Inflammation associated with increased mortality risk for patients with HIV, even when CD4 cell count high

High levels of two markers of inflammation – fibrinogen and C-reactive protein – are independently associated with an increased risk of mortality for patients with HIV, even when they have a strong immune system, US investigators report in the online edition of the Journal of Acquired Immune Deficiency Syndromes.

“We found that elevated levels of fibrinogen and CRP [C-reactive protein] were strong and independent predictors of 5-year mortality risk. Our findings suggest an important role for inflammation in mortality risk”, comment the investigators.

The study’s findings could help explain why, despite effective antiretroviral therapy, mortality rates remain higher amongst individuals with HIV than in the general population.

Only one earlier study (the SMART treatment interruption study) has found an association between inflammation and an increased risk of mortality for HIV-positive patients in the era of modern antiretroviral therapy. This research showed that there was a strong association between levels of the inflammatory markers D-dimer, Il-6, and C-reactive protein and mortality.

Separate research conducted by investigators from the Fat Redistribution and Metabolic Change in HIV Infection (FRAM) study group identified an association between HIV and elevated levels of fibrinogen, an inflammatory marker connected with clotting.

The FRAM investigators hypothesised that inflammation, indicated by elevated levels of fibrinogen and C-reactive protein, would be independently associated with an increased risk of death during five years of follow-up in their cohort of 922 patients.

The patients were stratified according to their baseline fibrinogen levels ( below 319 mg/ml; 319-406 mg/dl; and above 406 mg/dl), and according to their CD4 cell counts (below 200; 200-350; 350-500; and, above 500 cells/mm³).

Compared to individuals with lowest fibrinogen levels, those with fibrinogen above 406 mg/dl were significantly older (41 vs. 43years, p = 0.008), were more likely to be African American (29 vs. 50%, p = 0.018), to be using medication to control blood pressure (12 vs. 16%, p 0.012), to have higher total cholesterol p = 0.014) and lower HDL cholesterol (p = 0.041) and to have higher levels of C-reactive protein (p < 0.0001).

Over the five-year period of the study, individuals with the highest fibrinogen had a mortality rate of 25% compared to a rate of just 7% for those with the lowest fibrinogen levels.

Mortality rates also differed according to baseline levels of C-reactive protein. Individuals with a C-reactive protein level above 3 mg/dl had a mortality rate of 19% compared to a rate of 7% for those with C-reactive protein levels below 1 mg/dl.

Compared to individuals with fibrinogen below 319 mg/ml, those with the levels of this marker of inflammation had a three-fold increase in their mortality risk (OR = 3.35; 95% CI, 1.99-5.65, p < 0.001).

In addition, high levels of C-reactive protein were also significantly associated with an increased risk of death, the mortality risk being almost four-fold higher for those with a level above 3 mg/dl than those with C-reactive protein below 1 mg/dl (OR = 3.72; 95% CI, 2.09-6.63, p < 0.001).

When fibrinogen and C-reactive protein were included in a model together, high levels of both remained independently associated with an increased risk of death (fibrinogen, p = 0.001; C-reactive protein, p = 0.002).

Next the investigators examined the relationship between CD4 cell count, inflammation and mortality.

In every CD4 cell category, each 100 mg/dl increase in fibrinogen increased the risk of death (1.93 for those with a CD4 cell count below 200 cells/mm³; 1.30 for those with a CD4 cell count above 500 cells/mm³).

Even when the investigators adjusted their results for evidence of renal disease, higher levels of both markers were associated with an increased risk of mortality in each CD4 cell category.

“We conclude”, write the investigators, “that elevated levels of fibrinogen and CRP are strong and independent predictors of all-cause mortality in HIV-infected adults.”

They continue, “our findings that fibrinogen and CRP remained associated with higher odds of death regardless of the degree of immunosuppression suggests that inflammation remains an important factor even in those with relatively preserved CD4 cells.”

The investigators call for further research “to determine whether interventions to reduce fibrinogen and CRP levels might decrease mortality risk in HIV-infected adults.”