title: Distinct evolution and predictive value of hepatitis B virus precore and basal core promoter mutations in interferon-induced hepatitis B e antigen seroconversion.
abstract: Precore (PC) (G1896A) and basal core promoter (BCP) (A1762T/G1764A) mutations of the hepatitis B virus (HBV) genome often emerge in chronic hepatitis B (CHB) patients. Their roles in hepatitis B e antigen (HBeAg) seroconversion induced by interferon (IFN) therapy remain controversial, partly because quantitative analysis for these mutants is lacking. This study aimed to develop a new assay to accurately quantify the PC and BCP mutant percentages and correlate their dynamic changes with IFN-induced HBeAg seroconversion in HBeAg-positive CHB patients. The PC and BCP mutant percentages were analyzed by polymerase chain reaction (PCR)-pyrosequencing. Our results showed that this quantitative assay for PC and BCP mutants achieved high accuracy (R(2) > 0.99) within a range between 10% and 90% mutants. We examined dynamic changes of the PC and BCP mutant percentages following IFN treatment in 203 HBeAg-positive CHB patients. By multiple logistic regression analysis, we found that the chance of HBeAg seroconversion increased by 2.2% (odds ratio [OR] = 1.022, 95% confidence interval [CI]: 1.009-1.034, P = 0.001) and 2.3% (OR = 1.023, 95% CI: 1.010-1.037, P = 0.001) per 1% increase of the pretreatment PC and BCP mutant percentages, respectively, after adjustment for other predictors. However, only the pretreatment PC mutation percentage was significantly associated with HBeAg seroconversion with HBV DNA < 2,000 IU/mL (OR = 1.030, 95% CI: 1.014-1.047, P < 0.001). Furthermore, the mutant percentage of PC, but not BCP, in patients achieving HBeAg seroclearance with HBV DNA < 20,000 IU/mL increased significantly during IFN treatment (P = 0.039). Interestingly, patients with HBeAg seroconversion who had a high PC mutant percentage at the end of IFN treatment tended to exhibit high viremia after seroconversion.
  
  
  CONCLUSIONS
  Quantitative analysis of PC and BCP mutants can predict IFN-induced HBeAg seroconversion and demonstrate their distinct evolution patterns during HBeAg seroconversion. (HEPATOLOGY 2013).
authors.affiliation: Department of Microbiology, Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, and Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Hung-Chih
authors.initials: HC
authors.lastname: Yang
authors.forename: Chi-Ling
authors.initials: CL
authors.lastname: Chen
authors.forename: Yueh-Chi
authors.initials: YC
authors.lastname: Shen
authors.forename: Cheng-Yuan
authors.initials: CY
authors.lastname: Peng
authors.forename: Chun-Jen
authors.initials: CJ
authors.lastname: Liu
authors.forename: Tai-Chung
authors.initials: TC
authors.lastname: Tseng
authors.forename: Tung-Hung
authors.initials: TH
authors.lastname: Su
authors.forename: Wan-Long
authors.initials: WL
authors.lastname: Chuang
authors.forename: Ming-Lung
authors.initials: ML
authors.lastname: Yu
authors.forename: Chia-Yen
authors.initials: CY
authors.lastname: Dai
authors.forename: Chen-Hua
authors.initials: CH
authors.lastname: Liu
authors.forename: Pei-Jer
authors.initials: PJ
authors.lastname: Chen
authors.forename: Ding-Shinn
authors.initials: DS
authors.lastname: Chen
authors.forename: Jia-Horng
authors.initials: JH
authors.lastname: Kao
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use; D016903:Drug Monitoring / Q000379:methods*; D024882:Drug Resistance, Viral / Q000235:genetics; D005260:Female; D006510:Hepatitis B Antibodies / Q000097:blood*; D006513:Hepatitis B e Antigens / Q000235:genetics* / Q000276:immunology; D006515:Hepatitis B virus / Q000235:genetics* / Q000276:immunology; D019694:Hepatitis B, Chronic / Q000188:drug therapy / Q000276:immunology / Q000821:virology; D006801:Humans; D007372:Interferons / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016133:Polymerase Chain Reaction / Q000379:methods / Q000592:standards; D011237:Predictive Value of Tests; D011401:Promoter Regions, Genetic / Q000235:genetics; D012254:Ribavirin / Q000627:therapeutic use; D017422:Sequence Analysis, DNA / Q000379:methods* / Q000592:standards; D019562:Viral Load / Q000187:drug effects / Q000235:genetics; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D006510:Hepatitis B Antibodies; D006513:Hepatitis B e Antigens; D012254:Ribavirin; D007372:Interferons