Randomized Controlled Trial of Entecavir Prophylaxis for Rituximab-Associated Hepatitis B Virus Reactivation in Patients With Lymphoma and Resolved Hepatitis B Yi-Hsiang Huang, Liang-Tsai Hsiao, Ying-Chung Hong, Tzeon-Jye Chiou, Yuan-Bin Yu, Jyh-Pyng Gau, Chun-Yu Liu, Muh-Hwa Yang, Cheng-Hwai Tzeng, Pui-Ching Lee, Han-Chieh Lin, and Shou-Dong Lee Processed as a Rapid Communication manuscript. Yi-Hsiang Huang, Liang-Tsai Hsiao, Ying-Chung Hong, Tzeon-Jye Chiou, Yuan-Bin Yu, Jyh-Pyng Gau, Chun-Yu Liu, Muh-Hwa Yang, Cheng-Hwai Tzeng, Pui-Ching Lee, Han-Chieh Lin, Taipei Veterans General Hospital; Yi-Hsiang Huang, Liang-Tsai Hsiao, Tzeon-Jye Chiou, Yuan-Bin Yu, Jyh-Pyng Gau, Chun-Yu Liu, Muh-Hwa Yang, Cheng-Hwai Tzeng, Han-Chieh Lin, National Yang-Ming University School of Medicine; Shou-Dong Lee, Cheng Hsin General Hospital, Taipei, Taiwan. Published online ahead of print at www.jco.org on June 17, 2013. Supported by Grant No. NSC 99-2314- B-010-052-MY2 from the National Science Council and Grant No. VGHUST98-P1-07 from the Taipei Veterans General Hospitals University System of Taiwan, Taipei, Taiwan. Y.-H.H. and S.-D.L. contributed equally to this work. Authors’ disclosures of potential con- flicts of interest and author contribu- tions are found at the end of this article. Clinical trial information: NCT00926757. Corresponding author: Yi-Hsiang Huang, MD, PhD, Division of Gastroenterology, Department of Medicine, Taipei Veter- ans General Hospital, 201 Shih-Pai Rd, Sec 2, Taipei 112, Taiwan; e-mail: yhhuang@vghtpe.gov.tw. © 2013 by American Society of Clinical Oncology 0732-183X/13/3122w-2765w/$20.00 DOI: 10.1200/JCO.2012.48.5938 A B S T R A C T Purpose The role of antiviral prophylaxis in preventing hepatitis B virus (HBV) reactivation before rituximab-based chemotherapy in patients with lymphoma and resolved hepatitis B is unclear. Patients and Methods Eighty patients with CD20 + lymphoma and resolved hepatitis B were randomly assigned to receive either prophylactic entecavir (ETV) before chemotherapy to 3 months after completing chemotherapy (ETV prophylactic group, n = 41) or to receive therapeutic ETV at the time of HBV reactivation and hepatitis B surface antigen (HBsAg) reverse seroconversion since chemotherapy (control group, n = 39). Results Fifty-eight patients (72.5%) were positive for hepatitis B surface antibody, and HBV DNA was undetectable in 50 patients (62.5%). During a mean 18-month follow-up period, one patient (2.4%) in the ETV prophylactic group and seven patients (17.9%) in the control group developed HBV reactivation (P = .027). The cumulative HBV reactivation rates at months 6, 12, and 18 after chemotherapy were 8%, 11.2%, and 25.9%, respectively, in the control group, and 0%, 0%, and 4.3% in the ETV prophylactic group (P = .019). Four patients (50%) in the control group had HBsAg reverse seroconversion after HBV reactivation. The cumulative HBsAg reverse seroconversion rates at months 6, 12, and 18 since chemotherapy were 0%, 6.4%, and 16.3% in the control group, respectively, which were significantly higher than those in the ETV prophylactic group (P = .032). Patients with detectable or undetectable viral load could develop HBV reactivation and HBsAg reverse seroconversion. Conclusion Undetectable HBV viral load before chemotherapy did not confer reactivation-free status. Antiviral prophylaxis can potentially prevent rituximab-associated HBV reactivation in patients with lym- phoma and resolved hepatitis B. J Clin Oncol 31:2765-2772. © 2013 by American Society of Clinical Oncology INTRODUCTION There are already 350 million people worldwide chronically infected by hepatitis B virus (HBV). 1 Although most of these people are inactive carriers, 2 HBV reactivation induced by immunosuppressive or cytotoxic chemotherapy is not uncommon and is potentially life-threatening in carriers. 3 Reactivation results in a variety of outcomes, ranging from asymptomatic to severe hepatitis with fatal conse- quences. 4 HBV reactivation is typically confirmed by an increase in serum HBV DNA levels with active viral replication that may be accompanied by reap- pearance of hepatitis B e antigen (HBeAg). Usually, HBV viral loads increase when receiving immuno- suppressant or cytotoxic chemotherapy. Host im- mune rebound and hepatitis flare develop after withdrawal of such treatments. 4 HBV reactivation during cytotoxic chemo- therapy can occur in a wide variety of patients with cancer and underlying HBV infection. 5,6 Lymphoma is the most well studied cancer in such patients and the majority of randomized con- trolled trials has focused on it. 7,8 Rituximab is a chimeric mouse human anti-CD20 monoclonal antibody that can reduce B cell numbers and an- tibody levels, and it is used in combination cyto- toxic therapy for CD20 + lymphomas, such as JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T VOLUME 31  NUMBER 22  AUGUST 1 2013 © 2013 by American Society of Clinical Oncology 2765 July 28, 2013 from 203.64.247.101 Information downloaded from jco.ascopubs.org and provided by at Medical Library of Taipei Veterans General Hospital on Copyright © 2013 American Society of Clinical Oncology. All rights reserved.