Abstract
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.
No relevant conflicts of interest to declare.
Author notes
Asterisk with author names denotes non-ASH members.
