New Biomarker Shows Promise in Predicting Liver Cancer Risk in Chronic Hepatitis B Patients
Chronic hepatitis B (CHB) is a significant global health concern, affecting approximately 296 million people worldwide and increasing the risk of liver cirrhosis and hepatocellular carcinoma (HCC), or liver cancer. While advancements in antiviral therapy have dramatically improved patient outcomes, the risk of HCC remains, even in those achieving viral suppression. Now, researchers have identified a novel biomarker, hepatitis B viral RNA (HBV RNA), that may more accurately predict HCC development than currently used methods.
The Challenge of Preventing Liver Cancer in Chronic Hepatitis B
Nucleoside (nucleotide) analog (NA) therapy has revolutionized the treatment of CHB, effectively suppressing viral replication and reducing disease progression. However, because the hepatitis B virus (HBV) is a DNA virus that can integrate into the host genome, a complete cure is often unattainable. This means that even with successful viral suppression, the risk of HCC persists, necessitating reliable biomarkers to identify high-risk patients.
HBV RNA: A Novel Predictor of HCC Risk
Researchers at Gifu Kyoritsu University and Hiroshima University investigated the potential of HBV RNA as a biomarker for HCC risk. Their findings, published in Alimentary Pharmacology & Therapeutics on December 2, 2025, suggest that detectable HBV RNA levels in patients with suppressed HBV DNA are associated with a significantly higher risk of developing HCC.
“The introduction of NA medications has dramatically improved outcomes for patients with chronic hepatitis B,” says Takashi Kumada, specially appointed professor, Gifu Kyoritsu University; visiting professor, Graduate School of Biomedical and Health Sciences, Hiroshima University; and first and corresponding author of the study. “However, because HBV is a DNA virus that integrates into the host genome, a complete cure is not achievable. We cannot completely prevent the development of hepatocellular carcinoma (HCC). There has been a strong need for reliable biomarkers to accurately predict HCC occurrence in these patients.”
Study Details and Findings
The retrospective study involved 311 chronic hepatitis B patients who received NA therapy at Ogaki Municipal Hospital between December 2000 and May 2024. All patients achieved undetectable HBV DNA levels. Researchers analyzed stored serum samples for HBV core-related antigen (HBcrAg) and HBV RNA.
Over the follow-up period, 31 patients developed HCC, with a median time to diagnosis of 7.8 years. The study revealed that patients with quantifiable HBV RNA levels had a 3.2-fold increased risk of HCC, independent of traditional risk factors. Researchers found that HBV RNA demonstrated better predictive performance than HBcrAg.
“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. We found that HBV RNA shows better predictive performance than HBcrAg,” Kumada said.
The researchers noted that patients with quantifiable HBV RNA levels, particularly those with concurrent liver dysfunction (ALBI grade 2–3), represent a high-risk subgroup requiring intensified HCC surveillance.
Future Directions and Collaborative Research
Kumada acknowledges the limitations of the single-center study and emphasizes the need for validation through multicenter collaborative research. “Our study was conducted at a single center with 311 patients, so the findings need validation,” Kumada concludes. “Our next important step is to confirm these results through multicenter collaborative research. We would greatly appreciate hearing from institutions interested in participating in such collaborative studies.” Further research is similarly needed to determine if the findings apply to different HBV genotypes, as the predominant genotype in this study was C (88.5% of cases).
Hidenori Toyoda, Satoshi Yasuda, Yuichi Koshiyama & Takanori Ito at the Ogaki Municipal Hospital; and Tomoyuki Akita & Junko Tanaka at Hiroshima University co-authored the study.