In our nationally representative cohort of HIV-infected individuals in the recent HAART era, we found that elevated levels of fibrinogen and CRP were strong and independent predictors of five-year mortality risk. Our findings suggest an important role for inflammation in mortality risk beyond demographic, cardiovascular, and HIV-related factors. Furthermore, when HIV-infected participants were stratified by degree of immunosuppression, fibrinogen and CRP were independently associated with higher odds of death in every CD4 category. While fibrinogen and CRP appeared to have stronger associations in those with low CD4 count, the associations remained even in the highest CD4 category.
Our findings support the observations from the SMART trial [6
], which reported an association of IL-6, D-dimer, and CRP with mortality in HIV-infected participants from the recent HAART era. Their case control analysis however, included only 255 HIV-infected participants; the majority of whom had relatively preserved CD4 counts (median baseline CD4 count >500). While our study did not test the association of IL-6 and D-dimer with mortality, we found that fibrinogen (also an inflammatory marker in the clotting cascade) was strongly associated. Our results are also consistent with a study from the pre-HAART era that found an association between CRP and all-cause mortality [20
]. That study was limited to HIV-infected women from Brooklyn, New York with a median CD4 count of 290. Taken together, these observations suggest that inflammation is an important risk factor for mortality in HIV-infected persons.
A 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. As expected, we found that the OR 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. 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. 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 [4
]. While we did observe that the OR was greater for those with CD4 count <200, this could be due to other factors such as infections or malignancies that are a consequence of a low CD4 count that may increase inflammation, for which we were not able to adequately adjust. Interestingly, a recent study found that early initiation of antiretroviral therapy (before the CD4 count fell below 500) improved survival in HIV-infected individuals [25
]. It is not yet known whether reduction of inflammation was a mechanism for the beneficial effect of antiretroviral therapy. Whether or not levels of fibrinogen and CRP might be an additional prognostic marker warrants investigation.
The novel association of fibrinogen with all-cause mortality in HIV-infected individuals is also noteworthy. Fibrinogen is a coagulation protein that is thought to play a major role in platelet aggregation and thus vascular-related morbidity and mortality. However, a large meta-analysis of HIV-uninfected individuals found moderately strong associations between plasma fibrinogen levels and non-vascular mortality (mainly cancer), in addition to coronary heart disease, stroke, and other vascular mortality [10
]. Interestingly, fibrinogen is increased in smokers (who are at risk for vascular and non-vascular morbidities) and has been shown to decrease with cessation of smoking [26
]. Smoking is highly prevalent in HIV-infected individuals and is a key predictor of mortality risk in HIV infection [5
]. Nevertheless, after controlling for cardiovascular risk factors including smoking, fibrinogen remained independently associated with mortality in HIV-infected individuals. The relationship of fibrinogen levels to D-dimer levels must also be explored; unfortunately we were unable to assay D-dimer and IL-6 levels on our participants.
There are limitations to our study. First, vital status could not be determined in 23% of the HIV-infected participants who could not be contacted, which may have led to an underestimation of the mortality rate. We therefore used a multiple imputation and inverse probability weighting approach to model the participant’s probability of having a known death status. Additional sensitivity analyses produced results that were similar to our primary modeling approach. Second, we did not have information regarding the cause of death and were therefore unable to discern whether the independent association of fibrinogen and CRP with mortality in HIV-infected individuals was due to cardiovascular or non-cardiovascular deaths. Finally, as with all observational studies, our findings are subject to possible unmeasured confounding.
We conclude that elevated levels of fibrinogen and CRP are strong and independent predictors of all-cause mortality in HIV-infected adults. 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. Investigation is needed to determine whether interventions to reduce fibrinogen and CRP levels might decrease mortality risk in HIV-infected individuals.