Natural History of Chronic Hepatitis B: Time-dependent Health Events resulting from Host-Virus Interaction

Abstract

Chronic hepatitis B is a worldwide public health challenge. The knowledge of natural history of chronic hepatitis B is important for the management of the disease. A community-based prospective cohort study was carried out to evaluate the risk predictors of progression of chronic hepatitis B in Taiwan. A total of 23,820 participants were enrolled in 1991-1992 from seven townships in Taiwan. Their serum samples were collected at study entry and follow-up examinations and tested for hepatitis B virus (HBV) surface antigen (HBsAg) and e antigen (HBeAg), serum levels of alanine aminotransferase (ALT) and HBV DNA, andα-fetoprotein (AFP). Newly developed cases of cirrhosis and hepatocellular carcinoma (HCC) were ascertained through follow-up examination and data linkage with profiles of National Cancer Registry, National Health Insurance Database and Death Certification System. The incidence of both HCC and cirrhosis was significantly associated with serum levels of ALT, HBV DNA and HBsAg at study entry in a dose-response relationship. The biological gradient of HCC risk with increasing serum HBV DNA and ALT levels repeatedly measured at follow-up examinations has also been observed. The risk of cirrhosis and HCC is significantly associated with HBV genotype, precore G1896A mutant and basal core promoter A1762T/G1764A double mutant. Nomograms have been developed for the long-term risk prediction of cirrhosis and HCC for patients with chronic hepatitis B. Serum HBV DNA level at study entry is a major predictor of spontaneous seroclearance of HBeAg, HBV DNA and HBsAg. Spontaneous seroclearance of HBV DNA rather than HBeAg and HBsAg is the most important risk predictor of HCC. Genetic polymorphisms of human leukocyte antigen are associated with the serum HBV DNA level and the development of HCC. A causal model of “evolutionary spiral” has been proposed to describe the natural history of liver disease progression in chronic hepatitis B with emphasis on time-dependent health events resulting from host-virus interaction.