title: Characteristics and determinants of T-cell phenotype normalization in HIV-1-infected individuals receiving long-term antiretroviral therapy.
abstract: OBJECTIVE
  Although combination antiretroviral therapy (cART) can restore CD4 T-cell numbers in HIV infection, alterations in T-cell regulation and homeostasis persist. We assessed the incidence and predictors of reversing these alterations with cART.
  
  
  METHODS
  ART-naïve adults (n = 4459) followed within the Canadian Observational Cohort and exhibiting an abnormal T-cell phenotype (TCP) prior to cART initiation were studied. Abnormal TCP was defined as having (1) a low CD4 T-cell count (< 532 cells/μL), (2) lost T-cell homeostasis (CD3 < 65% or > 85%) or (3) CD4:CD8 ratio dysregulation (ratio < 1.2). To thoroughly evaluate the TCP, CD4 and CD8 T-cell percentages and absolute counts were also analysed for a median duration of 3.14 years [interquartile range (IQR) 1.48-5.47 years]. Predictors of TCP normalization were assessed using adjusted Cox proportional hazards models.
  
  
  RESULTS
  At baseline, 96% of pateints had CD4 depletion, 32% had lost homeostasis and 99% exhibited ratio dysregulation. With treatment, a third of patients had normalized CD4 T-cell counts, but only 85 individuals (2%) had normalized their TCP. In a multivariable model adjusted for age, measurement frequency and baseline regimen, higher baseline CD4 T-cell counts and time-dependent viral suppression independently predicted TCP normalization [hazard ratio (HR) for baseline CD4 T-cell count = 1.42 (1.31-1.54) per 100 cells/μL increase; P ≤ 0.0001; HR for time-dependent suppressed viral load = 3.69 (1.58-8.61); P-value ≤ 0.01].
  
  
  CONCLUSIONS
  Despite effective cART, complete TCP recovery occurred in very few individuals and was associated with baseline CD4 T-cell count and viral load suppression. HIV-induced alterations of the TCP are incompletely reversed by long-term ART.
authors.affiliation: McGill University Health Centre, Montreal, Canada.
authors.forename: P
authors.initials: P
authors.lastname: Ndumbi
authors.forename: J
authors.initials: J
authors.lastname: Gillis
authors.forename: J
authors.initials: J
authors.lastname: Raboud
authors.forename: C
authors.initials: C
authors.lastname: Cooper
authors.forename: R S
authors.initials: RS
authors.lastname: Hogg
authors.forename: J S G
authors.initials: JS
authors.lastname: Montaner
authors.forename: A N
authors.initials: AN
authors.lastname: Burchell
authors.forename: M R
authors.initials: MR
authors.lastname: Loutfy
authors.forename: N
authors.initials: N
authors.lastname: Machouf
authors.forename: M B
authors.initials: MB
authors.lastname: Klein
authors.forename: C
authors.initials: C
authors.lastname: Tsoukas
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods; D016516:CD4-CD8 Ratio; D002170:Canada; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology* / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects*; D006706:Homeostasis; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D016016:Proportional Hazards Models; D013601:T-Lymphocytes / Q000378:metabolism*; D019562:Viral Load / Q000187:drug effects*
chemical_list: D019380:Anti-HIV Agents
keywords: Canadian Observational Cohort (CANOC); HIV; T-cell homeostasis; antiretroviral therapy; immune dysregulation; immune recovery