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

Abstract

We appreciate the interest of Yang in our study [1, 2] on the association between viral replication activity and postoperative recurrence of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), and we welcome the opportunity to clarify certain aspects of our study and address the points raised.

First and foremost, we would like to clarify that patients who initiated antiviral therapy (AVT) more than 3 months after surgery were excluded in order to avoid immortal time bias. We agree that HBV viral activity is dynamic and that postoperative monitoring may provide additional prognostic information. However, our study specifically focused on the prognostic significance of preoperative baseline viral replication activity, which remains clinically relevant in many real-world settings where preoperative decisions must be made based on limited dynamic data. Furthermore, we consider that the ‘field effect’—potentially partially reflected by HBV DNA levels—may persist for a prolonged period even under AVT, thereby influencing hepatocarcinogenesis or recurrence [3, 4].

Second, the primary purpose of our competing risk analysis was to account for death or liver transplantation as events that may preclude HCC recurrence and thereby influence outcomes. In this context, the occurrence of such competing events is what matters, rather than the evaluation of their specific causes [5].

Third, we used imaging criteria in accordance with internationally accepted guidelines [6, 7], which have demonstrated high diagnostic accuracy, particularly in experienced centres. Given that the diagnosis of HCC is predominantly based on imaging rather than pathological confirmation, we find it difficult to agree that the absence of pathological confirmation for recurrence significantly compromises the reliability of our study results.

Finally, to our knowledge, few studies have followed a large cohort of 2384 patients with very early- or early-stage HBV-related HCC for a median of 4.9 years. Considering the decreased risk of recurrence beyond 5 years post-surgery [8] and the gradual attenuation of the ‘field effect’ over time, we believe that both the sample size and follow-up duration are sufficient to support the validity of our study outcomes.

We acknowledge the limitations inherent in a retrospective, non-confirmatory study, including the possibility of unmeasured confounding and residual bias, and agree that further research is warranted.