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  • 1. Aims and Scope

    Gut and Liver is an international journal of gastroenterology, focusing on the gastrointestinal tract, liver, biliary tree, pancreas, motility, and neurogastroenterology. Gut atnd Liver delivers up-to-date, authoritative papers on both clinical and research-based topics in gastroenterology. The Journal publishes original articles, case reports, brief communications, letters to the editor and invited review articles in the field of gastroenterology. The Journal is operated by internationally renowned editorial boards and designed to provide a global opportunity to promote academic developments in the field of gastroenterology and hepatology. +MORE

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    Yong Chan Lee Professor of Medicine
    Director, Gastrointestinal Research Laboratory
    Veterans Affairs Medical Center, Univ. California San Francisco
    San Francisco, USA

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    Deputy Editor
    Jong Pil Im Seoul National University College of Medicine, Seoul, Korea
    Robert S. Bresalier University of Texas M. D. Anderson Cancer Center, Houston, USA
    Steven H. Itzkowitz Mount Sinai Medical Center, NY, USA
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    All papers submitted to Gut and Liver are reviewed by the editorial team before being sent out for an external peer review to rule out papers that have low priority, insufficient originality, scientific flaws, or the absence of a message of importance to the readers of the Journal. A decision about these papers will usually be made within two or three weeks.
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Quantitative Hepatitis B Surface Antigen, the Trustworthy Biomarker for Functional Cure of Chronic Hepatitis B

Jonggi Choi

Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

Correspondence to: Jonggi Choi
ORCID https://orcid.org/0000-0002-7470-5850
E-mail j.choi@amc.seoul.kr

See “Long-term Hepatitis B Surface Antigen Profile and Seroclearance after Severe Acute Flares of Chronic Hepatitis B” by Ka-Yin Hui, et al. on page 280, Vol. 17, No. 2, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Gut Liver 2023;17(2):179-180. https://doi.org/10.5009/gnl230070

Published online March 15, 2023, Published date March 15, 2023

Copyright © Gut and Liver.

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.

  1. Kim GA, Lee HC, Kim MJ, et al. Incidence of hepatocellular carcinoma after HBsAg seroclearance in chronic hepatitis B patients: a need for surveillance. J Hepatol 2015;62:1092-1099.
    Pubmed CrossRef
  2. Kim GA, Lim YS, An J, et al. HBsAg seroclearance after nucleoside analogue therapy in patients with chronic hepatitis B: clinical outcomes and durability. Gut 2014;63:1325-1332.
    Pubmed CrossRef
  3. Yoo S, Kim JY, Lim YS, Han S, Choi J. Impact of HBsAg seroclearance on late recurrence of hepatitis B virus-related hepatocellular carcinoma after surgical resection. J Hepatol 2022;77:939-946.
    Pubmed CrossRef
  4. Hui KY, Fung J, Cheung KS, Mak LY, Seto WK, Yuen MF. Long-term hepatitis B surface antigen profile and seroclearance after severe acute flares of chronic hepatitis B. Gut Liver 2023;17:280-287.
    Pubmed CrossRef
  5. Hirode G, Choi HSJ, Chen CH, et al. Off-therapy response after nucleos(t)ide analogue withdrawal in patients with chronic hepatitis B: an international, multicenter, multiethnic cohort (RETRACT-B Study). Gastroenterology 2022;162:757-771.
    Pubmed CrossRef

Article

Editorial

Gut and Liver 2023; 17(2): 179-180

Published online March 15, 2023 https://doi.org/10.5009/gnl230070

Copyright © Gut and Liver.

Quantitative Hepatitis B Surface Antigen, the Trustworthy Biomarker for Functional Cure of Chronic Hepatitis B

Jonggi Choi

Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

Correspondence to:Jonggi Choi
ORCID https://orcid.org/0000-0002-7470-5850
E-mail j.choi@amc.seoul.kr

See “Long-term Hepatitis B Surface Antigen Profile and Seroclearance after Severe Acute Flares of Chronic Hepatitis B” by Ka-Yin Hui, et al. on page 280, Vol. 17, No. 2, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Body

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.

ACKNOWLEDGEMENTS

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

CONFLICTS OF INTEREST

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

References

  1. Kim GA, Lee HC, Kim MJ, et al. Incidence of hepatocellular carcinoma after HBsAg seroclearance in chronic hepatitis B patients: a need for surveillance. J Hepatol 2015;62:1092-1099.
    Pubmed CrossRef
  2. Kim GA, Lim YS, An J, et al. HBsAg seroclearance after nucleoside analogue therapy in patients with chronic hepatitis B: clinical outcomes and durability. Gut 2014;63:1325-1332.
    Pubmed CrossRef
  3. Yoo S, Kim JY, Lim YS, Han S, Choi J. Impact of HBsAg seroclearance on late recurrence of hepatitis B virus-related hepatocellular carcinoma after surgical resection. J Hepatol 2022;77:939-946.
    Pubmed CrossRef
  4. Hui KY, Fung J, Cheung KS, Mak LY, Seto WK, Yuen MF. Long-term hepatitis B surface antigen profile and seroclearance after severe acute flares of chronic hepatitis B. Gut Liver 2023;17:280-287.
    Pubmed CrossRef
  5. Hirode G, Choi HSJ, Chen CH, et al. Off-therapy response after nucleos(t)ide analogue withdrawal in patients with chronic hepatitis B: an international, multicenter, multiethnic cohort (RETRACT-B Study). Gastroenterology 2022;162:757-771.
    Pubmed CrossRef
Gut and Liver

Vol.18 No.3
May, 2024

pISSN 1976-2283
eISSN 2005-1212

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