title: Molecular characterization of a novel entecavir mutation pattern isolated from a multi-drug refractory patient with chronic hepatitis B infection.
abstract: BACKGROUND
  Prolonged antiviral treatment results in selection and accumulation of resistant strains in quasispecies pool in hepatitis B virus (HBV) infection.
  
  
  OBJECTIVE
  The aim of this study was to characterise a novel HBV pattern which shows resistance to lamivudine, adefovir dipivoxil and entecavir using in vitro phenoyping assay.
  
  
  METHODS
  A male 36 years old patient diagnosed with anti HBe-positive chronic hepatitis B (CHB) had received lamivudine treatment for 7 years following an initial unsuccessfull interferon treatment. The therapy had been switched to adefovir and then to entecavir when breakthrough occcured during each treatment. This led only to a temporary HBV DNA decline which soon was followed by viral breakthrough despite the lack of known entecavir resistance mutations. Patient died after 9 months of entecavir treatment from liver failure. A total of 434 clones from 6 different serum samples were analysed retrospectively. HBV genomes bearing mutation patterns suggestive of antiviral resistance were analysed by in vitro phenotyping assay.
  
  
  RESULTS
  Dominance of a clone carrying L80LV, L91I, M204I, S219A, N238D, Y245H changes was detected in the last serum sample of the patient just before his death. This pattern displayed 30.4 fold resistance to entecavir when compared with the wild type HBV by in vitro phenotyping assay.
  
  
  CONCLUSIONS
  A novel mutation pattern showing a high degree of resistance to entecavir was documented. In this pattern, the S219A and Y245H mutations mainly seem to contribute to the emergence of ETV resistance.
authors.affiliation: Ankara University, Institute of Hepatology, Ankara, Turkey.
authors.forename: Ersin
authors.initials: E
authors.lastname: Karatayli
authors.forename: Senem C
authors.initials: SC
authors.lastname: Karatayli
authors.forename: Kubilay
authors.initials: K
authors.lastname: Cinar
authors.forename: Selma
authors.initials: S
authors.lastname: Gokahmetoglu
authors.forename: Kadri
authors.initials: K
authors.lastname: Güven
authors.forename: Ramazan
authors.initials: R
authors.lastname: Idilman
authors.forename: Cihan
authors.initials: C
authors.lastname: Yurdaydin
authors.forename: A Mithat
authors.initials: AM
authors.lastname: Bozdayi
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000328:Adult; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D024921:Drug Resistance, Multiple, Viral; D017809:Fatal Outcome; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006515:Hepatitis B virus / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008826:Microbial Sensitivity Tests; D009154:Mutation; D063065:Organophosphonates / Q000494:pharmacology / Q000627:therapeutic use; D014779:Virus Replication
chemical_list: D000998:Antiviral Agents; D063065:Organophosphonates; D019259:Lamivudine; C413685:entecavir; D006147:Guanine; D000225:Adenine; C106812:adefovir dipivoxil