Risk of hepatitis B reactivation in HBsAg-negative/HBcAb-positive patients with undetectable serum HBV DNA after treatment with rituximab for lymphoma: a meta-analysis
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Hepatitis B surface antigen (HBsAg)-negative/hepatitis B core antibody (HBcAb)-positive patients with undetectable serum hepatitis B virus (HBV) DNA have experienced and resolved hepatitis B virus (HBV) infection. Lymphoma patients with resolved HBV infection have high risk of HBV reactivation when treated with robust immunosuppressive agents, but the reported rate varies extensively between different studies. This study aims to estimate the risk of HBV reactivation in HBsAg-negative/HBcAb-positive patients receiving rituximab-containing chemotherapy for lymphoma.
Databases were searched for papers published in English until 8 August 2016. The pooled risk of HBV reactivation was estimated using a random-effects model.
Data from 15 studies were retrieved, including a total of 1312 HBsAg-negative/HBcAb-positive lymphoma patients treated with rituximab-containing chemotherapy. The results revealed HBV reactivation rate of 9.0 % [95 % confidence interval (CI) 0.05–0.15]. In subgroup analysis, the reactivation rates for prospective and retrospective studies were 17 % (I 2 = 87.3 %; 95 % 0.08–0.39, p < 0.001) and 7 % (I 2 = 43.1 %; 95 % CI 0.05–0.11, p = 0.07), respectively.
This meta-analysis confirms a measurable and potentially substantial risk of HBV reactivation in HBsAg-negative/HBcAb-positive patients with rituximab treatment for lymphoma. Prophylactic use of anti-HBV agents should be seriously considered for such patients.
KeywordsHepatitis B virus Rituximab Hepatitis B reactivation Lymphoma
This work was supported by the National Natural Science Foundation (81373136, 81572010), Application Research of Capital Clinical Characteristic and Promotion of Achievements (Z151100004015011), and the Capital Health Development Research Special Independent Innovation Project (2016-2-5032).
Compliance with ethical standards
Conflict of interest
Zilin Tang, Xiaodong Li, Shunquan Wu, Yan Liu, Qiao Yan, Dongping Xu, and Jin Li declare that there are no conflicts of interest.
Human and animal rights statement
This study was approved by the ethics committee of Beijing 302 Hospital. This article does not contain any studies with human or animal subjects.
- 1.Smith MR. Rituximab (monoclonal anti-CD20 antibody): mechanisms of action and resistance. Oncogene 2003;22:359–368Google Scholar
- 2.Feugier P, Van Hoof A, Sebban C, Solal-Celigny P, Bouabdallah R, Fermé C, et al. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d’Etude des Lymphomes del’Adulte. J Clin Oncol 2005;23:4117–4126Google Scholar
- 3.Yeo W, Chan TC, Leung NW, Lam WY, Mo FK, Chu MT, et al. Hepatitis B virus reactivation in lymphoma patients with prior resolved hepatitis B undergoing anticancer therapy with or without rituximab. J Clin Oncol 2009;27:605–611Google Scholar
- 4.Loomba R, Liang TJ. Hepatitis B reactivation associated with immune suppressive and biological modifier therapies: current concepts, management strategies, and future directions. Gastroenterology 2017;152:1297–1309Google Scholar
- 5.Merli M, Rattotti S, Gotti M, Arcaini L. Antiviral therapies for managing viral hepatitis in lymphoma patients. Expert Opin Pharmacother 2017;18:363–376Google Scholar
- 6.Yuen MF, Wong DK, Fung J, Ip P, But D, Hung I, et al. HBsAg seroclearance in chronic hepatitis B in Asian patients: replicative level and risk of hepatocellular carcinoma. Gastroenterology 2008;135:1192–1199Google Scholar
- 7.Koo YX, Tay M, Teh YE, Teng D, Tan DS, Tan IB, et al. Risk of hepatitis B virus (HBV) reactivation in hepatitis B surface antigen negative/hepatitis B core antibody positive patients receiving rituximab-containing combination chemotherapy without routine antiviral prophylaxis. Ann Hematol 2011;90:1219–1223Google Scholar
- 8.Seto WK, Chan TS, Hwang YY, Wong DK, Fung J, Liu KS, et al. Hepatitis B reactivation in patients with previous hepatitis B virus exposure undergoing rituximab-containing chemotherapy for lymphoma: a prospective study. J Clin Oncol 2014;32:3736–3743Google Scholar
