Predictors of hepatic flares after nucleos(t)ide analogue cessation - Results of a global cohort study (RETRACT-B study)

Edo J Dongelmans; Grishma Hirode; Bettina E Hansen; Chien-Hung Chen; Tung-Hung Su; Wai-Kay Seto; Arno Furquim d'Almeida; Stijn van Hees; Margarita Papatheodoridi; Sabela Lens; Grace L H Wong; Sylvia M Brakenhoff; Rong-Nan Chien; Jordan J Feld; Henry L Y Chan; Xavier Forns; George V Papatheodoridis; Thomas Vanwolleghem; Man-Fung Yuen; Yao-Chun Hsu; Jia-Horng Kao; Markus Cornberg; Milan J Sonneveld; Wen-Juei Jeng; Harry L A Janssen; RETRACT-B study group

doi:10.1016/j.jhep.2024.08.015

Predictors of hepatic flares after nucleos(t)ide analogue cessation - Results of a global cohort study (RETRACT-B study)

J Hepatol. 2024 Aug 31:S0168-8278(24)02493-0. doi: 10.1016/j.jhep.2024.08.015. Online ahead of print.

Authors

Edo J Dongelmans¹, Grishma Hirode², Bettina E Hansen³, Chien-Hung Chen⁴, Tung-Hung Su⁵, Wai-Kay Seto⁶, Arno Furquim d'Almeida⁷, Stijn van Hees⁸, Margarita Papatheodoridi⁹, Sabela Lens¹⁰, Grace L H Wong¹¹, Sylvia M Brakenhoff¹, Rong-Nan Chien¹², Jordan J Feld², Henry L Y Chan¹³, Xavier Forns¹⁰, George V Papatheodoridis⁹, Thomas Vanwolleghem⁸, Man-Fung Yuen⁶, Yao-Chun Hsu¹⁴, Jia-Horng Kao⁵, Markus Cornberg¹⁵, Milan J Sonneveld¹, Wen-Juei Jeng¹², Harry L A Janssen¹⁶; RETRACT-B study group

Affiliations

¹ Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
² Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Canada; The Toronto Viral Hepatitis Care Network (VIRCAN), Toronto, Canada; Institute of Medical Science, University of Toronto, Toronto, Canada.
³ Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Canada; Department of Epidemiology, Biostatistics, Erasmus MC University Medical Center, Rotterdam, Netherlands; Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada.
⁴ Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung City, Taiwan.
⁵ Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
⁶ Department of Medicine and State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong Special Administrative Region of China.
⁷ Viral Hepatitis Research Group, Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Antwerp, Belgium.
⁸ Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium.
⁹ Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, Athens, Greece.
¹⁰ Liver Unit, Hospital Clínic de Barcelona, IDIBAPS and CIBEREHD, University of Barcelona, Barcelona, Spain.
¹¹ Medical Data Analytics Centre (MDAC), The Chinese University of Hong Kong, Hong Kong Special Administrative Region of China.
¹² Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital Linkou Medical Center, Chang Gung University, Taoyuan, Taiwan.
¹³ Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region of China.
¹⁴ Division of Gastroenterology and Hepatology, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan.
¹⁵ Department of Gastroenterology, Hepatolology and Endocrinology, Hannover Medical School, Germany; Centre for Individualized Infection Medicine (CiiM), Hannover, Germany.
¹⁶ Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, the Netherlands; Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Toronto, Canada. Electronic address: h.janssen@erasmusmc.nl.

PMID: 39773379
DOI: 10.1016/j.jhep.2024.08.015

Abstract

Background & aims: Flares after nucleos(t)ide analogue (NA) cessation are common and potentially harmful. Predictors of flares are required for risk stratification and to guide off-treatment follow-up.

Method: This multicenter cohort study included virally suppressed patients with chronic hepatitis B (CHB) who were hepatitis B e antigen negative at NA cessation. Hepatic flares were defined based on ALT levels of ≥5x, 10x or 20x the upper limit of normal (ULN). Multivariable Cox regression analyses were performed with censoring at retreatment, HBsAg loss or loss to follow-up. A sub-analysis was performed including HBV DNA levels within the first 12 weeks as a time-dependent covariate.

Results: Of the 1,552 included patients, 350 developed a flare (ALT ≥5x ULN), of whom 70.6% did within the first year. One-year cumulative incidences for ALT flares ≥5x, ≥10x, ≥20x ULN were 18.6%, 10.2% and 3.4%, respectively. Severity of flares decreased over time, but severe flares still occurred after 1 year. Thirteen patients decompensated after a flare, of whom three died. Flares did not seem to be associated with increased rates of HBsAg loss (adjusted hazard ratio [aHR] 1.42, p = 0.28). Multivariable analyses showed that older age (aHR 1.02, p = 0.001), male sex (aHR 1.57, p = 0.003), HBsAg levels at NA withdrawal (100-1,000 IU/ml; aHR 1.99, p <0.001; >1,000 IU/ml; aHR 2.65, p <0.001) and tenofovir disoproxil fumarate vs. entecavir therapy (aHR 2.99, p <0.001) were predictive of flares (≥5x ULN). Early HBV DNA levels >5log₁₀ IU/ml were associated with the highest risk of flares (aHR 2.36, p <0.001).

Conclusion: Flares are common after NA withdrawal, especially within the first year and can result in hepatic decompensation and death. Older age, male sex, higher HBsAg levels at end of treatment and tenofovir therapy were associated with a higher risk of flares. Close monitoring and retreatment should be considered if HBV DNA levels exceed 5log₁₀ IU/ml within the first 12 weeks.

Impact and implications: This is the first large global multi-centered cohort study which provides detailed data about flares after nucleos(t)ide analogue cessation in patients with chronic hepatitis B. Older age, male sex, higher HBsAg levels at end of treatment and tenofovir therapy were associated with a higher risk of flares. These results could guide follow-up after withdrawal, helping clinicians identify high-risk patients and decide when to restart anti-viral therapy, which we recommend if HBV DNA levels exceed 5log₁₀ IU/ml within the first 12 weeks.

Clinical trial number: not applicable.

Keywords: Antiviral; Discontinuation; Flares; HBV; Predictors.