This is the first study to demonstrate that markers of inflammation and coagulation measured immediately before ART is initiated are strongly associated with all-cause mortality in patients with advanced HIV-infection. In this case control study, patients who died after commencing ART had significantly elevated levels of D-dimers, hsCRP and IL-6 compared to matched controls, and strong risk gradients were observed for increasing levels of all three biomarkers. In addition, elevated baseline levels of inflammatory markers were more predictive of early mortality than late mortality after ART initiation. This association persisted in analyses that considered stage of HIV disease, hemoglobin, aspartate aminotransferase, platelet and white blood cell count. These findings suggest that HIV-induced activation of inflammatory and coagulation pathways in late-HIV infection have an adverse affect on mortality.
In our cohort of 100 random Phidisa II patients who initiated ART, IL-6 and D-dimer levels significantly decreased at month 6, whereas hsCRP did not. This association between IL-6 and D-dimer is consistent with other studies including HIV-infected as well as uninfected patients. 
. Also, whereas positive correlations were found with HIV viral load and hsCRP and D-dimer levels, a correlation did not exist between HIV viral load and IL-6 levels. This suggests that, in this population with advanced HIV infection, the pathway that leads to elevated IL-6 levels during HIV infection may be different than the pathway leading to elevations of other inflammatory biomarkers such as hsCRP. Other studies are needed to confirm this finding.
A study of inflammatory and coagulation biomarkers in HIV-infected patients in the SMART trial also demonstrated that baseline IL-6 and D-dimer levels were strongly related to all-cause mortality 
. Although the same biomarker assays were used in the SMART and our Phidisa II analyses, any comparison of biomarker levels between these studies must be made with a number of caveats: plasma from PPT was used in our study whereas plasma from EDTA tubes was used in SMART, the assays were performed at different laboratories, and there were differences in sample processing timelines (specimens in Phidisa II may have taken up to 24 hours to arrive in the laboratory for processing). With these caveats in mind, median baseline biomarker levels appear to be considerably higher in the Phidisa II mortality cases compared to those in SMART (hsCRP
11.25 vs. 4.26 ug/ml; D-dimer
1.41 vs. 0.49 ug/ml; IL-6
9.02 vs. 3.8 pg/ml, respectively). This is likely due to the fact that the patient populations enrolled in these studies were notably different. The SMART study population was relatively healthy and did not have advanced HIV disease; at baseline, the majority of participants were on ART and had a relatively high CD4+ T cell count [median
408, 693)]. In contrast, our study population was not on ART and had advanced HIV disease with low CD4+ T cell counts [median
9, 102)]. This supports the hypothesis that advanced immunosuppression in the context of unsuppressed HIV replication leads to an activation of inflammatory and coagulation pathways and, subsequently, increases mortality.
We also examined levels of hsCRP, IL-6 and D-dimer among HIV-uninfected patients, and patients with early and late HIV infection. In general, uninfected patients had lower levels of these biomarkers compared to patients with early disease, who in turn had lower levels compared to those patients with late disease, except for IL-6. This finding is consistent with other studies demonstrating that, compared with those who are HIV-uninfected, HIV-infected individuals have higher levels of inflammatory and coagulation markers 
A limitation to our study is that a definitive cause of death could not be established for all mortality cases in Phidisa II. It is known that 37 of the 208 deaths in Phidisa II followed a confirmed or probable AIDS event, and tuberculosis was the most common AIDS event observed in that trial. Nevertheless, analyses of the relationship between biomarker levels and cause of mortality could not be performed. Another limitation is that other potential confounding variables that may affect biomarker levels, such as smoking and hepatitis C status, were not collected and could not be adjusted for in our analyses.
In summary, among patients with advanced HIV disease, elevated pre-ART levels of hsCRP, IL-6 and D-dimer are strongly associated with early mortality after commencing ART. While the reasons for the increased risk are not fully understood, interventions other than ART that might decrease levels of inflammatory and coagulation markers warrant investigation. Until such interventions are found, more aggressive clinical monitoring may be warranted in patients with elevated biomarkers after commencing ART. Further studies are warranted to understand the underlying pathophysiology leading to these elevations in biomarker in order to develop interventions that may improve clinical outcomes in HIV infected patients starting ART.