title: Pre-therapy inflammation and coagulation activation and long-term CD4 count responses to the initiation of antiretroviral therapy.
abstract: OBJECTIVE
  Pre-antiretroviral therapy (ART) inflammation and coagulation activation predict clinical outcomes in HIV-positive individuals. We assessed whether pre-ART inflammatory marker levels predicted the CD4 count response to ART.
  
  
  METHODS
  Analyses were based on data from the Strategic Management of Antiretroviral Therapy (SMART) trial, an international trial evaluating continuous vs. interrupted ART, and the Flexible Initial Retrovirus Suppressive Therapies (FIRST) trial, evaluating three first-line ART regimens with at least two drug classes. For this analysis, participants had to be ART-naïve or off ART at randomization and (re)starting ART and have C-reactive protein (CRP), interleukin-6 (IL-6) and D-dimer measured pre-ART. Using random effects linear models, we assessed the association between each of the biomarker levels, categorized as quartiles, and change in CD4 count from ART initiation to 24 months post-ART. Analyses adjusted for CD4 count at ART initiation (baseline), study arm, follow-up time and other known confounders.
  
  
  RESULTS
  Overall, 1084 individuals [659 from SMART (26% ART naïve) and 425 from FIRST] met the eligibility criteria, providing 8264 CD4 count measurements. Seventy-five per cent of individuals were male with the mean age of 42 years. The median (interquartile range) baseline CD4 counts were 416 (350-530) and 100 (22-300) cells/μL in SMART and FIRST, respectively. All of the biomarkers were inversely associated with baseline CD4 count in FIRST but not in SMART. In adjusted models, there was no clear relationship between changing biomarker levels and mean change in CD4 count post-ART (P for trend: CRP, P = 0.97; IL-6, P = 0.25; and D-dimer, P = 0.29).
  
  
  CONCLUSIONS
  Pre-ART inflammation and coagulation activation do not predict CD4 count response to ART and appear to influence the risk of clinical outcomes through other mechanisms than blunting long-term CD4 count gain.
authors.affiliation: Kirby Institute, UNSW Australia, Sydney, NSW, Australia.
authors.forename: A C
authors.initials: AC
authors.lastname: Achhra
authors.affiliation: Research Department of Infection & Population Health, University College London, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Phillips
authors.affiliation: Kirby Institute, UNSW Australia, Sydney, NSW, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Emery
authors.affiliation: Wayne State University, Detroit, MI, USA.
authors.forename: R D
authors.initials: RD
authors.lastname: MacArthur
authors.affiliation: Infectious Diseases, University Hospital, Bern, Switzerland.
authors.forename: H
authors.initials: H
authors.lastname: Furrer
authors.affiliation: Department of Infectious Diseases, CHU Saint-Pierre, Brussels, Belgium.
authors.forename: S
authors.initials: S
authors.lastname: De Wit
authors.affiliation: J.M. Ramos Mejía Hospital, Buenos Aires, Argentina.
authors.forename: M
authors.initials: M
authors.lastname: Losso
authors.affiliation: Kirby Institute, UNSW Australia, Sydney, NSW, Australia.
authors.forename: M G
authors.initials: MG
authors.lastname: Law
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage*; D015415:Biomarkers / Q000097:blood; D001777:Blood Coagulation / Q000276:immunology; D002097:C-Reactive Protein / Q000276:immunology; D018791:CD4 Lymphocyte Count; D018450:Disease Progression; D005260:Female; D005338:Fibrin Fibrinogen Degradation Products / Q000276:immunology; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000097:blood*; D015850:Interleukin-6 / Q000276:immunology; D008297:Male; D011237:Predictive Value of Tests; D012189:Retrospective Studies; D012307:Risk Factors
chemical_list: D019380:Anti-HIV Agents; D015415:Biomarkers; D005338:Fibrin Fibrinogen Degradation Products; C508600:IL6 protein, human; D015850:Interleukin-6; C036309:fibrin fragment D; D002097:C-Reactive Protein
keywords: C-reactive protein; CD4 count; D-dimer; HIV; antiretroviral therapy; coagulation; highly active antiretroviral therapy; immunological response; inflammation; interleukin-6