Long-term hepatitis B surface antigen kinetics after nucleos(t)ide analog discontinuation in patients with noncirrhotic chronic hepatitis B

Abstract

Background and aim: Few studies have reported hepatitis B surface antigen (HBsAg) kinetics after nucleos(t)ide analog (NA) discontinuation in patients with noncirrhotic chronic hepatitis B (CHB). The study specifically investigated long-term HBsAg kinetics after NA discontinuation.

Methods: Between January 2014 to January 2024, this study prospectively enrolled 106 outpatients with noncirrhotic CHB who met the discontinuation criteria after NA consolidation treatment. Demographic, clinical, and laboratory data were collected and analyzed after NA discontinuation.

Results: Ninety-six patients who finished 5 years of follow-up were included. HBsAg remained undetectable in 29 patients with end of treatment (EOT) HBsAg negativity. Among 67 patients with EOT HBsAg positivity, HBsAg seroclearance occurred in 12 (17.9%) patients with an estimated annual incidence of HBsAg seroclearance of 3.6%. Patients with EOT HBsAg levels of < IU/mL had a higher HBsAg seroclearance rate than those with EOT HBsAg levels of >1000 IU/mL (33.3% vs. 5.4%). The proportion of patients with HBsAg < IU/mL increased during follow-up. Logistic regression analysis indicated that the EOT HBsAg level was an independent factor for HBsAg seroclearance and an HBsAg level decline exceeding 1 log10 IU/mL. The optimal EOT HBsAg cutoff for both HBsAg seroclearance and an HBsAg level decline exceeding 1 log10 IU/mL was 359 IU/mL.

Conclusions: Patients with EOT HBsAg negativity experienced no relapse and maintained HBsAg seroclearance during 5 years of follow-up after NA discontinuation. A higher HBsAg seroclearance rate can be obtained in patients with EOT HBsAg levels of < IU/mL during 5 years of follow-up after NA discontinuation. Close monitoring and proper NA retreatment are recommended to guarantee the safety of NA discontinuation.

Keywords

Hepatitis B virus (HBV) / Chronic hepatitis B (CHB) / Hepatitis B surface antigen (HBsAg) / Nucleos(t)ide analogs (NAs) / Quantitative HBsAg / Kinetics

Data availability statement

The data used to support the findings of this study are available from the corresponding authors ([e-mail] or [e-mail]) upon request. The study protocol, standard operating procedures, and patient information are also available upon request.

Authors’ contributions

Lina Wu, Jiadi Lai, and Qiumin Luo contributed equally to this work and shared first authorship. Lina Wu: Conceptualization, Data curation, Formal analysis, Writing e original draft. Jiadi Lai: Conceptualization, Data curation, Formal analysis, Writing e orig-inal draft. Qiumin Luo: Conceptualization, Data curation, Formal analysis, Writing e original draft. Yeqiong Zhang: Conceptualiza-tion, Data curation. Chaoshuang Lin: Conceptualization, Resources. Dongying Xie: Conceptualization, Resources. Youming Chen: Conceptualization, Resources. Hong Deng: Conceptualization, Re-sources. Zhiliang Gao: Conceptualization, Resources. Liang Peng: Conceptualization, Funding acquisition, Investigation, Methodol-ogy, Project administration, Resources, Supervision, Writing e re-view & editing. Wenxiong Xu: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Writing e review & editing.

Declaration of competing interest

Zhiliang Gao is an associate editor for Liver Research and was not involved in the editorial review or the decision to publish this article. The authors declare that they have no conflict of interest.

Acknowledgements

This study was supported by grants from the Natural Science Foundation of China (No. 82070611 to Liang Peng), Natural Science Foundation of Guangdong Province (No. 2020A1515010317 to Liang Peng), GuangDong Basic and Applied Basic Research Foundation (No. 21202104030000608 and 2021A1515220029 to Liang Peng), Guangzhou Science and Technology Plan Projects (No. 202102010204 and 2023B03J1287 to Liang Peng, No. 202102080064 to Wenxiong Xu), Sun Yat-Sen University Clinical Research 5010 Program (No. 2020007 and 2018009 to Liang Peng), Transformation of Scientific and Technological Achievements Project of Sun Yat-sen University (No. 82000-18843236 to Liang Peng), and the Five-Year Plan of Third Affiliated Hospital of Sun Yat-sen University (No. K00006 and P02421 to Liang Peng).

References

[1] Ott JJ, Stevens GA, Groeger J, Wiersma ST. Global epidemiology of hepatitis B virus infection: new estimates of age-specific HBsAg seroprevalence and endemicity. Vaccine. 2012;30:2212-2219. https://doi.org/10.1016/j.vaccine.2011.12.116.

