title: When to start antiretroviral therapy in children aged 2-5 years: a collaborative causal modelling analysis of cohort studies from southern Africa.
abstract: BACKGROUND
  There is limited evidence on the optimal timing of antiretroviral therapy (ART) initiation in children 2-5 y of age. We conducted a causal modelling analysis using the International Epidemiologic Databases to Evaluate AIDS-Southern Africa (IeDEA-SA) collaborative dataset to determine the difference in mortality when starting ART in children aged 2-5 y immediately (irrespective of CD4 criteria), as recommended in the World Health Organization (WHO) 2013 guidelines, compared to deferring to lower CD4 thresholds, for example, the WHO 2010 recommended threshold of CD4 count <750 cells/mm(3) or CD4 percentage (CD4%) <25%.
  
  
  RESULTS
  ART-naïve children enrolling in HIV care at IeDEA-SA sites who were between 24 and 59 mo of age at first visit and with ≥1 visit prior to ART initiation and ≥1 follow-up visit were included. We estimated mortality for ART initiation at different CD4 thresholds for up to 3 y using g-computation, adjusting for measured time-dependent confounding of CD4 percent, CD4 count, and weight-for-age z-score. Confidence intervals were constructed using bootstrapping. The median (first; third quartile) age at first visit of 2,934 children (51% male) included in the analysis was 3.3 y (2.6; 4.1), with a median (first; third quartile) CD4 count of 592 cells/mm(3) (356; 895) and median (first; third quartile) CD4% of 16% (10%; 23%). The estimated cumulative mortality after 3 y for ART initiation at different CD4 thresholds ranged from 3.4% (95% CI: 2.1-6.5) (no ART) to 2.1% (95% CI: 1.3%-3.5%) (ART irrespective of CD4 value). Estimated mortality was overall higher when initiating ART at lower CD4 values or not at all. There was no mortality difference between starting ART immediately, irrespective of CD4 value, and ART initiation at the WHO 2010 recommended threshold of CD4 count <750 cells/mm(3) or CD4% <25%, with mortality estimates of 2.1% (95% CI: 1.3%-3.5%) and 2.2% (95% CI: 1.4%-3.5%) after 3 y, respectively. The analysis was limited by loss to follow-up and the unavailability of WHO staging data.
  
  
  CONCLUSIONS
  The results indicate no mortality difference for up to 3 y between ART initiation irrespective of CD4 value and ART initiation at a threshold of CD4 count <750 cells/mm(3) or CD4% <25%, but there are overall higher point estimates for mortality when ART is initiated at lower CD4 values. Please see later in the article for the Editors' Summary.
authors.affiliation: Centre for Infectious Disease Epidemiology and Research, University of Cape Town, Cape Town, South Africa.
authors.forename: Michael
authors.initials: M
authors.lastname: Schomaker
authors.forename: Matthias
authors.initials: M
authors.lastname: Egger
authors.forename: James
authors.initials: J
authors.lastname: Ndirangu
authors.forename: Sam
authors.initials: S
authors.lastname: Phiri
authors.forename: Harry
authors.initials: H
authors.lastname: Moultrie
authors.forename: Karl
authors.initials: K
authors.lastname: Technau
authors.forename: Vivian
authors.initials: V
authors.lastname: Cox
authors.forename: Janet
authors.initials: J
authors.lastname: Giddy
authors.forename: Cleophas
authors.initials: C
authors.lastname: Chimbetete
authors.forename: Robin
authors.initials: R
authors.lastname: Wood
authors.forename: Thomas
authors.initials: T
authors.lastname: Gsponer
authors.forename: Carolyn
authors.initials: C
authors.lastname: Bolton Moore
authors.forename: Helena
authors.initials: H
authors.lastname: Rabie
authors.forename: Brian
authors.initials: B
authors.lastname: Eley
authors.forename: Lulu
authors.initials: L
authors.lastname: Muhe
authors.forename: Martina
authors.initials: M
authors.lastname: Penazzato
authors.forename: Shaffiq
authors.initials: S
authors.lastname: Essajee
authors.forename: Olivia
authors.initials: O
authors.lastname: Keiser
authors.forename: Mary-Ann
authors.initials: MA
authors.lastname: Davies
mesh_terms: D000353:Africa, Southern; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D023241:Antiretroviral Therapy, Highly Active; D018791:CD4 Lymphocyte Count; D002675:Child, Preschool; D015331:Cohort Studies; D003299:Cooperative Behavior; D018450:Disease Progression; D004334:Drug Administration Schedule; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D008954:Models, Biological
chemical_list: D019380:Anti-HIV Agents