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Hepatitis B core-related antigen(HBcrAg) is a new biomarker for Chronic Hepatitis B(CHB) but its performance has not been critically or systematically appraised.We evaluated the biological pathway of HBcrAg, and performed a systematic review of PubMed for clinical trials, cohort studies, and case-control studies that evaluated the clinical utility of HBcrAg. The effectiveness of HBcrAg in predicting HBV-specific clinical events (e.g. HBeAg seroconversion, phases of CHB, HBsAg loss, treatment response, and relapse after stopping therapy) was examined using receiver operating characteristic(AUROC) curves. The correlation coefficients of HBcrAg with HBV DNA, quantitative HBsAg (qHBsAg), HBV RNA, and cccDNA were summarised from published studies. Median values were used as estimates.HBcrAg consists of three precore/core protein products: Hepatitis B core antigen(HBcAg), HBeAg, and 22kDa precore protein(p22cr). In HBeAg(+) CHB, HBeAg contributed 72±10%, HBcAg 17±8% and p22cr 15±9%, but in HBeAg(-) CHB contributions were unquantifiable. The false-positive rate was 9.3% with a false negative rate between 12-35%. The new iTACT-HBcrAg is more sensitive but does not resolve false positive performance. A PubMed search found 248 papers on HBcrAg but after exclusions, 59 were suitable for analysis. The clinical performance was evaluated using AUROC, with median AUROC for HBeAg seroconversion 0.860, predicting HBeAg(-) hepatitis 0.867, HBsAg loss 0.645, treatment response 0.757, and relapse after stopping therapy 0.688. The median correlation coefficient(r) with HBV DNA was 0.630, qHBsAg 0.414, HBV RNA 0.619 and cccDNA 0.550. Correlation decreased during antiviral therapy but combined biomarkers improved performance.HBcrAg has a mixed performance and has a poor correlation with HBsAg loss and antiviral therapy, hence HBcrAg results should be interpretated with caution. Impact and implications • Hepatitis B core-related antigen (HBcrAg) has been used to assess management of Chronic Hepatitis B (CHB) patients without a systematic and critical review of its performance • We found that HBcrAg had false positive rate of 9% and false negative of 12-35% raises concerns although larger studies are need for validation • A systematic review showed that the performance of HBcrAg was variable depending on the CHB endpoint; it was excellent to predict HBeAg seroconversion and HBeAg negative chronic hepatitis (versus chronic infection), hence should be used mainly for this but it was poor for relapse after stopping antiviral therapy and for HBsAg loss. • The results of HBcrAg should be interpreted with considerable caution particularly by physicians, researchers, guideline committees and agencies that approve diagnostic tests. |
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