JHEP Reports · Published 2026-05-01 · DOI 10.1016/j.jhepr.2026.101875
Background & Aims: Hepatic flares frequently occur after nucleos(t)ide analogue (NA) cessation in patients with chronic hepatitis B (CHB) and can be beneficial (‘good flares’) or harmful (‘bad flares’). We characterised flares after NA cessation aiming to identify predictors and immunological correlates of good and bad flares. Methods: This study was nested in the prospective Nuc-Stop study, in which 127 patients with e-antigen negative CHB discontinued NA treatment with a 36-month follow-up. Flares were defined as an alanine aminotransferase (ALT) increase >2 × the upper limit of normal or >2 × baseline. Predictors of flares were identified by logistic regression. In 32 patients with flares without treatment restart, we compared clinical characteristics and soluble immune marker profiles of good flares (HBsAg loss or >1 log10 decline or sustained virological control) and bad flares (neither HBsAg decline nor virological control). Results: Flares occurred in 58.3% of patients. Age (per 1-year increment; adjusted odds ratio [aOR], 1.07; 95% confidence intervals [CI] 1.02–1.12) and end-of-treatment HBsAg level (per 1 log10 IU/ml increment; aOR, 2.09; 95% CI 1.20–3.62) independently predicted flares. Good flares displayed less ALT variability after the initial spike than bad flares (standard deviation 9.7 vs. 22.7 U/L, p = 0.002). Analysis of soluble immune markers confirmed distinct clusters for good and bad flares at end-of-treatment, with higher serum levels of specific proteins in good flares (e.g. IL-13, TRAIL) and bad flares (e.g. CXCL11, OPG, TNF). Conclusions: Flares occurred in over half the patients after NA cessation and were associated with age and end-of-treatment HBsAg levels. ALT variability following the initial flare and soluble marker profiles might serve as prognostic factors and distinguish good from bad flares. Impact and implications: NA cessation in HBeAg-negative CHB may facilitate functional cure, but hepatic flares are common and potentially detrimental, making careful patient selection essential. In this prospective, multicentre trial, flares occurred in over half of the patients, with severe flares in 12.6%. Increasing age and higher end-of-treatment HBsAg levels were predictors of flares and should be considered when deciding on treatment discontinuation. Close monitoring, particularly during the first 6 months, is critical for safe patient management, whereas ALT variability following the initial flare and soluble immune markers may help differentiate good from bad flares and guide retreatment decisions. Clinical Trials Registration (for the Nuc-Stop study): NCT03681132.
Abstract from DOAJ. Public domain (CC0 1.0).
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