Although not ideal, effective antiviral treatment for hepatitis B virus (HBV) has over the past several decades, helped to prevent liver disease progression and reduce development of hepatocellular carcinoma (HCC). Currently, more attention is being given to achieving a functional cure, as defined as hepatitis B surface antigen (HBsAg) seroclearance. Given the biology of HBV, functional cure is considered a realistic and feasible therapeutic goal in the management of chronic hepatitis B (CHB). In fact, HBsAg seroclearance has been proven to further reduce HCC development and even to decrease the rate of HCC recurrence following curative HCC treatment.^1-3 Nevertheless, the annual rate of HBsAg seroclearance is very low, ranging from 0.2% to 2%, regardless of the way it occurs (spontaneous or therapy induced). Thus, the focus is shifting to enhancing HBsAg seroclearance and early prediction before HBsAg seroclearance through use of biomarkers such as quantitative HBsAg (qHBsAg) and hepatitis B core-related antigen.

In the study by Hui et al.,⁴ a severe acute flare of CHB (AFOCHB), which was defined as alanine aminotransferase ≥10× upper limit of normal and HBV DNA ≥4 log IU/mL on presentation, was associated with a higher rate of HBsAg seroclearance compared to controls with alanine aminotransferase <10× upper limit of normal. Although the baseline median qHBsAg level appeared to be higher in the AFOCHB group than in the control group, the AFOCHB group showed a significantly greater annual decline in qHBsAg over time. Moreover, lower baseline qHBsAg levels were associated with HBsAg seroclearance, particularly if the qHBsAg level was lower than 200 IU/mL. These findings suggest two important aspects.

First, HBV-infected hepatocytes may be vigorously attacked by robust activation of the host immune system, which is likely indicated by severe AFOCHB. These immune reaction may eliminate and replace HBV-infected hepatocytes carrying covalently closed circular DNA, which may result in a progressive decline in qHBsAg levels and demonstrates that the immune system still plays a crucial role in the HBsAg seroclearance process. Indeed, some newly developed drugs for HBV cure programs aim to reinstate the host’s exhausted immune system caused by chronic exposure to HBV. Notably, attempts to increase the rate of HBsAg seroclearance with finite antiviral treatment have been studied recently, though the results remain controversial. The rationale for this finite strategy is to reinvigorate the host’s immune system by ceasing antiviral treatment and re-exposing the host to HBV; the immune system may then function to eliminate HBV, probably in a manner more effective than before, manifesting as an acute hepatitis flare. The biologic basis of this acute flare may be similar, at least partly, to that occurring in patients in this study who presented with AFOCHB.

Second, as previously shown, qHBsAg is a reliable marker for predicting the likelihood of HBsAg seroclearance. Although cutoff levels may vary based on ethnicity, HBV genotypes, sex, or type of antiviral treatment, the basic notion is the same: the lower the qHBsAg level, the higher the likelihood of HBsAg seroclearnce.⁵

However, there is concern, regarding the increased incidence of HCC in the severe AFOCHB group compared to the control group, even after excluding those with cirrhosis or advanced fibrosis, as defined as FIB-4 ≥3.25. The goal for patients presenting with severe AFOCHB is HBsAg seroclearance without damage caused by interaction between the virus and immune system, namely, reducing the development of HCC. Unfortunately, in the study, the AFOCHB patients actually showed a higher fibrosis index after 6 months of severe AFOCHB compared to controls without AFOCHB. The underlying mechanism of why these patients in the severe AFOCHB group had a higher incidence of HCC than controls and whether this higher fibrotic burden due to AFOCHB leads to increased risk of HCC should be further investigated.

Taken together, to achieve functional cure (i.e., HBsAg seroclearance), more efforts and evidence should be accumulated until the introduction of highly effective, curative drugs for CHB, similar to treatment of hepatitis C. Furthermore, the reliable biomarkers such as qHBsAg reported in this study may aid in paving the way toward a functional cure for CHB.

This study was supported by grants from the National Research Foundation of Korea by the Korean government (Ministry of Science and ICT) (No.2021R1G1A1009506).

No potential conflict of interest relevant to this article was reported.