title: Precore stop codon mutation of hepatitis B virus is associated with low breakthrough rate following long-term lamivudine therapy.
abstract: BACKGROUND
  Frequent viral breakthroughs limit the usefulness of lamivudine in the treatment of chronic hepatitis B (CHB). The purpose of the present study was to evaluate the effects of precore stop codon mutation (G to A mutation at nucleotide 1896; A(1896)) of hepatitis B virus (HBV) on the occurrence of viral breakthrough following lamivudine therapy.
  
  
  METHODS
  Among 260 consecutive CHB patients treated with lamivudine for >12 months, 231 patients whose pretreatment sera were available were tested for A(1896) variant of HBV using direct sequencing.
  
  
  RESULTS
  Between patients with A(1896) variant (n = 74) and those without it (n = 157), there was no difference in age, gender, serum alanine aminotransferase (ALT) level, the duration of therapy and prevalence of core promoter mutants. Serum hepatitis B e antigen (HBeAg) positivity and HBV-DNA level were lower (P = 0.00 and P = 0.01) and liver cirrhosis was more commonly associated in patients with A(1896) variant mutant compared with those without it. In univariate analysis, viral breakthrough was more frequent in HBeAg-positive patients (P = 0.03) and in those with high serum HBV-DNA level (P = 0.01) as well as in those without A(1896) variant (P = 0.01). However, in multivariate analysis, the absence of A(1896) variant (P = 0.02) and high serum HBV-DNA level (P = 0.03) were independent factors for viral breakthrough following lamivudine therapy. The cumulative viral breakthrough rates at 1 and 2 years were much lower in patients with A(1896) variant compared with those without it (P = 0.01).
  
  
  CONCLUSIONS
  The stop codon mutation at the precore region of HBV in addition to low serum HBV-DNA level may be associated with low breakthrough rate following lamivudine therapy.
authors.affiliation: Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, 388-1 Poongnap-dong Songpa-ku, 138-040 Seoul, Korea.
authors.forename: Jung Woo
authors.initials: JW
authors.lastname: Shin
authors.forename: Young-Hwa
authors.initials: YH
authors.lastname: Chung
authors.forename: Min Hee
authors.initials: MH
authors.lastname: Choi
authors.forename: Jeong A
authors.initials: JA
authors.lastname: Kim
authors.forename: Soo Hyung
authors.initials: SH
authors.lastname: Ryu
authors.forename: Myoung Kuk
authors.initials: MK
authors.lastname: Jang
authors.forename: In Sook
authors.initials: IS
authors.lastname: Kim
authors.forename: Neung Hwa
authors.initials: NH
authors.lastname: Park
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: D000328:Adult; D018388:Codon, Terminator / Q000235:genetics*; D004279:DNA, Viral / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D006513:Hepatitis B e Antigens / Q000276:immunology; D006515:Hepatitis B virus / Q000187:drug effects / Q000235:genetics* / Q000276:immunology; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D019259:Lamivudine / Q000627:therapeutic use*; D008297:Male; D009154:Mutation; D016133:Polymerase Chain Reaction; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*; D017422:Sequence Analysis, DNA; D013997:Time Factors; D016896:Treatment Outcome; D019562:Viral Load
chemical_list: D018388:Codon, Terminator; D004279:DNA, Viral; D006513:Hepatitis B e Antigens; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine