title: Emergence of the rtA181T/sW172* mutant increased the risk of hepatoma occurrence in patients with lamivudine-resistant chronic hepatitis B.
abstract: BACKGROUND
  Development of the hepatitis B virus (HBV) rtA181T/sW172* mutant could occur during prolonged lamivudine (LAM) therapy, conferring cross resistance to adefovir. Recent studies demonstrated an increased oncogenic potential of this mutant in NIH3T3 cells. In this study, we aimed to investigate the clinical significance of this finding.
  
  
  METHODS
  Serum samples from 123 LAM-resistant chronic hepatitis B patients were submitted for virological assays. A highly sensitive amplification created restriction enzyme site (ACRES) method was devised to detect small amounts of the rtA181T mutant in the serum. Virological factors including HBV-DNA level, genotype, precore G1896A, BCP A1762T/G1764A, rtM204I/V, rtA181T and pre-S internal deletion mutations as well as clinical variables including subsequent use of rescue drugs were submitted for outcome analysis.
  
  
  RESULTS
  By use of the highly sensitive ACRES method, the rtA181T mutant was detectable in 10 of the 123 LAM-resistant patients. During the mean follow-up period of 26.2 ± 16.4 months (range 2 to 108 months), 3 of the 10 (30.0%) rtA181T-positive patients and 2 of the 113 (1.8%) rtA181T-negative patients developed hepatocellular carcinoma (HCC). Kaplan-Meier analysis indicated that the presence of rtA181T mutation (P < 0.001), age > 50 years (P = 0.001), and liver cirrhosis (P < 0.001) were significantly associated with subsequent occurrence of HCC. All 5 HCC patients belonged to the older age and cirrhosis groups.
  
  
  CONCLUSIONS
  Emergence of the rtA181T/sW172* mutant in LAM-resistant patients increased the risk of HCC development in the subsequent courses of antiviral therapy.
authors.affiliation: Liver Research Center, Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital, Taipei, Taiwan. chautingy@gmail.com
authors.forename: Chau-Ting
authors.initials: CT
authors.lastname: Yeh
authors.forename: Tiffany
authors.initials: T
authors.lastname: Chen
authors.forename: Chao-Wei
authors.initials: CW
authors.lastname: Hsu
authors.forename: Yi-Cheng
authors.initials: YC
authors.lastname: Chen
authors.forename: Ming-Wei
authors.initials: MW
authors.lastname: Lai
authors.forename: Kung-Hao
authors.initials: KH
authors.lastname: Liang
authors.forename: Tse-Ching
authors.initials: TC
authors.lastname: Chen
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000998:Antiviral Agents / Q000009:adverse effects / Q000627:therapeutic use; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000821:virology*; D004279:DNA, Viral / Q000097:blood / Q000235:genetics; D024882:Drug Resistance, Viral; D005260:Female; D006515:Hepatitis B virus / Q000235:genetics*; D019694:Hepatitis B, Chronic / Q000188:drug therapy / Q000821:virology*; D006801:Humans; D015994:Incidence; D019259:Lamivudine / Q000009:adverse effects / Q000627:therapeutic use*; D008103:Liver Cirrhosis; D008113:Liver Neoplasms / Q000821:virology*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D021141:Nucleic Acid Amplification Techniques; D012189:Retrospective Studies; D012307:Risk Factors
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D019259:Lamivudine