Milan J Sonneveld1, Shao-Ming Chiu2, Jun Yong Park3, Sylvia M Brakenhoff4, Apichat Kaewdech5, Wai-Kay Seto6, Yasuhito Tanaka7, Ivana Carey8, Margarita Papatheodoridi9, Florian van Bömmel10, Thomas Berg10, Fabien Zoulim11, Sang Hoon Ahn3, George N Dalekos12, Nicole S Erler13, Christoph Höner Zu Siederdissen14, Heiner Wedemeyer14, Markus Cornberg15, Man-Fung Yuen6, Kosh Agarwal8, Andre Boonstra4, Maria Buti16, Teerha Piratvisuth5, George Papatheodoridis9, Chien-Hung Chen2, Benjamin Maasoumy14. 1. Departments of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands. Electronic address: m.j.sonneveld@erasmusmc.nl. 2. Department of Internal Medicine, Koahsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. 3. Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea. 4. Departments of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands. 5. Faculty of Medicine, Prince of Songkla University, Hatyai, Thailand. 6. Department of Medicine, State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong. 7. Department of Gastroenterology & Hepatology, Kumamoto University, Kumamoto, Japan. 8. Institute of Liver Studies, King's College Hospital, London, United Kingdom. 9. Department of Gastroenterology, "Laiko" General Hospital of Athens, National and Kapodistrian University of Athens, Greece. 10. Division of Hepatology, Clinic for Oncology, Gastroenterology, Hepatology, Infectious Diseases and Pneumology, University Clinic Leipzig, Germany. 11. INSERM Unit 1052, Lyon, France. 12. Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Larissa, Greece. 13. Department of Biostatistics, Erasmus MC University Medical Center, Rotterdam, The Netherlands; Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands. 14. Department of Gastroenterology and Hepatology, Hannover Medical School, Hannover, Germany. 15. Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands. 16. Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron and Ciberehd del Intituto Carlos III de Barcelona, Spain.
Abstract
BACKGROUND & AIMS: Nucleo(s)tide analogue (NUC) withdrawal may result in HBsAg clearance in a subset of patients. However, predictors of HBsAg loss after NUC withdrawal remain ill-defined. METHODS: We studied predictors of HBsAg loss in a global cohort of HBeAg-negative patients with undetectable HBV DNA who discontinued long-term NUC therapy. Patients requiring retreatment after treatment cessation were considered non-responders. RESULTS: We enrolled 1,216 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 HBV core-related antigen (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 vs. 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 treatment withdrawal. LAY SUMMARY: A subset of patients may achieve clearance of hepatitis B surface antigen (HBsAg) - so-called functional cure - after withdrawal of nucleo(s)tide analogue therapy. In this multicentre study of 1,216 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.
BACKGROUND & AIMS: Nucleo(s)tide analogue (NUC) withdrawal may result in HBsAg clearance in a subset of patients. However, predictors of HBsAg loss after NUC withdrawal remain ill-defined. METHODS: We studied predictors of HBsAg loss in a global cohort of HBeAg-negative patients with undetectable HBV DNA who discontinued long-term NUC therapy. Patients requiring retreatment after treatment cessation were considered non-responders. RESULTS: We enrolled 1,216 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 HBV core-related antigen (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 vs. 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 treatment withdrawal. LAY SUMMARY: A subset of patients may achieve clearance of hepatitis B surface antigen (HBsAg) - so-called functional cure - after withdrawal of nucleo(s)tide analogue therapy. In this multicentre study of 1,216 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.
Authors: Yongzhen Liu; Debby Park; Thomas R Cafiero; Yaron Bram; Vasuretha Chandar; Anna Tseng; Hans P Gertje; Nicholas A Crossland; Lishan Su; Robert E Schwartz; Alexander Ploss Journal: JHEP Rep Date: 2022-07-09