High Titers of Hepatitis B Surface Antibodies Indicating Low Risk of Hepatitis B Virus-Related Hepatitis in Lymphoma Patients Treated with Rituximab-Based Chemotherapy

Introduction: Hepatitis B virus (HBV) reactivation is a well-known complication after rituximab (R)-based chemotherapy in B-cell lymphoma patients with resolved HBV infection. The rate of HBV-related hepatitis after R-based chemotherapy is 4-25%. Patients who are positive for qualitative hepatitis B surface antibodies (anti-HBs) have been shown to have lower risk of, but are not entirely free from HBV reactivation. The strength of anti-HBs is standardized in international units (IU) and high anti-HBs titers (> 100 mIU/mL) was ever shown as a protective factor in a small study; no one with high anti-HBs titers developed HBV-related hepatitis after R-based therapy. In this study, we would like to validate the protective role of high anti-HBs titers with large cohort in our institute.

Methods: Medical records of all 752 patients with lymphoma seen at Kaohsiung Chang Gung Memorial Hospital between 2008 and 2013 were screened. Those who were negative for hepatitis B surface antigen (HBsAg-), positive for hepatitis B core antibody (anti-HBc+), positive for antiHBs with titers more than 100 mIU/mL, negative for hepatitis C antibody (anti-HCV-), and treated with first-line R-containing chemotherapy were analyzed. Hepatitis was defined as alanine aminotransferase (ALT) levels > 2.5 times upper normal limit. HBV-related hepatitis was defined as hepatitis accompanied with positive HBsAg and/or HBV viremia.

Results: Forty-three patients were eligible for analysis. About half patients were females (56%) and had a median age of 60 years. Pathology subtypes included diffuse large B cell lymphoma (74%), follicular lymphoma (21%), and other low grade lymphomas (5%). Most patients (77%) were stage III or IV, and 38% of patients had high IPI scores (4 or 5). Most patients (63%) received R-CHOP regimen. Hepatitis complicated in 5 (11.6%) patients and none was HBV-related. The etiology of hepatitis in these 5 patients included congestive liver (1), fatty liver (1), hemophagocytic syndrome (1), sepsis (1), and unknown (1). Only one patient (2.3%) developed HBV reactivation with HBsAg seroreversion after 4 cycles of R-COP regimen. His initial anti-HBs titer was more than 1000 mIU/mL and the titer did not diminish after chemotherapy, even at the time of HBsAg turning positive. However, this patient did not develop HBV-related hepatitis and his highest ALT level was 95 IU/L, which occurred after the first cycle of R-COP and his HBsAg at that time was still negative. Sequencing analysis of PCR products amplified from the HBV S region revealed multiple mutations: K24R, L97V, Q121H, T113S, T114S, K122R, T123S, P127L, G145A, A159G, E164D, Q181R; and the P127L and G145A are escape mutations.

Conclusion: Pre-treatment high anti-HBs titers prevent most HBV-related hepatitis in lymphoma patients receiving R-containing therapies. Although rare mutants of HBV may escape anti-HBs protective surveillance, the HBV mutant did not cause clinically significant hepatic injury in our study.