Letter: Association Between Viral Replication Activity and Post‐Transplant Recurrence of <scp>HBV</scp> ‐Related Hepatocellular Carcinoma

We read with great interest the study by Heo et al. which revealed that the tumour recurrence associated with the baseline viral replication activity in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients who underwent hepatectomy varied according to cirrhosis status [1]. Notably, patients who underwent liver transplantation were not included in this study; thus, the association between the HCC recurrence and the baseline viral replication activity for these individuals remains unclear. Liver transplantation stands as the optimal curative treatment for HCC patients [2]. However, tumour recurrence significantly compromises the efficacy of the operation [3, 4]. Our previous studies have identified HBV reactivation following liver transplantation as a critical risk factor for post-transplant tumour recurrence of HCC patients [5-7]. Here, we conducted a retrospective analysis of our cohort (NCT06114251), which included 462 patients with HBV-related HCC. Our aim was to explore the association between baseline viral replication activity and both HCC recurrence and HBV reactivation in these individuals with cirrhotic status. Among the 462 HBV-related HCC patients, 211 (45.7%) had detectable HBV-DNA prior to transplantation, while 431 (93.3%) had cirrhosis. The cumulative HCC recurrence rates at 1, 2, and 5 years were 23.6%, 32.3%, and 36.0%, respectively. The cumulative HBV reactivation rates at 1, 2, and 5 years were 12.3%, 15.5%, and 17.8%, respectively. Antiviral therapy with nucleotide analogues was routinely administered after the diagnosis of HBV infection prior to surgery. However, some patients were unaware of their HBV infection until HCC was diagnosed and thus may not have received adequate antiviral treatment before transplantation. Other baseline characteristics of these patients can be found in our previous research [5]. In cirrhotic patients, HCC recurrence risk showed a non-linear association with baseline HBV DNA, peaking at 2–4 log10 IU/mL. Compared to the non-detectable (ND) HBV DNA group, the adjusted HR was 1.72 (95% CI, 1.07–2.77; p = 0.025) for the 2–3 log10 IU/mL group and 1.73 (95% CI, 1.03–2.95; p = 0.038) for the 3–4 log10 IU/mL group. Risks at levels ≥ 4 log10 IU/mL were non-significant (Figure 1A). A similar pattern was observed for HBV reactivation risk, which was elevated at 2–3 log10 IU/mL (adjusted HR, 2.30; 95% CI, 1.23–4.31; p = 0.009) but lower at ≥ 4 log10 IU/mL (Figure 1B). Our analysis confirms a non-linear association between baseline HBV DNA levels and the risks of HCC recurrence or HBV reactivation after transplantation in cirrhotic patients. This result is inconsistent with that reported by Heo et al. The discrepancy may be attributed to some factors. First, the cohort in Heo et al. exclusively comprised BCLC 0-A patients, whereas such patients constituted only 9.3% of our cohort. Second, the distinct context of liver transplantation-involving complete native liver removal, graft-recipient interactions, long-term immunosuppression, and so on-fundamentally differs from that of hepatectomy. Unfortunately, the sample size of this study was not large enough. There were only 31 non-cirrhotic patients in our cohort, preventing a corresponding analysis. We look forward to future validation of our conclusions in larger, multicenter cohorts and to more comprehensive analyses. Huigang Li: writing and original draft, conceptualization, methodology, software, formal analysis, investigation, validation, data curation. Ruijie Zhao: conceptualization, methodology, software, formal analysis, investigation, validation, data curation. Jinyan Chen: conceptualization, methodology, software, formal analysis, investigation, validation, data curation. Shusen Zheng: conceptualization, writing and review editing, resources, project administration, supervision. Di Lu: writing and original draft, writing and review editing, conceptualization, methodology, software, data curation, supervision, visualization, validation. Xiao Xu: conceptualization, methodology, supervision, funding acquisition, resources, writing and review editing, writing and original draft, project administration. This work was supported by the Key Research & Development Plan of Zhejiang Province (2024C03051), the Major Research Plan of the National Natural Science Foundation of China (92159202), the Innovation Team, Hangzhou Medical College (CXLJ202401), and Ningbo Top Medical and Health Research Program (2024020818). Ethical approval for the HBV-related HCC cohort was obtained from the Ethics Committee of two centers (Shulan (Hangzhou) Hospital and the First Affiliated Hospital, Zhejiang University School of Medicine), consistent with prior research (approval IDs: No. 2020–510 and No. KY2021014). The authors declare no conflicts of interest. This article is linked to Heo et al. paper. To view this article, visit https://doi.org/10.1111/apt.70085. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.