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

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 >5log 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 5log 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 5log IU/ml within the first 12 weeks.

Clinical Trial Number: not applicable.