High Risk of Hepatitis B Virus Reactivation in Isolated Anti-Hbc Positive Patients with B-Cell Lymphoma Receiving Rituximab Containing Chemotherapy.

Abstract 1944

Poster Board I-967

Reactivation of hepatitis B virus (HBV) infection in patients receiving chemotherapy, immunosuppressive therapy, and organ transplantation is well-recognized complication in patients with HBsAg positive patients. Although, prophylaxis with anti-viral drug is proposed for HBV surface antigen (HBsAg) positive patients and is considered as a standard managements, the risk of developing HBV reactivation and optimal therapy in HBsAg negative but anti-HBV core antigen (anti-HBc) positive patients remained to be elucidated. In addition the use of rituximab has been reported to cause even fatal HBV related hepatic failure in these patients. We retrospectively investigated the occurrence of HBV reactivation after rituximab containing chemotherapy in HBsAg negative 261 consecutive patients with CD20 positive B-cell lymphoma who admitted Kameda General Hospital over past 5 years. Prior to September 2006, anti-HBc and antibody to HBsAg (anti-HBs) were performed at the discretion of the treating physician. After October 2006, anti-HBc and anti-HBs tests were performed for all patients. HBV reactivation was defined by the seroconversion from HBsAg negative to positive with or without an increase of HBV-DNA from base line levels (>2.6 log copies/ml). Hepatitis attributable to reactivation was defined as a serum alanine aminotransferase (ALT) level greater than 3 folds above the normal upper limit of 2 consecutive determinations more than 5 days apart without feature of hepatitis A, hepatitis C or other causes. Lymphoma subtypes were diffuse large B cell lymphoma (DLBCL; 162 cases, 61%), follicular lymphoma (FL; 58 cases, 22%), mantle cell lymphoma (MCL; 11 cases, 4%), Burkitt lymphoma (BL; 6 cases, 2%), chronic lymphocytic leukemia (CLL; 6 cases, 2%), and other B cell lymphomas (18 cases, 7%) and various courses and treatments containing rituximab were performed such as CHOP, ESHAP, hyper-CVAD etc. Among the 261 patients, the prevalence of HBsAg positive is 9 (3.4%) and all of them were successfully treated by rituximab containing regimens and concurrent use of antiviral agents without development of severe hepatitis. Twenty-two patients were not tested both anti-HBc and anti-HBs before rituximab administration. Therefore, 230 patients were tested both HBsAg and anti-HBc before treatment. Fifty-six of 230 patients (24.3%) were isolated anti-HBc positive and the rest of 174 patients were anti-HBc negative. Anti-HBc IgM was tested in 29 of 56 anti-HBc positive patients and all of the 29 patients were negative for anti-HBc IgM. Anti-HBs was positive in 5/174 patients (2.8%) and 36/56 patients (65.4%) in anti-HBc negative patients and positive patients, respectively. Among 56 patients with positive anti-HBc, 5 patients (13.9%) became HBsAg positive after rituximab containing therapy, while none of 174 patients with negative anti-HBc became positive for HBsAg with median follow up of 24 months. Among 5 patients with HBV reactivation, 4 patients were isolated anti-HBc and one patient who received allogeneic stem cell transplantation was both anti-HBs and anti-HBc positive before the start of rituximab, although his anti-HBs decline and disappeared after transplantation with the use of prednisone for chronic GVHD. All of the 5 patients received entecavir on detection of HBsAg and showed prompt decrease of HBV-DNA, however, 4 of 5 patients exhibited mild to moderate elevation of ALT. None of them developed fulminant hepatic failure. We conclude that patients with isolated anti-HBc are at high risk for HBV reactivation (p=0.011, by Fisher's exact test) and should be monitored closely for HBsAg, anti-HBs, HBV-DNA, transaminase levels during and after rituximab containing treatment. Although preemptive use of entecavir from detection of HBsAg or HBV-DNA enabled us to manage hepatitis B virus reactivation and liver injury successfully, mild to moderate hepatic flare could not prevented in our patients. Therefore, these approaches should be further evaluated in the context of clinical usefulness, safety, cost-effectiveness.