Letter on “Association Between Viral Replication Activity and Postoperative Recurrence of HBV-Related Hepatocellular Carcinoma”

Abstract

We read with great interest the article by Heo et al. [1] exploring the association between baseline viral replication activity and postoperative recurrence of HBV-related hepatocellular carcinoma (HCC). The authors are to be commended for their thoughtful stratification based on cirrhosis status and detailed analysis of baseline hepatitis B virus (HBV) DNA levels, addressing a clinically relevant gap given that antiviral therapy initiation is still largely restricted to patients with elevated alanine aminotransferase levels despite evidence of hepatocarcinogenesis occurring without significant inflammation [2-4]. Their work provides valuable evidence that could inform future refinements in antiviral therapy initiation and postoperative surveillance strategies.

While the study presents significant advances, several aspects warrant further discussion. First, although the recurrence risk patterns were elegantly illustrated, some internal variations were noted. Among cirrhotic patients, initiation-antiviral therapy (AVT) was associated with a significantly higher risk of early recurrence compared to ongoing-AVT, whereas no difference was observed for late recurrence. However, within the initiation-AVT group, the plateau-shaped association between baseline HBV DNA levels and recurrence risk became more pronounced during late recurrence. This may reflect the inherent challenges of capturing long-term recurrence dynamics within a relatively short median follow-up period of 4.9 years [5, 6].

Second, we observed that the subgroup with low baseline HBV DNA levels (< 3.30 log₁₀ IU/mL) demonstrated a paradoxical profile—higher rates of significant inflammation yet lower recurrence risk in non-cirrhotic patients. As this subgroup constituted more than half of the non-cirrhotic cohort after matching, a separate analysis of this population could provide insights into biological heterogeneity beyond cirrhosis status alone. Incorporating additional stratification by markers such as platelet count, fibrosis stage, or composite scores (e.g., mPAGE-B) might enhance future risk models [7, 8].

Third, information regarding the use of postoperative adjuvant therapies, such as intensified antiviral regimens, immune checkpoint inhibitors, targeted therapies, or transarterial chemoembolization, could further be detailed in the study. As these interventions are increasingly integrated into the management of HCC and can significantly influence recurrence dynamics, accounting for their use is critical for isolating the true impact of baseline viral replication activity. Clarifying these aspects would strengthen the causal inferences drawn from the observed associations [9].

Lastly, while the authors excluded patients who initiated AVT more than 3 months after surgery, prior evidence suggests that even delayed AVT initiation can confer survival benefits by suppressing ongoing viral activity [10]. Including this subgroup could have offered a more comprehensive view of antiviral therapy's role across different clinical scenarios and better mirrored real-world practice, where delays in initiating therapy are not uncommon. A sensitivity analysis including these patients could substantiate the study's main conclusions.

Despite these considerations, Heo et al. have made a meaningful contribution by highlighting the importance of baseline viral replication activity in HBV-related HCC prognosis. We anticipate that future prospective studies with longer follow-up, dynamic viral monitoring, and more detailed treatment data will build upon these findings and further optimise recurrence prevention strategies.