title: Reactivity of routine HIV antibody tests in children who initiated antiretroviral therapy in early infancy as part of the Children with HIV Early Antiretroviral Therapy (CHER) trial: a retrospective analysis.
abstract: BACKGROUND
  Early antiretroviral therapy (ART) and virological suppression can affect evolving antibody responses to HIV infection. We aimed to assess frequency and predictors of seronegativity in infants starting early ART.
  
  
  METHODS
  We compared HIV antibody results between two of three treatment groups of the Children with HIV Early Antiretroviral Therapy (CHER) trial, done from July, 2005, until July, 2011, in which infants with HIV infection aged 5·7-12·0 weeks with a percentage of CD4-positive T lymphocytes of at least 25% were randomly assigned to immediate ART for 96 weeks (ART-96W) or deferred ART until clinical or immunological progression (ART-Def). We measured antibody from all available stored samples for ART-96W and ART-Def at trial week 84 using three assays: fourth-generation enzyme immunoassay HIV antigen-antibody combination, HIV-1 and HIV-2 rapid antibody test, and quantitative anti-gp120 IgG ELISA. We also assessed odds of seropositivity with respect to age of ART initiation and cumulative viral load. The CHER trial was registered with ClinicalTrials.gov, number NCT00102960.
  
  
  RESULTS
  The median age of the infants from when samples were taken (184 samples from 268 infants) was 92 weeks (IQR 90·6-93·4). More specimens from the ART-96W group were seronegative than from the ART-Def group by enzyme immunoassay (ART-96W 49 [46%] of 107 vs ART-Def eight [11%] of 75; p<0·0001) and rapid antibody test (54 [53%] of 101 vs eight [11%] of 74; p<0·0001). Median anti-gp120 IgG concentration was lower in the ART-96W group (230 μg/μL [IQR 133-13 129]) than in the ART-Def group (6870 μg/μL [1706-53 645]; p<0·0001). If ART was started between 12 and 24 weeks of age, odds of seropositivity were increased 13·7 times (95% CI 3·1-60·2; p=0·001) compared with starting it between 0 and 12 weeks. All children starting ART aged older than 24 weeks were seropositive. Cumulative viral load to week 84 correlated with anti-gp120 IgG concentrations (coefficient 0·54; p<0·0001) and increased odds of seropositivity (odds ratio 1·59 [95% CI 1·1-2·3]) adjusted for ART initiation age.
  
  
  CONCLUSIONS
  About half of children starting ART before 12 weeks of age were HIV seronegative by almost 2 years of age. HIV antibody tests cannot be used to reconfirm HIV diagnosis in children starting early ART. Long-term effects of seronegativity need further study. Clear guidelines are needed for retesting alongside improved diagnostic tests.
  
  
  BACKGROUND
  Wellcome Trust, Medical Research Council, and National Institutes of Health.
authors.affiliation: Institute of Child Health, University College London, London, UK. Electronic address: helenpayne@doctors.org.uk.
authors.forename: Helen
authors.initials: H
authors.lastname: Payne
authors.affiliation: Centre for HIV and Sexually Transmitted Infections, National Institute for Communicable Diseases of the National Health Laboratory Services, Johannesburg, South Africa.
authors.forename: Nonhlanhla
authors.initials: N
authors.lastname: Mkhize
authors.affiliation: Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Kennedy
authors.initials: K
authors.lastname: Otwombe
authors.affiliation: Centre for Maths and Physics in the Life Sciences and Experimental Biology, University College London, London, UK.
authors.forename: Joanna
authors.initials: J
authors.lastname: Lewis
authors.affiliation: Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Ravindre
authors.initials: R
authors.lastname: Panchia
authors.affiliation: Institute of Child Health, University College London, London, UK; Centre for Maths and Physics in the Life Sciences and Experimental Biology, University College London, London, UK.
authors.forename: Robin
authors.initials: R
authors.lastname: Callard
authors.affiliation: Centre for HIV and Sexually Transmitted Infections, National Institute for Communicable Diseases of the National Health Laboratory Services, Johannesburg, South Africa.
authors.forename: Lynn
authors.initials: L
authors.lastname: Morris
authors.affiliation: Clinical Trials Unit, Medical Research Council, London, UK.
authors.forename: Abdel
authors.initials: A
authors.lastname: Babiker
authors.affiliation: Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Avy
authors.initials: A
authors.lastname: Violari
authors.affiliation: Children's Infectious Diseases Clinical Research Unit, Department of Paediatrics and Child Health, Stellenbosch University, Cape Town, South Africa.
authors.forename: Mark F
authors.initials: MF
authors.lastname: Cotton
authors.affiliation: Institute of Child Health, University College London, London, UK.
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Klein
authors.affiliation: Clinical Trials Unit, Medical Research Council, London, UK.
authors.forename: Diana M
authors.initials: DM
authors.lastname: Gibb
mesh_terms: D015492:AIDS Serodiagnosis; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D002846:Chromatography, Affinity; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015483:HIV Antibodies / Q000097:blood*; D018023:HIV Seronegativity / Q000187:drug effects*; D006679:HIV Seropositivity / Q000188:drug therapy* / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D015498:HIV-2 / Q000276:immunology*; D006801:Humans; D007223:Infant; D008297:Male; D012189:Retrospective Studies; D013997:Time Factors; D019562:Viral Load
chemical_list: D019380:Anti-HIV Agents; D015483:HIV Antibodies