title: HIV replication, inflammation, and the effect of starting antiretroviral therapy on plasma asymmetric dimethylarginine, a novel marker of endothelial dysfunction.
abstract: BACKGROUND
  HIV infection is associated with premature development of cardiovascular disease. Understanding the effects of HIV replication on endothelial dysfunction and platelet activation may identify treatment targets to reduce cardiovascular disease risk.
  
  
  METHODS
  A subgroup of HIV-infected participants in the Strategies for Management of Antiretroviral Therapy study off antiretroviral therapy (ART) at entry enabled a randomized comparison of immediate versus deferred ART initiation of changes in asymmetric dimethylarginine (ADMA), soluble CD40 ligand (sCD40L), and P-selectin levels.
  
  
  RESULTS
  At study entry, median (interquartile range) levels of ADMA, sCD40L, and P-selectin were 0.57 (0.49-0.66) μg/mL, 251 (135-696) μmol/L, and 34 (28-44) pg/mL. Compared to those randomized to deferral of ART (n = 114), participants randomized to immediate ART (n = 134) had 10.3% lower ADMA levels (P = 0.003) at 12 months; treatment differences in sCD40L (95% confidence interval: -17% to 44%; P = 0.53) and P-selectin (95% confidence interval: -10% to 10%; P = 0.95) were not significant. The difference in ADMA for those assigned immediate ART compared with those assigned ART deferral was greater among younger patients and those with higher levels of high-sensitivity C-reactive protein and D-dimer (P ≤ 0.05 for interaction for both) but not HIV RNA level at baseline (P = 0.51).
  
  
  CONCLUSIONS
  ART initiation leads to declines in ADMA levels, a marker of nitric oxide-mediated endothelial dysfunction. Improvement in ADMA levels was related to the degree of inflammation and coagulation, suggesting that upregulation of these pathways contributes to premature vascular disease among individuals with HIV infection. Whether declines in ADMA levels impact risk of disease requires further research.
authors.affiliation: Department of Medicine, University of Minnesota, Minneapolis, MN 55415, USA. baker459@umn.edu
authors.forename: Jason V
authors.initials: JV
authors.lastname: Baker
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Neuhaus
authors.forename: Daniel
authors.initials: D
authors.lastname: Duprez
authors.forename: Matthew
authors.initials: M
authors.lastname: Freiberg
authors.forename: Jose I
authors.initials: JI
authors.lastname: Bernardino
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Badley
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Nixon
authors.forename: Jens D
authors.initials: JD
authors.lastname: Lundgren
authors.forename: Russell P
authors.initials: RP
authors.lastname: Tracy
authors.forename: James D
authors.initials: JD
authors.lastname: Neaton
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage*; D023241:Antiretroviral Therapy, Highly Active; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood; D015415:Biomarkers / Q000097:blood; D019013:CD40 Antigens / Q000097:blood; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D006801:Humans; D007249:Inflammation / Q000097:blood*; D008297:Male; D008875:Middle Aged; D019007:P-Selectin / Q000097:blood; D010949:Plasma / Q000737:chemistry; D016032:Randomized Controlled Trials as Topic; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D019380:Anti-HIV Agents; D015415:Biomarkers; D019013:CD40 Antigens; D019007:P-Selectin; C018524:N,N-dimethylarginine; D001120:Arginine