Inflammatory Biomarkers and Mortality Risk Among HIV-Suppressed Men: A Multisite Prospective Cohort Study

Abstract

Background: Human immunodeficiency virus (HIV)-induced inflammation and immune activation persist after initiation of combination antiretroviral therapy (cART) and HIV suppression and may contribute to mortality risks that exceed those in HIV-uninfected populations, though associations are unclear.

Methods: In the prospective Multicenter AIDS Cohort Study, comprising men who have sex with men from Baltimore, Chicago, Los Angeles, and Pittsburgh, concentrations of 24 biomarkers of inflammation and immune activation were measured in stored serum from HIV-positive men obtained after cART-induced HIV suppression between 1996 and 2009. The outcome was nonaccidental death, with follow-up until 2014. We used Cox proportional hazards models to test whether biomarker concentrations predict time from HIV suppression to death and adjusted for multiple tests. Exploratory factor analysis (EFA) was employed to identify groupings of biomarkers that predict mortality risk.

Results: Of 670 men followed up from HIV suppression, 54 died by the end of 2013. After adjustment for age, CD4(+) cell count, hepatitis B or C virus infection, and smoking, concentrations in the highest quartile of 4 biomarkers were significantly associated with mortality risk after controlling the false discovery rate at 5%: interleukin (IL) 6 (hazard ratio, 3.54; 95% confidence interval, 2.06-6.10), soluble IL 2Rα (3.29, 1.85-5.85), soluble CD14 (2.67, 1.55-4.61), and chemokine (CXC motif) ligand 13 (CXCL13; 2.26; 1.29-3.95). EFA yielded 2 biomarker groupings that were independent predictors of mortality risk.

Conclusions: Despite having undetectable HIV RNA levels during cART, men with higher concentrations of several biomarkers (particularly IL 6, soluble IL 2Rα, soluble CD14, and CXCL13) had higher hazards of long-term mortality. Correlations observed among biomarker concentrations may represent underlying inflammatory processes that contribute to mortality risk.

Keywords: HIV; biomarkers; cART; inflammation; mortality.

Figure 1.

Mortality hazard ratios (HRs) for men with the highest quartile of biomarker concentrations relative to the lower 3 quartiles, displayed on a natural log scale. Models are adjusted for age, CD4⁺ cell count, hepatitis B or C infection, and smoking status. Error bars represent 95% confidence intervals. Red squares denote HRs that are statistically significant after adjustment for multiple tests, with the Benjamini-Hochberg procedure used to control the false discovery rate at 5% [24]; orange squares, HRs significant at P < .05. Abbreviations: BAFF, B-cell activating factor; CCL, chemokine (CC motif) ligand; CRP, C-reactive protein; CXCL, chemokine (CXC motif) ligand; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; IL-1β, interleukin 1β; IL-2, interleukin 2; IL-6, interleukin 6; IL-8, interleukin 8; IL-10, interleukin 10; IL-12p70, interleukin 12p70; sCD14, soluble CD14; sCD27, soluble CD27; sGP130, soluble GP130; sIL-2Rα, soluble interleukin 2Rα; sIL-6R, soluble interleukin 6R; sTNFR2, soluble tumor necrosis factor receptor 2; TNF, tumor necrosis factor.