The role of hepatitis B core-related antigen in predicting HBV reactivation among HBsAg-negative, anti-HBc-positive individuals undergoing immunosuppressive therapy

Abstract

BACKGROUND: Hepatitis B core-related antigen (HBcrAg) detects an identical amino-acid sequence shared by hepatitis B e antigen, hepatitis B core antigen and 22kDa precore protein. Serum HBcrAg correlates with disease activity of chronic hepatitis B (CHB), and can be detected in a considerable proportion of CHB patients after hepatitis B surface antigen (HBsAg) seroclearance. Its role in predicting HBV reactivation among HBsAg-negative, antibody to hepatitis B core antigen (anti-HBc) positive has not been explored. METHODS: We retrieved stored plasma samples of HBsAg-negative, anti-HBc positive, patients with undetectable HBV DNA at baseline who were enrolled into two prospective studies, which aimed at investigating the rate of HBV reactivation during rituximab-containing chemotherapy and hematopoietic stem-cell transplantation (HSCT) (ClinicalTrials. gov identifier NCT01502397 and NCT01481647 respectively). HBV reactivation was defined as detectable HBV DNA (≥10 IU/mL). Serum HBcrAg (lower limit of detection 100 U/mL) was measured using a chemiluminscent enzyme immunoassay (Fujirebio Inc, Tokyo, Japan) at baseline and at every 3 months up to the date of last follow-up. RESULTS: We included 131 HBsAg-negative, anti-HBc positive patients (rituximab/HSCT 47.3%/52.7%), with a mean age of 57.4 (±15.1) years and a mean follow-up duration of 53.3 (±35.0) weeks. 32 patients developed HBV reactivation (rituximab/HSCT 56.3%/43.7%); the 2-year cumulative rate of HBV reactivation was 39.2%. 21 patients (16.0%) and 25 patients (19.1%) had detectable serum HBcrAg at either baseline or any time point before reactivation respectively. The median detectable baseline HBcrAg level was 400 (range 200-5,300) U/mL. Baseline serum HBcrAg positivity, compared to baseline HBcrAg-negative patients, had a significantly higher 2-year cumulative rate of HBV reactivation (75.8% versus 29.9% respectively, p<0.001). When comparing HBcrAg-positivity at any time point before reactivation versus persistent HBcrAg-negativity, the difference was even greater (83.6% versus 23.2% respectively, p<0.001). Baseline HBcrAg-positivity was independently associated with HBV reactivation via multivariate Cox regression for both rituximab (n=62) (p=0.003, OR 4.9, 95% CI 1.7-13.9) and HSCT (n=69) (p=0.012, HR 4.8, 95% CI 1.4-16.1). The association of HBcrAg-positivity with HBV reactivation among rituximab patients was stronger than that of anti-HBs negativity (p=0.050, OR 2.6, 95% CI 1.0-6.8). CONCLUSION: Serum HBcrAg could potentially play a role in identifying HBsAg-negative, anti-HBc positive patients who would best benefit from prophylactic nucleoside analogue therapy.