title: Increased viral quasispecies evolution in HBeAg seroconverter patients treated with oral nucleoside therapy.
abstract: OBJECTIVE
  Increased viral diversity and evolution appear to be a pre-HBeAg-seroconversion feature in spontaneous and interferon-treated seroconverters. The aim of this study was to examine the viral evolution pattern in nucleoside analogue related HBeAg-seroconversion.
  
  
  METHODS
  This was a case control study consisting of ten lamivudine-treated HBeAg-seroconverters and ten lamivudine-treated non-seroconverters as matching controls. All patients in this study were followed as long as 6 years after starting lamivudine, and cases had three serum time points before HBeAg-seroconversion while controls had three matching serum time points. Nested PCR, cloning and sequencing of HBV precore/core gene were performed. Sequences were aligned with Clustal X 2.0. Phylogenetic trees were constructed and viral diversity, evolutionary rates and patterns of positive selection were evaluated.
  
  
  RESULTS
  After starting lamivudine treatment, HBV viral diversity increased in both seroconverters and non-seroconverters, but seroconverters showed a significantly higher level of viral diversity that persisted over time by 2.1-fold (p = 0.009). The increased viral diversity correlated with reduced HBV DNA levels (p <0.001). Lamivudine-treated seroconverters had significant reduced HBV DNA concurrent with increased viral diversity after starting treatment (p = 0.001, compared to non-seroconverters, and resembled those of interferon-seroconverters published previously). There was evidence of positive selection in seroconverters with significantly increased amino acid changes compared to non-seroconverters (p <0.001), occurring in recognized T-cell and B-cell epitopes.
  
  
  CONCLUSIONS
  Lamivudine-treated HBeAg-seroconverters showed a higher viral diversity than non-seroconverters, and the pattern resembled that of interferon-treated seroconverters. The findings strengthen the evidence that increased viral diversity is strongly associated with HBeAg-seroconversion.
authors.affiliation: Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Yan
authors.initials: Y
authors.lastname: Cheng
authors.forename: Stephane
authors.initials: S
authors.lastname: Guindon
authors.forename: Allen
authors.initials: A
authors.lastname: Rodrigo
authors.forename: Seng Gee
authors.initials: SG
authors.lastname: Lim
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000956:Antigens, Viral / Q000097:blood; D016022:Case-Control Studies; D004279:DNA, Viral / Q000235:genetics; D019143:Evolution, Molecular; D005260:Female; D006513:Hepatitis B e Antigens / Q000097:blood*; D006515:Hepatitis B virus / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D019259:Lamivudine / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D009705:Nucleosides / Q000008:administration & dosage / Q000627:therapeutic use*; D010802:Phylogeny; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D012699:Serology
chemical_list: D000956:Antigens, Viral; D004279:DNA, Viral; D006513:Hepatitis B e Antigens; D009705:Nucleosides; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine