Clinical course and core variability in HBV infected patients without detectable anti-HBc antibodies

The presence of anti-HBc antibodies indicates direct encounter of the immune system with hepatitis B virus (HBV).

Aim of our study was to seek for anti-HBc negative but HBV replicating patients and analyze their clinical course and preconditions.

From 1568 HBV-DNA positive patients, 29 patients (1.85%) tested negative for anti-HBc. The absence of anti-HBc could be confirmed in 19 patients using an alternative assay. In 16 of 19 cases, a partial or full HBV genome analysis was performed with NGS sequencing to evaluate if specific mutations were associated with anti-HBc absence. As a control group samples from 32 matched HBV infected patients with detectable anti-HBc were sequenced.

Patients with detectable HBV-DNA and sequenced HBV core region in the confirmed absence of anti-HBc were diagnosed with acute HBV infection (n=3), HBV reactivation (n=9) and chronic hepatitis B (n=4). Most patients (12/16) were immunosuppressed: 3/16 patients had an HIV coinfection, 7/16 patients suffered from a malignant disease and 4/16 patients underwent solid organ transplantation (from which 2/4 had a malignant disease). Compared to the control cohort, HBV variants from anti-HBc negative patients showed less variability in the core region.

In the absence of anti-HBc, HBV-DNA was most often found in immunocompromised hosts. Distinct mutations or deletions in the core region did not explain anti-HBc negativity. It would be advisable not to rely only on a single result of anti-HBc negativity to exclude HBV infection in immunocompromised hosts, but to measure anti-HBc repeatedly or with different methods.