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Reactivation of hepatitis B virus following systemic chemotherapy for malignant lymphoma

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Abstract

Reactivation of hepatitis B virus (HBV) has been reported not only in HBsAg-positive patients undergoing systemic chemotherapy, but also in a proportion of HBsAg-negative patients with HBc antibody and/or HBs antibody. Recently, rituximab-plus-steroid combination chemotherapy (R-CHOP, etc.) has been identified as a risk factor for HBV reactivation in HBsAg-negative patients with malignant lymphoma. Prophylaxis with antiviral drugs is essential for preventing HBV reactivation in HBsAg-positive patients, but there is little evidence on which to base the choice of drug or appropriate duration of prophylaxis. There are also few clinical data on HBsAg-negative patients and no established standard of care for such patients with HBV reactivation. Based on the limited number of previous reports, preemptive therapy, guided by serial HBV-DNA monitoring, is a reasonable strategy to prevent HBV reactivation in HBsAg-negative patients. However, clinical evidence alone is insufficient for determining optimal frequency of HBV-DNA monitoring during and after chemotherapy, or for determining when to stop preemptive therapy for HBV reactivation. Thus, well-designed clinical trials should be carried out to investigate the efficacy and safety of such preemptive therapy. Additionally, assessment of viral factors such as HBV genotypes and gene mutations may assist in the development of strategies to prevent the occurrence of severe hepatitis. In this review, we summarize the characteristics of HBV reactivation after systemic chemotherapy including rituximab, and propose a management strategy for malignant lymphoma patients suffering from HBV reactivation.

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Abbreviations

HBV:

Hepatitis B virus

HBsAg:

Hepatitis B surface antigen

Anti-HBc:

hepatitis B core antibody

Anti-HBs:

Hepatitis B surface antibody

HBeAg:

Hepatitis B e antigen

Anti-HBe:

Hepatitis B e antibody

ALT:

Aminotransferase

RTD-PCR:

Real-time detection polymerase chain reaction

NAT:

Nucleic acid amplification test

CHOP:

Cyclophosphamide, doxorubicin, vincristine, prednisolone

R-CHOP:

Rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone

References

  1. 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. doi:10.1038/nm1096-1104.

    Article  CAS  PubMed  Google Scholar 

  2. 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. doi:10.1056/NEJM200101043440120.

    Article  CAS  PubMed  Google Scholar 

  3. 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. doi:10.1097/00007890-199809150-00012.

    Article  CAS  PubMed  Google Scholar 

  4. 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. doi:10.1053/j.gastro.2006.04.015.

    Article  CAS  PubMed  Google Scholar 

  5. 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. doi:10.1038/sj.bmt.1700744.

    Article  CAS  PubMed  Google Scholar 

  6. 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. doi:10.1053/j.gastro.2003.09.026.

    Article  CAS  PubMed  Google Scholar 

  7. 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.

    Article  CAS  PubMed  Google Scholar 

  8. 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. doi:10.1038/sj.bmt.1703614.

    Article  CAS  PubMed  Google Scholar 

  9. Westhoff TH, Jochimsen F, Schmittel A, Stoffler-Meilicke M, Schafer JH, Zidek W, et al. Fatal hepatitis B virus reactivation by an escape mutant following rituximab therapy. Blood. 2003;102:1930. doi:10.1182/blood-2003-05-1403.

    Article  CAS  PubMed  Google Scholar 

  10. 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. doi:10.1200/JCO.2004.05.161.

    Article  CAS  PubMed  Google Scholar 

  11. 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. doi:10.1200/JCO.2008.18.0182.

    Article  CAS  PubMed  Google Scholar 

  12. Yeo W, Johnson PJ. Diagnosis, prevention and management of hepatitis B virus reactivation during anticancer therapy. Hepatology. 2006;43:209–20. doi:10.1002/hep.21051.

    Article  CAS  PubMed  Google Scholar 

  13. 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. doi:10.1053/jhep.2003.50220.

    Article  CAS  PubMed  Google Scholar 

  14. 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. doi:10.1038/sj.bmt.1703826.

    Article  CAS  PubMed  Google Scholar 

  15. 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. doi:10.1002/1096-9071(200011)62:3<299::AID-JMV1>3.0.CO;2-0.

