Do Biomarkers of Inflammation, Monocyte Activation, and Altered Coagulation Explain Excess Mortality Between HIV Infected and Uninfected People?
HIV infection and biomarkers of inflammation [measured by interleukin-6 (IL-6)], monocyte activation [soluble CD14 (sCD14)], and coagulation (D-dimer) are associated with morbidity and mortality. We hypothesized that these immunologic processes mediate (explain) some of the excess risk of mortality among HIV infected (HIV+) versus uninfected people independently of comorbid diseases.



Among 2350 (1521 HIV+) participants from the Veterans Aging Cohort Study Biomarker Cohort (VACS BC), we investigated whether the association between HIV and mortality was altered by adjustment for IL-6, sCD14, and D-dimer, accounting for confounders. Participants were followed from date of blood draw for biomarker assays (baseline) until death or July 25, 2013. Analyses included ordered logistic regression and Cox Proportional Hazards regression.



During 6.9 years (median), 414 deaths occurred. The proportional odds of being in a higher quartile of IL-6, sCD14, or D-dimer were 2-3 fold higher for viremic HIV+ versus uninfected people. Mortality rates were higher among HIV+ compared with uninfected people [incidence rate ratio (95% CI): 1.31 (1.06 to 1.62)]. Mortality risk increased with increasing quartiles of IL-6, sCD14, and D-dimer regardless of HIV status. Adjustment for IL-6, sCD14, and D-dimer partially attenuated mortality risk among HIV+ people with unsuppressed viremia (HIV-1 RNA ≥10,000 copies per milliliter) compared with uninfected people-hazard ratio (95% CI) decreased from 2.18 (1.60 to 2.99) to 2.00 (1.45 to 2.76).



HIV infection is associated with elevated IL-6, sCD14, and D-dimer, which are in turn associated with mortality. Baseline measures of these biomarkers partially mediate excess mortality risk among HIV+ versus uninfected people.
*Department of Medicine, Boston University School of Medicine, Boston, MA; †Section of General Internal Medicine, VA Connecticut Healthcare System, West Haven, CT; ‡Department of Internal Medicine, Yale University School of Medicine, New Haven, CT; §Center for Health Equity Research and Promotion, VA Pittsburgh Healthcare System, Pittsburgh, PA; ‖Hamad Healthcare Quality Institute, Hamad Medical Corporation, Doha, Qatar; ¶Department of Medicine, Weill Cornell Medical College, Doha, Qatar and New York, NY; #Cell and Molecular Biology Department, John A. Burns School of Medicine, University of Hawaii-Manoa, Honolulu, HI; **Medical Service/Infectious Diseases, VA Medical Center, Washington, DC; ††Department of Medicine, George Washington University Medical Center, Washington, DC; ‡‡Infectious Diseases Section, VA Greater Los Angeles Healthcare System, Los Angeles, CA; §§Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA; ‖‖Medical Service, VA Medical Center, Atlanta, GA; ¶¶Medical Service, Emory University School of Medicine, Atlanta, GA; ##Infectious Diseases Section, Michael E. DeBakey VA Medical Center, Houston, TX; ***Infectious Diseases Section, Baylor College of Medicine, Houston, TX; †††Department of Medicine, Los Angeles Biomedical Research Institute, Torrance, CA; ‡‡‡Section of General Internal Medicine, Boston University School of Medicine, Boston, MA; §§§Department of Community Health Sciences, Boston University School of Public Health, Boston, MA; ‖‖‖Department of General Internal Medicine, Boston Medical Center, Boston, MA; ¶¶¶Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA; ###Department of Medicine, Positive Health Program, San Francisco General Hospital, San Francisco, CA; ****Division of Pulmonary and Critical Care, Department of Internal Medicine, University of Washington, Seattle, WA; ††††Departments of Pathology and Laboratory Medicine and Biochemistry, College of Medicine, University of Vermont, Burlington, VT; ‡‡‡‡Department of Medicine, University of Washington School of Medicine, Seattle, WA; §§§§Department of Medicine, Baltimore VA Medical Center, Baltimore, MD; ‖‖‖‖Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD; ¶¶¶¶Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN; and ####Geriatric Research, Education, and Clinical Center, VA Tennessee Valley Healthcare System, Nashville, TN.
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D000328:Adult; D000375:Aging / Q000276:immunology; D000704:Analysis of Variance; D015415:Biomarkers / Q000097:blood; D001778:Blood Coagulation Disorders / Q000276:immunology / Q000401:mortality / Q000821:virology*; D005260:Female; D005338:Fibrin Fibrinogen Degradation Products / Q000276:immunology; D015658:HIV Infections / Q000097:blood / Q000150:complications / Q000276:immunology* / Q000401:mortality; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000276:immunology* / Q000401:mortality; D015850:Interleukin-6 / Q000097:blood; D018950:Lipopolysaccharide Receptors / Q000097:blood; D016015:Logistic Models; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology*; D014481:United States / Q000453:epidemiology; D014728:Veterans
D015415:Biomarkers; D005338:Fibrin Fibrinogen Degradation Products; C508600:IL6 protein, human; D015850:Interleukin-6; D018950:Lipopolysaccharide Receptors; C036309:fibrin fragment D