title: First-line antiretroviral drug discontinuations in children.
abstract: BACKGROUND
  There are a limited number of paediatric antiretroviral drug options. Characterising the long term safety and durability of different antiretrovirals in children is important to optimise management of HIV infected children and to determine the estimated need for alternative drugs in paediatric regimens. We describe first-line antiretroviral therapy (ART) durability and reasons for discontinuations in children at two South African ART programmes, where lopinavir/ritonavir has been recommended for children <3 years old since 2004, and abacavir replaced stavudine as the preferred nucleoside reverse transcriptase inhibitor in 2010.
  
  
  METHODS
  We included children (<16 years at ART initiation) who initiated ≥3 antiretrovirals between 2004-2014 with ≥1 follow-up visit on ART. We estimated the incidence of first antiretroviral discontinuation using Kaplan-Meier analysis. We determined the reasons for antiretroviral discontinuations using competing risks analysis. We used Cox regression to identify factors associated with treatment-limiting toxicity.
  
  
  RESULTS
  We included 3579 children with median follow-up duration of 41 months (IQR 14-72). At ART initiation, median age was 44 months (IQR 13-89) and median CD4 percent was 15% (IQR 9-21%). At three and five years on ART, 72% and 26% of children respectively remained on their initial regimen. By five years on ART, the most common reasons for discontinuations were toxicity (32%), treatment failure (18%), treatment simplification (5%), drug interactions (3%), and other or unspecified reasons (18%). The incidences of treatment limiting toxicity were 50.6 (95% CI 46.2-55.4), 1.6 (0.5-4.8), 2.0 (1.2-3.3), and 1.3 (0.6-2.8) per 1000 patient years for stavudine, abacavir, efavirenz and lopinavir/ritonavir respectively.
  
  
  CONCLUSIONS
  While stavudine was associated with a high risk of treatment-limiting toxicity, abacavir, lopinavir/ritonavir and efavirenz were well-tolerated. This supports the World Health Organization recommendation to replace stavudine with abacavir or zidovudine in paediatric first-line ART regimens in order to improve paediatric first-line ART durability.
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Melony
authors.initials: M
authors.lastname: Fortuin-de Smidt
authors.affiliation: Centre for Infectious Disease Epidemiology and Research, School of Public Health and Family Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Reneé
authors.initials: R
authors.lastname: de Waal
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Karen
authors.initials: K
authors.lastname: Cohen
authors.affiliation: Empilweni Services and Research Unit, Department of Paediatrics and Child Health, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Karl-Günter
authors.initials: KG
authors.lastname: Technau
authors.affiliation: Centre for Infectious Disease Epidemiology and Research, School of Public Health and Family Medicine, University of Cape Town, Cape Town, South Africa.|Médecins Sans Frontières, Khayelitsha, South Africa.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Stinson
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Gary
authors.initials: G
authors.lastname: Maartens
authors.affiliation: Centre for Infectious Disease Epidemiology and Research, School of Public Health and Family Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Andrew
authors.initials: A
authors.lastname: Boulle
authors.affiliation: US Centers for Disease Control and Prevention, Pretoria, South Africa.
authors.forename: Ehimario U
authors.initials: EU
authors.lastname: Igumbor
authors.affiliation: Centre for Infectious Disease Epidemiology and Research, School of Public Health and Family Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Mary-Ann
authors.initials: MA
authors.lastname: Davies
mesh_terms: D000480:Alkynes; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D048588:Benzoxazines / Q000009:adverse effects / Q000627:therapeutic use; D018791:CD4 Lymphocyte Count; D002648:Child; D002675:Child, Preschool; D003521:Cyclopropanes; D015224:Dideoxynucleosides / Q000009:adverse effects / Q000627:therapeutic use; D004338:Drug Combinations; D005500:Follow-Up Studies; D006678:HIV / Q000187:drug effects*; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D007223:Infant; D053208:Kaplan-Meier Estimate; D061466:Lopinavir / Q000009:adverse effects / Q000627:therapeutic use; D017063:Outcome Assessment, Health Care / Q000379:methods / Q000706:statistics & numerical data; D016016:Proportional Hazards Models; D019438:Ritonavir / Q000009:adverse effects / Q000627:therapeutic use; D013019:South Africa; D018119:Stavudine / Q000008:administration & dosage / Q000627:therapeutic use; D028761:Withholding Treatment; D015215:Zidovudine / Q000009:adverse effects / Q000627:therapeutic use; D000099227:Abacavir
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D015224:Dideoxynucleosides; D004338:Drug Combinations; D061466:Lopinavir; D019438:Ritonavir; D018119:Stavudine; D015215:Zidovudine; D000099227:Abacavir; C558899:lopinavir-ritonavir drug combination; C098320:efavirenz