title: Multiple dideoxynucleoside analogue-resistant (MddNR) HIV-1 strains isolated from patients from different European countries.
abstract: OBJECTIVE
  To study the prevalence of multiple dideoxynucleoside (ddN)-resistant (MddNR) HIV-1 in European patients under treatment with multiple ddN analogues, and to characterize MddNR strains genotypically and phenotypically.
  
  
  METHODS
  Blood samples from patients after > or = 6 months of treatment with multiple ddN were screened for the MddNR mutation Q151M. After confirmation of MddNR in 15 patients from five European countries, genotypic resistance was evaluated by DNA sequencing of the reverse transcriptase (RT) gene. Phenotypic resistance was measured by the recombinant virus assay. Results were compared with the clinical evolution of the patients.
  
  
  RESULTS
  The prevalence of MddNR strains in European patients treated with multiple ddN analogues was 3.5%. Viruses typically contained amino acid substitutions V75F, F77L, F116Y and Q151M in the RT gene. A new mutation, S68G, was frequently associated with MddNR. Phenotypically, viruses displayed high-level resistance to zidovudine (ZDV), didanosine (ddl), zalcitabine (ddC), stavudine (d4T) and partial resistance to lamivudine (3TC) once multiple mutations were present. Under in-vivo treatment pressure, some MddNR strains additionally developed resistance to protease inhibitors or non-nucleoside RT inhibitors (NNRTI). Clinically, most patients had advanced HIV disease with low CD4 cell counts, high viral loads and a rapid progression, but two patients harbouring MddNR virus responded well to dual protease inhibitor associations.
  
  
  CONCLUSIONS
  MddNR resistant HIV-1 can be found in European patients. MddNR is characterized by a specific set of drug resistance mutations, cross-resistance to most ddN analogues and a fast clinical progression. MddNR can be associated with protease inhibitor or NNRTI resistance.
authors.affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
authors.forename: J C
authors.initials: JC
authors.lastname: Schmit
authors.forename: K
authors.initials: K
authors.lastname: Van Laethem
authors.forename: L
authors.initials: L
authors.lastname: Ruiz
authors.forename: P
authors.initials: P
authors.lastname: Hermans
authors.forename: S
authors.initials: S
authors.lastname: Sprecher
authors.forename: A
authors.initials: A
authors.lastname: Sönnerborg
authors.forename: M
authors.initials: M
authors.lastname: Leal
authors.forename: T
authors.initials: T
authors.lastname: Harrer
authors.forename: B
authors.initials: B
authors.lastname: Clotet
authors.forename: V
authors.initials: V
authors.lastname: Arendt
authors.forename: E
authors.initials: E
authors.lastname: Lissen
authors.forename: M
authors.initials: M
authors.lastname: Witvrouw
authors.forename: J
authors.initials: J
authors.lastname: Desmyter
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
authors.forename: A M
authors.initials: AM
authors.lastname: Vandamme
mesh_terms: D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D015224:Dideoxynucleosides / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D018432:Drug Resistance, Multiple / Q000235:genetics*; D004359:Drug Therapy, Combination; D005060:Europe; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D006801:Humans; D008969:Molecular Sequence Data; D010641:Phenotype; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity
chemical_list: D019380:Anti-HIV Agents; D015224:Dideoxynucleosides; D018894:Reverse Transcriptase Inhibitors