New Biomarkers Indicate Higher Liver Cancer Risk in Chronic Hepatitis B Patients

While modern antiviral treatments can suppress the virus and significantly improve outcomes, they cannot fully eliminate the risk of hepatocellular carcinoma. Researchers have now identified new blood biomarkers that more accurately predict which patients remain at risk, even after achieving strong treatment responses.

In the new study, researchers from Hiroshima University (Hiroshima, Japan) and Gifu Kyoritsu University (Gifu, Japan) focused on evaluating novel biomarkers to improve risk prediction of hepatocellular carcinoma in patients undergoing nucleoside analog therapy. Nucleoside analog therapy suppresses viral replication and often leads to undetectable hepatitis B viral DNA levels. However, because the virus integrates into the host genome, the risk of liver cancer persists even in patients who achieve a functional cure.

To address this gap, the researchers analyzed 311 patients treated at Ogaki Municipal Hospital who had achieved undetectable viral DNA levels. They examined traditional markers such as hepatitis B surface antigen along with newer biomarkers, including hepatitis B core-related antigen and hepatitis B viral RNA. During a median follow-up period of 7.8 years, 31 patients developed hepatocellular carcinoma. The results showed that patients with detectable hepatitis B viral RNA levels had a significantly higher risk of developing liver cancer.

Specifically, quantifiable HBV RNA levels were associated with a 3.2-fold increased risk of hepatocellular carcinoma, independent of traditional risk factors. The study also found that HBV RNA outperformed other biomarkers, including HBcrAg, in predicting cancer risk. Patients with detectable HBV RNA and concurrent liver dysfunction were identified as a particularly high-risk group requiring closer monitoring.

The findings, published in Alimentary Pharmacology & Therapeutics, highlight the limitations of current monitoring strategies in chronic hepatitis B, where undetectable viral DNA does not necessarily indicate elimination of cancer risk. HBV RNA provides a more sensitive indicator of ongoing viral activity and disease processes, allowing clinicians to better stratify patients based on their long-term risk. This could help guide more personalized surveillance strategies, ensuring that high-risk individuals receive more intensive follow-up and earlier intervention.

The researchers emphasize that further validation in larger, multicenter studies is needed to confirm these findings across different populations and viral genotypes. If validated, HBV RNA testing could become an important tool in routine clinical practice, improving early detection of liver cancer and supporting more effective long-term management of chronic hepatitis B.

“Our study demonstrates for the first time that among patients with undetectable HBV DNA, those who test positive for serum HBV RNA have a significantly higher risk of developing HCC,” said Takashi Kumada, first and corresponding author of the study.

Related Links:
Hiroshima University
Gifu Kyoritsu University