Hepatitis B Core-Related Antigen is a Biomarker for off-Treatment Relapse After Long-Term Nucleos(t)ide Analog Therapy in Patients with Chronic Hepatitis B

OBJECTIVE: It remains unknown how to stratify the risk of clinical relapse of chronic hepatitis B (CHB) patients after stopping nucleos(t)ide analogs (NAs) antiviral therapy. METHODS: The current post hoc analysis included 122 non-cirrhotic patients with chronic hepatitis B virus infection who were positive for hepatitis B envelope antigen (HBeAg) and discontinued long-term NA therapy after achieving HBeAg seroconversion for a median of 2.5 years. Post hoc analysis of end-of-treatment (EOT) hepatitis B core-related antigen (HBcrAg) levels was performed using a chemiluminescent enzyme immunoassay. RESULTS: A total of 78/122 (63.9%) patients experienced sustained response after NAs cessation, and 44/122 (36.1%) patients experienced clinical relapse. In multivariate analysis, EOT HBcrAg (hazard ratio [HR] = 2.105 95% CI: 1.440–3.077, p < 0.001), hepatitis B surface antigen (HBsAg) ≥100 IU/mL (HR = 4.406, 95% CI 1.567–12.389, p = 0.005) and age (HR = 1.051, 95% CI: 1.010–1.093, p = 0.049) were independently associated with clinical relapse. A cut-off value of 4.0 log(10) U/mL of HBcrAg was defined by maximized Youden’s index. An EOT HBcrAg level of ≥4.0 log(10) U/mL was associated with higher risks of clinical relapse (65.8% vs 23.2%, p<0.001) and HBeAg reversion (27.5% vs 1.6%, p < 0.001). In majority of patients (n = 91) who had a high EOT HBsAg level (≥100 IU/mL), serum HBcrAg level could further discriminate patients at low risk of clinical relapse. Patients with an HBcrAg level ≥4.0 log(10) U/mL had significantly higher cumulative incidence rates of clinical relapse (78.1% vs 29.4%, p < 0.001) and HBeAg reversion (29.4% vs 0%, p < 0.001). CONCLUSION: Serum EOT HBcrAg level can be a predictor of off-treatment relapse in patients with CHB. An HBcrAg level of 4.0 log(10) U/mL may identify patients at high risk of clinical relapse after treatment cessation.