title: rtL180M mutation of hepatitis B virus is closely associated with frequent virological resistance to adefovir dipivoxil therapy.
abstract: OBJECTIVE
  We intended to investigate the effects of pre-existing mutations at reverse transcriptase region of hepatitis B virus (HBV) on the occurrence of virological breakthrough (VB) to adefovir dipivoxil (ADV) in patients with lamivudine (LAM)-resistant chronic hepatitis B (CHB).
  
  
  METHODS
  Ninety-seven patients with LAM-resistant CHB were treated with ADV at a dose of 10 mg daily, and were followed for a median period of 13 months. Just before the initiation of ADV therapy, the whole length of reverse transcriptase region of serum HBV-DNA was sequenced using direct sequencing.
  
  
  RESULTS
  All patients had genotype C HBV and mutations in the YMDD motif, specifically, YIDD (65%), YVDD (28%), or both (7%). The rtL180M and rtL80V/I mutations were identified in 68% and 69%, respectively. The cumulative probability of VB was 19% and 27% at 1 and 2 years, respectively. There was no difference in the occurrence of VB with regard to types of YMDD mutation or rtL80V/I. However, interestingly, patients carrying rtL180M experienced VB during ADV monotherapy more frequently than those not carrying rtL180M (2-year cumulative probability of VB: 37% vs 3% at 2 years, P < 0.01). On multivariate Cox proportional hazards analysis, rtL180M (hazard ratio [HR]: 8.62, 95% confidence interval: 1.08-69.09, P = 0.042) and decrease in HBV-DNA for 1 year of treatment (HR: 0.69, 95% CI: 0.51-0.95, P = 0.024) are independently associated with VB.
  
  
  CONCLUSIONS
  The rtL180M mutation of HBV, as well as a small decrease in HBV-DNA after 1 year of treatment might be closely associated with frequent occurrence of virological resistance to ADV in patients with LAM-resistant CHB.
authors.affiliation: Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.
authors.forename: Yoon-Seon
authors.initials: YS
authors.lastname: Lee
authors.forename: Young-Hwa
authors.initials: YH
authors.lastname: Chung
authors.forename: Jeong A
authors.initials: JA
authors.lastname: Kim
authors.forename: Young Joo
authors.initials: YJ
authors.lastname: Jin
authors.forename: Won Hyung
authors.initials: WH
authors.lastname: Park
authors.forename: Sung Eun
authors.initials: SE
authors.lastname: Kim
authors.forename: Danbi
authors.initials: D
authors.lastname: Lee
authors.forename: Ju Hyun
authors.initials: JH
authors.lastname: Shim
authors.forename: Kang Mo
authors.initials: KM
authors.lastname: Kim
authors.forename: Young Suk
authors.initials: YS
authors.lastname: Lim
authors.forename: Han Chu
authors.initials: HC
authors.lastname: Lee
authors.forename: Yung Sang
authors.initials: YS
authors.lastname: Lee
authors.forename: Dong Jin
authors.initials: DJ
authors.lastname: Suh
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D004252:DNA Mutational Analysis; D004279:DNA, Viral / Q000097:blood; D024882:Drug Resistance, Viral / Q000235:genetics*; D005838:Genotype; D006515:Hepatitis B virus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics*; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000821:virology*; D006801:Humans; D053208:Kaplan-Meier Estimate; D015999:Multivariate Analysis; D009154:Mutation; D063065:Organophosphonates / Q000627:therapeutic use*; D010641:Phenotype; D016016:Proportional Hazards Models; D012194:RNA-Directed DNA Polymerase / Q000235:genetics*; D056910:Republic of Korea; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D019562:Viral Load
chemical_list: D015415:Biomarkers; D004279:DNA, Viral; D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; D012194:RNA-Directed DNA Polymerase; D000225:Adenine; C106812:adefovir dipivoxil