Prediction of Sustained Response After Nucleo(s)tide Analogue Cessation Using HBsAg and HBcrAg Levels: A Multicenter Study (CREATE)

CREATE Study Group

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

Background & Aims: Predictors of successful nucleo(s)tide analogue (NA) therapy withdrawal remain elusive. We studied the relationship between end-of-treatment levels of hepatitis B core-related antigen (HBcrAg) and hepatitis B surface antigen (HBsAg) and outcome after therapy cessation. Methods: Patients who discontinued NA therapy in centers in Asia and Europe were enrolled. HBcrAg and HBsAg were measured at treatment cessation, and associations with off-treatment outcomes were explored. The SCALE-B (Surface antigen, Core-related antigen, Age, ALT, and tenofovir for HBV) score was calculated as previously reported. End points included sustained virologic response (VR; hepatitis B virus DNA level <2000 IU/mL), HBsAg loss, and alanine aminotransferase (ALT) flares (>3× upper limit of normal). Re-treated patients were considered nonresponders. Results: We analyzed 572 patients, 457 (80%) were Asian and 95 (17%) were hepatitis B e antigen positive at the start of NA therapy. The median treatment duration was 295 weeks. VR was observed in 267 (47%), HBsAg loss was observed in 24 (4.2%), and ALT flare was observed in 92 (16%). VR (67% vs 42%) and HBsAg loss (15% vs 1.5%) was observed more frequently in non-Asian patients when compared to Asian patients (P < .001). Lower HBcrAg levels were associated with higher rates of VR (odds ratio [OR], 0.701; P < .001) and HBsAg loss (OR, 0.476; P < .001), and lower rates of ALT flares (OR, 1.288; P = .005). Similar results were observed with HBsAg (VR: OR, 0.812; P = .011; HBsAg loss: OR, 0.380; P < .001; and ALT flare: OR, 1.833; P < .001). Lower SCALE-B scores were associated with higher rates of VR, HBsAg loss, and lower rates of ALT flares in both Asian and non-Asian patients (P < .001). Conclusions: In this multicenter study, off-treatment outcomes after NA cessation varied with ethnicity. Lower levels of HBcrAg and HBsAg were associated with favorable outcomes. A risk score comprising both factors can be used for risk stratification.

Original languageEnglish
JournalClinical Gastroenterology and Hepatology
DOIs
Publication statusAccepted/In press - 2021

