title: Associations of inflammatory markers with AIDS and non-AIDS clinical events after initiation of antiretroviral therapy: AIDS clinical trials group A5224s, a substudy of ACTG A5202.
abstract: BACKGROUND
  The association of inflammatory biomarkers with clinical events after antiretroviral therapy initiation is unclear.
  
  
  METHODS
  A5202 randomized 1857 treatment-naive subjects to abacavir/lamivudine or tenofovir-DF/emtricitabine with efavirenz or atazanavir/ritonavir. Substudy A5224s measured inflammatory biomarkers on subjects with available plasma from baseline and week 24 or 96. An exploratory analysis of the association of high-sensitivity C-reactive protein, interleukin-6 (IL-6), soluble receptors of tumor necrosis factor α (sTNF)-RI, sTNF-RII, TNF-α, soluble vascular cellular adhesion molecules (sVCAM-1), and soluble intercellular adhesion molecules (sICAM-1) with times to AIDS and to non-AIDS events used Cox proportional hazards models.
  
  
  RESULTS
  Analysis included 244 subjects; 85% men and 48% white non-Hispanic with median age 39 years, HIV-1 RNA of 4.6 log10 copies per milliliter, and CD4 of 240 cells per microliter. Overall, 13 AIDS events (9 opportunistic infections, 3 AIDS-cancers, and 1 recurrent bacterial pneumonia) and 18 non-AIDS events (6 diabetes, 4 cancers, 3 cardiovascular, and 5 pneumonias) occurred. Higher baseline IL-6, sTNF-RI, sTNF-RII, and sICAM-1 were significantly associated with increased risk of AIDS-defining events. Adjustment for baseline HIV-1 RNA did not change results, whereas adjusting for baseline CD4 count left only sTNF-RI and sICAM-1 significantly associated with increased risk. Time-updated values of IL-6, sTNFR-I and II, and sICAM-1 were also associated with an increased risk. For non-AIDS events, only higher baseline high-sensitivity C-reactive protein was significantly associated with increased risk, whereas higher IL-6 was marginally associated with higher risk. Analyses of time-updated biomarker values showed tumor necrosis factor α to be significantly associated with increased risk, even after adjustment for antiretroviral therapy, and CD4 count or HIV-1 RNA.
  
  
  CONCLUSIONS
  Higher levels of several inflammatory biomarkers were independently associated with increased risk of AIDS and non-AIDS events.
authors.affiliation: *Rainbow Babies and Children's Hospital, Case Western Reserve University, Cleveland, OH; †Harvard School of Public Health, Boston, MA; ‡Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; §Social & Scientific Systems, Inc., Silver Spring, MD; ‖Gilead Sciences, Foster City, CA; ¶GlaxoSmithKline, Research Triangle, NC; #Department of Medicine, Johns Hopkins University, Baltimore, MD; **Frontier Science and Technology Research Foundation, Amherst, NY; ††Department of Geriatric Medicine and Gerontology, Johns Hopkins University, Baltimore, MD; ‡‡Department of Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA.
authors.forename: Grace A
authors.initials: GA
authors.lastname: McComsey
authors.forename: Douglas
authors.initials: D
authors.lastname: Kitch
authors.forename: Paul E
authors.initials: PE
authors.lastname: Sax
authors.forename: Camlin
authors.initials: C
authors.lastname: Tierney
authors.forename: Nasreen C
authors.initials: NC
authors.lastname: Jahed
authors.forename: Kathleen
authors.initials: K
authors.lastname: Melbourne
authors.forename: Belinda
authors.initials: B
authors.lastname: Ha
authors.forename: Todd T
authors.initials: TT
authors.lastname: Brown
authors.forename: Anthony
authors.initials: A
authors.lastname: Bloom
authors.forename: Neal
authors.initials: N
authors.lastname: Fedarko
authors.forename: Eric S
authors.initials: ES
authors.lastname: Daar
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000473:pathology*; D000293:Adolescent; D000328:Adult; D044966:Anti-Retroviral Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods*; D015415:Biomarkers / Q000097:blood*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D055815:Young Adult
chemical_list: D044966:Anti-Retroviral Agents; D015415:Biomarkers