A critique and systematic review of the clinical utility of hepatitis B core-related antigen

Background and aims: Hepatitis B core-related antigen (HBcrAg) is a new biomarker for chronic hepatitis B (CHB) whose performance has not been critically or systematically appraised. Herein, a systematic review was performed to determine its clinical utility.
Methods: The authors evaluated the biological pathway of HBcrAg and performed a systematic review of PubMed for clinical trials, cohort stud-ies, and case-control studies that evaluated the clinical utility of HBcrAg. The effectiveness of HBcrAg in predicting hepatitis B virus (HBV)-specific clinical events (e.g. hepatitis B e antigen [HBeAg] seroconversion, phases of CHB, hepatitis B surface antigen [HBsAg] loss, treatment response, and relapse after stopping therapy) was examined using receiver-operating characteristic curves (ROCs). The correlation coefficients of HBcrAg with HBV DNA, quantitative HBsAg (qHBsAg), HBV RNA, and cccDNA were summarized from published studies. Median values were used as estimates.
Results: HBcrAg consists of 3 precore/core protein products: hepatitis B core antigen (HBcAg), HBeAg, and a 22 kDa precore protein. HBcrAg assays have been associated with false-positive rates of 9.3% and false-negative rates of 12–35% for CHB. The new iTACT-HBcrAg is more sensi-tive but does not reduce the false-positive rate. A PubMed search found 248 papers on HBcrAg, of which 59 were suitable for analysis. The clinical performance of HBcrAg was evaluated using AUROC (area under ROC) analyses, with median AUROCs of 0.860 for HBeAg seroconversion, 0.867 for predicting HBeAg-negative hepatitis, 0.645 for HBsAg loss, 0.757 for treatment response, and 0.688 for relapse after stopping therapy. The median correlation coefficient (r) was 0.630 with HBV DNA, 0.414 with qHBsAg, 0.619 with HBV RNA and 0.550 with cccDNA. Correlation de-creased during antiviral therapy, but combined biomarkers improved performance.

Conclusions: Hepatitis B core-related antigen (HBcrAg) has a mixed performance and has a poor correlation with loss of hepatitis B surface antigen and antiviral therapy, hence HBcrAg results should be interpreted with caution.

Prof. Dr. S.G. Lim, Division of Gastroenterology and Hepatology, National University Hospital, Singapore, Singapore,
E-Mail: mdclimsg@nus.edu.sg

DOI: 10.1016/j.jhep.2022.12.017

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