title: Relevance of Interleukin-6 and D-Dimer for Serious Non-AIDS Morbidity and Death among HIV-Positive Adults on Suppressive Antiretroviral Therapy.
abstract: Despite effective antiretroviral treatment (ART), HIV-positive individuals are at increased risk of serious non-AIDS conditions (cardiovascular, liver and renal disease, and cancers), perhaps due in part to ongoing inflammation and/or coagulation. To estimate the potential risk reduction in serious non-AIDS conditions or death from any cause that might be achieved with treatments that reduce inflammation and/or coagulation, we examined associations of interleukin-6 (IL-6), D-dimer, and high-sensitivity C-reactive protein (hsCRP) levels with serious non-AIDS conditions or death in 3 large cohorts.
  
  
  
  In HIV-positive adults on suppressive ART, associations of IL-6, D-dimer, and hsCRP levels at study entry with serious non-AIDS conditions or death were studied using Cox regression. Hazard ratios (HR) adjusted for age, gender, study, and regression dilution bias (due to within-person biomarker variability) were used to predict risk reductions in serious non-AIDS conditions or death associated with lower "usual" levels of IL-6 and D-dimer.
  
  
  
  Over 4.9 years of mean follow-up, 260 of the 3766 participants experienced serious non-AIDS conditions or death. IL-6, D-dimer and hsCRP were each individually associated with risk of serious non-AIDS conditions or death, HR = 1.45 (95% CI: 1.30 to 1.63), 1.28 (95% CI: 1.14 to 1.44), and 1.17 (95% CI: 1.09 to 1.26) per 2x higher biomarker levels, respectively. In joint models, IL-6 and D-dimer were independently associated with serious non-AIDS conditions or death, with consistent results across the 3 cohorts and across serious non-AIDS event types. The association of IL-6 and D-dimer with serious non-AIDS conditions or death was graded and persisted throughout follow-up. For 25% lower "usual" IL-6 and D-dimer levels, the joint biomarker model estimates a 37% reduction (95% CI: 28 to 46%) in the risk of serious non-AIDS conditions or death if the relationship is causal.
  
  
  
  Both IL-6 and D-dimer are independently associated with serious non-AIDS conditions or death among HIV-positive adults with suppressed virus. This suggests that treatments that reduce IL-6 and D-dimer levels might substantially decrease morbidity and mortality in patients on suppressive ART. Clinical trials are needed to test this hypothesis.
authors.affiliation: School of Statistics, University of Minnesota, Minneapolis, MN, United States of America.
authors.forename: Birgit
authors.identifier: 0000-0003-4275-7880
authors.initials: B
authors.lastname: Grund
authors.affiliation: Hennepin County Medical Center, Minneapolis, MN, United States of America.|Department of Medicine, University of Minnesota, Minneapolis, MN, United States of America.
authors.forename: Jason V
authors.initials: JV
authors.lastname: Baker
authors.affiliation: University of California San Francisco, San Francisco, CA, United States of America.|San Francisco General Hospital, San Francisco, CA, United States of America.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Deeks
authors.affiliation: Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, United States of America.
authors.forename: Julian
authors.initials: J
authors.lastname: Wolfson
authors.affiliation: Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, United States of America.
authors.forename: Deborah
authors.initials: D
authors.lastname: Wentworth
authors.affiliation: University College London, London, United Kingdom.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Cozzi-Lepri
authors.affiliation: Medical Affairs Department, Gilead Sciences, Foster City, CA, United States of America.
authors.forename: Calvin J
authors.initials: CJ
authors.lastname: Cohen
authors.affiliation: University College London, London, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Phillips
authors.affiliation: Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jens D
authors.initials: JD
authors.lastname: Lundgren
authors.affiliation: Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, United States of America.
authors.forename: James D
authors.initials: JD
authors.lastname: Neaton
mesh_terms: D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000378:metabolism; D023381:Endpoint Determination; D005260:Female; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism*; D006679:HIV Seropositivity / Q000097:blood* / Q000188:drug therapy / Q000401:mortality*; D006801:Humans; D015850:Interleukin-6 / Q000097:blood*; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009017:Morbidity; D040242:Risk Reduction Behavior
chemical_list: D015415:Biomarkers; D005338:Fibrin Fibrinogen Degradation Products; D015850:Interleukin-6; C036309:fibrin fragment D; D002097:C-Reactive Protein