title: Clinical impact of altered T-cell homeostasis in treated HIV patients enrolled in a large observational cohort.
abstract: OBJECTIVE
  We investigated the probability of transitioning in or out of the CD3⁺ T-cell homeostatic range during antiretroviral therapy, and we assessed the clinical impact of lost T-cell homeostasis (TCH) on AIDS-defining illnesses (ADIs) or death.
  
  
  METHODS
  Within the Canadian Observational Cohort (CANOC), we studied 4463 antiretroviral therapy (ART)-naive HIV-positive patients initiating combination ART (cART) between 2000 and 2010.
  
  
  METHODS
  CD3⁺ trajectories were estimated using a four state Markov model. CD3⁺ T-cel percentage states were classified as follows: very low (<50%), low (50-64%), normal (65-85%), and high (>85%). Covariates associated with transitioning between states were examined. The association between CD3⁺ T-cell percentage states and time to ADI/death from cART initiation was determined using Cox proportional hazards models.
  
  
  RESULTS
  A total of 4463 patients were followed for a median of 3 years. Two thousand, five hundred and eight (56%) patients never transitioned from their baseline CD3⁺ T-cell percentage state; 85% of these had normal TCH. In multivariable analysis, individuals with time-updated low CD4⁺ cell count, time-updated detectable viral load, older age, and hepatitis C virus (HCV) coinfection were less likely to maintain TCH. In the multivariable proportional hazards model, both very low and high CD3⁺ T-cell percentages were associated with increased risk of ADI/death [adjusted hazard ratio=1.91 (95% confidence interval, CI: 1.27-2.89) and hazard ratio=1.49 (95% CI: 1.13-1.96), respectively].
  
  
  CONCLUSIONS
  Patients with very low or high CD3⁺ T-cell percentages are at risk for ADIs/death. To our knowledge, this is the first study linking altered TCH and morbidity/mortality in cART-treated HIV-positive patients.
authors.affiliation: aMcGill University Health Centre, Montreal, Quebec bToronto General Research Institute, University Health Network, Toronto cDalla Lana School of Public Health, University of Toronto dUniversity of Ottawa, The Ottawa Hospital Research Institute, Ottawa, Ontario eSimon Fraser University, Burnaby fBritish Columbia Centre for Excellence in HIV/AIDS, Vancouver gDepartment of Medicine, University of British Columbia, Vancouver, British Columbia hOntario HIV Treatment Network, Toronto iDepartment of Medicine, University of Toronto jWomen's Health Research Institute, Toronto kMaple Leaf Medical Clinic, Toronto, Ontario lClinique Médicale l'Actuel, Montreal mMcGill University Health Centre, Division of Infectious Diseases and Chronic Viral Illness Service, Montreal, Quebec, Canada. *The members of the CANOC Collaboration are listed in the Acknowledgements.
authors.forename: Patricia
authors.initials: P
authors.lastname: Ndumbi
authors.forename: Jennifer
authors.initials: J
authors.lastname: Gillis
authors.forename: Janet M
authors.initials: JM
authors.lastname: Raboud
authors.forename: Curtis
authors.initials: C
authors.lastname: Cooper
authors.forename: Robert S
authors.initials: RS
authors.lastname: Hogg
authors.forename: Julio S G
authors.initials: JS
authors.lastname: Montaner
authors.forename: Ann N
authors.initials: AN
authors.lastname: Burchell
authors.forename: Mona R
authors.initials: MR
authors.lastname: Loutfy
authors.forename: Nima
authors.initials: N
authors.lastname: Machouf
authors.forename: Marina B
authors.initials: MB
authors.lastname: Klein
authors.forename: Chris M
authors.initials: CM
authors.lastname: Tsoukas
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D017252:CD3 Complex / Q000032:analysis*; D015331:Cohort Studies; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D006706:Homeostasis; D006801:Humans; D008297:Male; D008875:Middle Aged; D016019:Survival Analysis; D016176:T-Lymphocyte Subsets / Q000737:chemistry / Q000276:immunology* / Q000502:physiology*
chemical_list: D019380:Anti-HIV Agents; D017252:CD3 Complex