Bibliographical note

Funding Information:
Conflicts of interest These authors disclose the following: Milan J. Sonneveld has received speaker’s fees and research support from Roche, Gilead, BMS, and Fujirebio; J. Y. Park is an investigator in clinical trials sponsored by AbbVie, Gilead Sciences, Hanmi, and Norvatis; W. K. Seto has received speaker’s fees from Mylan, AbbVie, and Gilead Sciences, has consulted for AbbVie and Gilead Sciences, and has received research funding from Gilead Sciences; Y. Tanaka has received lecture fees from Bristol-Myers Squibb, Fujirebio, Sysymex, and Gilead Sciences, has received research fees from Fujifilm Corp, Janssen Pharmaceutical K.K, Gilead Sciences, Glaxosmithkline Pharmaceuticals, Ltd, and Stanford Junior University, and scholarship donations from Chugai Pharmaceutical Co, Ltd, and Bristol-Myers Squibb; F. van Bömmel has received research support and consulted for Roche; T. Berg currently acts as an advisor to AbbVie, Alexion, Bayer, BMS, Gilead, Intercept, Janssen, MSD/Merck, Merz, Novartis, and Sequana Medical, has received speaking honoraria from AbbVie, Alexion, Bayer, BMS, Eisai, Gilead, Intercept, Ipsen, Janssen, MSD/Merck, Merz, Novartis, Sirtex, and Sequana Medical in the past 2 years, and has received grant support from AbbVie, BMS, Gilead, Humedics, Intercept, Janssen, MSD/Merck, Merz, Novartis, and Sequana Medical; F. Zoulim is an advisor for Aligos, Assembly, Gilead, GSK, Myr Pharma, Roche MD, Spring-Bank, and Transgene, and has received research grants from Evotec and Roche; S. H. Ahn has acted as an advisor and lecturer for BMS, Gilead Sciences, MSD, AbbVie, Janssen, Assembly Biosciences, Arbutus Biopharma, GreenCross, and Ildong, and has received an unrestricted grant from Gilead Sciences for investigator-initiated trials; G. N. Dalekos is an advisor or lecturer for Ipsen, Pfizer, Genkyotex, and Novartis, has received research grants from AbbVie and Gilead, and has served as principal investigator in studies for AbbVie, Novartis, Gilead, Novo Nordisk, Genkyotex, Regulus Therapeutics, Inc, Tiziana Life Sciences, Bayer, and Astellas; C. Höner zu Siederdissen has received travel grants from Novartis and Gilead; H. Wedemeyer has received research grants from Abbott, AbbVie, BMS, Gilead, Merck, Novartis, Roche, Roche Diagnostics, and Siemens, has received consulting fees from Abbott, AbbVie, BMS, Boehringer Ingelheim, Gilead, JJ/Janssen-Cilag, Merck/Schering-Plough, Novartis, Roche, Roche Diagnostics, Siemens, Transgene, and ViiV, and has received speaker fees from Abbott, AbbVie, BMS, Boehringer Ingelheim, Gilead, JJ/Janssen-Cilag, Merck/Schering-Plough, Novartis, Roche, Roche Diagnostics, Siemens, Transgene, and ViiV; M. Cornberg has received personal fees from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen-Cilag, Merck (MSD), Biogen, Falk Foundation, Boehringer Ingelheim, Siemens, and Spring Bank, and grants and personal fees from Roche; M. F. Yuen consulted and/or received research funding from AbbVie, Arbutus Biopharma, Assembly Biosciences, Bristol-Myers Squibb, Dicerna Pharmaceuticals, GlaxoSmithKline, Gilead Sciences, Janssen, Merck Sharp and Dohme, Clear B Therapeutics, and Springbank Pharmaceuticals, and received research funding from Arrowhead Pharmaceuticals, Fujirebio Incorporation, and Sysmex Corporation; K. Agarwal has consulted and/or served on the speaker’s bureau for Assembly, Aligos, Arbutus, Gilead, Immunocore, Janssen, Roche, Sobi, Springbank, and Vir, and has received research support from Abbott, Gilead, and MSD; A. Boonstra has received research fees from Fujirebio, Gilead Sciences, and Janssen Pharma; M. Buti has received consultancy and lecture honoraria from AbbVie, Arbutus, Gilead, Janssen, Merck/MSD, and Spring-Bank; G. Papatheodoridis has served as an advisor/lecturer for AbbVie, BMS, Dicerna, Gilead, GSK, Janssen, Ipsen, MSD, Roche, and Spring-Bank, and has received research grants from AbbVie, BMS, and Gilead; and B. Maasoumy has received speaker and/or consulting fees from Abbott Molecular, Astellas, Intercept, Falk, AbbVie, Norgine, Bristol Myers Squibb, Fujirebio, Janssen-Cilag, Merck (MSD), and Roche, and has received research support from Abbott Molecular, Altona Diagnostics, Fujirebio, and Roche. The remaining authors disclose no conflicts.

