The natural history of chronic hepatitis B virus infection.

Under most circumstances, HBV is not cytopathic and it is the immune response of the host that determines the outcome of infection. The most complete immune response is associated with the most severe liver injury and the greatest likelihood of viral clearance, whereas an immature immune response leads to chronic hepatitis. The natural history of chronic hepatitis B is similar to that of acute HBV infection except for the different time frame, and can be viewed in four stages. The first stage is characterized by high viral loads and immune tolerance. In acute infection, this corresponds to the incubation period, but with neonatal chronic infection, this period often lasts for decades. In the second stage, an immunologic response develops leading to hepatocyte necrosis. In patients with chronic infection, stage 2 may persist for 10-20 years and lead to cirrhosis and its complications. When the immune response decreases the number of infected cells, a third stage begins with low viral replication, referred to as the inactive carrier state. In this stage, HBeAg is no longer detectable, a marked decrease in HBV viral load is observed, and aminotransferase levels become normal. During stage 3, some patients continue to have high levels of serum HBV DNA and amino-transferases (referred to as HBeAg-negative chronic hepatitis), because of HBV variants that prevent the production of HBeAg. In the fourth stage, patients become negative for HBeAg and positive for anti-HBs, and HBV DNA is usually no longer detectable in serum, although still present in liver tissue. Immune clearance occurs at a rate of about 1% per year in chronic carriers of HBV During stage 4, some patients can reactivate their hepatitis B when given chemotherapy or immuno-suppressive treatment. Patients with active HBV replication are at increased risk for cirrhosis, hepatic decompensation and hepatocellular carcinoma compared to inactive carriers. Available evidence indicates that control of HBV replication with antiviral agents decreases the incidence of these complications.