Skip to main content

Advertisement

Log in

Prevention and management of hepatitis B virus reactivation in cancer patients

  • Review Article
  • Published:
Hepatology International Aims and scope Submit manuscript

Abstract

Hepatitis B virus (HBV) reactivation during immunosuppressive therapy is common in patients with solid tumor or hematological malignancies. It is associated with significant morbidity and mortality due to hepatitis flare and/or hepatic decompensation. These consequences arising from HBV reactivation are, however, largely preventable. Routine screening for HBV serologic status is recommended for all cancer patients undergoing chemotherapy or biologics. By recognizing different serological patterns (which represent either overt or occult HBV infection) and the types of immunosuppressive therapies prescribed, a risk-adapted approach can be established. Prophylactic therapy with nucleos(t)ide analogues (prior to or concomitantly with the commencement of immunosuppressive therapies) is more effective than pre-emptive therapy (starting antiviral when HBV DNA level is rising) in high-risk individuals. Entecavir has been proven to be more effective than lamivudine according to recent studies. Close monitoring of serum HBV level is the preferred strategy in low-risk patients. However, the optimal interval of DNA monitoring and the duration of therapy remain unknown.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Gupta S, Govindarajan S, Fong TL, Redeker AG. Spontaneous reactivation in chronic hepatitis B: patterns and natural history. J Clin Gastroenterol 1990;12:562–568

    Article  CAS  PubMed  Google Scholar 

  2. Pattullo V. Hepatitis B reactivation in the setting of chemotherapy and immunosuppression—prevention is better than cure. World J Hepatol 2015;7:954–967

    Article  PubMed  PubMed Central  Google Scholar 

  3. 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;100:182–188

    CAS  PubMed  Google Scholar 

  4. Markovic S, Drozina G, Vovk M, Fidler-Jenko M. Reactivation of hepatitis B but not hepatitis C in patients with malignant lymphoma and immunosuppressive therapy. A prospective study in 305 patients. Hepatogastroenterology 1999;46:2925–2930

    CAS  PubMed  Google Scholar 

  5. Di Bisceglie AM, Lok AS, Martin P, Terrault N, Perrillo RP, Hoofnagle JH. Recent US Food and Drug Administration warnings on hepatitis B reactivation with immune-suppressing and anticancer drugs: just the tip of the iceberg? Hepatology 2015;61:703–711

    Article  PubMed  Google Scholar 

  6. Yang PL, Althage A, Chung J, Maier H, Wieland S, Isogawa M, et al. Immune effectors required for hepatitis B virus clearance. Proc Natl Acad Sci USA 2010;107:798–802

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Raimondo G, Pollicino T, Cacciola I, Squadrito G. Occult hepatitis B virus infection. J Hepatol 2007;46:160–170

    Article  PubMed  Google Scholar 

  8. 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;2:1104–1108

    Article  CAS  PubMed  Google Scholar 

  9. 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;135:1192–1199

    Article  CAS  PubMed  Google Scholar 

  10. Civan J, Hann HW. Giving rituximab in patients with occult or resolved hepatitis B virus infection: are the current guidelines good enough? Expert Opin Drug Saf 2015;14:865–875

    Article  CAS  PubMed  Google Scholar 

  11. Perrillo RP, Gish R, Falck-Ytter YT. American Gastroenterological Association Institute technical review on prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy. Gastroenterology 2015;148(221–244):e3

    PubMed  Google Scholar 

  12. 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;32:3736–3743

    Article  CAS  PubMed  Google Scholar 

  13. 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

    Article  CAS  PubMed  Google Scholar 

  14. 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;27:605–611

    Article  CAS  PubMed  Google Scholar 

  15. Hammond SP, Borchelt AM, Ukomadu C, Ho VT, Baden LR, Marty FM. Hepatitis B virus reactivation following allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2009;15:1049–1059

    Article  PubMed  Google Scholar 

  16. Mikulska M, Nicolini L, Signori A, Rivoli G, Del Bono V, Raiola AM, et al. Hepatitis B reactivation in HBsAg-negative/HBcAb-positive allogeneic haematopoietic stem cell transplant recipients: risk factors and outcome. Clin Microbiol Infect 2014;20:O694–O701

