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Prevention of hepatitis B virus reactivation in immunosuppressive therapy or chemotherapy

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Abstract

In recent years, hepatitis B virus (HBV) has been found to reproliferate either during or following immunosuppressive therapy or chemotherapy, with hepatitis caused by HBV reactivation now considered a serious issue. HBV reactivation is categorized into occurrence in HBsAg- and anti-HBe-positive asymptomatic carriers, and in HBsAg-negative, anti-HBc low-titer-positive, and/or anti-HBs-positive resolved HBV infection cases. Despite the fact that “clinical cure” is claimed for such resolved HBV cases, low levels of ongoing HBV production are now recognized as being sustained within the liver or in peripheral blood mononuclear cells, with the infection thus now considered to be virologically persistent. The risk of HBV reactivation rises as the level of immunosuppression intensifies, but in recent years HBV reactivation risk has been clearly shown to increase in cases of rituximab plus steroid-containing regimen for treatment of malignant lymphoma. In particular, the incidence of fulminant hepatitis caused by HBV reactivation in cases with resolved HBV infection is reported to be higher than that brought about by acute hepatitis B. Therefore, for all cases in which immunosuppressive therapy or chemotherapy treatment regimens are used, screening for HBV infection and appropriate management in accordance with the status of HBV-related markers are crucial, aimed at preventing occurrence of HBV reactivation. The foundation of the aforementioned management, regardless of HBsAg status, is administration of nucleoside analogues, with their powerful anti-viral properties, when HBV DNA levels reach detectable levels.

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References

  1. Ohishi W, Fujiwara S, Cologne JB, Suzuki G, Akahoshi M, Nishi N, et al. Risk factors for hepatocellular carcinoma in a Japanese population: a nested case-control study. Cancer Epidemiol Biomarkers Prev. 2008;17:846–54.

    Article  CAS  PubMed  Google Scholar 

  2. Lee WM. Hepatitis B virus infection. N Engl J Med. 1997;337:1733–45.

    Article  CAS  PubMed  Google Scholar 

  3. Wands JR, Chura CM, Roll FJ, Maddrey WC. Serial studies of hepatitis-associated antigen and antibody in patients receiving antitumor chemotherapy for myeloproliferative and lymphoproliferative disorders. Gastroenterology. 1975;68:105–12.

    CAS  PubMed  Google Scholar 

  4. 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 

  5. Seth P, Alrajhi AA, Kagevi I, Chaudhary MA, Colcol E, Sahovic E, Aljurf M, Gyger M. Hepatitis B virus reactivation with clinical flare in allogeneic stem cell transplants with chronic graft-versus-host disease. Bone Marrow Transpl. 2002;30:189–94.

    Article  CAS  Google Scholar 

  6. Parfrey PS, Forbes RD, Hutchinson TA, Beaudoin JG, Dauphinee WD, Hollomby DJ, et al. The clinical and pathological course of hepatitis B liver disease in renal transplant recipients. Transplantation. 1984;37:461–6.

    Article  CAS  PubMed  Google Scholar 

  7. Parfrey PS, Forbes RD, Hutchinson TA, Kenick S, Farge D, Dauphinee WD, et al. The impact of renal transplantation on the course of hepatitis B liver disease. Transplantation. 1985;39:610–5.

    Article  CAS  PubMed  Google Scholar 

  8. Demetris AJ, Jaffe R, Sheahan DG, Burnham J, Spero J, Iwatsuki S, et al. Recurrent hepatitis B in liver allograft recipients. Differentiation between viral hepatitis B and rejection. Am J Pathol. 1986;125:161–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Samuel D, Bismuth A, Mathieu D, Arulnaden JL, Reynes M, Benhamou JP, et al. Passive immunoprophylaxis after liver transplantation in HBsAg-positive patients. Lancet. 1991;337:813–5.

    Article  CAS  PubMed  Google Scholar 

  10. Todo S, Demetris AJ, Van Thiel D, Teperman L, Fung JJ, Starzl TE. Orthotopic liver transplantation for patients with hepatitis B virus-related liver disease. Hepatology. 1991;13:619–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Samuel D, Muller R, Alexander G, Fassati L, Ducot B, Benhamou JP, et al. Liver transplantation in European patients with the hepatitis B surface antigen. N Engl J Med. 1993;329:1842–7.

    Article  CAS  PubMed  Google Scholar 

  12. 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.

    Article  CAS  PubMed  Google Scholar 

  13. 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.

    Article  CAS  PubMed  Google Scholar 

  14. Umemura T, Tanaka E, Kiyosawa K, Kumada H, Japan de novo Hepatitis B Research Group. 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.

    Article  PubMed  Google Scholar 

  15. Tubouchi 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 Disease Study Group of Japan and the Japanese Study Group of the Standard Antiviral Therapy for Viral Hepatitis. Acta Hepatol Japonica. 2009;50:38–42.

    Article  Google Scholar 

  16. Yotsuyanagi H, Okuse C, Yasuda K, Orito E, Nishiguchi S, Toyoda J, et al. Distinct geographic distributions of hepatitis B virus genotypes in patients with acute infection in Japan. J Med Virol. 2005;77:39–46.

    Article  CAS  PubMed  Google Scholar 

  17. Suzuki Y, Kobayashi M, Ikeda K, Suzuki F, Arase Y, Akuta N, et al. Persistence of acute infection with hepatitis B virus genotype A and treatment in Japan. J Med Virol. 2005;76:33–9.

