Editorial: How to Interpret Clinical Impact of Viral Replication Activity for Postoperative Recurrence of HBV-Related HCC

Hepatitis B virus (HBV) is a major driver of hepatocellular carcinoma (HCC) [1, 2]. Baseline viral load, as reflected in serum HBV-DNA levels, is a key risk factor for hepatocellular carcinoma (HCC) even in patients undergoing antiviral therapy (AVT) [3]. There is no doubt that entecavir or tenofovir can induce complete virological response by reducing serum HBV-DNA level rapidly. Nevertheless, somewhat paradoxical findings were observed; patients with ‘moderate’ baseline viral load, particularly around 6 log₁₀ IU/mL, demonstrated the highest on-treatment HCC risk, compared to those with ‘high’ baseline viral load (≥ 8.00 log₁₀ IU/mL) [3]. One of the plausible mechanisms is that ‘moderate’ baseline viral load, in reference to ‘high’ baseline viral load, might signify a condition of transition from immune-tolerant to immune-active phase, leading to more heightened necroinflammation and/or increased integration of HBV-DNA into human genomes. However, to date, whether this phenomenon extends to postoperative HCC recurrence remains unclear.

In this issue, Heo et al. [4] evaluated the relationship between baseline viral load and postoperative HCC recurrence. A key finding is the differential impact of baseline viral load on HCC recurrence based on cirrhosis status. Among cirrhotic patients, the ongoing-AVT group had a lower HCC recurrence risk than the initiation-AVT group, particularly within the first 2 years post-surgery. This suggests that prolonged pre-operative viral suppression by AVT may improve postoperative outcomes, emphasising the need for early and sustained AVT use, especially in cirrhotic patients. However, among non-cirrhotic patients, overall HCC recurrence rates were comparable between the two groups. Another noteworthy finding is the non-linear parabolic association between baseline viral load and HCC recurrence in non-cirrhotic patients. In other words, patients with moderate viral loads (5.00–5.99 log10 IU/mL HBV-DNA) exhibited the highest HCC recurrence risk, mirroring findings from prior studies by the same research group [3].

Despite these insights, several important questions remain. First, discrepancies exist between this study and previous research. A separate study performed in South Korea reproducibly reported comparable outcomes between ongoing-AVT and initiation-AVT groups. It is most likely owing to the retrospective natures of both studies, introducing several kinds of bias [3, 5]. So, further studies with well-controlled cohorts are required. Second, it remains unclear how the conclusion by Heo et al. [4] will modify the current practice guidelines. While the necessity of AVT for detectable HBV-DNA in cirrhotic patients is widely accepted, the implications for non-cirrhotic patients require further discussion [6, 7]. Third, tumour biology must be considered when discussing postoperative HCC recurrence. Unfortunately, many aspects of tumour biology in terms of viral, host, environmental factors and finally their interactions, remain poorly understood [8-10]. Last, the ultimate study goal should be to refine the optimal indication of AVT to prevent liver disease progression. While AVT is essential for controlling HBV replication, it is not a panacea, particularly in young patients with immune-tolerant phase [7].

In conclusion, integrating viral dynamics into clinical decision-making could lead to more effective, personalised treatment plans, ultimately reducing post-operative HCC recurrence risk. Future research should focus on the biological mechanisms explaining such an association.

Beom Kyung Kim: conceptualization, supervision, writing – original draft.

The author has nothing to report.

This article is linked to Heo et al papers. To view these articles, visit https://doi.org/10.1111/apt.70085 and https://doi.org/10.1111/apt.70143.