title: Evolutionary patterns of hepatitis B virus quasispecies under different selective pressures: correlation with antiviral efficacy.
abstract: OBJECTIVE
  To investigate the evolution of hepatitis B virus (HBV) quasispecies (QS) within the reverse transcriptase (RT) region during the early stage of entecavir treatment and its impact on virological response, and to compare evolutionary patterns under different selective pressures.
  
  
  METHODS
  31 patients with chronic hepatitis B receiving entecavir (17 responders and 14 partial responders according to the HBV DNA levels at week 48) and 25 patients receiving lamivudine (14 responders and 11 non-responders) as controls were included. An average of 26 clones (2892 total from both groups) spanning the RT region per sample was sequenced.
  
  
  RESULTS
  QS complexity and diversity, in addition to alanine aminotransferase and HBV DNA levels, were comparable between responders and partial responders at baseline. However, QS complexity in responders at week 4 was statistically lower than that in partial responders at the nucleotide level (0.6494 vs. 0.7723, p=0.039). Net changes in diversity as well as the viral nucleotide substitution rate of responders were higher than those of partial responders, and both correlated with virological responses at both week 48 and the final visit (mean: 28 months). A preliminary model of QS evolution variables predicted 16 of 17 responders and 13 of 14 partial responders in the entecavir group. Despite significant differences between responders to entecavir and responders to lamivudine at week 4, the characteristics of QS were quite similar between partial responders to entecavir and non-responders to lamivudine.
  
  
  CONCLUSIONS
  The evolutionary patterns of HBV RT QS differ between responders and partial responders during the early stage of entecavir treatment. Characteristics of HBV QS evolution during the first 4 weeks contribute to the prediction of long-term virological responses. The similar patterns of HBV RT QS in partial responders and non-responders receiving different nucleoside analogues may imply a novel mechanism of drug resistance, which warrants further investigation.
authors.affiliation: Department of Infectious Diseases, Institute of Infectious & Respiratory Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin Er Rd, Shanghai 200025, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.forename: De-Min
authors.initials: DM
authors.lastname: Yu
authors.forename: Lin
authors.initials: L
authors.lastname: Deng
authors.forename: Rong
authors.initials: R
authors.lastname: Chen
authors.forename: Yin
authors.initials: Y
authors.lastname: Jiang
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
authors.forename: Su-Yuan
authors.initials: SY
authors.lastname: Huang
authors.forename: Jia-Lun
authors.initials: JL
authors.lastname: Yu
authors.forename: Qi-Ming
authors.initials: QM
authors.lastname: Gong
authors.forename: Xin-Xin
authors.initials: XX
authors.lastname: Zhang
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000627:therapeutic use; D004279:DNA, Viral / Q000097:blood / Q000235:genetics; D024882:Drug Resistance, Viral / Q000235:genetics; D019143:Evolution, Molecular; D005260:Female; D014644:Genetic Variation; D006147:Guanine / Q000031:analogs & derivatives / Q000627:therapeutic use; D006515:Hepatitis B virus / Q000145:classification / Q000187:drug effects / Q000235:genetics* / Q000302:isolation & purification; D019694:Hepatitis B, Chronic / Q000188:drug therapy / Q000821:virology*; D006801:Humans; D019259:Lamivudine / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010802:Phylogeny; D012194:RNA-Directed DNA Polymerase / Q000235:genetics; D012189:Retrospective Studies; D012641:Selection, Genetic; D017422:Sequence Analysis, DNA / Q000379:methods; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D019259:Lamivudine; C413685:entecavir; D006147:Guanine; D012194:RNA-Directed DNA Polymerase