Overt and Occult Hepatitis B in Hemodialysis Patients: Insights from High-Sensitivity Testing and Genetic Analysis

Background/Objectives: Occult hepatitis B infection (OBI) remains a diagnostic challenge, particularly in hemodialysis (HD) patients, who are vulnerable to HBV infection due to immune dysfunction and repeated exposure. Methods: We evaluated the prevalence and molecular characteristics of OBI among 874 HD patients in St. Petersburg, Russia, using high-sensitivity nested real-time PCR targeting the S and X genes. Results: HBV DNA was detected in 3.7% (32/874), as reflected in subcategories: overt CHB in 2.1% (18/874) and OBI in 1.6% (14/874). Genotype D predominated (93.8%), with subgenotypes D2 (56.3%), D1 (25.0%), and D3 (12.5%) present. OBI patients had low viral loads (6.0–148.3 IU/mL), whereas CHB patients showed high viremia (7843–64,870,000 IU/mL). Immune escape mutations were significantly more frequent in OBI (92.9%) than CHB (16.7%; p < 0.0001), with A128V being most common (31.3%). Core mutations were nearly universal (93.7%). Drug resistance mutations were found in 6.3% of cases without prior antiviral therapy. Seronegative infections (i.e., negative for anti-HBc IgG and anti-HBs IgG) were common, comprising 77.8% of CHB and 14.3% of OBI cases. Anti-HBc prevalence increased with dialysis vintage (3.8% to 43.1%, p < 0.0001), while anti-HBs declined with age (rs = −0.85, p = 0.0001). Conclusions: In conclusion, OBI affects 1.6% of HD patients in this cohort, with immune escape mutations as a key molecular driver of the occult phenotype. These findings suggest that HBV DNA screening may warrant consideration in HD patients, as serological results alone are inadequate for ruling out occult infection.