her colleagues examined frozen blood samples taken from people with HIV who had participated in the Fat Redistribution and Metabolic Change in HIV Infection (FRAM) study between 2000 and 2002. In all, Tien's group was able to test samples from 922 people and link them with health outcomes over a five-year period. The majority of those in the study were on ARV treatment.

Tien and her colleagues found that inflammation was relatively common, with roughly one third of the study participants having high levels of at least one of two inflammatory proteins: fibrinogen and C-reactive protein (CRP). This was true even in people with CD4 counts over 500. Generally, high levels of either protein were associated with older age, higher viral loads and lower CD4 cell counts.

Tien's group also found that high levels of fibrinogen and CRP were associated with higher mortality. People with the highest blood levels of fibrinogen were almost two and a half times as likely to die within five years as people with the lowest fibronogen levels. People with the highest CRP levels were also more than twice as likely to die during the follow-up period than people with the lowest levels. There was an increased risk of death even in people with CD4 counts over 500, though the increase was smaller than in those with lower CD4 counts.

It should be noted that the overall death rates were relatively low in people who had both low fibrinogen and low CRP levels—five percent over five years—especially given that the study was conducted nearly a decade ago. The authors did not provide data on the mortality rates broken out by CD4 count, though numerous studies have documented that people with very high CD4 counts are at particularly low risk of death over a five-year period.

Nevertheless, the authors state that the connection they found between inflammation and increased mortality is worrisome. They note that a recent study found that starting ARV therapy when CD4 counts are above 500 did increase survival, and other studies have shown significant (though not complete) reductions in inflammation after ARVs are initiated. Nevertheless, Tien and her colleagues suggest that studies of other medications that can lower inflammation are warranted. “Investigation is needed to determine whether interventions to reduce fibrinogen and CRP levels might decrease mortality risk in HIV-infected individuals,” they conclude.