Editorial: HBV Integration: A Possible Key Driver in the Course of Patients With Chronic HBV Infection Under Viral Suppression

The development of hepatocellular carcinoma (HCC) and the disappearance of hepatitis B virus (HBV) surface antigen (HBsAg) are two main events that can occur in patients with chronic HBV infection that is successfully controlled by anti-HBV therapy. The integration of HBV may be a key driver of both of these events.

Gu et al. [1] investigated the association between the metrics of HBV integration and HBsAg loss by anti-HBV therapy with nucleoside analogue (NUC) and peginterferon (PEG-IFN) using high through-put sequencing for detecting HBV integration. They found that a lower number of breakpoint types at baseline was related to a higher rate of HBsAg loss. In contrast, no association was found between HBsAg loss and the frequency of breakpoints. These results are novel and may provide insight into the association between low HBsAg or HBsAg loss and a reduced risk of developing HCC in patients undergoing anti-HBV therapy.

HBV-related HCC has a distinct type of development that is specific to HBV infection, which involves the development of HCC without advanced liver fibrosis or even with no fibrosis. HCCs with other etiologies usually develop only in patients with cirrhosis or advanced liver fibrosis. Liver function is ameliorated and liver fibrosis, which is the most important risk factor for developing HCC, is regressed in HBV-infected patients under viral suppression by anti-HBV therapy, thus reducing the risk of developing HCC. However, the risk of HCC from this type of development is not reduced with continuous suppression of HBV by anti-HBV therapy.

The integration of HBV into the human host genome is considered the main cause for this phenomenon. A higher number of breakpoint types may increase the likelihood of HBV integration at the site flanking host genes associated with hepatocarcinogenesis. Therefore, a higher number of breakpoint types could play a role in a decreased likelihood of HBsAg loss and increased risk of developing HCC. This possibility may explain, at least in part, the known clinical association between a lower HBsAg titre or HBsAg loss and a reduced risk of HCC in patients with HBV under viral suppression.

Unfortunately, PEG-IFN is not routinely used as anti-HBV therapy in current clinical practice, and the prediction of HBsAg loss by PEG-IFN would have less clinical impact. Patients undergoing anti-HBV therapy with solely NUC could not achieve loss of HBsAg in this study. Whether viral suppression by NUC has a preventive effect on developing HCC without liver fibrosis is unknown. Additionally, whether PEG-IFN should be used for HBsAg loss and further reduction of the risk of HCC is unclear. It may be possible that the association between the HBsAg loss by PEG-IFN and a low risk of HCC was simply the two results from a lower number of breakpoint types of HBV integration. Further studies should investigate the associations between HBV integration metrics, HBsAg loss, and the risk of HCC, particularly in patients who undergo novel drugs targeting HBsAg loss in the near future.

Hidenori Toyoda: conceptualization, writing – original draft, writing – review and editing.

H.T. reports speaker honoraria from AbbVie, Gilead Sciences, AstraZeneca, Kowa, Fujifilm Wako, Terumo, and Bayer.

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.70321.