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Background/Aims: The long-term outcomes in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B are distinct from those in HBeAg-positive chronic hepatitis. However, the molecular virological factors that contribute to the progression of liver disease in this special clinical setting remain largely unknown. We thus investigated the association of hepatitis B virus (HBV) genotypes as well as precore/basal core-promoter mutations with the clinical and virological characteristics of patients with HBeAg-negative chronic hepatitis B in Taiwan.
Methods: HBV genotypes and sequences of precore and basal core-promoter regions of the HBV genome were determined in 174 HBeAg-negative chronic HBV infection patients including 62 inactive carriers and 112 with different stages of liver disease.
Results: HBV carriers with older age (>50 years) (odds ratio, 9.09; 95% confidence interval (CI), 3.22-25, P <0.001) and basal core-promoter mutant of HBV (odds ratio, 4.12; 95% CI, 1.41-12.03, P = 0.01) were associated with the development of liver cirrhosis and hepatocellular carcinoma (HCC). The gender-related risk factors associated with the development of liver cirrhosis and HCC were further analyzed, and basal core-promoter mutant was only associated with the development of liver cirrhosis and HCC in male carriers (odds ratio, 4.35; 95% CI, 1.30-14.52, P = 0.02).
Conclusions: The risk of development of liver cirrhosis and HCC is significantly increased in patients with advanced age as well as with basal core-promoter mutant of HBV. In addition, basal core-promoter mutant might contribute to the gender difference of the progression of liver disease in HBeAg-negative chronic hepatitis B in Taiwan.
The hepatitis B virus (HBV) affects more than 350 million people worldwide. HBV is the major cause of acute and chronic liver diseases, and persistent HBV infection is closely associated with the development of cirrhosis and hepatocellular carcinoma (HCC), accounting for ~1 million deaths annually.
During the natural course of chronic HBV infection, patients undergo a process of hepatitis B e antigen (HBeAg) seroconversion. Subsequently, their liver enzymes return to normal or nearly normal. The prevalence of HBeAg negativity in chronic HBV infection has reached more than 70% in a previous report. Nevertheless, HBV mutants selected during HBeAg seroconversion, which allow the persistence of viral replication after loss of HBeAg with associated liver damage have been reported. Among these mutants, precore stop codon mutation (G1896A) that abolishes the synthesis of HBeAg has been extensively studied and may play a role in HBeAg-negative chronic hepatitis B. In addition, double mutations in the basal core promoter (A1762T and G1764A) are also demonstrated to reduce the synthesis of HBeAg by suppressing the transcription of precore mRNA in both HBeAg-positive and -negative patients.
The natural history of HBeAg-negative chronic HBV infection becomes clearer, and a significant proportion of patients may have advanced liver fibrosis at presentation. In general, the long-term outcomes including risk of liver cirrhosis and HCC development in patients with HBeAg-negative chronic hepatitis B are distinct from those with HBeAg-positive chronic hepatitis.
Chronic persistent infection, cirrhosis, male gender and advanced age are the well-known risk factors associated with the development of HBV-related HCC. In addition, the clinical relevance of HBV genotypes has been emphasized. In summary, patients with genotype C infection have a higher positive rate of HBeAg and more severe liver disease. Our recent study also showed that basal core-promoter mutant of HBV may increase the risk of HCC development for both genotypes B and C infection. Of particular note is all these studies were based on HBV carriers irrespective of HBeAg status. A recent report indicated that HBeAg positivity is significantly associated with the development of HCC in male carriers, suggesting chronic inflammation may provide a carcinogenic background for hepatocyte. Therefore, it is interesting and important to clarify the molecular virologic factors that contribute to the progression of liver disease in HBeAg-negative chronic hepatitis B. In this study, we thus investigated the association of HBV genotypes as well as precore/basal core-promoter mutants with the clinical and virological characteristics of patients with HBeAg-negative chronic HBV infection in Taiwan.
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