title: Combination and evolution of HBV mutant strains in the HBeAg-positive status predict clinical outcomes after HBeAg seroconversion.
abstract: OBJECTIVE
  We investigated whether the combined presence and evolution of hepatitis B virus (HBV) mutant strains in the hepatitis B e antigen (HBeAg)-positive status can predict clinical outcomes after HBeAg seroconversion.
  
  
  METHODS
  One hundred and eighty-six patients with spontaneous HBeAg seroconversion were enrolled into this longitudinal study. The sequences of pre-S, core promoter, and precore regions were determined at study entry and at the visit immediately before HBeAg seroconversion.
  
  
  RESULTS
  Age ≥40 years at HBeAg seroconversion, male sex, and higher HBV DNA levels at entry were independent predictors for HBeAg-negative chronic hepatitis B (CHB). Patients with combined mutations of pre-S deletions and T1762/A1764 had a significantly increased risk of cirrhosis and hepatocellular carcinoma (HCC) compared to patients with the wild type at both genomic regions. Combinations of pre-S deletions and T1762/A1764 were found on the same HBV genome by cloning analysis of full-length HBV genomes. Patients with a persistent presence of pre-S deletions and T1762/A1764 mutations, and new development of pre-S deletions in the HBeAg-positive status were significantly at an increased risk of HBeAg-negative CHB, cirrhosis, and HCC after HBeAg seroconversion than those with a persistent presence of the wild type at both genomic regions. After adjusting the other risk factors, the evolution of pre-S deletions was an independent predictor for cirrhosis [hazard ratio (HR): 1.52, 95 % confidence interval (CI) 1.02-2.25] and HCC (HR: 4.0, 95 % CI 1.6-10.1).
  
  
  CONCLUSIONS
  The combined presence and evolution of pre-S deletions and T1762/A1764 in the HBeAg-positive status was a useful factor significantly predictive of clinical outcomes in patients with spontaneous HBeAg seroconversion.
authors.affiliation: Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, 123 Ta Pei Road, Kaohsiung, Taiwan.|School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Chien-Hung
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, 123 Ta Pei Road, Kaohsiung, Taiwan.|School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Chuan-Mo
authors.initials: CM
authors.lastname: Lee
authors.affiliation: Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, 123 Ta Pei Road, Kaohsiung, Taiwan.|School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Jing-Houng
authors.initials: JH
authors.lastname: Wang
authors.affiliation: Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, 123 Ta Pei Road, Kaohsiung, Taiwan.|School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Tsung-Hui
authors.initials: TH
authors.lastname: Hu
authors.affiliation: Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, 123 Ta Pei Road, Kaohsiung, Taiwan.|School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Chao-Hung
authors.initials: CH
authors.lastname: Hung
authors.affiliation: Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, 123 Ta Pei Road, Kaohsiung, Taiwan.|School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Chi-Sin
authors.initials: CS
authors.lastname: Changchien
authors.affiliation: Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, 123 Ta Pei Road, Kaohsiung, Taiwan. juten@ms17.hinet.net.|School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan. juten@ms17.hinet.net.
authors.forename: Sheng-Nan
authors.initials: SN
authors.lastname: Lu
keywords: Cirrhosis; Core promoter mutation; Hepatitis B virus; Hepatocellular carcinoma; Pre-S deletion