    Article  CAS  PubMed  Google Scholar 

  16. 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. doi:10.1038/sj.bjc.6601699.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Okamoto H, Tsuda F, Sakugawa H, Sastrosoewignjo RI, Imai M, Miyakawa Y, et al. Typing hepatitis B virus by homology in nucleotide sequence: comparison of surface antigen subtypes. J Gen Virol. 1988;69(Pt 10):2575–83. doi:10.1099/0022-1317-69-10-2575.

    Article  CAS  PubMed  Google Scholar 

  18. Chu CJ, Lok AS. Clinical significance of hepatitis B virus genotypes. Hepatology. 2002;35:1274–6. doi:10.1053/jhep.2002.33161.

    Article  PubMed  Google Scholar 

  19. 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. doi:10.1086/590968.

    Article  PubMed  Google Scholar 

  20. 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. doi:10.1002/hep.21249.

    Article  CAS  PubMed  Google Scholar 

  21. 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.

    Article  CAS  PubMed  Google Scholar 

  22. Liang TJ, Hasegawa K, Rimon N, Wands JR, Ben-Porath E. A hepatitis B virus mutant associated with an epidemic of fulminant hepatitis. N Engl J Med. 1991;324:1705–9.

    Article  CAS  PubMed  Google Scholar 

  23. Liang TJ, Hasegawa K, Munoz SJ, Shapiro CN, Yoffe B, McMahon BJ, et al. Hepatitis B virus precore mutation and fulminant hepatitis in the United States: a polymerase chain reaction-based assay for the detection of specific mutation. J Clin Invest. 1994;93:550–5. doi:10.1172/JCI117006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Hui CK, Sun J, Au WY, Lie AK, Yueng YH, Zhang HY, et al. Occult hepatitis B virus infection in hematopoietic stem cell donors in a hepatitis B virus endemic area. J Hepatol. 2005;42:813–9. doi:10.1016/j.jhep.2005.01.018.

    Article  CAS  PubMed  Google Scholar 

  25. Umemura T, Kiyosawa K. Fatal HBV reactivation in a subject with anti-HBs and anti-HBc. Intern Med. 2006;45:747–8. doi:10.2169/internalmedicine.45.0158.

    Article  PubMed  Google Scholar 

  26. Loomba R, Rowley A, Wesley R, Liang TJ, Hoofnagle JH, Pucino F, et al. Systematic review: the effect of preventive lamivudine on hepatitis B reactivation during chemotherapy. Ann Intern Med. 2008;148:519–28.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Hui CK, Cheung WW, Au WY, Lie AK, Zhang HY, Yueng YH, et al. Hepatitis B reactivation after withdrawal of pre-emptive lamivudine in patients with haematological malignancy on completion of cytotoxic chemotherapy. Gut. 2005;54:1597–603. doi:10.1136/gut.2005.070763.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 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. doi:10.1016/j.hepres.2006.08.005.

    Article  CAS  PubMed  Google Scholar 

  29. 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. doi:10.1128/JCM.00366-07.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Liaw YF, Sung JJ, Chow WC, Farrell G, Lee CZ, Yuen H, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med. 2004;351:1521–31. doi:10.1056/NEJMoa033364.

    Article  CAS  PubMed  Google Scholar 

  31. Lok AS, Lai CL, Leung N, Yao GB, Cui ZY, Schiff ER, et al. Long-term safety of lamivudine treatment in patients with chronic hepatitis B. Gastroenterology. 2003;125:1714–22. doi:10.1053/j.gastro.2003.09.033.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors thank Mrs. Kazumi Takagi for support with the analysis of the specimen information from the Nagoya City University Hospital. The authors also thank the ZENYAKU Company for providing clinical data on 111 patients who developed serious hepatitis B after systemic chemotherapy containing rituximab. Financial Support was provided by the Ministry of Health, Labour and Welfare of Japan (grant-in-aid H20-kanen-014 to S.·K.).

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Correspondence to Shigeru Kusumoto.

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Kusumoto, S., Tanaka, Y., Mizokami, M. et al. Reactivation of hepatitis B virus following systemic chemotherapy for malignant lymphoma. Int J Hematol 90, 13–23 (2009). https://doi.org/10.1007/s12185-009-0359-5

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  • DOI: https://doi.org/10.1007/s12185-009-0359-5

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