title: HIV-1 coreceptor usage and CXCR4-specific viral load predict clinical disease progression during combination antiretroviral therapy.
abstract: BACKGROUND
  Although combination antiretroviral therapy (cART) dramatically reduces rates of AIDS and death, a minority of patients experience clinical disease progression during treatment.
  
  
  OBJECTIVE
  To investigate whether detection of CXCR4(X4)-specific strains or quantification of X4-specific HIV-1 load predict clinical outcome.
  
  
  METHODS
  From the Swiss HIV Cohort Study, 96 participants who initiated cART yet subsequently progressed to AIDS or death were compared with 84 contemporaneous, treated nonprogressors. A sensitive heteroduplex tracking assay was developed to quantify plasma X4 and CCR5 variants and resolve HIV-1 load into coreceptor-specific components. Measurements were analyzed as cofactors of progression in multivariable Cox models adjusted for concurrent CD4 cell count and total viral load, applying inverse probability weights to adjust for sampling bias.
  
  
  RESULTS
  Patients with X4 variants at baseline displayed reduced CD4 cell responses compared with those without X4 strains (40 versus 82 cells/microl; P = 0.012). The adjusted multivariable hazard ratio (HR) for clinical progression was 4.8 [95% confidence interval (CI) 2.3-10.0] for those demonstrating X4 strains at baseline. The X4-specific HIV-1 load was a similarly independent predictor, with HR values of 3.7 (95% CI, 1.2-11.3) and 5.9 (95% CI, 2.2-15.0) for baseline loads of 2.2-4.3 and > 4.3 log10 copies/ml, respectively, compared with < 2.2 log10 copies/ml.
  
  
  CONCLUSIONS
  HIV-1 coreceptor usage and X4-specific viral loads strongly predicted disease progression during cART, independent of and in addition to CD4 cell count or total viral load. Detection and quantification of X4 strains promise to be clinically useful biomarkers to guide patient management and study HIV-1 pathogenesis.
authors.affiliation: Division of Infectious Diseases, Wadsworth Center, New York State Department of Health, Albany, New York 12208, USA. weiser@wadsworth.org
authors.forename: Barbara
authors.initials: B
authors.lastname: Weiser
authors.forename: Sean
authors.initials: S
authors.lastname: Philpott
authors.forename: Thomas
authors.initials: T
authors.lastname: Klimkait
authors.forename: Harold
authors.initials: H
authors.lastname: Burger
authors.forename: Christina
authors.initials: C
authors.lastname: Kitchen
authors.forename: Philippe
authors.initials: P
authors.lastname: Bürgisser
authors.forename: Meri
authors.initials: M
authors.lastname: Gorgievski
authors.forename: Luc
authors.initials: L
authors.lastname: Perrin
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Piffaretti
authors.forename: Bruno
authors.initials: B
authors.lastname: Ledergerber
mesh_terms: D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D018450:Disease Progression; D004812:Epidemiologic Methods; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology; D015497:HIV-1; D006801:Humans; D008297:Male; D019718:Receptors, CXCR4 / Q000378:metabolism*; D016896:Treatment Outcome; D019562:Viral Load
chemical_list: D019718:Receptors, CXCR4