title: High-level cross-resistance to didanosine observed in South African children failing an abacavir- or stavudine-based 1st-line regimen.
abstract: BACKGROUND
  The knowledge-base of emerging drug resistance profiles in children exposed to abacavir-based antiretroviral regimens in South Africa is very limited. This study investigated the suitability of didanosine-based 2nd-line regimens for children in the context of antiretroviral drug resistance patterns emerging after 1st-line virologic failure.
  
  
  METHODS
  A retrospective dataset of 354 antiretroviral drug resistant genotypes from children failing either abacavir (n = 81) or stavudine (n = 273) based 1st-line regimens, was analysed. Samples were sent to the HIV genotyping laboratory at Charlotte Maxeke Johannesburg Academic Hospital, for routine testing. Pol sequences were submitted to the Stanford HIV drug resistance database for genotypic predictions.
  
  
  RESULTS
  Children were exposed to abacavir or stavudine-based 1st-line regimens for an average of 21 and 36 months, respectively. The frequency of reduced susceptibility to didanosine was substantial in the abacavir-exposed group (69.1%).This reduced susceptibility was commonly attributed to L74V/I (n = 44) and to a lesser extent K65R (n = 10) mutations. Didanosine resistance was observed in 43.2% of patients exposed to stavudine-based regimens. In contrast, most children remained susceptible to stavudine regardless of exposure to abacavir (77.8%) or stavudine (74.7%). At least 80% of children remained susceptible to zidovudine irrespective of stavudine or abacavir-exposure. The presence of the K65R mutation was more common after abacavir pressure (12.3% vs 1.8%).
  
  
  CONCLUSIONS
  Analysis revealed that didanosine-based 2nd-line regimens have limitations for South African children, given the high frequency of mutations that confer cross-resistance to didanosine; especially after abacavir-exposure. This data has influenced South African paediatric treatment guidelines, which now recommend zidovudine-based 2nd-line regimens.
authors.affiliation: Department of Haematology and Molecular Medicine, University of Witwatersrand, Johannesburg, South Africa; National Health Laboratory Services, Johannesburg, South Africa.
authors.forename: Kim
authors.initials: K
authors.lastname: Steegen
authors.affiliation: Right to Care, Johannesburg, South Africa.
authors.forename: Leon
authors.initials: L
authors.lastname: Levin
authors.affiliation: Department of Haematology and Molecular Medicine, University of Witwatersrand, Johannesburg, South Africa; National Health Laboratory Services, Johannesburg, South Africa.
authors.forename: Irene
authors.initials: I
authors.lastname: Ketseoglou
authors.affiliation: Department of Haematology and Molecular Medicine, University of Witwatersrand, Johannesburg, South Africa; National Health Laboratory Services, Johannesburg, South Africa.
authors.forename: Michelle
authors.initials: M
authors.lastname: Bronze
authors.affiliation: Department of Haematology and Molecular Medicine, University of Witwatersrand, Johannesburg, South Africa.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Papathanasopoulos
authors.affiliation: Department of Haematology and Molecular Medicine, University of Witwatersrand, Johannesburg, South Africa; National Health Laboratory Services, Johannesburg, South Africa.
authors.forename: Sergio
authors.initials: S
authors.lastname: Carmona
authors.affiliation: Department of Haematology and Molecular Medicine, University of Witwatersrand, Johannesburg, South Africa; National Health Laboratory Services, Johannesburg, South Africa.
authors.forename: Wendy
authors.initials: W
authors.lastname: Stevens
mesh_terms: D019380:Anti-HIV Agents / Q000627:therapeutic use*; D001483:Base Sequence; D002648:Child; D016049:Didanosine / Q000627:therapeutic use*; D015224:Dideoxynucleosides / Q000627:therapeutic use; D024921:Drug Resistance, Multiple, Viral / Q000235:genetics*; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics; D017422:Sequence Analysis, DNA; D013019:South Africa; D018709:Statistics, Nonparametric; D018119:Stavudine / Q000627:therapeutic use; D054302:pol Gene Products, Human Immunodeficiency Virus / Q000235:genetics; D000099227:Abacavir
chemical_list: D019380:Anti-HIV Agents; D016049:Didanosine; D015224:Dideoxynucleosides; D018119:Stavudine; D054302:pol Gene Products, Human Immunodeficiency Virus; D000099227:Abacavir