    Article  CAS  PubMed  Google Scholar 

  17. 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;148:519–528

    Article  PubMed  PubMed Central  Google Scholar 

  18. 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;116:4769–4776

    Article  PubMed  Google Scholar 

  19. Kim SJ, Hsu C, Song YQ, Tay K, Hong XN, Cao J, et al. Hepatitis B virus reactivation in B-cell lymphoma patients treated with rituximab: analysis from the Asia Lymphoma Study Group. Eur J Cancer 2013;49:3486–3496

    Article  CAS  PubMed  Google Scholar 

  20. 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;59:2092–2100

    Article  CAS  PubMed  Google Scholar 

  21. Mozessohn L, Chan KK, Feld JJ, Hicks LK. Hepatitis B reactivation in HBsAg-negative/HBcAb-positive patients receiving rituximab for lymphoma: a meta-analysis. J. Viral Hepat 2015;22:842–849

    Article  CAS  PubMed  Google Scholar 

  22. Shouval D, Shibolet O. Immunosuppression and HBV reactivation. Semin Liver Dis. 2013;33:167–77.

    Article  CAS  PubMed  Google Scholar 

  23. Chen WC, Cheng JS, Chiang PH, Tsay FW, Chan HH, Chang HW, et al. A comparison of entecavir and lamivudine for the prophylaxis of hepatitis B virus reactivation in solid tumor patients undergoing systemic cytotoxic chemotherapy. PLoS ONE 2015;10:e0131545

    Article  PubMed  PubMed Central  Google Scholar 

  24. Salpini R, Colagrossi L, Bellocchi MC, Surdo M, Becker C, Alteri C, et al. Hepatitis B surface antigen genetic elements critical for immune escape correlate with hepatitis B virus reactivation upon immunosuppression. Hepatology 2015;61:823–833

    Article  CAS  PubMed  Google Scholar 

  25. 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;90:1306–1311

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 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;37:1320–1328

    Article  CAS  PubMed  Google Scholar 

  27. Lai CL, Yuen MF. Systemic corticosteroid and reactivation of chronic hepatitis B. Respirology 2010;15:1017–1018

    Article  PubMed  Google Scholar 

  28. Ling WH, Soe PP, Pang AS, Lee SC. Hepatitis B virus reactivation risk varies with different chemotherapy regimens commonly used in solid tumours. Br J Cancer 2013;108:1931–1935

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Tamori A, Koike T, Goto H, Wakitani S, Tada M, Morikawa H, et al. Prospective study of reactivation of hepatitis B virus in patients with rheumatoid arthritis who received immunosuppressive therapy: evaluation of both HBsAg-positive and HBsAg-negative cohorts. J Gastroenterol 2011;46:556–564

    Article  CAS  PubMed  Google Scholar 

  30. Flowers MA, Heathcote J, Wanless IR, Sherman M, Reynolds WJ, Cameron RG, et al. Fulminant hepatitis as a consequence of reactivation of hepatitis B virus infection after discontinuation of low-dose methotrexate therapy. Ann Intern Med 1990;112:381–382

    Article  CAS  PubMed  Google Scholar 

  31. Hagiyama H, Kubota T, Komano Y, Kurosaki M, Watanabe M, Miyasaka N. Fulminant hepatitis in an asymptomatic chronic carrier of hepatitis B virus mutant after withdrawal of low-dose methotrexate therapy for rheumatoid arthritis. Clin Exp Rheumatol 2004;22:375–376

    CAS  PubMed  Google Scholar 

  32. Lai GM, Yan SL, Chang CS, Tsai CY. Hepatitis B reactivation in chronic myeloid leukemia patients receiving tyrosine kinase inhibitor. World J Gastroenterol 2013;19:1318–1321

    Article  PubMed  PubMed Central  Google Scholar 

  33. Kang BW, Lee SJ, Moon JH, Kim SN, Chae YS, Kim JG, et al. Chronic myeloid leukemia patient manifesting fatal hepatitis B virus reactivation during treatment with imatinib rescued by liver transplantation: case report and literature review. Int J Hematol 2009;90:383–387

    Article  PubMed  Google Scholar 

  34. Lakhani S, Davidson L, Priebat DA, Sherker AH. Reactivation of chronic hepatitis B infection related to imatinib mesylate therapy. Hepatol Int 2008;2:498–499

