title: Predicting patterns of long-term CD4 reconstitution in HIV-infected children starting antiretroviral therapy in sub-Saharan Africa: a cohort-based modelling study.
abstract: BACKGROUND
  Long-term immune reconstitution on antiretroviral therapy (ART) has important implications for HIV-infected children, who increasingly survive into adulthood. Children's response to ART differs from adults', and better descriptive and predictive models of reconstitution are needed to guide policy and direct research. We present statistical models characterising, qualitatively and quantitatively, patterns of long-term CD4 recovery.
  
  
  RESULTS
  CD4 counts every 12 wk over a median (interquartile range) of 4.0 (3.7, 4.4) y in 1,206 HIV-infected children, aged 0.4-17.6 y, starting ART in the Antiretroviral Research for Watoto trial (ISRCTN 24791884) were analysed in an exploratory analysis supplementary to the trial's pre-specified outcomes. Most (n = 914; 76%) children's CD4 counts rose quickly on ART to a constant age-corrected level. Using nonlinear mixed-effects models, higher long-term CD4 counts were predicted for children starting ART younger, and with higher CD4 counts (p<0.001). These results suggest that current World Health Organization-recommended CD4 thresholds for starting ART in children ≥5 y will result in lower CD4 counts in older children when they become adults, such that vertically infected children who remain ART-naïve beyond 10 y of age are unlikely ever to normalise CD4 count, regardless of CD4 count at ART initiation. CD4 profiles with four qualitatively distinct reconstitution patterns were seen in the remaining 292 (24%) children. Study limitations included incomplete viral load data, and that the uncertainty in allocating children to distinct reconstitution groups was not modelled.
  
  
  CONCLUSIONS
  Although younger ART-naïve children are at high risk of disease progression, they have good potential for achieving high CD4 counts on ART in later life provided ART is initiated following current World Health Organization (WHO), Paediatric European Network for Treatment of AIDS, or US Centers for Disease Control and Prevention guidelines. In contrast, to maximise CD4 reconstitution in treatment-naïve children >10 y, ART should ideally be considered even if there is a low risk of immediate disease progression. Further exploration of the immunological mechanisms for these CD4 recovery profiles should help guide management of paediatric HIV infection and optimise children's immunological development. Please see later in the article for the Editors' Summary.
authors.affiliation: Institute of Child Health, University College London, London, United Kingdom ; Institut de Santé Publique, d'Épidémiologie et de Développement, Centre Inserm U897-Epidemiologie-Biostatistique, University of Bordeaux, Bordeaux, France ; Department of Medical Information, Bordeaux University Hospital, Bordeaux, France.
authors.forename: Marie-Quitterie
authors.initials: MQ
authors.lastname: Picat
authors.forename: Joanna
authors.initials: J
authors.lastname: Lewis
authors.forename: Victor
authors.initials: V
authors.lastname: Musiime
authors.forename: Andrew
authors.initials: A
authors.lastname: Prendergast
authors.forename: Kusum
authors.initials: K
authors.lastname: Nathoo
authors.forename: Addy
authors.initials: A
authors.lastname: Kekitiinwa
authors.forename: Patricia
authors.initials: P
authors.lastname: Nahirya Ntege
authors.forename: Diana M
authors.initials: DM
authors.lastname: Gibb
authors.forename: Rodolphe
authors.initials: R
authors.lastname: Thiebaut
authors.forename: A Sarah
authors.initials: AS
authors.lastname: Walker
authors.forename: Nigel
authors.initials: N
authors.lastname: Klein
authors.forename: Robin
authors.initials: R
authors.lastname: Callard
mesh_terms: D000293:Adolescent; D017954:Africa South of the Sahara; D019380:Anti-HIV Agents / Q000627:therapeutic use; D018791:CD4 Lymphocyte Count; D002648:Child; D002675:Child, Preschool; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male
chemical_list: D019380:Anti-HIV Agents