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

Milan J. Sonneveld; Shao Ming Chiu; the CREATE study group; 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

doi:10.1016/j.jhep.2022.01.007

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

Milan J. Sonneveld^*
, Shao Ming Chiu
, the CREATE study group
, 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

^*Corresponding author for this work

Chang Gung Memorial Hospital
Yonsei University
Prince of Songkla University
The University of Hong Kong
Kumamoto University
King’s College Hospital
University of Athens
University Hospital Leipzig
University Lyon 1
University Hospital of Larissa
Hannover Medical School
Erasmus University Rotterdam
Hospital Vall d'Hebron & ARADyAL research network

Research output: Contribution to journal › Article › Academic › peer-review

121 Citations (Scopus)

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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.

Original language	English
Pages (from-to)	1042-1050
Number of pages	9
Journal	Journal of Hepatology
Volume	76
Issue number	5
DOIs	https://doi.org/10.1016/j.jhep.2022.01.007
Publication status	Published - May 2022

Bibliographical note

Funding Information:
The CREATE study was supported by Fujirebio . No additional funding was obtained for this follow-up analysis.

Publisher Copyright: © 2022 The Author(s)

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SDG 3 Good Health and Well-being

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Sonneveld, M. J., Chiu, S. M., the CREATE study group, Park, J. Y., Brakenhoff, S. M., Kaewdech, A., Seto, W. K., Tanaka, Y., Carey, I., Papatheodoridi, M., van Bömmel, F., Berg, T., Zoulim, F., Ahn, S. H., Dalekos, G. N., Erler, N. S., Höner zu Siederdissen, C., Wedemeyer, H., Cornberg, M., ... Maasoumy, B. (2022). Probability of HBsAg loss after nucleo(s)tide analogue withdrawal depends on HBV genotype and viral antigen levels. Journal of Hepatology, 76(5), 1042-1050. https://doi.org/10.1016/j.jhep.2022.01.007

@article{eebbff8c6a0f448f83864b40ac00d785,

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

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.",

author = "Sonneveld, \{Milan J.\} and Chiu, \{Shao Ming\} and \{the CREATE study group\} and Park, \{Jun Yong\} and Brakenhoff, \{Sylvia M.\} and Apichat Kaewdech and Seto, \{Wai Kay\} and Yasuhito Tanaka and Ivana Carey and Margarita Papatheodoridi and \{van B{\"o}mmel\}, Florian and Thomas Berg and Fabien Zoulim and Ahn, \{Sang Hoon\} and Dalekos, \{George N.\} and Erler, \{Nicole S.\} and \{H{\"o}ner zu Siederdissen\}, Christoph and Heiner Wedemeyer and Markus Cornberg and Yuen, \{Man Fung\} and Kosh Agarwal and Andre Boonstra and Maria Buti and Teerha Piratvisuth and George Papatheodoridis and Chen, \{Chien Hung\} and Benjamin Maasoumy",

note = "Funding Information: The CREATE study was supported by Fujirebio . No additional funding was obtained for this follow-up analysis. Publisher Copyright: {\textcopyright} 2022 The Author(s)",

year = "2022",

month = may,

doi = "10.1016/j.jhep.2022.01.007",

language = "English",

volume = "76",

pages = "1042--1050",

journal = "Journal of Hepatology",

issn = "0168-8278",

publisher = "Elsevier",

number = "5",

}

Sonneveld, MJ, Chiu, SM, the CREATE study group, Park, JY, Brakenhoff, SM, Kaewdech, A, Seto, WK, Tanaka, Y, Carey, I, Papatheodoridi, M, van Bömmel, F, Berg, T, Zoulim, F, Ahn, SH, Dalekos, GN, Erler, NS, Höner zu Siederdissen, C, Wedemeyer, H, Cornberg, M, Yuen, MF, Agarwal, K, Boonstra, A, Buti, M, Piratvisuth, T, Papatheodoridis, G, Chen, CH & Maasoumy, B 2022, 'Probability of HBsAg loss after nucleo(s)tide analogue withdrawal depends on HBV genotype and viral antigen levels', Journal of Hepatology, vol. 76, no. 5, pp. 1042-1050. https://doi.org/10.1016/j.jhep.2022.01.007

TY - JOUR

T1 - Probability of HBsAg loss after nucleo(s)tide analogue withdrawal depends on HBV genotype and viral antigen levels

AU - Sonneveld, Milan J.

AU - Chiu, Shao Ming

AU - the CREATE study group

AU - Park, Jun Yong

AU - Brakenhoff, Sylvia M.

AU - Kaewdech, Apichat

AU - Seto, Wai Kay

AU - Tanaka, Yasuhito

AU - Carey, Ivana

AU - Papatheodoridi, Margarita

AU - van Bömmel, Florian

AU - Berg, Thomas

AU - Zoulim, Fabien

AU - Ahn, Sang Hoon

AU - Dalekos, George N.

AU - Erler, Nicole S.

AU - Höner zu Siederdissen, Christoph

AU - Wedemeyer, Heiner

AU - Cornberg, Markus

AU - Yuen, Man Fung

AU - Agarwal, Kosh

AU - Boonstra, Andre

AU - Buti, Maria

AU - Piratvisuth, Teerha

AU - Papatheodoridis, George

AU - Chen, Chien Hung

AU - Maasoumy, Benjamin

PY - 2022/5

Y1 - 2022/5

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85125447702

U2 - 10.1016/j.jhep.2022.01.007

DO - 10.1016/j.jhep.2022.01.007

M3 - Article

C2 - 35092743

AN - SCOPUS:85125447702

SN - 0168-8278

VL - 76

SP - 1042

EP - 1050

JO - Journal of Hepatology

JF - Journal of Hepatology

IS - 5

ER -

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

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