Revisiting the Natural History of Chronic HBV Infection

Although effective vaccines have been available for more than three decades, hepatitis B virus (HBV) infection remains a global public health issue. It is estimated around 248 million people are chronically infected by HBV, and most of them are residing in the Asia-Pacific region. In HBV-endemic regions, the virus is primarily transmitted during the perinatal period or early childhood with an immature immune system, so it has a high rate of chronicity. Based on the virological and clinical manifestations, the natural course of chronic hepatitis B can be divided into four classical phases: immune tolerance, immune clearance, inactive carrier, and reactivation phases. The majority of patients will undergo spontaneous HBeAg seroconversion and enter an inactive carrier state. However, a small portion of patients may encounter intermittent or persistent hepatitis and eventually lead to severe adverse outcomes, such as liver cirrhosis, hepatic failure, or hepatocellular carcinoma. With recent advances in molecular and immunological technologies, several viral and host factors that may affect the clinical outcomes of chronic HBV infection have been identified. By integration of these emerging serological and viral biomarkers, the natural history of chronic HBV infection should be revisited. In conclusion, accurate definition of the natural history of chronic HBV infection not only sheds light on the pathogenesis of chronic hepatitis B but also helps determine the optimal timing for antiviral therapy to cure HBV.