Funding Information:
The authors would like to thank Laura Vernoux (Fujirebio) for supporting this project. Milan Sonneveld, MD PhD (Conceptualization: Lead; Data curation: Lead; Formal analysis: Lead; Writing (Conceptualization: Lead, J.Y. Park (Conceptualization: Supporting; Data curation: Supporting; Writing he receive editing: Equal), A. Kaewdech (Data curation: Supporting; Investigation: Supporting; Writing g he recei editing: Supporting), W.K. Seto (Data curation: Supporting; Investigation: Supporting; Writing g g he rec editing: Supporting), Y. Tanaka (Data curation: Supporting; Investigation: Supporting; Writing ? review & editing: Supporting), I. Carey (Data curation: Supporting; Investigation: Supporting; Writing ? review editing: Supporting), M. Papatheodoridi (Data curation: Supporting; Methodology: Supporting; Writing e review & editing: Supporting), F. van B editing: Supporting)ion: Supporting; Methodology: Supporting; Writing ew &ei & editing: Supporting), T. Berg (Data curation: Supporting; Investigation: Supporting; Writing Writing ew editing: Supporting), F. Zoulim (Data curation: Supporting; Investigation: Supporting; Writing ? review & editing: Supporting), S.H. Ahn (Data curation: Supporting; Investigation: Supporting; Writing ? review editing: Supporting), G.N. Dalekos (Data curation: Supporting; Investigation: Supporting; Writing ? review & editing: Supporting), N.S. Erler (Data curation: Supporting; Formal analysis: Equal; Investigation: Supporting; Writing ng;(Data curation: Supporting;, C. Hing ng;(Data curation: Supporting; Formal analysis: Equal; Investigation: review &e ?. Hing ng;(Data curation: Supp, H. Wedemeyer (Data curation: Supporting; Investigation: Supporting; Writing: review & editing: Supporting), M. Cornberg (Data curation: Supporting; Investigation: Supporting; Writing: review editing: Supporting), M.F. Yuen (Data curation: Supporting; Investigation: Supporting; Writing ? review & editing: Supporting), K. Agarwal (Data curation: Supporting; Investigation: Supporting; Writing review &w editing: Supporting), A. Boonstra (Conceptualization: Supporting; Data curation: Supporting; Investigation: Supporting; Writing ualization: Supporting; Data cu, M. Buti (Data curation: Supporting; Investigation: Supporting; Writing Investigat editing: Supporting), T. Piratvisuth (Data curation: Supporting; Investigation: Supporting; Writing ? review & editing: Supporting), G. Papatheodoridis (Data curation: Supporting; Investigation: Supporting; Writing v review & editing: Supporting), B. Maasoumy (Conceptualization: Equal; Data curation: Equal; Formal analysis: Equal; Investigation: Equal; Methodology: Equal; Supervision: Lead; Writing ? original draft: Equal) Conflicts of interest These authors disclose the following: Milan J. Sonneveld has received speaker's fees and research support from Roche, Gilead, BMS, and Fujirebio; J. Y. Park is an investigator in clinical trials sponsored by AbbVie, Gilead Sciences, Hanmi, and Norvatis; W. K. Seto has received speaker's fees from Mylan, AbbVie, and Gilead Sciences, has consulted for AbbVie and Gilead Sciences, and has received research funding from Gilead Sciences; Y. Tanaka has received lecture fees from Bristol-Myers Squibb, Fujirebio, Sysymex, and Gilead Sciences, has received research fees from Fujifilm Corp, Janssen Pharmaceutical K.K, Gilead Sciences, Glaxosmithkline Pharmaceuticals, Ltd, and Stanford Junior University, and scholarship donations from Chugai Pharmaceutical Co, Ltd, and Bristol-Myers Squibb; F. van B?mmel has received research support and consulted for Roche; T. Berg currently acts as an advisor to AbbVie, Alexion, Bayer, BMS, Gilead, Intercept, Janssen, MSD/Merck, Merz, Novartis, and Sequana Medical, has received speaking honoraria from