title: Hepatitis B Virus (HBV) Core-Related Antigen During Nucleos(t)ide Analog Therapy Is Related to Intra-hepatic HBV Replication and Development of Hepatocellular Carcinoma.
abstract: BACKGROUND
  Although nucleos(t)ide analog (NA) therapy effectively reduces the hepatitis B virus (HBV) DNA load in the serum of patients with chronic hepatitis B, it does not completely reduce the incidence of hepatocellular carcinoma (HCC).
  
  
  RESULTS
  A total of 109 patients who had chronic hepatitis B and were receiving NA therapy were analyzed. Multivariate Cox regression analysis showed that age (>60 years had a hazard ratio [HR] of 2.66), FIB-4 index (an index of >2.1 had a HR of 2.57), and the presence of HBV core-related antigen (HBcrAg; HR, 3.53) during treatment were significantly associated with the development of HCC. The amount of HBV DNA and pregenomic RNA in liver were significantly higher in 16 HBcrAg-positive patients, compared with 12 HBcrAg-negative patients, suggesting active HBV replication in HBcrAg-positive livers. Hepatic gene expression profiling showed that HBV-promoting transcriptional factors, including HNF4α, PPARα, and LRH1, were upregulated in HBcrAg-positive livers. HepAD38 cells overexpressing LRH1 increased HBV replication, characterized by higher HBV DNA and pregenomic RNA levels, during long-term exposure to entecavir. Conversely, overexpression of precore/core in HepG2 cells increased levels of these transcriptional factors. Metformin efficiently repressed HBV replication in primary human hepatocytes.
  
  
  CONCLUSIONS
  Modulating HBV transcriptional factors by metformin in combination with NA therapy would potentiate anti-HBV activity and reduce the incidence of HCC in HBcrAg-positive patients.
authors.affiliation: Department of Gastroenterology, Kanazawa University Graduate School of Health Medicine, Japan Department of Advanced Medical Technology, Kanazawa University Graduate School of Health Medicine, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Honda
authors.affiliation: Department of Gastroenterology, Kanazawa University Graduate School of Health Medicine, Japan Department of Advanced Medical Technology, Kanazawa University Graduate School of Health Medicine, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Shirasaki
authors.affiliation: Department of Gastroenterology, Kanazawa University Graduate School of Health Medicine, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Terashima
authors.affiliation: Department of Gastroenterology, Kanazawa University Graduate School of Health Medicine, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kawaguchi
authors.affiliation: Department of Gastroenterology, Kanazawa University Graduate School of Health Medicine, Japan.
authors.forename: Mikiko
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Department of Gastroenterology, Kanazawa University Graduate School of Health Medicine, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Oishi
authors.affiliation: Department of Gastroenterology, Kanazawa University Graduate School of Health Medicine, Japan.
authors.forename: Xuyang
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, Kanazawa University Graduate School of Health Medicine, Japan.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Shimakami
authors.affiliation: Department of Gastroenterology, Kanazawa University Graduate School of Health Medicine, Japan.
authors.forename: Hikari
authors.initials: H
authors.lastname: Okada
authors.affiliation: Department of Gastroenterology, Kanazawa University Graduate School of Health Medicine, Japan.
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Arai
authors.affiliation: Department of Gastroenterology, Kanazawa University Graduate School of Health Medicine, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Yamashita
authors.affiliation: Department of Gastroenterology, Kanazawa University Graduate School of Health Medicine, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Sakai
authors.affiliation: Department of Gastroenterology, Kanazawa University Graduate School of Health Medicine, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Yamashita
authors.affiliation: Department of Gastroenterology, Kanazawa University Graduate School of Health Medicine, Japan.
authors.forename: Eishiro
authors.initials: E
authors.lastname: Mizukoshi
authors.affiliation: Department of Gastroenterology, Kanazawa University Graduate School of Health Medicine, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Kaneko
mesh_terms: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000821:virology*; D045744:Cell Line, Tumor; D005260:Female; D006512:Hepatitis B Core Antigens / Q000097:blood*; D006515:Hepatitis B virus / Q000187:drug effects / Q000502:physiology; D019694:Hepatitis B, Chronic / Q000150:complications* / Q000188:drug therapy / Q000821:virology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008099:Liver / Q000821:virology; D008103:Liver Cirrhosis / Q000473:pathology; D008113:Liver Neoplasms / Q000821:virology*; D008297:Male; D008687:Metformin / Q000494:pharmacology; D008875:Middle Aged; D016016:Proportional Hazards Models; D059467:Transcriptome; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D006512:Hepatitis B Core Antigens; D007004:Hypoglycemic Agents; D008687:Metformin
keywords: covalently closed circular DNA; hepatitis B virus; hepatitis B virus DNA; hepatitis core-related antigen; hepatocellular carcinoma