title: It is time to consider third-line options in antiretroviral-experienced paediatric patients?
abstract: BACKGROUND
  The historic use of full-dose ritonavir as part of an unboosted protease inhibitor (PI)-based antiretroviral therapy regimen in some South African children contributes to the frequent accumulation of major PI resistance mutations.
  
  
  METHODS
  In order to describe the prevalence of major PI resistance in children failing antiretroviral therapy and to investigate the clinical, immunological and virological outcomes in children with PI resistance, we conducted a cross-sectional study, with a nested case series, following up those children with major PI resistance. The setting was public health sector antiretroviral clinics in the Western Cape province of South Africa, and the subjects were children failing antiretroviral therapy. The following outcome measures were investigated: CD4 count, viral load and resistance mutations.
  
  
  RESULTS
  Fourteen (17%) of 82 patients, referred from tertiary hospitals, had major PI resistance. All these patients were exposed to regimens that included ritonavir as a single PI. Immune reconstitution and clinical benefit were achieved when using a lopinavir/ritonavir-based treatment regimen in these children with prior PI resistance. At first HIV-1 viral load follow up after initial resistance testing (n = 11), only one patient had a viral load of less than 400 copies/ml; at a subsequent follow up (n = 9), the viral loads of five patients were less than 400 copies/ml. Patients retained on LPV/r had lower viral loads than those switched to a non-nucleoside reverse transcriptase inhibitor (NNRTI). However, two of three patients with follow-up resistance tests accumulated additional PI resistance.
  
  
  CONCLUSIONS
  In children with pre-existing PI resistance, although initially effective, the long-term durability of a lopinavir/ritonavir-based treatment regimen can be compromised by the accumulation of resistance mutations. Furthermore, a second-line NNRTI regimen is often not durable in these patients. As genotypic resistance testing and third-line treatment regimens are costly and limited in availability, we propose eligibility criteria to identify patients with high risk for resistance and guidance on drug selection for children who would benefit from third-line therapy.
authors.affiliation: Division of Medical Virology, Stellenbosch University, and National Health Laboratory Service Tygerberg, Parow, Cape Town, South Africa. guvz@sun.ac.za
authors.forename: Gert U van
authors.initials: GU
authors.lastname: Zyl
authors.forename: Helena
authors.initials: H
authors.lastname: Rabie
authors.forename: James J
authors.initials: JJ
authors.lastname: Nuttall
authors.forename: Mark F
authors.initials: MF
authors.lastname: Cotton
mesh_terms: D019380:Anti-HIV Agents / Q000008:administration & dosage*; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods*; D018791:CD4 Lymphocyte Count; D016022:Case-Control Studies; D002675:Child, Preschool; D003430:Cross-Sectional Studies; D024882:Drug Resistance, Viral; D005500:Follow-Up Studies; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology*; D017320:HIV Protease Inhibitors / Q000008:administration & dosage; D015497:HIV-1 / Q000187:drug effects* / Q000302:isolation & purification; D006801:Humans; D020125:Mutation, Missense; D015995:Prevalence; D019438:Ritonavir / Q000008:administration & dosage; D013019:South Africa; D017211:Treatment Failure; D019562:Viral Load
chemical_list: D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D019438:Ritonavir
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