Journal of Gastroenterology

, Volume 46, Issue 1, pp 9–16 | Cite as

Reactivation of hepatitis B virus following rituximab-plus-steroid combination chemotherapy

  • Shigeru Kusumoto
  • Yasuhito TanakaEmail author
  • Ryuzo Ueda
  • Masashi Mizokami


Reactivation of hepatitis B virus (HBV) has been reported as a fatal complication following systemic chemotherapy or other immunosuppressive therapy. The risk of HBV reactivation differs according to both the patient’s HBV infection status prior to systemic chemotherapy and the degree of immunosuppression due to chemotherapy. For establishing an optimal strategy for hepatitis prevention and treatment, it is necessary to understand the characteristics, the clinical course and the risk factors for HBV reactivation and to recognize the difference between hepatitis B surface antigen (HBsAg)-positive and -negative patients with HBV reactivation. Among the important viral risk factors, HBV-DNA level and HBV-related serum markers have been reported to be associated with HBV reactivation in addition to cccDNA, genotypes and gene mutations. Rituximab-plus-steroid combination chemotherapy has recently been identified as a host risk factor for HBV reactivation in hepatitis B core antibody (anti-HBc)-positive and/or hepatitis B surface antibody (anti-HBs) positive—but nonetheless HBsAg-negative—lymphoma patients. For these patients with resolved hepatitis B, preemptive therapy guided by serial HBV-DNA monitoring is a reasonable strategy to enable early diagnosis of HBV reactivation and initiation of antiviral therapy. In this review, we summarize the characteristics of HBV reactivation following rituximab-plus-steroid combination chemotherapy, mainly in HBsAg-negative lymphoma patients, and propose a strategy for managing HBV reactivation.


Reactivation HBV Rituximab 



Hepatitis B core antibody


Hepatitis B surface antibody


Covalently closed circular DNA


Cyclophosphamide, doxorubicin, vincristine, prednisolone


Hepatitis B surface antigen


Hepatitis B virus


Hematopoietic stem cell transplantation


Rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone


Real-time detection PCR



Financial support was provided by the Ministry of Health, Labour and Welfare of Japan (grant-in-aid H20-kanen-014 to S.K.).