    Article  PubMed  PubMed Central  Google Scholar 

  35. Walker EJ, Simko JP, Ko AH. Hepatitis B viral reactivation secondary to imatinib treatment in a patient with gastrointestinal stromal tumor. Anticancer Res 2014;34:3629–3634

    CAS  PubMed  Google Scholar 

  36. Seto WK. Hepatitis B virus reactivation during immunosuppressive therapy: appropriate risk stratification. World J Hepatol. 2015;7:825–30.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Shao W, Zhang F, Cong N, Li J, Song J. The hepatitis B virus reactivation after transarterial chemoembolization in Chinese hepatocellular carcinoma patients with low serum hepatitis B virus DNA level. Ther Clin Risk Manag 2015;11:1367–1370

    Article  PubMed  PubMed Central  Google Scholar 

  38. Lazdina U, Alheim M, Nystrom J, Hultgren C, Borisova G, Sominskaya I, et al. Priming of cytotoxic T cell responses to exogenous hepatitis B virus core antigen is B cell dependent. J Gen Virol 2003;84:139–146

    Article  CAS  PubMed  Google Scholar 

  39. Evens AM, Jovanovic BD, Su YC, Raisch DW, Ganger D, Belknap SM, et al. Rituximab-associated hepatitis B virus (HBV) reactivation in lymphoproliferative diseases: meta-analysis and examination of FDA safety reports. Ann Oncol 2011;22:1170–1180

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Mitka M. FDA: increased HBV reactivation risk with ofatumumab or rituximab. JAMA 2013;310:1664

    Article  CAS  PubMed  Google Scholar 

  41. Reddy KR, Beavers KL, Hammond SP, Lim JK, Falck-Ytter YT. American Gastroenterological Association Institute guideline on the prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy. Gastroenterology 2015;148:215–219 (quiz e16–e17)

    Article  CAS  PubMed  Google Scholar 

  42. Tan D, Tan SY, Lim ST, Kim SJ, Kim WS, Advani R, et al. Management of B-cell non-Hodgkin lymphoma in Asia: resource-stratified guidelines. Lancet Oncol 2013;14:e548–e561

    Article  PubMed  Google Scholar 

  43. Artz AS, Somerfield MR, Feld JJ, Giusti AF, Kramer BS, Sabichi AL, et al. American Society of Clinical Oncology provisional clinical opinion: chronic hepatitis B virus infection screening in patients receiving cytotoxic chemotherapy for treatment of malignant diseases. J Clin Oncol 2010;28:3199–3202

    Article  PubMed  Google Scholar 

  44. Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology 2009;50:661–662

    Article  PubMed  Google Scholar 

  45. Lok AS, Ward JW, Perrillo RP, McMahon BJ, Liang TJ. Reactivation of hepatitis B during immunosuppressive therapy: potentially fatal yet preventable. Ann Intern Med 2012;156:743–745

    Article  PubMed  PubMed Central  Google Scholar 

  46. EASL clinical practice guidelines. Management of chronic hepatitis B virus infection. J Hepatol 2012;57:167–185

    Article  Google Scholar 

  47. LeFevre ML. Screening for hepatitis B virus infection in nonpregnant adolescents and adults: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2014;161:58–66

    Article  PubMed  Google Scholar 

  48. Hwang JP, Fisch MJ, Zhang H, Kallen MA, Routbort MJ, Lal LS, et al. Low rates of hepatitis B virus screening at the onset of chemotherapy. J Oncol Pract 2012;8:e32–e39

    Article  PubMed  PubMed Central  Google Scholar 

  49. 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;22:927–934

    Article  CAS  PubMed  Google Scholar 

  50. Hwang JP, Lok AS. Management of patients with hepatitis B who require immunosuppressive therapy. Nat Rev Gastroenterol Hepatol 2014;11:209–219

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Hsu C, Hsiung CA, Su IJ, Hwang WS, Wang MC, Lin SF, et al. A revisit of prophylactic lamivudine for chemotherapy-associated hepatitis B reactivation in non-Hodgkin’s lymphoma: a randomized trial. Hepatology 2008;47:844–853

    Article  CAS  PubMed  Google Scholar 

  52. Raimondo G, Filomia R, Maimone S. Therapy of occult hepatitis B virus infection and prevention of reactivation. Intervirology 2014;57:189–195

