Letter: Association Between Viral Replication Activity and Postoperative Recurrence of HBV-Related Hepatocellular Carcinoma

We read with interest the article by Heo et al. [1] on the association between viral replication activity and postoperative recurrence of HBV-related HCC. While the study provides valuable insights, there are several areas for improvement to strengthen the conclusions.

First, relying solely on baseline HBV DNA levels to assess postoperative recurrence risk has a fundamental flaw. Baseline data are static, while viral activity is dynamic. The study did not account for the effects of postoperative antiviral therapy, viral suppression stability, or immune environment changes, leading to biased conclusions. For instance, the “highest risk with moderate baseline viral load” in non-cirrhotic patients might reflect a critical state of postoperative suppression, where moderate viral loads are caught between incomplete suppression and immune activation [2]. Surgical stress may also cause temporary viral rebound, which, if not monitored continuously, may be misinterpreted as baseline levels. Moreover, previous studies suggest that viral suppression at 6 months post-surgery is a more reliable predictor than baseline levels [3]. If sustained suppression eliminates baseline differences, static viral load risk stratification would lose clinical relevance, weakening the conclusions and potentially leading to clinical misjudgments.

Second, although the study conducted a competing risk analysis, it did not detail the specific causes of death or liver transplantation (e.g., liver failure vs. non-liver-related factors), which could significantly affect the interpretation of recurrence risk. If death or liver transplantation was related to liver disease, it could impact the accuracy of recurrence risk assessment because these factors may be linked to HBV replication activity and HCC recurrence. The lack of clarification could confuse the direct effect of death or transplantation on recurrence, leading to biased competing risk analysis results and affecting the study's conclusion.

Third, some recurrences were diagnosed using imaging (CT or MRI) instead of pathological confirmation, which could lead to missed micro-lesions or misdiagnosis of benign nodules. While imaging is effective in most cases, smaller lesions or atypical nodules may be missed, potentially overestimating or underestimating recurrence rates and affecting the study's reliability [4].

Finally, the median follow-up of 4.9 years may not be long enough to fully capture late recurrences (> 5 years), particularly in non-cirrhotic patients. HCC recurrence in non-cirrhotic patients may be related to the “field effect,” where chronic HBV infection induces persistent liver inflammation and microenvironmental changes. This process may take longer to manifest its carcinogenic effects [5]. A follow-up period that is too short may fail to capture late recurrences driven by chronic inflammation and viral activity, thus underestimating long-term recurrence risks.

Despite these limitations, the study provides valuable insights into the role of baseline viral replication in postoperative recurrence of HBV-related HCC. Future research should include dynamic viral load monitoring post-surgery, clarify causes of death or liver transplantation, and extend follow-up durations with pathological confirmation to improve accuracy and clinical relevance.