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Abstract Details
Probability of HBsAg loss after nucleo(s)tide analogue withdrawal depends on HBV genotype and viral antigen levels
J Hepatol. 2022 Jan 26;S0168-8278(22)00020-4. doi: 10.1016/j.jhep.2022.01.007.Online ahead of print.
M J Sonneveld1, S-M Chiu2, J Y Park3, S M Brakenhoff4, A Kaewdech5, W K Seto6, Y Tanaka7, I Carey8, M Papatheodoridi9, F van Bömmel10, T Berg11, F Zoulim12, S H Ahn13, G N Dalekos14, N S Erler15, C Höner Zu Siederdissen16, H Wedemeyer17, M Cornberg18, M F Yuen19, K Agarwal20, A Boonstra21, M Buti22, T Piratvisuth23, G Papatheodoridis24, C-H Chen25, B Maasoumy26, CREATE study group
Author information
Departments of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands. Electronic address: m.j.sonneveld@erasmusmc.nl.
Internal Medicine, Yonsei University College of Medicine, Seoul, Korea. Electronic address: DRPJY@yuhs.ac.
Departments of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands. Electronic address: s.brakenhoff@erasmusmc.nl.
Faculty of Medicine, Prince of Songkla University, Hatyai, Thailand. Electronic address: apichatka@hotmail.com.
Department of Medicine, State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong. Electronic address: wkseto@hku.hk.
Department of Gastroenterology & Hepatology, Kumamoto University, Kumamoto, Japan. Electronic address: ytanaka@kumamoto-u.ac.jp.
Institute of Liver Studies, King's College Hospital, London, United Kingdom. Electronic address: ivana.carey@nhs.net.
Department of Gastroenterology, "Laiko" General Hospital of Athens, National and Kapodistrian University of Athens, Greece. Electronic address: margarita.gpap@gmail.com.
Division of Hepatology, Clinic for Oncology, Gastroenterology, Hepatology, Infectious Diseases and Pneumology, University Clinic Leipzig, Germany. Electronic address: Florian.vanBoemmel@medizin.uni-leipzig.de.
Division of Hepatology, Clinic for Oncology, Gastroenterology, Hepatology, Infectious Diseases and Pneumology, University Clinic Leipzig, Germany. Electronic address: Thomas.Berg@medizin.uni-leipzig.de.
INSERM Unit 1052, Lyon, France. Electronic address: fabien.zoulim@inserm.fr.
Internal Medicine, Yonsei University College of Medicine, Seoul, Korea. Electronic address: Ahnsh@yuhs.ac.
Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece. Electronic address: georgedalekos@gmail.com.
Department of Biostatistics, Erasmus MC University Medical Center, Rotterdam, The Netherlands; Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands. Electronic address: n.erler@erasmusmc.nl.
Department of Gastroenterology and Hepatology, Hannover Medical School, Hannover, Germany. Electronic address: hoenerzusiederdissen.christoph@mh-hannover.de.
Department of Gastroenterology and Hepatology, Hannover Medical School, Hannover, Germany. Electronic address: wedemeyer.heiner@mh-hannover.de.
Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands. Electronic address: cornberg.markus@mh-hannover.de.
Department of Medicine, State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong. Electronic address: mfyuen@hkucc.hku.hk.
Institute of Liver Studies, King's College Hospital, London, United Kingdom. Electronic address: kosh.agarwal@nhs.net.
Departments of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands. Electronic address: p.a.boonstra@erasmusmc.nl.
Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron and Ciberehd del Intituto Carlos III de Barcelona, Spain. Electronic address: mbuti@vhebron.net.
Faculty of Medicine, Prince of Songkla University, Hatyai, Thailand. Electronic address: teerhap@gmail.com.
Department of Gastroenterology, "Laiko" General Hospital of Athens, National and Kapodistrian University of Athens, Greece. Electronic address: gepapath@med.uoa.gr.
Department of Gastroenterology and Hepatology, Hannover Medical School, Hannover, Germany. Electronic address: maasoumy.benjamin@mh-hannover.de.
Abstract
Background & aims: Nucleo(s)tide analogue (NUC) withdrawal may result in HBsAg clearance in a subset of patients, but predictors remain ill-defined.
Methods: We studied predictors of HBsAg loss after NUC withdrawal in a global cohort of HBeAg negative patients with undetectable HBV DNA who discontinued long-term NUC therapy. Patients requiring retreatment after therapy cessation were considered non-responders.
Results: We enrolled 1216 patients (991 with genotype data); 98 (8.1%) achieved HBsAg loss. The probability of HBsAg loss was higher in non-Asian patients (adjusted hazard ratio (aHR) 8.26, p<0.001), and in patients with lower HBsAg (aHR 0.243, p<0.001) and HBcrAg (aHR 0.718, p=0.001) levels. Combining HBsAg (<10, 10-100 or >100 IU/mL) and HBcrAg (<2log vs ≥2 log) levels improved prediction of HBsAg loss, with extremely low rates observed in patients with HBsAg >100 IU/mL with detectable HBcrAg. HBsAg loss rates also varied with HBV genotype; the highest rates were observed for genotypes A and D, and none of the patients with HBV genotype E experienced HBsAg loss (p<0.001 for the overall comparison across genotypes; p<0.001 for genotypes A/D versus genotypes B/C). HBV genotype C was independently associated with a higher probability of HBsAg loss when compared to genotype B among Asian patients (aHR 2.494, 95% CI: 1.490 - 4.174, p=0.001).
Conclusions: The probability of HBsAg loss after NUC cessation varies according to patient ethnicity, HBV genotype and end-of-treatment viral antigen levels. Patients with low HBsAg (<100 IU/ml) and/or undetectable HBcrAg levels, particularly if non-Asian or infected with HBV genotype C, appear to be the best candidates for therapy withdrawal.
Lay summary: A subset of patients may achieve clearance of HBsAg (so-called functional cure) after withdrawal of nucleo(s)tide analogue therapy. In this multicenter study of 1216 patients who discontinued antiviral therapy, we identified non-Asian ethnicity, HBV genotype C, and low hepatitis B surface antigen and hepatitis B core related antigen levels as factors associated with an increased chance of HBsAg loss.