Natural history of hepatitis B virus infection and disease

The natural history of hepatitis B virus (HBV) infection is complex and variable and is greatly influenced by the age at infection –the younger the age the higher the probability of chronicity– the level of HBV replication and host immune status. Chronic hepatitis B is usually characterized by an early replicative phase with hepatitis B e antigen (HBeAg)positivity, high serum HBV-DNA levels (> 105 copies/ml) and normal serum alanine aminotransferase (ALT) (HBeAg-positive chronic hepatitis in the “immunotolerant” phase) or raised serum ALT and active hepatitis (HBeAg-positive chronic hepatitis in the “immunoactive” phase) and a late inactive phase with HBeAg seroconversion, low or undetectable serum HBV-DNA, and liver disease remission (inactive carrier state). Another form of chronic hepatitis B is characterized by HBeAg negativity, detectable serum HBV-DNA levels (suggested threshold > 104 copies/ml) and active hepatitis due to HBV variants not expressing HBeAg (HBeAg-negative chronic hepatitis). HBeAg-negative chronic hepatitis represents a late phase of chronic HBV infection and its prevalence is increasing throughout the world. Chronic hepatitis B is associated with serious complications, including cirrhosis, hepatic decompensation and hepatocellular carcinoma (HCC). The incidence of cirrhosis ranges from 0.5 per 100 person years in HBeAg-positive chronic hepatitis in the immunotolerant phase to 2 to 5 per 100 person years in HBeAg-positive chronic hepatitis in the immunoactive phase, but may be as high as 8 to 10 in HBeAg-negative chronic hepatitis. The incidence of HCC appears to vary geographically and increases with the severity of liver disease (0.02 to 1.0 per 100 person years in carriers without cirrhosis at baseline to 2 to 3 per 100 person years in cirrhotic patients). The five-year mortality rate is about 15% for patients with compensated cirrhosis and 65% to 85% following decompensation. HCC and liver failure are the main causes of death. Viral-related factors (level and persistence of HBV replication, emergence of viral mutants, HBV genotype, viral coinfections), host-related factors (sex, age at infection, age at diagnosis, stage of liver disease at presentation, recurrent hepatitis flares, sustained aminotransferase normalization), and environmental factors (alcohol abuse, smoking and dietary carcinogens) may all be important determinants of the outcome of the disease