title: Second- and Third-line Antiretroviral Therapy for Children and Adolescents: A Scoping Review.
abstract: BACKGROUND
  The World Health Organization identified a need for evidence to inform revision of second- and third-line antiretroviral therapy (ART) options in children failing ART. We performed an in-depth scoping review of all available literature on second-line and subsequent ART regimens in children younger than 18 years.
  
  
  METHODS
  We comprehensively searched, without language or date limitations, the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, the World Health Organization's International Clinical Trials Registry Platform and ClinicalTrials.gov.
  
  
  RESULTS
  The search retrieved 1982 records. Eighteen studies provided efficacy data: 1 randomized controlled trial, 7 phase II trials, 5 prospective and 5 retrospective cohorts. Five studies evaluated regimens in children failing first-line ART, 4 in children with multidrug resistance and 9 in children with variable treatment experience. Only 10/18 studies reported week 48 or month 12 outcomes. The overall proportion of children with virologic suppression defined by study at week 48 was 61.8%. Although the randomized controlled trial had low risk of bias, outcomes were similar between groups because of highly active optimized background regimens. All phase II and prospective studies were judged to have moderate to high risk of bias. No study compared currently recommended lopinavir-based second-line regimens for nonnucleoside reverse transcriptase inhibitor failures to other non-nonnucleoside reverse transcriptase inhibitor regimens head-to-head.
  
  
  CONCLUSIONS
  We found no evidence comparing current World Health Organization-recommended second- and third-line ART regimens with regimens including drugs of interest: raltegravir, darunavir, etravirine and atazanavir. Randomized controlled trials or prospective cohort studies with comparator arms, and bridging studies, ideally conducted in resource-limited settings, are required to guide future recommendations.
authors.affiliation: From the *Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; †FAMCRU, Children's' Infectious Diseases Clinical Research Unit, Department of Paediatrics and Child Health, Stellenbosch University, Cape Town, South Africa; ‡World Health Organization, HIV Department, Treatment and Care Unit, Geneva, Switzerland; and §Centre for Evidence-based Health Care, Department of Interdisciplinary Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Stellenbosch, South Africa.
authors.forename: Erica
authors.initials: E
authors.lastname: Lazarus
authors.forename: Simone
authors.initials: S
authors.lastname: Nicol
authors.forename: Lisa
authors.initials: L
authors.lastname: Frigati
authors.forename: Martina
authors.initials: M
authors.lastname: Penazzato
authors.forename: Mark F
authors.initials: MF
authors.lastname: Cotton
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Centeno-Tablante
authors.forename: Avy
authors.initials: A
authors.lastname: Violari
authors.forename: Liesl
authors.initials: L
authors.lastname: Nicol
mesh_terms: D000293:Adolescent; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D000069446:Atazanavir Sulfate / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D017322:Clinical Trials, Phase II as Topic; D015331:Cohort Studies; D000069454:Darunavir / Q000627:therapeutic use; D004334:Drug Administration Schedule; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D008297:Male; D009570:Nitriles; D017410:Practice Guidelines as Topic; D011724:Pyridazines / Q000627:therapeutic use; D011743:Pyrimidines; D000068898:Raltegravir Potassium / Q000627:therapeutic use; D019562:Viral Load / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D009570:Nitriles; D011724:Pyridazines; D011743:Pyrimidines; C451734:etravirine; D000068898:Raltegravir Potassium; D000069446:Atazanavir Sulfate; D000069454:Darunavir