Fulminant B Hepatitis in a Hepatitis B Surface Antigen-Negative Patient after Rituximab Therapy for B-CLL.

Concerns about safety of rituximab in hepatitis B virus (HBV) carriers have risen at the light of reported cases of HBV reactivation following the administration of this agent. We recently observed a patient affected by B-cell Chronic Lymphocytic Leukemia (B-CLL) who developed this complication without any serological evidence of HBsAg expression.

Case report: the patient, a 51 old year’s male, was diagnosed as having B-CLL in November 1998 and followed until his death due to acute liver failure due to HBV reactivation of a mutant HBV strain in September 2004 (Table). At diagnosis of B-CLL no risk factors regarding liver diseases or viral infections were reported; serum HBsAg and HBeAg, antibodies against the B-core antigen (HBcAb), HBe (HBeAB), HBsAg (HBsAb), HCV, hepatitis A and Delta virus, Cytomegalovirus, and Epstein Barr virus were negative while HBcAb alone were positive. He presented stable disease until November 2001, when fludarabine was started because of progressive disease. A good partial response (GPR) was achieved so that he received four weekly standard doses (375 mg/m²) of rituximab as consolidation therapy (July 2002). A complete remission (CR) was obtained and he was then closely followed-up until about two years later (February 2004) when, for a disease recurrence, rituximab was given again. At that time all the above hepatitis markers remained unmodified. After four weekly standard doses of rituximab a GPR was recorded, and then six monthly courses (150 mg/m²) of the same agent were administered as maintenance therapy. In September 2004, being the patient in CR, he was admitted with acute hepatitis. HBV DNA strains (200,000 copies/mL) and HbcAb IgM were detected, whereas HbsAg-negative status persisted. The viral form was characterized as having D genotype and ayw3 serotype respectively.

Sequence analysis of polymerase chain reaction (PCR) products amplified from the S region revealed 5 remarkable mutations in the major antigenic regions (C124Y, A128V, G130D, P135R and G145R). These mutations were associated with the lack of HbsAg production and were compatible with an escape of a rare HBV strain from the patient’s own HbsAb. Despite treatment with lamivudine, the patient died of fulminant hepatic failure.

Conclusion: our experience indicates that patients receiving rituximab who are negative for HBsAg but positive for anti-HBc are still at risk for reactivation of latent HBV and should be considered for HBV DNA testing and prophylaxis with lamivudine.