Long-term Risk of Hepatocellular Carcinoma After Clearance of Hepatitis B Surface Antigen

Introduction

Chronic hepatitis B virus (HBV) infection is a major global health burden and an established risk factor for hepatocellular carcinoma (HCC), the most common primary liver cancer. The presence of hepatitis B surface antigen (HBsAg) in the blood generally indicates chronic infection, with many patients at risk of developing cirrhosis and liver cancer over time.

HBsAg seroclearance, the loss of detectable HBsAg from the bloodstream, is considered a functional cure of chronic hepatitis B (CHB) because it marks a significant reduction in viral replication and liver inflammation. However, whether viral clearance fully eliminates the risk of developing HCC, especially in the long term, remains an important clinical question. Understanding this risk is key to deciding surveillance strategies for HCC in patients post-HBsAg clearance.

Study Objectives

The aim of this large territory-wide study based in Hong Kong was to determine the incidence of hepatocellular carcinoma after HBsAg seroclearance in patients with chronic hepatitis B, and to compare this risk with that of the general population. Specifically, it assessed how age, sex, and the presence of cirrhosis influenced HCC risk after HBsAg loss.

Methods

This retrospective cohort study utilized a comprehensive healthcare database from Hong Kong, identifying adult patients with chronic hepatitis B who cleared HBsAg between 2000 and 2022. Patient characteristics such as age at seroclearance, sex, and cirrhosis status were recorded.

Annual incidences of HCC were calculated during a median follow-up period of approximately 5.6 years. For comparison, age- and sex-specific population statistics were obtained from the Hong Kong Cancer Registry and Census and Statistics Department to estimate the background incidence of HCC in the general population.

Results

Among 13,379 patients who achieved HBsAg seroclearance, the average age was approximately 60 years, with nearly 60% male and 14.6% diagnosed with cirrhosis. During follow-up, 274 patients (2.0%) developed hepatocellular carcinoma.

The overall annual incidence of HCC was higher in patients with cirrhosis, at 0.43% for those under 50 years and 0.62% for those 50 years or older at the time of HBsAg loss.

Notably, in patients without cirrhosis who cleared HBsAg before age 50, the annual incidence of HCC was extremely low at 0.03%, effectively comparable to the incidence in the general population. Specifically among males without cirrhosis, annual HCC rates were 0.02% in those younger than 40 and 0.09% in the 40–49 age group.

Among female patients without cirrhosis and younger than 50 at HBsAg seroclearance, no HCC cases occurred during 15 years of observation. For women aged 50 to 59 without cirrhosis, the annual incidence was slightly higher at 0.06%, still low relative to cirrhotic patients.

Clinical Implications

This study highlights a very low long-term risk of hepatocellular carcinoma among chronic hepatitis B patients who clear HBsAg at younger ages, particularly men under 40 and women under 50, provided there is no cirrhosis or other high-risk features. These findings suggest that intensive, routine cancer surveillance may not be necessary in these low-risk groups, which can reduce healthcare costs and patient burden.

In contrast, patients with cirrhosis remain at substantial risk for HCC despite viral clearance and should continue regular surveillance for liver cancer according to clinical guidelines.

Background on Mechanisms Linking HBV and HCC

HBV can cause liver inflammation, fibrosis, and cirrhosis, creating an environment conducive to liver cancer development. Even after HBsAg clearance, integrated viral DNA fragments can persist in hepatocytes, potentially contributing to carcinogenesis, especially in cirrhotic livers.

This ongoing risk reinforces the importance of individualized HCC screening plans based on multiple factors including age, sex, liver status, and viral history.

Current Treatment and Management of Chronic Hepatitis B

Antiviral therapies such as nucleos(t)ide analogues effectively suppress HBV replication, improving liver outcomes and reducing HCC risk. In some cases, patients may achieve HBsAg seroclearance under treatment or spontaneously.

Despite this, patients with advanced liver disease or other risk factors require ongoing monitoring. The emergence of novel therapeutic approaches aiming at complete HBV cure is under active investigation.

Conclusion

Patients with chronic hepatitis B who clear HBsAg at younger ages without cirrhosis present a very low risk of developing hepatocellular carcinoma, potentially eliminating the need for lifelong routine surveillance in this select population. However, those with cirrhosis or of older age require careful ongoing monitoring.

This study provides reassurance to many patients achieving viral clearance and informs clinicians on tailoring long-term management plans based on individualized HCC risk.

References

El-Debeiky S, Lam T H-F, Lai M S-M, Tse YK, Hui V W-K, Lai J C-T, Chan H L-Y, Wong V W-S, Wong G L-H, Yip T C-F. Long-term incidence of hepatocellular carcinoma after hepatitis B surface antigen seroclearance. Gastroenterology. 2026 Jul 13. PMID: 42442512.