title: Baseline Inflammatory Biomarkers Identify Subgroups of HIV-Infected African Children With Differing Responses to Antiretroviral Therapy.
abstract: Identifying determinants of morbidity and mortality may help target future interventions for human immunodeficiency virus (HIV)-infected children.
  
  
  
  CD4(+) T-cell count, HIV viral load, and levels of biomarkers (C-reactive protein, tumor necrosis factor α [TNF-α], interleukin 6 [IL-6], and soluble CD14) and interleukin 7 were measured at antiretroviral therapy (ART) initiation in the ARROW trial (case-cohort design). Cases were individuals who died, had new or recurrent World Health Organization clinical stage 4 events, or had poor immunological response to ART.
  
  
  
  There were 115 cases (54 died, 45 had World Health Organization clinical stage 4 events, and 49 had poor immunological response) and 485 controls. Before ART initiation, the median ages of cases and controls were 8.2 years (interquartile range [IQR], 4.4-11.4 years) and 5.8 years (IQR, 2.3-9.3 years), respectively, and the median percentages of lymphocytes expressing CD4 were 4% (IQR, 1%-9%) and 13% (IQR, 8%-18%), respectively. In multivariable logistic regression, cases had lower age-associated CD4(+) T-cell count ratio (calculated as the ratio of the subject's CD4(+) T-cell count to the count expected in healthy individuals of the same age; P < .0001) and higher IL-6 level (P = .002) than controls. Clustering biomarkers and age-associated CD4(+) and CD8(+) T-cell count ratios identified 4 groups of children. Group 1 had the highest frequency of cases (41% cases; 16% died) and profound immunosuppression; group 2 had similar mortality (23% cases; 15% died), but children were younger, with less profound immunosuppression and high levels of inflammatory biomarkers and malnutrition; group 3 comprised young children with moderate immunosuppression, high TNF-α levels, and high age-associated CD8(+) T-cell count ratios but lower frequencies of events (12% cases; 7% died); and group 4 comprised older children with low inflammatory biomarker levels, lower HIV viral loads, and good clinical outcomes (11% cases; 5% died).
  
  
  
  While immunosuppression is the major determinant of poor outcomes during ART, baseline inflammation is an additional important factor, identifying a subgroup of young children with similar mortality. Antiinflammatory interventions may help improve outcomes.
authors.affiliation: Queen Mary University of London MRC Clinical Trials Unit at University College London.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Prendergast
authors.affiliation: MRC Clinical Trials Unit at University College London.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Szubert
authors.affiliation: University of Zimbabwe, Harare.
authors.forename: Chipo
authors.initials: C
authors.lastname: Berejena
authors.affiliation: Joint Clinical Research Centre.
authors.forename: Godfrey
authors.initials: G
authors.lastname: Pimundu
authors.affiliation: MRC/UVRI Uganda Research Unit on AIDS, Entebbe, Uganda.
authors.forename: Pietro
authors.initials: P
authors.lastname: Pala
authors.affiliation: University of Zimbabwe, Harare.
authors.forename: Annie
authors.initials: A
authors.lastname: Shonhai
authors.affiliation: Joint Clinical Research Centre Makerere University College of Health Sciences.
authors.forename: Victor
authors.initials: V
authors.lastname: Musiime
authors.affiliation: University of Zimbabwe, Harare.
authors.forename: Mutsa
authors.initials: M
authors.lastname: Bwakura-Dangarembizi
authors.affiliation: Institute of Child Health, London, United Kingdom.
authors.forename: Hannah
authors.initials: H
authors.lastname: Poulsom
authors.affiliation: Institute of Child Health, London, United Kingdom.
authors.forename: Patricia
authors.initials: P
authors.lastname: Hunter
authors.affiliation: Paediatric Infectious Diseases Clinic/Baylor-Uganda, Kampala.
authors.forename: Philippa
authors.initials: P
authors.lastname: Musoke
authors.affiliation: Makerere University College of Health Sciences.
authors.forename: Macklyn
authors.initials: M
authors.lastname: Kihembo
authors.affiliation: MRC/UVRI Uganda Research Unit on AIDS, Entebbe, Uganda.
authors.forename: Paula
authors.initials: P
authors.lastname: Munderi
authors.affiliation: MRC Clinical Trials Unit at University College London.
authors.forename: Diana M
authors.initials: DM
authors.lastname: Gibb
authors.affiliation: MRC Clinical Trials Unit at University College London.
authors.forename: Moira
authors.initials: M
authors.lastname: Spyer
authors.affiliation: MRC Clinical Trials Unit at University College London.
authors.forename: A Sarah
authors.initials: AS
authors.lastname: Walker
authors.affiliation: Institute of Child Health, London, United Kingdom.
authors.forename: Nigel
authors.initials: N
authors.lastname: Klein
mesh_terms: D000349:Africa; D044966:Anti-Retroviral Agents / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood*; D002097:C-Reactive Protein / Q000032:analysis; D018791:CD4 Lymphocyte Count; D002648:Child; D002675:Child, Preschool; D005260:Female; D006678:HIV / Q000302:isolation & purification; D015658:HIV Infections / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D015850:Interleukin-6 / Q000097:blood; D018950:Lipopolysaccharide Receptors / Q000097:blood; D008137:Longitudinal Studies; D008297:Male; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D019562:Viral Load
chemical_list: D044966:Anti-Retroviral Agents; D015415:Biomarkers; C508600:IL6 protein, human; D015850:Interleukin-6; D018950:Lipopolysaccharide Receptors; D014409:Tumor Necrosis Factor-alpha; D002097:C-Reactive Protein
keywords: Africa; HIV; children; immunosuppression; inflammation