Global 
Deutschland Liver and Bile
J Hepatol. 2025;82(3):446-455
Predictors of hepatic flares after nucleos(t)ide analogue – Results of a global cohort study (RETRACT-B study)
Background and 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 ≥ 5 x, 10 x or 20 x the upper limit of normal (ULN). Multivariable Cox regression analyses were performed with censoring at retreatment, hepatitis B surface antigen (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 1552 included patients, 350 developed a flare (ALT ≥ 5 x ULN), of whom 70.6% did within the first year. One-year cumulative incidences for ALT flares ≥ 5 x, ≥ 10 x, ≥ 20 x ULN were 18.6%, 10.2% and 3.4%, respectively. Severity of flares decreased over time, but severe flares still occurred after 1 year. 13 patients decompensated after a flare, of whom 3 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 (100–1000 IU/ml; aHR = 1.99, p < 0.001; > 1000 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 (≥ 5 x ULN). Early HBV DNA levels > 5 log10 IU/ml were associated with the highest risk of flares (aHR = 2.36, p < 0.001).
Conclusion: Flares are common after nucleos(t)ide analogue 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 5 log10 IU/ml within the first 12 weeks.