Fulminant B Hepatitis in a Hepatitis B Surface Antigen-Negative Patient after Rituximab Therapy for B-CLL.
Authors: Niscola Pasquale , Del Giudice Maria Ilaria , Maurillo Luca , Solmone Mariacarmela , Capobianchi Maria Rosaria , Carletti Fabrizio , Piccioni Daniela , Venditti Adriano , Amadori Sergio , Del Poeta Giovanni 
Published: April 2020

Abstract
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.
Patient clinical features Clinical features Diagnosis (November 1998) Disease Progression (November 2001) Disease Recurrence (February 2004) B Hepatitis onset (September 2004) *D genotype, ayw3 serotype; C124Y, A128V, G130D, P135R and G145R mutations in the S region. NA:not available. Rai Clinical Stage I II II 0 CD38 Negative Negative Negative Negative Zap 70 Positive Positive Positive Negative CD4/CD8 0.95 0.90 0.85 0.80 Beta 2 microglobulin (mcg/L) 1503 1825 1844 1325 Serum Ig level (gr/L) 0,980 0,790 0,660 0,620 HBsAg Negative Negative Negative Negative HBsAb Negative Negative Negative Negative HBcAb Positive Positive Positive Positive HBeAg Negatrive Negative Negative Positive HBeAb Positive Positive Positive Positive HBV DNA* NA NA NA 200.000/μL