AbbVie, Alexion, Bayer, BMS, Eisai, Gilead, Intercept, Ipsen, Janssen, MSD/Merck, Merz, Novartis, Sirtex, and Sequana Medical in the past 2 years, and has received grant support from AbbVie, BMS, Gilead, Humedics, Intercept, Janssen, MSD/Merck, Merz, Novartis, and Sequana Medical; F. Zoulim is an advisor for Aligos, Assembly, Gilead, GSK, Myr Pharma, Roche MD, Spring-Bank, and Transgene, and has received research grants from Evotec and Roche; S. H. Ahn has acted as an advisor and lecturer for BMS, Gilead Sciences, MSD, AbbVie, Janssen, Assembly Biosciences, Arbutus Biopharma, GreenCross, and Ildong, and has received an unrestricted grant from Gilead Sciences for investigator-initiated trials; G. N. Dalekos is an advisor or lecturer for Ipsen, Pfizer, Genkyotex, and Novartis, has received research grants from AbbVie and Gilead, and has served as principal investigator in studies for AbbVie, Novartis, Gilead, Novo Nordisk, Genkyotex, Regulus Therapeutics, Inc, Tiziana Life Sciences, Bayer, and Astellas; C. H?ner zu Siederdissen has received travel grants from Novartis and Gilead; H. Wedemeyer has received research grants from Abbott, AbbVie, BMS, Gilead, Merck, Novartis, Roche, Roche Diagnostics, and Siemens, has received consulting fees from Abbott, AbbVie, BMS, Boehringer Ingelheim, Gilead, JJ/Janssen-Cilag, Merck/Schering-Plough, Novartis, Roche, Roche Diagnostics, Siemens, Transgene, and ViiV, and has received speaker fees from Abbott, AbbVie, BMS, Boehringer Ingelheim, Gilead, JJ/Janssen-Cilag, Merck/Schering-Plough, Novartis, Roche, Roche Diagnostics, Siemens, Transgene, and ViiV; M. Cornberg has received personal fees from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen-Cilag, Merck (MSD), Biogen, Falk Foundation, Boehringer Ingelheim, Siemens, and Spring Bank, and grants and personal fees from Roche; M. F. Yuen consulted and/or received research funding from AbbVie, Arbutus Biopharma, Assembly Biosciences, Bristol-Myers Squibb, Dicerna Pharmaceuticals, GlaxoSmithKline, Gilead Sciences, Janssen, Merck Sharp and Dohme, Clear B Therapeutics, and Springbank Pharmaceuticals, and received research funding from Arrowhead Pharmaceuticals, Fujirebio Incorporation, and Sysmex Corporation; K. Agarwal has consulted and/or served on the speaker's bureau for Assembly, Aligos, Arbutus, Gilead, Immunocore, Janssen, Roche, Sobi, Springbank, and Vir, and has received research support from Abbott, Gilead, and MSD; A. Boonstra has received research fees from Fujirebio, Gilead Sciences, and Janssen Pharma; M. Buti has received consultancy and lecture honoraria from AbbVie, Arbutus, Gilead, Janssen, Merck/MSD, and Spring-Bank; G. Papatheodoridis has served as an advisor/lecturer for AbbVie, BMS, Dicerna, Gilead, GSK, Janssen, Ipsen, MSD, Roche, and Spring-Bank, and has received research grants from AbbVie, BMS, and Gilead; and B. Maasoumy has received speaker and/or consulting fees from Abbott Molecular, Astellas, Intercept, Falk, AbbVie, Norgine, Bristol Myers Squibb, Fujirebio, Janssen-Cilag, Merck (MSD), and Roche, and has received research support from Abbott Molecular, Altona Diagnostics, Fujirebio, and Roche. The remaining authors disclose no conflicts. Funding The study was supported by Fujirebio. Materials for hepatitis B core-related antigen testing were provided free of charge to several participating centers. Fujirebio had no influence on the study design, data collection, data analysis, writing of the manuscript, or the decision to submit for publication.

Publisher Copyright:
© 2020 The Authors

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology

Fingerprint Dive into the research topics of 'Prediction of Sustained Response After Nucleo(s)tide Analogue Cessation Using HBsAg and HBcrAg Levels: A Multicenter Study (CREATE)'. Together they form a unique fingerprint.

Cite this