Editorial: Predicting Hepatocellular Cancer in Clinical Practice. Authors' Reply

Abstract

We thank Professor Taha for the insightful Editorial on our study addressing hepatocellular carcinoma (HCC) risk prediction after hepatitis B surface antigen (HBsAg) seroclearance [1, 2]. His comments appropriately highlight emerging priorities in the future management of HCC, particularly the need for refined risk stratification and stage-shifting surveillance strategies [3]. We are encouraged that the clinical relevance of our model, particularly its capacity to identify early-stage HCC, has been recognized. Our study was designed to address a clinically under-recognized population, patients achieving HBsAg seroclearance, who retain a measurable but heterogeneous residual risk of HCC [4]. By focusing specifically on this population, our model integrates six routinely available clinical parameters to provide a simple and clinically implementable tool for risk stratification. We acknowledge that the CAMP-B model has also demonstrated robust performance in this setting [5]. Our model builds upon these prior efforts by further refining risk stratification in this population and offering complementary clinical value. Importantly, the limitations highlighted in the Editorial also point towards several directions for future research. The absence of detailed viral factors, performance status, and potentially protective exposures reflects inherent constraints of real-world retrospective datasets, but also underscores the need for prospective cohorts with more comprehensive phenotyping. In the context of HBsAg seroclearance, viral replication is typically minimal or undetectable, as serum HBsAg levels are thought to reflect intrahepatic cccDNA transcriptional activity and HBV DNA integration-derived transcripts [6]. However, this suggests that traditional virological markers may have limited ability to capture the underlying biological heterogeneity in this setting, thereby necessitating the exploration of alternative biomarkers. Importantly, HBV DNA integration can persist within the host genome even after effective viral suppression, and the burden of viral integration—particularly the number of integration breakpoints—has been shown to correlate with the likelihood of HBsAg loss [7]. These findings highlight that integration-related heterogeneity may contribute to differential clinical outcomes following seroclearance. In addition, performance status, such as Eastern Cooperative Oncology Group score, has been well established as a prognostic factor in oncology [8]. However, in real-world outpatient cohorts with regular follow-up, there may be an inherent selection towards patients with preserved functional status. Future studies are therefore warranted to clarify the role of functional status in both HBsAg seroclearance and subsequent HCC risk. Furthermore, metabolic comorbidities, including diabetes, metabolic associated fatty liver disease, and hypertension, have been increasingly recognized as contributors to hepatocarcinogenesis [9]. Correspondingly, medications targeting these conditions may exert protective effects on HCC development in patients after HBsAg seroclearance, although robust evidence remains limited. This highlights an important avenue for future investigation, particularly in relation to optimizing long-term management strategies in this population. From a translational perspective, our findings support a shift towards risk-adapted surveillance strategies. Further external validation and prospective studies will be essential to confirm its clinical utility and to facilitate its integration into routine practice. Combining clinical risk scores with emerging machine learning approaches or multi-omics data may offer opportunities to refine individualized prediction and improve early detection. In conclusion, our findings provide a pragmatic framework for risk stratification after HBsAg seroclearance. Yan Lou: conceptualization, writing – original draft, writing – review and editing, project administration, supervision. Shuaibing Ying: conceptualization, writing – original draft. Yunqing Qiu: conceptualization, supervision, project administration, writing – original draft, writing – review and editing. The authors' declarations of personal and financial interests are unchanged from those in the original article [2]. This article is linked to Ying et al. papers. To view these articles, visit https://doi.org/10.1111/apt.70637 and https://doi.org/10.1111/apt.70644. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.