- 9.Hsu C, Tsou HH, Lin SJ, Wang MC, Yao M, Hwang WL, et al. Chemotherapy-induced hepatitis B reactivation in lymphoma patients with resolved HBV infection: a prospective study. Hepatology 2014;59:2092–2100Google Scholar
- 10.Persico E, De Renzo A, La Mura V, Bruno S, Masarone M, Torella R, et al. Occult hepatitis B virus infection in patients with non Hodgkin lymphoma: the need for early diagnosis in anti-Hbc positive patients. Gut 2007;56:1470–1471Google Scholar
- 11.Ji D, Cao J, Hong X, Li J, Wang J, Chen F, et al. Low rate of hepatitis B virus reactivation during chemotherapy among diffuse large B-cell lymphoma patients who are HBsAg-negative/HBcAb-positive: a multicenter retrospective study. Eur J Haematol 2010;85:243–250Google Scholar
- 12.Matsue K, Kimura S, Takanashi Y, Iwama K, Fujiwara H, Yamakura M, et al. Reactivation of hepatitis B virus after rituximab-containing treatment in patients with CD20-positive B-cell lymphoma. Cancer 2010;116:4769–4776Google Scholar
- 13.Lu S, Xu Y, Mu Q, Cao L, Chen J, Zhu Z, et al. The risk of hepatitis B virus reactivation and the role of antiviral prophylaxis in hepatitis B surface antigen negative/hepatitis B core antibody positive patients with diffuse large B-cell lymphoma receiving rituximab-based chemotherapy. Leuk Lymphoma 2015;56:1027–1032Google Scholar
- 14.Wu CY, Hsiao LT, Chiou TJ, Gau JP, Liu JH, Yu YB, et al. Lymphocyte/monocyte ratio and cycles of rituximab-containing therapy are risk factors for hepatitis B virus reactivation in patients with diffuse large B-cell lymphoma and resolved hepatitis B. Leuk Lymphoma 2014;56:2357–2364Google Scholar
- 15.Chen KL, Chen J, Rao HL, Guo Y, Huang HQ, Zhang L, et al. Hepatitis B virus reactivation and hepatitis in diffuse large B-cell lymphoma patients with resolved hepatitis B receiving rituximab-containing chemotherapy: risk factors and survival. Chin J Cancer 2015;34:225–236Google Scholar
- 16.Hsiao LT, Chiou TJ, Gau JP, Yang CF, Yu YB, Liu CY, et al. Risk of reverse seroconversion of hepatitis B virus surface antigen in rituximab-treated non-Hodgkin lymphoma patients: a large cohort retrospective study. Medicine (Baltimore) 2015; 94:e1321Google Scholar
- 17.Targhetta C, Cabras MG, Mamusa AM, Mascia G, Angelucci E. Hepatitis B virus-related liver disease in isolated anti-hepatitis B-core positive lymphoma patients receiving chemo- or chemo-immune therapy. Haematologica 2008;93:951–952Google Scholar
- 18.Méndez-Navarro J, Corey KE, Zheng H, Barlow LL, Jang JY, Lin W et al. Hepatitis B screening, prophylaxis and re-activation in the era of rituximab-based chemotherapy. Liver Int 2011;31:330–339Google Scholar
- 19.Oh MJ, Lee HJ. A study of hepatitis B virus reactivation associated with rituximab therapy in real-world clinical practice: a single-center experience. Clin Mol Hepatol 2013;19:51–59Google Scholar
- 20.Fukushima N, Mizuta T, Tanaka M, Yokoo M, Ide M, Hisatomi T, et al. Retrospective and prospective studies of hepatitis B virus reactivation in malignant lymphoma with occult HBV carrier. Ann Oncol 2009;20:2013–2017Google Scholar
- 21.Zhang MY, Zhu GQ, Zheng JN, Cheng Z, Van Poucke S, Shi KQ, et al. Nucleos(t)ide analogues for preventing HBV reactivation in immunosuppressed patients with hematological malignancies: a network meta-analysis. Expert Rev Anti-infective Ther 2017;15:503–513Google Scholar
- 22.Huang H, Li X, Zhu J, Ye S, Zhang H, Wang W, et al. Entecavir vs lamivudine for prevention of hepatitis B virus reactivation among patients with untreated diffuse large B-cell lymphoma receiving R-CHOP chemotherapy: a randomized clinical trial. JAMA 2014; 312:2521–2530Google Scholar
- 23.Mozessohn L, Chan KK, Feld JJ, et al. Hepatitis B reactivation in HBsAg-negative/HBcAb-positive patients receiving rituximab for lymphoma: a meta-analysis. J Viral Hepat 2015; 22(10):842Google Scholar
- 24.Tian Q, Jia J. Hepatitis B virus genotypes: epidemiological and clinical relevance in Asia. Hepatol Int 2016;10:854–860Google Scholar
- 25.Huang YH, Lin HC, Lee SD. Reply to S. Kusumoto et al. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 2013; 31(35):4481Google Scholar
- 26.Paul S, Dickstein A, Saxena A, et al. Role of surface antibody in hepatitis B reactivation in patients with resolved infection and hematologic malignancy: a meta-analysis. Hepatology 2017. doi: 10.1002/hep.29082