title: A prospective study of endothelial activation biomarkers, including plasma angiopoietin-1 and angiopoietin-2, in Kenyan women initiating antiretroviral therapy.
abstract: BACKGROUND
  HIV-1-related inflammation is associated with increased levels of biomarkers of vascular adhesion and endothelial activation, and may increase production of the inflammatory protein angiopoietin-2 (ANG-2), an adverse prognostic biomarker in severe systemic infection. We hypothesized that antiretroviral therapy (ART) initiation would decrease endothelial activation, reducing plasma levels of ANG-2.
  
  
  METHODS
  Antiretroviral-naïve Kenyan women with advanced HIV infection were followed prospectively. Endothelial activation biomarkers including soluble intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), and E-selectin, and plasma ANG-2 and angiopoietin-1 (ANG-1) were tested in stored plasma samples from 0, 6, and 12 months after ART initiation. We used Wilcoxon matched-pairs signed rank tests to compare endothelial activation biomarkers across time-points, generalized estimating equations to analyze associations with change in log10-transformed biomarkers after ART initiation, and Cox proportional-hazards regression to analyze associations with mortality.
  
  
  RESULTS
  The 102 HIV-1-seropositive women studied had advanced infection (median CD4 count, 124 cells/μL). Soluble ICAM-1 and plasma ANG-2 levels decreased at both time-points after ART initiation, with concomitant increases in the beneficial protein ANG-1. Higher ANG-2 levels after ART initiation were associated with higher plasma HIV-1 RNA, oral contraceptive pill use, pregnancy, severe malnutrition, and tuberculosis. Baseline ANG-2 levels were higher among five women who died after ART initiation than among women who did not (median 2.85 ng/mL [inter-quartile range (IQR) 2.47-5.74 ng/mL] versus median 1.32 ng/mL [IQR 0.35-2.18 ng/mL], p = 0.01). Both soluble ICAM-1 and plasma ANG-2 levels predicted mortality after ART initiation.
  
  
  CONCLUSIONS
  Biomarkers of endothelial activation decreased after ART initiation in women with advanced HIV-1 infection. Changes in plasma ANG-2 were associated with HIV-1 RNA levels over 12 months of follow-up. Soluble ICAM-1 and plasma ANG-2 levels represent potential biomarkers for adverse outcomes in advanced HIV-1 infection.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Graham
authors.forename: Nimerta
authors.initials: N
authors.lastname: Rajwans
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Tapia
authors.forename: Walter
authors.initials: W
authors.lastname: Jaoko
authors.forename: Benson B A
authors.initials: BB
authors.lastname: Estambale
authors.forename: R Scott
authors.initials: RS
authors.lastname: McClelland
authors.forename: Julie
authors.initials: J
authors.lastname: Overbaugh
authors.forename: W Conrad
authors.initials: WC
authors.lastname: Liles
mesh_terms: D000328:Adult; D042683:Angiopoietin-1 / Q000097:blood*; D042702:Angiopoietin-2 / Q000097:blood*; D044966:Anti-Retroviral Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D015415:Biomarkers / Q000097:blood; D015815:Cell Adhesion Molecules / Q000097:blood; D005260:Female; D015658:HIV Infections / Q000097:blood* / Q000188:drug therapy*; D015497:HIV-1 / Q000302:isolation & purification*; D006801:Humans; D007630:Kenya; D008297:Male; D011247:Pregnancy; D011446:Prospective Studies
chemical_list: D042683:Angiopoietin-1; D042702:Angiopoietin-2; D044966:Anti-Retroviral Agents; D015415:Biomarkers; D015815:Cell Adhesion Molecules