Editorial: HBV Integration—A Possible Key Driver on the Course of Patients With Chronic HBV Infection Under Viral Suppression. Authors' Reply

We thank Dr. Toyoda for his insightful comments on our study [1]. We agree that a higher number of hepatitis B virus (HBV) integration breakpoint types is associated with a reduced likelihood of hepatitis B surface antigen (HBsAg) loss after pegylated interferon (Peg-IFN) therapy, potentially explaining why some patients do not achieve HBsAg clearance [2]. We also concur that HBV integration is a key driver of hepatocellular carcinoma (HCC) development [3].

Our study further found that the duration of prior nucleos(t)ide analogue (NUC) therapy (initiated upon hepatitis flares), along with alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, positively correlated with hepatocyte clonal expansion levels. This suggests that recurrent flares and prolonged inflammation promote clonal expansion, thereby increasing future HCC risk [4]. Crucially, NUC therapy does not fully eliminate HCC risk, especially in non-cirrhotic patients [5]. Therefore, patients with high breakpoint types or elevated clonal expansion warrant long-term HCC surveillance.

Even though the frequently integrated genes and associated signalling pathways observed in our NUC-experienced and virally suppressed chronic hepatitis B (CHB) patients differ from those previously reported in advanced HCC patients [2, 3, 6], the increased number of breakpoint types elevates the likelihood of HBV integration near oncogenes or tumour-related genes. This creates favourable conditions for widespread hepatocyte clonal expansion and consequently increases HCC risk [3, 4].

In fact, none of the patients in this study developed cirrhosis or HCC during treatment and follow-up. Future studies should extend the follow-up period to further investigate the relationship between HBV integration, HBsAg seroclearance and HCC development, as the precise molecular mechanisms remain complex.

We propose that Peg-IFN therapy suppresses viral replication and modulates immune responses (e.g., cytotoxic T lymphocytes activity) [7]. For NUC-experienced patients with low levels of HBsAg (< 3000 IU/mL), sequential or combined Peg-IFN may improve functional cure rates [7]. Future research should prioritise investigating the relationship between HBV integration metrics, HBsAg loss and HCC risk in CHB patients, as seen in our ongoing OCEAN study. Given the challenges of obtaining liver tissue, developing non-invasive circulating biomarkers as surrogates for HBV integration also warrants exploration.

Qin Ning: writing – original draft, writing – review and editing. Meifang Han: writing – original draft, writing – review and editing.

The authors declare no conflicts of interest.

This article is linked to Gu et al. papers. To view these articles, visit https://doi.org/10.1111/apt.70270 and https://doi.org/10.1111/apt.70285.