  1. 1.
    Dervite I, Hober D, Morel P. Acute hepatitis B in a patient with antibodies to hepatitis B surface antigen who was receiving rituximab. N Engl J Med. 2001;344:68–9.CrossRefPubMedGoogle Scholar
  2. 2.
    Hui CK, Cheung WW, Zhang HY, Au WY, Yueng YH, Leung AY, et al. Kinetics and risk of de novo hepatitis B infection in HBsAg-negative patients undergoing cytotoxic chemotherapy. Gastroenterology. 2006;131:59–68.CrossRefPubMedGoogle Scholar
  3. 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;27:605–11.CrossRefPubMedGoogle Scholar
  4. 4.
    Kusumoto S, Tanaka Y, Mizokami M, Ueda R. Reactivation of hepatitis B virus following systemic chemotherapy for malignant lymphoma. Int J Hematol. 2009;90:13–23.CrossRefPubMedGoogle Scholar
  5. 5.
    McLaughlin P, Grillo-Lopez AJ, Link BK, Levy R, Czuczman MS, Williams ME, et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol. 1998;16:2825–33.PubMedGoogle Scholar
  6. 6.
    Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:235–42.CrossRefPubMedGoogle Scholar
  7. 7.
    Edwards JC, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, Close DR, et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med. 2004;350:2572–81.CrossRefPubMedGoogle Scholar
  8. 8.
    Scully M, Cohen H, Cavenagh J, Benjamin S, Starke R, Killick S, et al. Remission in acute refractory and relapsing thrombotic thrombocytopenic purpura following rituximab is associated with a reduction in IgG antibodies to ADAMTS-13. Br J Haematol. 2007;136:451–61.CrossRefPubMedGoogle Scholar
  9. 9.
    Godeau B, Porcher R, Fain O, Lefrere F, Fenaux P, Cheze S, et al. Rituximab efficacy and safety in adult splenectomy candidates with chronic immune thrombocytopenic purpura: results of a prospective multicenter phase 2 study. Blood. 2008;112:999–1004.CrossRefPubMedGoogle Scholar
  10. 10.
    Voog E, Morschhauser F, Solal-Celigny P. Neutropenia in patients treated with rituximab. N Engl J Med. 2003;348:2691–4. (discussion 2691–4).CrossRefPubMedGoogle Scholar
  11. 11.
    Yokoyama H, Watanabe T, Maruyama D, Kim SW, Kobayashi Y, Tobinai K. Progressive multifocal leukoencephalopathy in a patient with B-cell lymphoma during rituximab-containing chemotherapy: case report and review of the literature. Int J Hematol. 2008;88:443–7.CrossRefPubMedGoogle Scholar
  12. 12.
    Dienstag JL. Hepatitis B virus infection. N Engl J Med. 2008;359:1486–500.CrossRefPubMedGoogle Scholar
  13. 13.
    Rehermann B, Ferrari C, Pasquinelli C, Chisari FV. The hepatitis B virus persists for decades after patients’ recovery from acute viral hepatitis despite active maintenance of a cytotoxic T-lymphocyte response. Nat Med. 1996;2:1104–8.CrossRefPubMedGoogle Scholar
  14. 14.
    Yeo W, Chan PK, Zhong S, Ho WM, Steinberg JL, Tam JS, et al. Frequency of hepatitis B virus reactivation in cancer patients undergoing cytotoxic chemotherapy: a prospective study of 626 patients with identification of risk factors. J Med Virol. 2000;62:299–307.CrossRefPubMedGoogle Scholar
  15. 15.
    Yeo W, Zee B, Zhong S, Chan PK, Wong WL, Ho WM, et al. Comprehensive analysis of risk factors associating with Hepatitis B virus (HBV) reactivation in cancer patients undergoing cytotoxic chemotherapy. Br J Cancer. 2004;90:1306–11.CrossRefPubMedGoogle Scholar
  16. 16.
    Lau GK, Leung YH, Fong DY, Au WY, Kwong YL, Lie A, et al. High hepatitis B virus (HBV) DNA viral load as the most important risk factor for HBV reactivation in patients positive for HBV surface antigen undergoing autologous hematopoietic cell transplantation. Blood. 2002;99:2324–30.CrossRefPubMedGoogle Scholar
  17. 17.
    Umemura T, Tanaka E, Kiyosawa K, Kumada H. Mortality secondary to fulminant hepatic failure in patients with prior resolution of hepatitis B virus infection in Japan. Clin Infect Dis. 2008;47:e52–6.CrossRefPubMedGoogle Scholar
  18. 18.
    Borentain P, Colson P, Coso D, Bories E, Charbonnier A, Stoppa AM, et al. Clinical and virological factors associated with hepatitis B virus reactivation in HBsAg-negative and anti-HBc antibodies-positive patients undergoing chemotherapy and/or autologous stem cell transplantation for cancer. J Viral Hepat. 2010. doi: 10.1111/j.1365-2893.2009.01239.x.
  19. 19.
    Cheng AL, Hsiung CA, Su IJ, Chen PJ, Chang MC, Tsao CJ, et al. Steroid-free chemotherapy decreases risk of hepatitis B virus (HBV) reactivation in HBV-carriers with lymphoma. Hepatology. 2003;37:1320–8.CrossRefPubMedGoogle Scholar
  20. 20.
    Dhedin N, Douvin C, Kuentz M, Saint Marc MF, Reman O, Rieux C, et al. Reverse seroconversion of hepatitis B after allogeneic bone marrow transplantation: a retrospective study of 37 patients with pretransplant anti-HBs and anti-HBc. Transplantation. 1998;66:616–9.CrossRefPubMedGoogle Scholar
