Hepatitis B reactivation in HBsAg-/anti-HB-negative patients diagnosed with hematological malignancy: A case series

Background: Hepatitis B virus (HBV) reactivation is a well-recognized complication of immunosuppressive therapy in patients with hematologic malignancies. It usually occurs in those with chronic or resolved HBV infection identified by positive hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (anti-HBc). Reactivation in patients who test negative for both markers is exceedingly rare and poses a diagnostic challenge. Methods: We report on three patients with hematologic malignancies who developed HBV reactivation despite negative baseline serology. Cases were identified and managed at a tertiary liver centre in Canada. Clinical, virologic, and treatment data were reviewed, including HBV serology, viral load, chemotherapy exposure, and outcomes following antiviral therapy. Results: All three patients originated from HBV-endemic regions and had received potent immunosuppressive regimens, including B cell-depleting agents or hematopoietic stem cell transplantation. Two were completely seronegative (HBsAg-/anti-HBc-/hepatitis B surface antibody [anti-HBs]-negative), and one had isolated anti-HBs positivity that was subsequently lost before reactivation. HBV DNA became detectable months to years after treatment initiation. All patients received antiviral therapy with entecavir or tenofovir, resulting in viral suppression and biochemical recovery. Conclusions: This case series highlights a critical limitation of current HBV screening strategies that rely solely on antibody-based testing. Loss of humoral immunity may obscure prior HBV exposure, leading to unrecognized reactivation risk. Clinicians should maintain a high index of suspicion and consider serial ALT and HBsAg monitoring in immunosuppressed patients with humoral (B cell) immune deficiencies, particularly those from HBV-endemic regions.