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

Abstract

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 an ALT-levels of ≥5-, 10- or 20 x upper limit of normal (ULN). Multivariable Cox regression analyses were performed censoring at retreatment, HBsAg-loss and loss-to-follow-up. A sub-analysis was performed including HBV DNA levels Results Of the 1552 included patients, 350 developed a flare (ALT≥5xULN), of whom 70% within the first year. One-year cumulative incidences for ALT flares ≥5x, ≥10x, ≥20xULN were 18.6%, 10.2% and 3.4%, respectively. Severity of flares decreased over time, but severe flares still occurred after one year. Thirteen patients decompensated after a flare, of whom 3 died. Flares seemed not 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 (TDF) vs. Entecavir therapy (aHR:2.99,P<0.001) were predictive for flares (≥5xULN). 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 TDF 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.

Lay summary

Hepatic flares are common after NA cessation, even after 1 year. More caution is warranted in older patients, HBsAg levels >100 IU/mL, males and after TDF therapy. Furthermore, intensified follow up and retreatment is needed if HBV DNA levels exceeded 5log₁₀ IU/mL during the first 12 weeks.

Impact and implications

This is the first large global multi-centered cohort study which provides detailed data about flares after NA cessation in patients with chronic hepatitis B. These results could guide follow-up after withdrawal, helping clinicians identify high risk patients and deciding when to restart anti-viral therapy.

Clinical trial number

Not applicable.