Hepatic flares, their immune signatures, and ALT variability after nucleos(t)ide analogue cessation in HBeAg-negative hepatitis B

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: decline or sustained virological control) and bad flares (neither HBsAg decline nor virological control). RESULTS: 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.