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

Abstract

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.

Serious adverse events after cessation of nucleos(t)ide analogues in individuals with chronic hepatitis B: A systematic review and meta-analysis

“…1 ). [12] , [13] , [14] , [17] , [18] , [19] , 27 , [30] , [31] , [32] , [33] , [34] , [35] , [36] , [37] , [38] , [39] , [40] , [41] , [42] , [43] , [44] , [45] , [46] , [47] , [48] , [49] , [50] , [51] , [52] , [53] , [54] , [55] , [56] , [57] , [58] , [59] , [60] , [61] , [62] , [63] , [64] , [65] , [66] , [67] , [68] , [69] , [70] , [71] , [72] One of the studies involved two distinct cohorts, of which one consisted exclusively of individuals with prior severe acute exacerbation and the other consisted of patients who had never experienced such an event. 31 Therefore, 50 studies with 51 cohorts were included in the meta-research analysis.…”

Incidence and Predictors of Relapse After Stopping Antiviral Therapy in Pediatric Chronic Hepatitis B

“…The important predictors of relapse after stopping antivirals in adults include (1) higher qHBsAg level at the time of stopping the therapy 19-21 ; (2) shorter duration of consolidation therapy 20,22-24 ; (3) slower HBV-DNA decline while on therapy 25 ; (4) baseline pretreatment HBV-DNA 26,27 ; (5) hepatitis B core-related antigen (HBcrAg) 28,29 ; and (6) hepatitis B virus-ribonucleic acid (HBV-RNA)-. 29 The maximum 19 qHBsAg levels were not significantly higher in the patients who relapsed in the present study either on the univariate or in the multivariate model. HBcrAg and HBV-RNA are among the newer serological markers predicting relapse either singly or in combination.…”

“…HBcrAg and HBV-RNA are among the newer serological markers predicting relapse either singly or in combination. 28,29 We evaluated the role of liver tissue ccc-DNA which although higher in relapse was not statistically different. This could be due to the smaller sample size and would need evaluation in larger multicentric studies.…”

“…7 The high rates of early relapse (69.2%) seen in HBeAg-positive children in the present study suggest that treatment withdrawal should not be attempted in the absence of HBeAg seroconversion. The important predictors of relapse after stopping antivirals in adults include (1) higher qHBsAg level at the time of stopping the therapy 19–21 ; (2) shorter duration of consolidation therapy 20,22–24 ; (3) slower HBV-DNA decline while on therapy 25 ; (4) baseline pretreatment HBV-DNA 26,27 ; (5) hepatitis B core-related antigen (HBcrAg) 28,29 ; and (6) hepatitis B virus- ribonucleic acid (HBV-RNA)-. 29 The maximum emphasis is on qHBsAg levels at the time of stopping therapy and recently Asia Pacific Association for Study of Liver Diseases has suggested less than 100 IU/ml as a safe endpoint for stopping long term antivirals.…”

“…The important predictors of relapse after stopping antivirals in adults include (1) higher qHBsAg level at the time of stopping the therapy 19–21 ; (2) shorter duration of consolidation therapy 20,22–24 ; (3) slower HBV-DNA decline while on therapy 25 ; (4) baseline pretreatment HBV-DNA 26,27 ; (5) hepatitis B core-related antigen (HBcrAg) 28,29 ; and (6) hepatitis B virus- ribonucleic acid (HBV-RNA)-. 29 The maximum emphasis is on qHBsAg levels at the time of stopping therapy and recently Asia Pacific Association for Study of Liver Diseases has suggested less than 100 IU/ml as a safe endpoint for stopping long term antivirals. 19 qHBsAg levels were not significantly higher in the patients who relapsed in the present study either on the univariate or in the multivariate model.…”