  21. 21.
    Locasciulli A, Bruno B, Alessandrino EP, Meloni G, Arcese W, Bandini G, et al. Hepatitis reactivation and liver failure in haemopoietic stem cell transplants for hepatitis B virus (HBV)/hepatitis C virus (HCV) positive recipients: a retrospective study by the Italian group for blood and marrow transplantation. Bone Marrow Transplant. 2003;31:295–300.CrossRefPubMedGoogle Scholar
  22. 22.
    Lau GK, Liang R, Chiu EK, Lee CK, Lam SK. Hepatic events after bone marrow transplantation in patients with hepatitis B infection: a case controlled study. Bone Marrow Transplant. 1997;19:795–9.CrossRefPubMedGoogle Scholar
  23. 23.
    Seth P, Alrajhi AA, Kagevi I, Chaudhary MA, Colcol E, Sahovic E, et al. Hepatitis B virus reactivation with clinical flare in allogeneic stem cell transplants with chronic graft-versus-host disease. Bone Marrow Transplant. 2002;30:189–94.CrossRefPubMedGoogle Scholar
  24. 24.
    Wong DK, Tanaka Y, Lai CL, Mizokami M, Fung J, Yuen MF. Hepatitis B virus core-related antigens as markers for monitoring chronic hepatitis B infection. J Clin Microbiol. 2007;45:3942–7.CrossRefPubMedGoogle Scholar
  25. 25.
    Shinkai N, Tanaka Y, Orito E, Ito K, Ohno T, Hirashima N, et al. Measurement of hepatitis B virus core-related antigen as predicting factor for relapse after cessation of lamivudine therapy for chronic hepatitis B virus infection. Hepatol Res. 2006;36:272–6.CrossRefPubMedGoogle Scholar
  26. 26.
    Yoshida T, Kusumoto S, Inagaki A, Mori F, Ito A, Ri M, et al. Reactivation of hepatitis B virus in HBsAg-negative patients with multiple myeloma: two case reports. Int J Hematol. 2010;91:844–9.CrossRefPubMedGoogle Scholar
  27. 27.
    Kurbanov F, Tanaka Y, Mizokami M. Geographical and genetic diversity of the human hepatitis B virus. Hepatol Res. 2010;40:14–30.CrossRefPubMedGoogle Scholar
  28. 28.
    Miyakawa Y, Mizokami M. Classifying hepatitis B virus genotypes. Intervirology. 2003;46:329–38.CrossRefPubMedGoogle Scholar
  29. 29.
    Tanaka Y, Hasegawa I, Kato T, Orito E, Hirashima N, Acharya SK, et al. A case-control study for differences among hepatitis B virus infections of genotypes A (subtypes Aa and Ae) and D. Hepatology. 2004;40:747–55.CrossRefPubMedGoogle Scholar
  30. 30.
    Omata M, Ehata T, Yokosuka O, Hosoda K, Ohto M. Mutations in the precore region of hepatitis B virus DNA in patients with fulminant and severe hepatitis. N Engl J Med. 1991;324:1699–704.CrossRefPubMedGoogle Scholar
  31. 31.
    Ozasa A, Tanaka Y, Orito E, Sugiyama M, Kang JH, Hige S, et al. Influence of genotypes and precore mutations on fulminant or chronic outcome of acute hepatitis B virus infection. Hepatology. 2006;44:326–34.CrossRefPubMedGoogle Scholar
  32. 32.
    Pfreundschuh M, Trumper L, Osterborg A, Pettengell R, Trneny M, Imrie K, et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol. 2006;7:379–91.CrossRefPubMedGoogle Scholar
  33. 33.
    Shortt J, Spencer A. Adjuvant rituximab causes prolonged hypogammaglobulinaemia following autologous stem cell transplant for non-Hodgkin’s lymphoma. Bone Marrow Transplant. 2006;38:433–6.CrossRefPubMedGoogle Scholar
  34. 34.
    Lim SH, Zhang Y, Wang Z, Esler WV, Beggs D, Pruitt B, et al. Maintenance rituximab after autologous stem cell transplant for high-risk B-cell lymphoma induces prolonged and severe hypogammaglobulinemia. Bone Marrow Transplant. 2005;35:207–8.CrossRefPubMedGoogle Scholar
  35. 35.
    Kim EB, Kim DS, Park SJ, Park Y, Rho KH, Kim SJ. Hepatitis B virus reactivation in a surface antigen-negative and antibody-positive patient after rituximab plus CHOP chemotherapy. Cancer Res Treat. 2008;40:36–8.CrossRefPubMedGoogle Scholar
  36. 36.
    Sakamaki H, Sato Y, Mori SI, Ohashi K, Tanikawa S, Akiyama H, et al. Hepatitis B virus reactivation in a patient with chronic GVHD after allogeneic peripheral blood stem cell transplantation. Int J Hematol. 2001;74:342–6.CrossRefPubMedGoogle Scholar
  37. 37.
    Matsue K, Aoki T, Odawara J, Fujiwara H, Iwama K, Kimura S, et al. High risk of hepatitis B-virus reactivation after hematopoietic cell transplantation in hepatitis B core antibody-positive patients. Eur J Haematol. 2009;83:357–64.CrossRefPubMedGoogle Scholar
  38. 38.
    Oshima K, Sato M, Okuda S, Terasako K, Nakasone H, Kako S, et al. Reverse seroconversion of hepatitis B virus after allogeneic hematopoietic stem cell transplantation in the absence of chronic graft-versus-host disease. Hematology. 2009;14:73–5.CrossRefPubMedGoogle Scholar
