Use of hepatitis B virus core‐related antigen to evaluate natural history of chronic hepatitis B

Abstract

Background and Aim: Hepatitis B core-related antigen (HBcrAg) has been shown to correlate with various viral markers in chronic hepatitis B, but its role in defining natural history is not well studied. We aimed to investigate the use of HBcrAg to define different phases of chronic hepatitis B. Methods: Stored residual serum samples from longitudinal cohorts of chronic hepatitis B patients in Hong Kong and Japan were studied. Viral markers were measured in three serial serum samples for each patient. Patients were divided into six groups for analysis: hepatitis B e antigen (HBeAg)-positive chronic infection (EPI), HBeAg-positive chronic hepatitis (EPH), HBeAg seroconversion (ES), HBeAg-negative chronic hepatitis (ENH), HBeAg-negative chronic infection (ENI), and HBsAg seroclearance (SS). Results: In total, 166 patients followed up for 100 (76-113) months were included. HBcrAg was correlated with hepatitis B virus DNA and HBsAg levels in both HBeAg-positive and HBeAg-negative patients. HBcrAg cutoff of ≥ 6.0 log U/mL could best differentiate HBeAg-positive from HBeAg-negative patients (area under receiver operating characteristic curve of 0.99, P < 0.001). HBcrAg could not differentiate patients in EPI and EPH phases, but HBcrAg declined dramatically at HBeAg seroconversion. In HBeAg-negative patients, HBcrAg ≥ 4.0 log U/mL could best differentiate ENH from ENI (area under receiver operating characteristic curve of 0.81; P < 0.001), with high specificity (81.6%) but only moderate sensitivity (65.7%) at baseline. Undetectable HBcrAg was found in 17%, 63%, and 89% patients in ENH, ENI, and SS groups at the last visit, respectively. Conclusions: HBcrAg provides useful information to stage the natural history of chronic hepatitis B, particularly identifying HBeAg-positive patients and HBeAg-negative patients with active disease. Echosens, Gilead Sciences, Janssen, and Roche. Vincent Wong has served as an advisory committee member for 3V-BIO, AbbVie, Allergan, Echosens, Gilead Sciences, Janssen, Novartis, Novo Nordisk, Perspectum Diagnostics, Pfizer, and Terns and as a speaker for Bristol-Myers Squibb, Echosens, Gilead Sciences, and Merck. He has also received a research grant from Gilead Sciences. Takashi Kumada served as a speaker for Gilead and MSD. Hidenori Toyoda has served as a speaker for AbbVie, Bayer, Gilead, and MSD. The other authors declare that they have no competing interests.

Hepatitis B Core-Related Antigen: From Virology to Clinical Application

“…In retrospective studies from Asia and Europe, the median serum HBcrAg level was 8.4 to 8.8 log U/mL in patients with HBeAg-positive chronic infection, 7.9 to 8.5 log U/mL in those with HBeAg-positive chronic hepatitis, 4.5 to 4.9 log U/mL in those with HBeAg-negative chronic hepatitis, and 2.0 to 3.1 log U/mL in those with HBeAg-negative chronic infection. [17][18][19] In general, serum HBcrAg level is correlated with serum HBV DNA and HBsAg levels. A meta-analysis of 74 studies involving 5,591 HBV-infected patients found that a HBcrAg cut-off of 5.3 log U/mL was optimum for identifying patients with HBV DNA !200,000 IU/mL (sensitivity: 91.8%; specificity: 90.5%), while HBcrAg cut-off at 3.6 log U/mL was useful for identifying patients with HBV DNA !2,000 IU/mL (sensitivity: 85.2%; specificity: 84.7%).…”

“…6.0 log U/mL had 97.3% sensitivity and 93.4% specificity for differentiating HBeAgpositive from HBeAg-negative samples. 19 No viral marker can predict HBeAg seroconversion 1 to 2 years ahead. 19 However, HBcrAg tends to drop significantly before HBeAg seroconversion, which suggests a possible role of serial monitoring of HBcrAg in clinical practice.…”

“…19 However, HBcrAg tends to drop significantly before HBeAg seroconversion, which suggests a possible role of serial monitoring of HBcrAg in clinical practice. In HBeAgpositive patients, HBcrAg level is typically higher during the chronic infection phase than in the chronic hepatitis phase, [17][18][19] suggesting greater immune control in HBeAgpositive patients with a low HBcrAg level. However, the significant overlap in HBcrAg levels between these two HBeAg-positive phases precludes a distinct cut-off.…”

“…4.0 log U/mL differentiates between HBeAg-negative patients with active versus inactive disease with high specificity (81.6%) but only moderate sensitivity (65.7%). 19 The suboptimal performance of HBcrAg in HBeAg-negative patients may relate in part to the lack of sensitivity of the HBcrAg assay; the lower limit of quantification is 3 log U/mL. Between 42 and 93% of patients with inactive disease had an HBcrAg level of < 3 log U/mL.…”

Biomarkers for the clinical development of antiviral therapies

“…HBcrAg can still be detected in patients with undetectable serum HBV DNA or loss of HBsAg, and reduction in HBcrAg level is strongly associated with favorable outcomes. This novel marker appears to correlate with serum HBV DNA and intrahepatic cccDNA copy number (Chan et al, 2020 (online ahead of print)). Unlike HBsAg and HBeAg, the use of HBcrAg as a marker is still largely confined to the research setting.…”