Editorial: How to Interpret Clinical Impact of Viral Replication Activity for Postoperative Recurrence of HBV-Related HCC—Authors' Reply

Abstract

We sincerely thank Kim for his insightful editorial on our recent study [1, 2] and for recognising its key findings—particularly the differential impact of the timing of antiviral treatment (AVT) on hepatocellular carcinoma (HCC) recurrence after curative resection according to cirrhosis status, and the observation of a non-linear parabolic association between hepatitis B virus (HBV) DNA levels and postoperative recurrence risk in non-cirrhotic patients. We also welcome the opportunity to further elaborate on our findings and to address the important discussion points raised by Kim in his editorial.

First, the impact of AVT timing on HCC recurrence after curative therapy has long been debated [3, 4], likely due to variations across studies in the stages of HCC included, whether only surgically treated cases were analysed or non-surgical treatments such as local ablative therapy were also included, and differences in the proportion of patients with cirrhosis. To enhance both the internal and external validity of our findings, we analysed a large-scale multinational cohort of 2384 patients with BCLC stage 0 or A HBV-related HCC who underwent curative resection, and demonstrated a differential effect of AVT timing based on cirrhosis status—one of the cornerstone findings of our study [1], and notably, a distinction that has not been clearly delineated in previous studies [3, 4].

Second, while current guidelines support AVT initiation in cirrhotic patients with any detectable HBV DNA level—a recommendation further reinforced by our findings—our study also suggests that the timing of AVT in non-cirrhotic patients, particularly those with moderate HBV DNA levels between 5 and 7 log₁₀ IU/mL, warrants further investigation [5], given the potential ongoing impact of viral replication activity-associated genome integration and clonal hepatocyte expansion on not only the development but also the recurrence of HCC [6, 7].

Third, although we adjusted for major tumour pathological features—such as microvascular invasion and the presence of satellite nodules—using detailed histopathologic data, we recognise that our study is limited in its ability to capture the full complexity of tumour biology. Specifically, as a retrospective clinical study, our analysis could not comprehensively address the dynamic interplay among viral, host, and environmental factors, nor their roles in shaping the tumour microenvironment and influencing disease progression [8]. We fully agree that further research is needed to elucidate these multifactorial interactions and their contributions to tumour biology.

Despite the inherent limitations of being a retrospective study, we believe that our study meaningfully extends the discussion on viral dynamics and the optimal timing of AVT from the secondary to the tertiary preventive setting of HCC. The editorial discussion reinforces the clinical relevance of our findings but also underscores the need for continued research to refine risk stratification and optimise management strategies for patients with HBV-related HCC.

Subin Heo: conceptualization, writing – review and editing. Won-Mook Choi: conceptualization, supervision, writing – original draft, writing – review and editing, resources, project administration.

The authors' declarations of personal and financial interests are unchanged from those in the original article [1].

This article is linked to Heo et al. papers. To view these articles, visit, https://doi.org/10.1111/apt.70085 and https://doi.org/10.1111/apt.70118.