  39. 39.
    Yeo W, Johnson PJ. Diagnosis, prevention and management of hepatitis B virus reactivation during anticancer therapy. Hepatology. 2006;43:209–20.CrossRefPubMedGoogle Scholar
  40. 40.
    Umemura T, Kiyosawa K. Fatal HBV reactivation in a subject with anti-HBs and anti-HBc. Intern Med. 2006;45:747–8.CrossRefPubMedGoogle Scholar
  41. 41.
    Lok AS, Liang RH, Chiu EK, Wong KL, Chan TK, Todd D. Reactivation of hepatitis B virus replication in patients receiving cytotoxic therapy. Report of a prospective study. Gastroenterology. 1991;100:182–8.PubMedGoogle Scholar
  42. 42.
    Yeo W, Chan PK, Ho WM, Zee B, Lam KC, Lei KI, et al. Lamivudine for the prevention of hepatitis B virus reactivation in hepatitis B s-antigen seropositive cancer patients undergoing cytotoxic chemotherapy. J Clin Oncol. 2004;22:927–34.CrossRefPubMedGoogle Scholar
  43. 43.
    Lau GK, Yiu HH, Fong DY, Cheng HC, Au WY, Lai LS, et al. Early is superior to deferred preemptive lamivudine therapy for hepatitis B patients undergoing chemotherapy. Gastroenterology. 2003;125:1742–9.CrossRefPubMedGoogle Scholar
  44. 44.
    Pei SN, Chen CH, Lee CM, Wang MC, Ma MC, Hu TH, et al. Reactivation of hepatitis B virus following rituximab-based regimens: a serious complication in both HBsAg-positive and HBsAg-negative patients. Ann Hematol. 2010;89:255–62.CrossRefPubMedGoogle Scholar
  45. 45.
    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;20:2013–7.CrossRefPubMedGoogle Scholar
  46. 46.
    Hassan MM, Li D, El-Deeb AS, Wolff RA, Bondy ML, Davila M, et al. Association between hepatitis B virus and pancreatic cancer. J Clin Oncol. 2008;26:4557–62.CrossRefPubMedGoogle Scholar
  47. 47.
    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;93:951–2.CrossRefPubMedGoogle Scholar
  48. 48.
    Francisci D, Falcinelli F, Schiaroli E, Capponi M, Belfiori B, Flenghi L, et al. Management of hepatitis B virus reactivation in patients with hematological malignancies treated with chemotherapy. Infection. 2010;38:58–61.CrossRefPubMedGoogle Scholar
  49. 49.
    Bedognetti D, Zoppoli G, Sertoli MR, Zanardi E, Blandini P, Uccellini L, et al. Relevance of HBV/HBcAb screening in lymphoma patients treated in the Rituximab era. Int J Hematol. 2010;91:342–4. (author reply 5–6).CrossRefPubMedGoogle Scholar
  50. 50.
    Koo YX, Tan DS, Tan IB, Tao M, Chow WC, Lim ST. Hepatitis B virus reactivation and role of antiviral prophylaxis in lymphoma patients with past hepatitis B virus infection who are receiving chemoimmunotherapy. Cancer. 2010;116:115–21.PubMedGoogle Scholar
  51. 51.
    Ji D, Cao J, Hong X, Li J, Wang J, Chen F, et al. Low incidence 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;85:243–50.CrossRefPubMedGoogle Scholar
  52. 52.
    Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009;50:661–2.CrossRefPubMedGoogle Scholar
  53. 53.
    Tsubouchi H, Kumada H, Kiyosawa K, Mochida S, Sakaida I, Tanaka E, et al. Prevention of immunosuppressive therapy or chemotherapy-induced reactivation of hepatitis B virus infection: joint report of the Intractable Liver Diseases Study Group of Japan and the Japanese Study Group of the Standard Antiviral Therapy for Viral Hepatitis. Kanzo. 2009;50:38–42.CrossRefGoogle Scholar
  54. 54.
    Weinbaum CM, Williams I, Mast EE, Wang SA, Finelli L, Wasley A, et al. Recommendations for identification and public health management of persons with chronic hepatitis B virus infection. MMWR Recomm Rep. 2008;57:1–20.PubMedGoogle Scholar
  55. 55.
    Ide Y, Ito Y, Takahashi S, Tokudome N, Kobayashi K, Sugihara T, et al. Hepatitis B virus reactivation in adjuvant chemotherapy for breast cancer. Breast Cancer 2010. doi: 10.1007/s12282-010-0213-x.
  56. 56.
    Matsumoto T, Marusawa H, Dogaki M, Suginoshita Y, Inokuma T. Adalimumab-induced lethal hepatitis B virus reactivation in an HBsAg-negative patient with clinically resolved hepatitis B virus infection. Liver Int. 2010;30:1241–2.CrossRefPubMedGoogle Scholar

Copyright information

© Springer 2010

Authors and Affiliations

  • Shigeru Kusumoto
    • 1
  • Yasuhito Tanaka
    • 2
    Email author
  • Ryuzo Ueda
    • 1
  • Masashi Mizokami
    • 3
  1. 1.Department of Medical Oncology and ImmunologyNagoya City University Graduate School of Medical Sciences Mizuho-ku, NagoyaJapan
  2. 2.Department of Virology and Liver UnitNagoya City University Graduate School of Medical Sciences Mizuho-ku, NagoyaJapan
  3. 3.Research Center for Hepatitis and ImmunologyInternational Medical Center of Japan Konodai HospitalIchikawaJapan

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