Pre-S Mutants and Combination Mutations of Pre-S/Core Promoter/Precore Regions of Hepatitis B Virus Related to Advanced Liver Disease in Hbeag-Positive Chronic Hepatitis B Patients---A Longitudinal Study

  • Lee, Chuan-mo (PI)
  • Chen, Chine Hung (CoPI)
  • Hu, Tsung Hui (CoPI)
  • Lu, Sheng-Nan (CoPI)

Project: National Science and Technology CouncilNational Science and Technology Council Academic Grants

Project Details

Abstract

Hepatitis B virus (HBV) infection is a major health problem leading to around one million deaths annually worldwide. A wide range of clinical manifestations has been established for chronic hepatitis B (CHB) virus infection from asymptomatic carriers, chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC). Hepatitis B e antigen (HBeAg) serves as a marker for active viral replication. Once HBeAg is cleared and remission has occurred, serum ALT levels generally remain normal and symptoms resolve. Early HBeAg seroconversion typically confers favorable long-term outcomes. In contrast, late or absent HBeAg seroconversion accelerates the progression of chronic hepatitis to cirrhosis and HCC. Previous studies showed pre-S deletions were associated with liver cirrhosis and HCC. However, the effect of pre-S mutants on advanced liver disease in HBeAg-positive CHB patients remains unclear. Further, previous studies reported that patients with pre-S deletions had higher rates of HBeAg-positive status, HBV genotype C and T1762/A1764 mutations than those without pre-S deletions. Thus, it is unclear whether these mutations are confounding or have synergistic effects on the development of liver cirrhosis or HCC in HBeAg-positive patients. Thus, further longitudinal studies should be performed to investigate these issues. Recently, it had been reported that HBV complex viral mutants were associated with progression of liver disease. However, it is unclear whether a specific combination of these mutations is associated with the development of advanced liver disease in HBeAg-positive patients. Further, these mutations identified by direct sequencing of HBV subgenomic regions may not co-locate on the same HBV genome. Thus, further studies by using cloning sequencing of full-length HBV genomes and functional analysis of complex HBV mutations may help clarify the exact role of complex HBV mutants in the pathogenesis of HBV infection. Our specific aims are as follows: 1. The effect of pre-S mutations on spontaneous HBeAg seroconversion and advanced liver disease (liver cirrhosis or HCC) in HBeAg-positive CHB patients. 2. Whether a specific combination mutations of pre-S/core promoter/precore regions is associated with the development of advanced liver disease (liver cirrhosis or HCC) in HBeAg-positive CHB patients. 3. Whether these complex mutations of HBV associated with advanced liver disease identified by direct sequencing are co-located on the same HBV genome by molecular cloning and sequencing. 4. Whether these complex mutations of HBV associated with advanced liver disease can affect the HBV protein synthesis (HBsAg, HBeAg) and replication capacity. Patients and methods: About 150 HBeAg-positive CHB patients without liver cirrhosis and HCC at study entry will be included in this prospective study. All patients will have a regular follow-up of at least 36 months. The HBV genotypes, HBV DNA levels, and the sequences of pre-S, precore/core promoter regions will be determined at study entry. Besides, we will test the pre-S/core promoter/precore sequences preceding the liver cirrhosis or HCC diagnoses or at the last follow-up examination for patients who had not developed liver cirrhosis. Cloning sequencing of full-length HBV genomes and functional analysis of complex HBV mutations associated with advanced liver disease will be performed. The sera has been frozen at -70°C until use.

Project IDs

Project ID:PC9902-1706
External Project ID:NSC98-2314-B182-045-MY2
StatusFinished
Effective start/end date01/08/1031/07/11

Keywords

  • Hepatitis B virus
  • genotype
  • pre-S deletion
  • precore mutation
  • core promoter

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