Early virologic relapse predicts alanine aminotransferase flares after nucleos(t)ide analogue withdrawal in patients with chronic hepatitis B.

When patients with chronic hepatitis B (CHB) stop nucleos(t)ide analogue (NA) therapy before achieving HBsAg loss, flares often ensue which are challenging to predict early. We determined the incidence, severity, outcome and predictors of flares after NA withdrawal. Forty-five patients enrolled in an RCT were included; 107 patients from an external, prospective cohort were used for validation. Retreatment criteria were pre-defined. Pre- and post-treatment predictors of alanine aminotransferase (ALT) flare (>5× ULN) were evaluated by Cox proportional-hazards regression. Seventy-two weeks after NA withdrawal, 23/45 (51%) patients had developed >5× ULN and 14 (31%) >20× ULN. Median time to develop ALT >5× ULN was 12 weeks after NA withdrawal. Independent predictors of ALT >5× ULN were male sex (HR [95% CI] 3.2 [1.2-8.9]; p = 0.03) and serum HBV DNA (1.2 [1.0-1.8]; p = 0.03) at Week 6 off-therapy. Specifically, week 6 HBV DNA >10,000 IU/ml predicted ALT >5× ULN (3.4 [1.4-8.4]; p = 0.01), which was externally validated. In conclusion, this study on post-treatment flares revealed a high cumulative incidence in CHB. Week 6 HBV DNA >10,000 IU/ml independently predicted flares. The proposed threshold enables prediction of imminent flares in patients who may benefit from closer monitoring and earlier retreatment.