Viral mutations and natural course of HBeAg negative chronic hepatitis B virus infection

Aims. To study the natural course of HBeAg negative chronic hepatitis B virus (HBV) infection, the mutations at the precore and core promoter regions of HBV during HBeAg seroconversion, and the predictors of active liver disease in HBeAg negative patients.; Methods. 4 studies were performed to address these issues. The studies included a cross-sectional study on the prevalence of HBeAg negative active disease and the HBV mutants, a retrospective cohort study on the predictive factors of active disease among HBeAg negative patients, a longitudinal study on the relationship of core promoter and precore HBV mutants with HBeAg seroconversion, and a study on the laboratory and virological predictors of histologic active disease in HBeAg negative patients. HBV DNA was quantified by the bDNA assay and the newer DNA cross-linking assay (NAXCOR XLnt™). I have validated the cross-linking assay to perform as good as the bDNA assay.; Results. 17% to 18% of HBeAg negative Hong Kong Chinese patients are suffering from active liver disease. Core promoter and precore stop codon mutations are present in the vast majority of HBeAg negative patients after HBeAg seroconversion. Different HBV genotypes with C or T at nucleoticle 1858 tend to develop different mutations at the core promoter and precore regions on HBeAg seroconversion. Core promoter mutations are preferentially selected in patients infected with HBV genotype C1858 that preclude the development of precore stop codon mutation. On the other hand, HBV genotype with T1858 predominantly develops precore stop codon mutation on HBeAg seroconversion. These mutations at the core promoter and precore regions, however, are not necessarily associated with more active liver disease. A normal serum ALT level has a high negative predictive value to identify HBeAg negative patients who have a low risk of hepatitis relapse. For patients with elevated ALT or suspected early liver cirrhosis, HBV DNA can be used to identify the high-risk patients with more severe histologic damage.; Conclusions. These findings are important in the understanding of the natural history as well as for the planning of future treatment strategies of HBeAg negative chronic HBV infection.