Rituximab increases the risk of hepatitis B virus reactivation in non-Hodgkin lymphoma patients who are hepatitis B surface antigen-positive or have resolved hepatitis B virus infection in a real-world setting: a retrospective study
Authors: Tsai Yu-Fen , Yang Ching-I , Du Jeng-Shiun , Lin Ming-Hui , Tang Shih-Hao , Wang Hui-Ching , Cho Shih-Feng , Liu Yi-Chang , Su Yu-Chieh , Dai Chia-Yen , Hsiao Hui-Hua 
Published: September 2019

Background
Hepatitis B virus (HBV) reactivation with a hepatitis flare is a common complication in lymphoma patients treated with immunotherapy and/or chemotherapy. Anti-HBV prophylaxis is suggested for non-Hodgkin lymphoma (NHL) patients undergoing rituximab therapy, even those with resolved HBV infection. Since anti-HBV prophylaxis for patients with resolved HBV infection is not covered by national health insurance in Taiwan, a proportion of these patients receive no prophylaxis. In addition, late HBV reactivation has emerged as a new issue in recent reports, and no consensus has been reached for the optimal duration of antiviral prophylaxis. Thus, the aim of our study was to investigate the incidence and outcomes of HBV reactivation in NHL patients in a real-world setting and to study the frequency of late HBV reactivation.

Materials
Non-Hodgkin lymphoma patients who received rituximab and/or chemotherapy at our institute between January 2011 and December 2015 and who were hepatitis B surface antigen (HBsAg)- or hepatitis B core antibody (HBcAb)-positive were reviewed retrospectively.

Results
A total of 388 patients were screened between January 2011 and December 2015. In total, 196 patients were excluded because HBsAg was not assessed, HBcAb was negative or not assessed, or they were not treated with immunosuppressive therapy. Finally, the retrospective study included 62 HBsAg-positive NHL patients and 130 NHL patients with resolved HBV infection (HBsAg-negative and HBcAb-positive). During a median 30.5-month follow-up period, seven patients experienced HBV reactivation, five of whom had a hepatitis flare. The incidence of HBV reactivation did not significantly differ between the HBsAg-positive patients and the resolved HBV infection population without anti-HBV prophylaxis (4.8% vs. 3.1%, P = 0.683). All patients with HBV reactivation were exposed to rituximab. Notably, late HBV reactivation was not uncommon (two of seven patients with HBV reactivation events, 28.6%). Hepatitis B virus reactivation did not influence the patients’ overall survival. An age ≥65 years and an advanced disease stage were independent risk factors for poorer overall survival.

Conclusion
The incidence of HBV reactivation was similar between the HBsAg-positive patients with antiviral prophylaxis and the resolved HBV infection population without anti-HBV prophylaxis. All HBV reactivation events occurred in NHL patients exposed to rituximab. Late reactivation was not uncommon. The duration of regular liver function monitoring for more than 1 year after immunosuppressive therapy or after withdrawal of prophylactic antiviral therapy should be prolonged. Determining the exact optimal duration of anti-HBV prophylaxis is warranted in a future prospective study for NHL patients treated with rituximab-containing therapy.