About 250 to 350 million people worldwide are chronically infected with hepatitis B virus(HBV), and about 700000 patients per year die of HBV-related cirrhosis or hepatocellular carcinoma(HCC). Several anti-viral agents, such as interferon and nucleos(t)ide analogues(NAs), have been used to treat this disease. NAs especially have been shown to strongly suppress HBV replication, slowing the progression to cirrhosis and the development of HCC. However, reactivation of HBV replication often occurs after cessation of treatment, because NAs alone cannot completely remove covalentlyclosed circular DNA(ccc DNA), the template of HBV replication, from the nuclei of hepatocytes. Anti-HBV immune responses, in conjunction with interferon-γ and tumor necrosis factor-α, were found to eliminate ccc DNA, but complete eradication of ccc DNA by immune response alone is difficult, as shown in patients who recover from acute HBV infection but often show long-term persistence of small amounts of HBV-DNA in the blood. Several new drugs interfering with the life cycle of HBV in hepatocytes have been developed, with drugs targeting ccc DNA theoretically the most effective for radical cure of chronic HBV infection. However, the safety of these drugs should be extensively examined before application to patients, and combinations of several approaches may be necessary for radical cure of chronic HBV infection.
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