[2] World Health Organization.Global Hepatitis Report, 2017. Geneva, Switzerland: World Health Organization; 2017. https://www.who.int/publications/i/item/global-hepatitis-report-2017.

[3] Liu J, Liang W, Jing W, Liu M. Countdown to 2030: eliminating hepatitis B disease, China. Bull World Health Organ. 2019;97:230-238. https://doi.org/10.2471/BLT.18.219469.

[4] Sarin SK, Kumar M, Lau GK, et al. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int. 2016; 10:1-98. https://doi.org/10.1007/s12072-015-9675-4.

[5] Huang H, Wang J, Li W, et al. Serum HBV DNA plus RNA shows superiority in reflecting the activity of intrahepatic cccDNA in treatment-naïve HBV-infected individuals. J Clin Virol. 2018;99e100:71-78. https://doi.org/10.1016/j.jcv.2017.12.016.

[6] Seeger C, Mason WS. HBV replication, pathobiology and therapy: unanswered questions. J Hepatol. 2016;64:S1eS3. https://doi.org/10.1016/j.jhep.2016.01.006.

[7] Jeng WJ, Sheen IS, Chen YC, et al. Off-therapy durability of response to entecavir therapy in hepatitis B e antigen-negative chronic hepatitis B patients. Hep-atology. 2013;58:1888-1896. https://doi.org/10.1002/hep.26549.

[8] Papatheodoridis GV, Manolakopoulos S, Su TH, et al. Significance of definitions of relapse after discontinuation of oral antivirals in HBeAg-negative chronic hepatitis B. Hepatology. 2018;68:415-424. https://doi.org/10.1002/hep.29497.

[9] Ma TL, Hu TH, Hung CH, Wang JH, Lu SN, Chen CH. Incidence and predictors of retreatment in chronic hepatitis B patients after discontinuation of entecavir or tenofovir treatment. PLoS One. 2019;14:e0222221. https://doi.org/10.1371/journal.pone.0222221.

[10] Chinese Society of Infectious Diseases, Chinese Medical Association; Chinese Society of Hepatology, Chinese Medical Association. The guidelines of pre-vention and treatment for chronic hepatitis B (2019 version) (in Chinese). Zhonghua Gan Zang Bing Za Zhi. 2019;27:938-961. https://doi.org/10.3760/cma.j.issn.1007-3418.2019.12.007.

[11] European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol. 2017; 67:370-398. https://doi.org/10.1016/j.jhep.2017.03.021.

[12] Terrault NA, Lok ASF, McMahon BJ, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018; 67:1560-1599. https://doi.org/10.1002/hep.29800.

[13] World Health Organization. Guidelines for the Prevention, Care and Treatment of Persons with Chronic Hepatitis B Infection. Geneva: World Health Organization; 2015 March. https://www.who.int/publications/i/item/9789241549059.

[14] Brunetto MR. A new role for an old marker, HBsAg. J Hepatol. 2010;52: 475-477. https://doi.org/10.1016/j.jhep.2009.12.020.

[15] Janssen HL, van Zonneveld M, Senturk H, et al. Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepati-tis B: a randomised trial. Lancet. 2005;365:123-129. https://doi.org/10.1016/S0140-6736(05)17701-0.

[16] Lau GK, Piratvisuth T, Luo KX, et al. Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med. 2005;352: 2682-2695. https://doi.org/10.1056/NEJMoa043470.

[17] Buster EH, Flink HJ, Cakaloglu Y, et al. Sustained HBeAg and HBsAg loss after long-term follow-up of HBeAg-positive patients treated with peginterferon alpha-2b. Gastroenterology. 2008;135:459-467. https://doi.org/10.1053/j.gastro.2008.05.031.

[18] Alawad AS, Auh S, Suarez D, Ghany MG. Durability of spontaneous and treatment-related loss of hepatitis B s antigen. Clin Gastroenterol Hepatol. 2020;18:700e 709 (e3). https://doi.org/10.1016/j.cgh.2019.07.018.

[19] Wu Y, Liu Y, Lu J, et al. Durability of interferon-induced hepatitis B surface antigen seroclearance. Clin Gastroenterol Hepatol. 2020;18:514e 516 (e2). https://doi.org/10.1016/j.cgh.2019.04.020.

[20] Chevaliez S, Hezode C, Bahrami S, Grare M, Pawlotsky JM. Long-term hepatitis B surface antigen (HBsAg) kinetics during nucleoside/nucleotide analogue therapy: finite treatment duration unlikely. J Hepatol. 2013;58:676-683. https://doi.org/10.1016/j.jhep.2012.11.039.

[21] Chen CH, Hung CH, Wang JH, Lu SN, Hu TH, Lee CM. Long-term incidence and predictors of hepatitis B surface antigen loss after discontinuing nucleoside analogues in noncirrhotic chronic hepatitis B patients. Clin Microbiol Infect. 2018;24:997-1003. https://doi.org/10.1016/j.cmi.2017.12.013.

