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

doi:10.1016/j.jhep.2022.01.007

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

Authors: 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

Citation: JOURNAL OF HEPATOLOGY, Vol.76(5) : 1042-1050, 2022-05

Journal Title: JOURNAL OF HEPATOLOGY

ISSN: 0168-8278

Issue Date: 2022-05

MeSH: 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

Keywords: HBV genotype ; HBcrAg ; HBsAg ; HBsAg loss

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.