title: Diminished selection for thymidine-analog mutations associated with the presence of M184V in Ethiopian children infected with HIV subtype C receiving lamivudine-containing therapy.
abstract: BACKGROUND
  We retrospectively studied the effect of the lamivudine-induced reverse transcription mutation M184V on selection of thymidine analog mutations (TAMs) in HIV subtype C-infected children and on clinical outcome.
  
  
  METHODS
  We genotyped 135 blood samples from 55 children. TAMs accumulation, viral load and clinical outcome were compared in children maintained on zidovudine/stavudine + lamivudine + protease inhibitor/nonnucleoside reverse transcriptase inhibitor (PI/NNRTI) despite loss of viral suppression and in children treated with, or switched to, other nucleoside reverse transcriptase inhibitors (NRTIs). Drug susceptibility and replication capacity of selected samples were measured.
  
  
  RESULTS
  M184V developed in 18 of 22 of children who had received only zidovudine/stavudine + lamivudine + PI/NNRTI during a mean of 23.2 +/- 3.2 months versus in 3 of 14 children treated with other drugs and/or having multiple regimen changes (P = 0.001). TAMs appeared, respectively, in 2 of 22 versus 12 of 14 (P < 0.0001). The 2 groups did not differ significantly in baseline HIV-RNA or CD4 count, sampling time, and follow-up period. In M184V-containing samples, we found large reductions in susceptibility to lamivudine and emtricitabine but not to other NRTIs. When T215Y was present without M184V, susceptibility to zidovudine was reduced 8-fold. When both M184V + T215Y occurred, susceptibility to zidovudine was substantially increased. Average inhibition concentration 50 values were similar to those documented in the Stanford database for subtype B HIV with these mutation patterns.
  
  
  CONCLUSIONS
  Maintaining a thymidine analog + lamivudine-based regimen reduced accumulation of TAMs and increased zidovudine susceptibility. This is likely the result of an increased susceptibility to thymidine analog (zidovudine) in the context of M184V documented here for the first time in subtype C-infected children. This retrospective study supports the strategy of maintaining lamivudine-containing therapy in subtype C-infected children. This strategy may be beneficially applied in the treatment of children in Africa, where thymidine analog + lamivudine-based regimen became available recently but further options are limited.
authors.affiliation: Hadassah University Medical Center, Jerusalem, Israel.
authors.forename: Diana
authors.initials: D
authors.lastname: Averbuch
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Schapiro
authors.forename: E Randall
authors.initials: ER
authors.lastname: Lanier
authors.forename: Serge
authors.initials: S
authors.lastname: Gradstein
authors.forename: Giora
authors.initials: G
authors.lastname: Gottesman
authors.forename: Eynat
authors.initials: E
authors.lastname: Kedem
authors.forename: Menachem
authors.initials: M
authors.lastname: Einhorn
authors.forename: Galia
authors.initials: G
authors.lastname: Grisaru-Soen
authors.forename: Michal
authors.initials: M
authors.lastname: Ofir
authors.forename: Dan
authors.initials: D
authors.lastname: Engelhard
authors.forename: Zehava
authors.initials: Z
authors.lastname: Grossman
mesh_terms: D019380:Anti-HIV Agents / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D024882:Drug Resistance, Viral / Q000235:genetics; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D017320:HIV Protease Inhibitors / Q000627:therapeutic use; D015497:HIV-1 / Q000145:classification* / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007223:Infant; D020128:Inhibitory Concentration 50; D019259:Lamivudine / Q000627:therapeutic use; D008297:Male; D008826:Microbial Sensitivity Tests; D009154:Mutation; D010641:Phenotype; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use; D012641:Selection, Genetic; D013936:Thymidine / Q000031:analogs & derivatives*; D014779:Virus Replication; D015215:Zidovudine / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D015215:Zidovudine; D013936:Thymidine