High rates of transition to immune active disease in a cohort of strictly defined immune tolerant patients with chronic hepatitis B: results from the RADICAL consortium

Background Patients with immune tolerant (IT) chronic hepatitis B (CHB) have high viral loads, minimal inflammation and minimal fibrosis. Nevertheless, the benign nature of this phase and the need for antiviral therapy remain controversial. Objective We explored the natural history of IT patients by assessing the risk of transition to immune active (IA) disease, fibrosis progression and hepatocellular carcinoma (HCC). Design This international multicentre study from the RADICAL consortium includes mono-infected patients with CHB from sites around the world. The IT-phase was strictly defined as persistently (1) hepatitis B e-antigen (HBeAg)-positive, (2) alanine aminotransferase (ALT) ≤40 U/L, (3) HBV DNA >7 log 10 IU/mL and (4) F0-1 during the first year after baseline. We assessed the probabilities of transition to IA disease (ALT ≥50 U/L), the risk of significant fibrosis (≥F2) and HCC. Results In total, 951 IT patients were included with a median age of 33, 40% were male with a median follow-up of 13 years. Median ALT and HBV DNA at baseline were 25.5 U/L and 8.4 log 10 IU/mL. The probability of transitioning to IA disease was 51%, 67% and 72% before 5 years, 10 years and 15 years. A high-normal ALT was associated with an increased risk of IA disease (subdistribution hazard ratio (sHR): 20–30 U/L: 1.744, p<0.001, sHR: >30U/L: 3.130, p<0.001). IT patients had a low risk of progression to significant fibrosis (15 years: 6.3%), and HCC (15 years: 1.1%). Conclusion The majority of this large cohort of well-defined IT patients transition to IA disease within 5 years of follow-up, with the highest risk observed in those with a high-normal ALT, suggesting that these patients may benefit from either more frequent monitoring or pre-emptive therapy.

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Journal
Gut
Published
2026-09-18
DOI
https://doi.org/10.1136/gutjnl-2026-338784
Primary Topic
Hepatitis B Virus Studies
Type
article
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article

High rates of transition to immune active disease in a cohort of strictly defined immune tolerant patients with chronic hepatitis B: results from the RADICAL consortium

Stéphanie Narguet, Tarik Asselah, Marc G. Ghany, Sabela Lens et al.
Gut
Hepatitis B Virus Studies
article

High rates of transition to immune active disease in a cohort of strictly defined immune tolerant patients with chronic hepatitis B: results from the RADICAL consortium

Stéphanie Narguet, Tarik Asselah, Marc G. Ghany, Sabela Lens, Norah A. Terrault, Terry Cheuk‐Fung Yip, Yao‐Chun Hsu, Bettina E. Hansen, Elena Vargas Accarino, Dirk Posthouwer, Jordan J. Feld, Zillah Cargill, Sara Battistella, Milan J. Sonneveld, Man‐Fung Yuen, Kosh Agarwal, Karen Cheuk‐Ying Ho, Özgür M. Koc, Maurizia Rossana Brunetto, Won‐Mook Choi, Young‐Suk Lim, Lisa M. van Velsen, Wai‐Kay Seto, R A J Post, Mai Kilany, Harry L A Janssen, Grace L H Wong, Maria Buti
article en

Abstract

Background Patients with immune tolerant (IT) chronic hepatitis B (CHB) have high viral loads, minimal inflammation and minimal fibrosis. Nevertheless, the benign nature of this phase and the need for antiviral therapy remain controversial. Objective We explored the natural history of IT patients by assessing the risk of transition to immune active (IA) disease, fibrosis progression and hepatocellular carcinoma (HCC). Design This international multicentre study from the RADICAL consortium includes mono-infected patients with CHB from sites around the world. The IT-phase was strictly defined as persistently (1) hepatitis B e-antigen (HBeAg)-positive, (2) alanine aminotransferase (ALT) ≤40 U/L, (3) HBV DNA >7 log 10 IU/mL and (4) F0-1 during the first year after baseline. We assessed the probabilities of transition to IA disease (ALT ≥50 U/L), the risk of significant fibrosis (≥F2) and HCC. Results In total, 951 IT patients were included with a median age of 33, 40% were male with a median follow-up of 13 years. Median ALT and HBV DNA at baseline were 25.5 U/L and 8.4 log 10 IU/mL. The probability of transitioning to IA disease was 51%, 67% and 72% before 5 years, 10 years and 15 years. A high-normal ALT was associated with an increased risk of IA disease (subdistribution hazard ratio (sHR): 20–30 U/L: 1.744, p<0.001, sHR: >30U/L: 3.130, p<0.001). IT patients had a low risk of progression to significant fibrosis (15 years: 6.3%), and HCC (15 years: 1.1%). Conclusion The majority of this large cohort of well-defined IT patients transition to IA disease within 5 years of follow-up, with the highest risk observed in those with a high-normal ALT, suggesting that these patients may benefit from either more frequent monitoring or pre-emptive therapy.

Gut
University of Pisa (IT), Ulsan College (KR), University of Southern California (US), National Institutes of Health (US), University Health Network (CA), Inserm (FR), Chinese University of Hong Kong (HK), Université Paris Cité (FR), Hôpital Beaujon (FR), Maastricht University Medical Centre (NL), Queen Mary Hospital (CN), Asan Medical Center (KR), Toronto General Hospital (CA), Erasmus MC (NL), Maastricht University (NL), University of Ulsan (KR), National Institute of Diabetes and Digestive and Kidney Diseases (US), E-Da Hospital (TW), Assistance Publique – Hôpitaux de Paris (FR), Centro de Investigación Biomédica en Red (ES), Hospital Clínic de Barcelona (ES), Vall d'Hebron Hospital Universitari (ES), King's College Hospital (GB), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), Azienda Ospedaliera Universitaria Pisana (IT), Universitat de Barcelona (ES), University of Hong Kong (HK)
Gilead Sciences, Stichting voor Lever- en Maag-Darm Onderzoek
Good health and well-being
Openalex Percentile: Top 11%
Hepatitis B Virus Studies
DOIOpen Access PDFOpenAlex
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