[22] Liaw YF, Kao JH, Piratvisuth T, et al. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2012 update. Hepatol Int. 2012;6: 531-561. https://doi.org/10.1007/s12072-012-9365-4.

[23] Seto WK, Hui AJ, Wong VW, et al. Treatment cessation of entecavir in Asian patients with hepatitis B e antigen negative chronic hepatitis B: a multicentre prospective study. Gut. 2015;64:667-672. https://doi.org/10.1136/gutjnl-2014-307237.

[24] Papatheodoridis G, Vlachogiannakos I, Cholongitas E, et al. Discontinuation of oral antivirals in chronic hepatitis B: a systematic review. Hepatology. 2016;63: 1481-1492. https://doi.org/10.1002/hep.28438.

[25] Yao CC, Hung CH, Hu TH, et al. Incidence and predictors of HBV relapse after cessation of nucleoside analogues in HBeAg-negative patients with HBsAg ≤ 200 IU/mL. Sci Rep. 2017;7:1839. https://doi.org/10.1038/s41598-017-02010-w.

[26] Liu J, Li T, Zhang L, Xu A. The role of hepatitis B surface antigen in nucleos(t)ide analogues cessation among Asian patients with chronic hepatitis B: a sys-tematic review. Hepatology. 2019;70:1045-1055. https://doi.org/10.1002/hep.30474.

[27] Berg T, Simon KG, Mauss S, et al. Long-term response after stopping tenofovir disoproxil fumarate in non-cirrhotic HBeAg-negative patients - FINITE study. J Hepatol. 2017;67:918-924. https://doi.org/10.1016/j.jhep.2017.07.012.

[28] Jeng WJ, Chen YC, Chien RN, Sheen IS, Liaw YF. Incidence and predictors of hepatitis B surface antigen seroclearance after cessation of nucleos(t)ide analogue therapy in hepatitis B e antigen-negative chronic hepatitis B. Hep-atology. 2018;68:425-434. https://doi.org/10.1002/hep.29640.

[29] Nagaoka S, Abiru S, Komori A, et al. Hepatic flares promote rapid decline of serum hepatitis B surface antigen (HBsAg) in patients with HBsAg seroclearance: a long-term follow-up study. Hepatol Res. 2016;46:E89eE99. https://doi.org/10.1111/hepr.12533.

[30] Jung MC, Spengler U, Schraut W, et al. Hepatitis B virus antigen-specific T-cell activation in patients with acute and chronic hepatitis B. J Hepatol. 1991;13: 310-317. https://doi.org/10.1016/0168-8278(91)90074-l.

[31] Bertoletti A, Ferrari C. Innate and adaptive immune responses in chronic hepatitis B virus infections: towards restoration of immune control of viral infection. Gut. 2012;61:1754-1764. https://doi.org/10.1136/gutjnl-2011-301073.

[32] Ning Q, Han M, Sun Y, et al. Switching from entecavir to PegIFN alfa-2a in patients with HBeAg-positive chronic hepatitis B: a randomised open-label trial (OSST trial). J Hepatol. 2014;61:777-784. https://doi.org/10.1016/j.jhep.2014.05.044.

[33] Hu P, Shang J, Zhang W, et al. HBsAg loss with peg-interferon alfa-2a in hep-atitis B patients with partial response to nucleos(t)ide analog: new switch study. J Clin Transl Hepatol. 2018;6:25-34. https://doi.org/10.14218/JCTH.2017.00072.

[34] Chan HLY, Chan FWS, Hui AJ, et al. Switching to peginterferon for chronic hepatitis B patients with hepatitis B e antigen seroconversion on entecavir - A prospective study. J Viral Hepat. 2019;26:126-135. https://doi.org/10.1111/jvh.13000.

[35] Zhang E, Kosinska A, Lu M, Yan H, Roggendorf M. Current status of immuno-modulatory therapy in chronic hepatitis B, fifty years after discovery of the virus: search for the "magic bullet" to kill cccDNA. Antiviral Res. 2015;123: 193-203. https://doi.org/10.1016/j.antiviral.2015.10.009.

[36] Thimme R, Dandri M. Dissecting the divergent effects of interferon-alpha on immune cells: time to rethink combination therapy in chronic hepa-titis B? JHepat.ol 2013;58:205-209. https://doi.org/10.1016/j.jhep.2012.11.007.

[37] Hirode G, Choi HSJ, Chen CH, et al. Off-therapy response after nucleos(t) ide analogue withdrawal in patients with chronic hepatitis B: an inter-national, multicenter, multiethnic cohort (RETRACT-B study). Gastroen-terology. 2022;162:757e 771 (e4). https://doi.org/10.1053/j.gastro.2021.11.002.