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

We read the paper “Association Between Viral Replication Activity and Postoperative Recurrence of HBV-Related Hepatocellular Carcinoma”, published in Alimentary Pharmacology & Therapeutics, with great interest [1]. We appreciate Heo et al.'s efforts in investigating the impact of HBV replication on HCC recurrence, particularly the stratification based on antiviral therapy (AVT) initiation timing. This study provides valuable insights into postoperative recurrence patterns. However, after careful evaluation, we have concerns regarding the study's methodology and interpretation, which may affect the reliability of its conclusions and prompted this letter.

First, the study suggests that preoperative antiviral therapy (AVT) reduces recurrence risk in cirrhotic patients but not in non-cirrhotic patients. However, this conclusion may be influenced by differences in baseline liver disease severity rather than a direct effect of viral suppression. The study could benefit from a deeper stratification based on liver function metrics such as the ALBI score or fibrosis stage, beyond the simple cirrhosis vs. non-cirrhosis classification. Additionally, while the authors argue that late recurrence is less influenced by viral replication, this perspective may underestimate the role of long-term HBV-induced epigenetic modifications in tumour recurrence [2].

Second, the reported parabolic relationship between HBV DNA levels (5–7 log10 IU/mL) and recurrence risk in non-cirrhotic patients is an interesting finding, but its biological interpretation remains speculative. The proposed mechanism of clonal selection and immune escape lacks direct validation. Incorporating additional molecular markers, such as circulating tumour DNA, HBV integration sites, or inflammatory cytokine profiles, would strengthen this hypothesis. Furthermore, the observed peak recurrence risk at moderate viral loads contradicts prior studies that suggested a dose-dependent relationship between HBV replication and HCC progression [3]. Addressing this discrepancy with mechanistic insights is crucial.

Third, microvascular invasion (MVI), a well-established predictor of HCC recurrence, differs significantly between the ongoing-AVT and initiation-AVT groups (22.5% vs. 33.2%, p < 0.001). While the authors apply propensity-score matching, residual confounding cannot be ruled out. More rigorous approaches, such as inverse probability weighting or mediation analysis, could clarify whether viral replication independently influences recurrence or is merely a surrogate for more aggressive tumour biology.

Finally, while the study highlights the importance of early AVT initiation, it does not address whether intensifying post-resection antiviral regimens or combining AVT with adjunctive therapies (e.g., immune checkpoint inhibitors, targeted therapies) could offer superior benefits. Given the high recurrence rates despite AVT, a discussion on optimising treatment beyond viral suppression is warranted.

In summary, while Heo et al. provide a valuable epidemiological analysis, the study would benefit from a more nuanced interpretation of its findings, deeper mechanistic exploration, and refined statistical modelling. Future prospective trials incorporating molecular profiling will be essential to fully elucidate the interplay between HBV replication, tumour recurrence, and treatment strategies.