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

We appreciate the interest of Qian et al. 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 address the issues raised.

First, the greater effect of preoperative antiviral therapy (AVT) in reducing recurrence among cirrhotic patients may be attributed to previous studies demonstrating a more substantial risk reduction for HCC in cirrhotic patients compared to non-cirrhotic patients [3, 4]. Regarding the impact of viral replication on early versus late recurrence, the timing of AVT had a more pronounced effect on early recurrence, likely due to its association with tumour aggressiveness, including microvascular invasion (MVI). In contrast, baseline HBV DNA levels had a lasting influence on both early and late recurrence, possibly reflecting the long-term effects of HBV-induced “field effect” and epigenetic modifications, as you noted.

Second, our findings do not contradict previous studies suggesting a dose-dependent relationship between HBV replication and HCC development [5]. Rather, by complementing previous studies with a greater number of patients with very high HBV DNA levels (above 5 log₁₀ IU/mL) and HBeAg positivity—who were difficult to analyse in earlier studies—we observed a non-linear, parabolic association between HBV DNA levels and HCC risk [6, 7], which may be attributed to hepatocyte clonal expansion, host genome integration and differences in background liver inflammation associated with HBV DNA levels, as outlined in the Discussion section of our study. In addition, we would like to highlight recent evidence suggesting that HBsAg⁺ hepatocytes, which produce surface antigen from integrated HBV DNA, may undergo clonal expansion more readily than HBV core⁺ hepatocytes with high cccDNA levels, possibly due to reduced CD8⁺ T cell infiltration that allows immune escape and confers a survival advantage [8].

Third, as you noted, the proportion of patients with MVI was higher in the initiation–AVT group compared with the ongoing–AVT group, which we adjusted for using propensity score matching and multivariable regression analyses. A mediation analysis to determine whether the effect of AVT timing on HCC recurrence is direct or mediated through MVI would be valuable.

Finally, although the impact of AVT and postoperative adjuvant therapies on HCC recurrence was beyond the scope of our study and therefore not specifically addressed, we agree that further research aimed at reducing recurrence is warranted, given the high rate of HCC recurrence even after curative treatment.