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Probability of HBsAg loss after nucleo(s)tide analogue withdrawal depends on HBV genotype and viral antigen levels

 Milan J Sonneveld  ;  Shao-Ming Chiu  ;  Jun Yong Park  ;  Sylvia M Brakenhoff  ;  Apichat Kaewdech  ;  Wai-Kay Seto  ;  Yasuhito Tanaka  ;  Ivana Carey  ;  Margarita Papatheodoridi  ;  Florian van Bömmel  ;  Thomas Berg  ;  Fabien Zoulim  ;  Sang Hoon Ahn  ;  George N Dalekos  ;  Nicole S Erler  ;  Christoph Höner Zu Siederdissen  ;  Heiner Wedemeyer  ;  Markus Cornberg  ;  Man-Fung Yuen  ;  Kosh Agarwal  ;  Andre Boonstra  ;  Maria Buti  ;  Teerha Piratvisuth  ;  George Papatheodoridis  ;  Chien-Hung Chen  ;  Benjamin Maasoumy  ;  CREATE study group 
 JOURNAL OF HEPATOLOGY, Vol.76(5) : 1042-1050, 2022-05 
Journal Title
Issue Date
Antiviral Agents / therapeutic use ; DNA, Viral ; Genotype ; Hepatitis B Core Antigens ; Hepatitis B Surface Antigens* ; Hepatitis B e Antigens ; Hepatitis B virus / genetics ; Hepatitis B, Chronic* / drug therapy ; Humans ; Probability
HBV genotype ; HBcrAg ; HBsAg ; 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.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Park, Jun Yong(박준용) ORCID logo https://orcid.org/0000-0001-6324-2224
Ahn, Sang Hoon(안상훈) ORCID logo https://orcid.org/0000-0002-3629-4624
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