    Article  CAS  PubMed  Google Scholar 

  53. Huang YH, Hsiao LT, Hong YC, Chiou TJ, Yu YB, Gau JP, et al. Randomized controlled trial of entecavir prophylaxis for rituximab-associated hepatitis B virus reactivation in patients with lymphoma and resolved hepatitis B. J Clin Oncol 2013;31:2765–2772

    Article  CAS  PubMed  Google Scholar 

  54. Kusumoto S, Tanaka Y, Suzuki R, Watanabe T, Nakata M, Takasaki H, et al. Monitoring of Hepatitis B Virus (HBV) DNA and Risk of HBV Reactivation in B-Cell Lymphoma: a Prospective Observational Study. Clin Infect Dis 2015;61:719–729

    Article  PubMed  Google Scholar 

  55. Shen LP, Zhang Y, Wang F, Zhang S, Yang JY, Fang KX, et al. Epidemiological changes in hepatitis B prevalence in an entire population after 20 years of the universal HBV vaccination programme. Epidemiol Infect 2011;139:1159–1165

    Article  CAS  PubMed  Google Scholar 

  56. Zhang H, Li Q, Sun J, Wang C, Gu Q, Feng X, et al. Seroprevalence and risk factors for hepatitis B infection in an adult population in Northeast China. Int J Med Sci 2011;8:321–331

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Pei SN, Ma MC, Wang MC, Kuo CY, Rau KM, Su CY, et al. Analysis of hepatitis B surface antibody titers in B cell lymphoma patients after rituximab therapy. Ann Hematol 2012;91:1007–1012

    Article  CAS  PubMed  Google Scholar 

  58. Seto WK, Chan SY, Hwang YY, Wong DK, Liu KS, Gill H, et al. A prospective study of hepatitis B reactivation in patients with prior HBV exposure undergoing hematopoietic stem cell transplantation: reactivation association with graft-versus-host disease (abstract). J Hepatol 2015;62:O009

    Google Scholar 

  59. Onozawa M, Hashino S, Darmanin S, Okada K, Morita R, Takahata M, et al. HB vaccination in the prevention of viral reactivation in allogeneic hematopoietic stem cell transplantation recipients with previous HBV infection. Biol Blood Marrow Transplant 2008;14:1226–1230

    Article  PubMed  Google Scholar 

  60. Jang JW, Choi JY, Bae SH, Yoon SK, Chang UI, Kim CW, et al. A randomized controlled study of preemptive lamivudine in patients receiving transarterial chemo-lipiodolization. Hepatology 2006;43:233–240

    Article  CAS  PubMed  Google Scholar 

  61. 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;312:2521–2530

    Article  PubMed  Google Scholar 

  62. Koskinas JS, Deutsch M, Adamidi S, Skondra M, Tampaki M, Alexopoulou A, et al. The role of tenofovir in preventing and treating hepatitis B virus (HBV) reactivation in immunosuppressed patients. A real life experience from a tertiary center. Eur J Intern Med 2014;25:768–771

    Article  CAS  PubMed  Google Scholar 

  63. Gara N, Zhao X, Collins MT, Chong WH, Kleiner DE, Jake Liang T, et al. Renal tubular dysfunction during long-term adefovir or tenofovir therapy in chronic hepatitis B. Aliment Pharmacol Ther 2012;35:1317–1325

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Pipili C, Cholongitas E, Papatheodoridis G. Review article: nucleos(t)ide analogues in patients with chronic hepatitis B virus infection and chronic kidney disease. Aliment Pharmacol Ther 2014;39:35–46

    Article  CAS  PubMed  Google Scholar 

  65. Tenney DJ, Rose RE, Baldick CJ, Pokornowski KA, Eggers BJ, Fang J, et al. Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naive patients is rare through 5 years of therapy. Hepatology 2009;49:1503–1514

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Man-Fung Yuen.

Ethics declarations

This article does not contain any studies with human or animal subjects.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cheung, KS., Seto, WK., Lai, CL. et al. Prevention and management of hepatitis B virus reactivation in cancer patients. Hepatol Int 10, 407–414 (2016). https://doi.org/10.1007/s12072-015-9692-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12072-015-9692-3

Keywords

Navigation