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Hepatitis B virus (HBV) infection is the leading cause of hepatocellular carcinoma (HCC) worldwide. Despite advancements in vaccination and antiviral treatment over several decades, the death toll of HBV-related HCC continues to rise globally. While available therapies effectively inhibit viral replication, the integration of HBV DNA into the host genome presents ongoing carcinogenic potential. This talk explores the carcinogenic implications of HBV DNA integration in the context of modern antiviral therapy.

We will discuss recent findings on the sites and patterns of HBV DNA integration, focusing on how these events may disrupt key cellular pathways and contribute to hepatocarcinogenesis. Empirical evidence will be examined, highlighting the role of integrated HBV DNA in altering gene expression, causing chromosomal instability, and affecting cell cycle regulation. Additionally, we will present data on long-lasting persistence of integration events in patients who have ostensibly recovered from the infection with seroclearance of viral biomarkers.

Our research suggests that nucleos(t)ide analogues (NAs) may indirectly reduce the occurrence of HBV integration events through remission of viremia by inhibiting the HBV reverse transcriptase. Nevertheless, NAs have no effects on existing integrations. Moreover, the integrated HBV sequences can continue to express viral proteins, such as HBx and HBsAg in truncated forms, which are potentially carcinogenic even in the absence of active viral replication. Emerging data indicate that the production of HBsAg switches from covalently closed circular DNA (cccDNA) to integrated sequences after long-term NA therapy, posing challenges for viral eradication. 

Finally, we will discuss the potential implications of these findings for cancer risk assessment, monitoring strategies, and the development of novel therapeutic approaches aimed at targeting integrated HBV DNA or its effects. The presentation will conclude with an outlook on future research directions and potential strategies to mitigate the carcinogenic risk associated with HBV DNA integration in the era of potent antiviral treatments.