Long‐Term Follow‐Up of Patients in a Prospective Study of NA Discontinuation Identifies Different Patterns of HBsAg Loss

Background and Aims Discontinuing nucleos(t)ide analogues (NAs) may lead to functional cure (HBsAg loss) in selected patients with chronic hepatitis B (CHB). We evaluated the rates and predictors of HBsAg loss during long‐term follow‐up in a prospective cohort. Methods This real‐world extension study followed participants from a prospective trial of NA discontinuation. All patients had HBeAg‐negative CHB without cirrhosis. Efficacy outcomes (including HBsAg loss and decline) and safety outcomes [including hepatitis flare and hepatocellular carcinoma (HCC)] were evaluated. Results Amongst 97 participants (85% Asian), with a median follow‐up of 7 years, the cumulative incidence of HBsAg loss was 10%, 13% and 22% at 5, 7 and 9 years after stopping NA. HBsAg loss was associated with a lower end‐of‐treatment (EOT) HBsAg level (HR = 0.28, p < 0.001), older age (HR = 1.14, p = 0.005) and peak off‐treatment HBV DNA level (OR = 0.50, p = 0.002). Participants with EOT HBsAg level ≤ 10 IU/mL experienced early HBsAg loss (< 96 weeks) without ALT flares whilst those with EOT HBsAg level ≥ 10 IU/mL experienced late (≥ 96 weeks) HBsAg loss, often following ALT flares (5/8 cases). No cases of hepatic decompensation, liver transplantation or death occurred. Median liver stiffness did not increase. HCC was diagnosed in three individuals (4.4/1000 person‐years). Conclusion The rate of functional cure increased during long‐term follow‐up but remained low. EOT HBsAg strongly predicted the likelihood and timing of HBsAg loss. ALT flares were associated with HBsAg decline, and in some cases, with delayed HBsAg loss. Trial Registration: The clinical study was supported by the National Health and Medical Research Council of the study clinical trial ID is NCT02581033