title: The M184V mutation in HIV-1 reverse transcriptase (RT) conferring lamivudine resistance does not result in broad cross-resistance to nucleoside analogue RT inhibitors.
abstract: OBJECTIVE
  To investigate the prevalence and magnitude of M184V-mediated changes in susceptibility to zalcitabine, didanosine, stavudine and abacavir (1592U89 succinate) in a cohort of lamivudine-treated patients.
  
  
  METHODS
  A total of 255 samples from patients treated with lamivudine and zidovudine with or without other nucleoside reverse transcriptase inhibitors (NRTI) were analysed for susceptibility to zidovudine, lamivudine, zalcitabine, didanosine and stavudine using a recombinant virus assay. Seventy-three samples originated from patients exposed to zidovudine and lamivudine only. A subset of 27 samples was investigated for cross-resistance to abacavir. Resistance was defined as a change in median inhibitory concentration more than fivefold compared with wild-type (high-level resistance, > 10-fold). A genotypic analysis of plasma-derived reverse transcriptase coding regions was carried out in samples with cross-resistance.
  
  
  RESULTS
  The majority of samples displayed wild-type or greater than wild-type sensitivity to zalcitabine, didanosine and stavudine: resistance was seen in 17.2, 9 and 6.3% of the total sample population, respectively. Of these, 1.2, 2.7 and 2.4%, respectively, showed high-level resistance. The prevalence of resistance to a particular NRTI was lower in samples from patients not pretreated with that NRTI and in samples from patients exposed to zidovudine-lamivudine only. Cross-resistance was more prevalent in samples with high ZDV resistance. There was no obvious correlation between cross-resistance and genotype; all but two samples were mutant at codon 184. There were no consistent changes at positions associated with zidovudine resistance. The majority of samples from a subset (n=27) were four- to eightfold less sensitive to abacavir. There were no other genotypic changes in addition to M184V known to be associated with abacavir resistance.
  
  
  CONCLUSIONS
  Cross-resistance was not commonly observed in this lamivudine-treated cohort. M184V per se is not expected to compromise subsequent treatment with NRTI such as didanosine-stavudine or combinations containing abacavir.
authors.affiliation: Zentrum der Inneren Medizin, J.W. Goethe Universität, Frankfurt, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Miller
authors.forename: M
authors.initials: M
authors.lastname: Stürmer
authors.forename: S
authors.initials: S
authors.lastname: Staszewski
authors.forename: B
authors.initials: B
authors.lastname: Gröschel
authors.forename: K
authors.initials: K
authors.lastname: Hertogs
authors.forename: M P
authors.initials: MP
authors.lastname: de Béthune
authors.forename: R
authors.initials: R
authors.lastname: Pauwels
authors.forename: P R
authors.initials: PR
authors.lastname: Harrigan
authors.forename: S
authors.initials: S
authors.lastname: Bloor
authors.forename: S D
authors.initials: SD
authors.lastname: Kemp
authors.forename: B A
authors.initials: BA
authors.lastname: Larder
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D015331:Cohort Studies; D016049:Didanosine / Q000494:pharmacology; D015224:Dideoxynucleosides / Q000494:pharmacology*; D004352:Drug Resistance, Microbial; D018432:Drug Resistance, Multiple / Q000235:genetics*; D004359:Drug Therapy, Combination; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology*; D008715:Methionine / Q000235:genetics; D017354:Point Mutation; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D018119:Stavudine / Q000494:pharmacology; D014633:Valine / Q000235:genetics; D016047:Zalcitabine / Q000494:pharmacology; D015215:Zidovudine / Q000494:pharmacology; D000099227:Abacavir
chemical_list: D019380:Anti-HIV Agents; D016049:Didanosine; D015224:Dideoxynucleosides; D054303:HIV Reverse Transcriptase; D019259:Lamivudine; D008715:Methionine; D018894:Reverse Transcriptase Inhibitors; D018119:Stavudine; D014633:Valine; D016047:Zalcitabine; D015215:Zidovudine; D000099227:Abacavir