    Article  PubMed  Google Scholar 

  18. Kobayashi M, Ikeda K, Arase Y, Suzuki F, Akuta N, Hosaka T, et al. Change of hepatitis B virus genotypes in acute and chronic infections in Japan. J Med Virol. 2008;80:1880–4.

    Article  PubMed  Google Scholar 

  19. Fong TL, Di Bisceglie AM, Gerber MA, Waggoner JG, Hoofnagle JH. Persistence of hepatitis B virus DNA in the liver after loss of HBsAg in chronic hepatitis B. Hepatology. 1993;18:1313–8.

    Article  CAS  PubMed  Google Scholar 

  20. Murakami Y, Minami M, Daimon Y, Okanoue T. Hepatitis B virus DNA in liver, serum, and peripheral blood mononuclear cells after the clearance of serum hepatitis B virus surface antigen. J Med Virol. 2004;72:203–14.

    Article  PubMed  Google Scholar 

  21. Kumada H, Ikeda K, Yoshida A, Seto S, Tsukada T, Kojima M, et al. Short-term prednisolone for inducing seroconversion from hepatitis B e antigen to antibody along with clinical improvement in patients with chronic active hepatitis type B. Jpn J Med. 1987;26:217–22.

    Article  CAS  PubMed  Google Scholar 

  22. Arase Y, Ikeda K, Murashima N, Chayama K, Tsubota A, Koida I, et al. Time course of histological changes in patients with a sustained biochemical and virological response to corticosteroid withdrawal therapy for chronic hepatitis B. Am J Gastroenterol. 1999;94(11):3304–9.

    Article  CAS  PubMed  Google Scholar 

  23. Akuta N, Suzuki F, Tsubota A, Arase Y, Suzuki Y, Someya T, et al. Long-term clinical remission induced by corticosteroid withdrawal therapy (CSWT) in patients with chronic hepatitis B infection: a prospective randomized controlled trial—CSWT with and without follow-up interferon-alpha therapy. Dig Dis Sci. 2002;47:405–14.

    Article  CAS  PubMed  Google Scholar 

  24. Ashwell JD, Lu FW, Vacchio MS. Glucocorticoids in T cell development and function. Annu Rev Immunol. 2000;18:309–45.

    Article  CAS  PubMed  Google Scholar 

  25. Tur-Kaspa R, Burk RD, Shaul Y, Shafritz DA. Hepatitis B virus DNA contains a glucocorticoid-responsive element. Proc Natl Acad Sci USA. 1986;83:1627–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Liaw YF. Hepatitis viruses under immunosuppressive agents. J Gastroenterol Hepatol. 1998;13:14–20.

    Article  CAS  PubMed  Google Scholar 

  27. 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.

    Article  CAS  PubMed  Google Scholar 

  28. Kusumoto S, Tanaka Y, Ueda R, Mizokami M. Reactivation of hepatitis B virus following rituximab-plus-steroid combination chemotherapy. J Gastroenterol. 2011;46:9–16.

    Article  CAS  PubMed  Google Scholar 

  29. Golay J, Zaffaroni L, Vaccari T, Lazzari M, Borleri GM, Bernasconi S, et al. Biologic response of B lymphoma cells to anti-CD20 monoclonal antibody rituximab in vitro: CD55 and CD59 regulate complement-mediated cell lysis. Blood. 2000;95:3900–8.

    CAS  PubMed  Google Scholar 

  30. Taji H, Kagami Y, Okada Y, Andou M, Nishi Y, Saito H, et al. Growth inhibition of CD20-positive B lymphoma cell lines by IDEC-C2B8 anti-CD20 monoclonal antibody. Jpn J Cancer Res. 1998;89:748–56.

    Article  CAS  PubMed  Google Scholar 

  31. Shan D, Ledbetter JA, Press OW. Apoptosis of malignant human B cells by ligation of CD20 with monoclonal antibodies. Blood. 1998;91:1644–52.

    CAS  PubMed  Google Scholar 

  32. Benz K, Dötsch J, Rascher W, Stachel D. Change of the course of steroid-dependent nephrotic syndrome after rituximab therapy. Pediatr Nephrol. 2004;19:794–7.

    Article  PubMed  Google Scholar 

  33. Nakayama M, Kamei K, Nozu K, Matsuoka K, Nakagawa A, Sako M, et al. Rituximab for refractory focal segmental glomerulosclerosis. Pediatr Nephrol. 2008;23:481–5.

    Article  PubMed  Google Scholar 

  34. Gilbert RD, Hulse E, Rigden S. Rituximab therapy for steroid-dependent minimal change nephrotic syndrome. Pediatr Nephrol. 2006;21:1698–700.

    Article  PubMed  Google Scholar 

  35. François H, Daugas E, Bensman A, Ronco P. Unexpected efficacy of rituximab in multirelapsing minimal change nephrotic syndrome in the adult: first case report and pathophysiological considerations. Am J Kidney Dis. 2007;49:158–61.

    Article  PubMed  Google Scholar 

  36. Dai MS, Chao TY, Kao WY, Shyu RY, Liu TM. Delayed hepatitis B virus reactivation after cessation of preemptive lamivudine in lymphoma patients treated with rituximab plus CHOP. Ann Hematol. 2004;83:769–74.

    Article  CAS  PubMed  Google Scholar 

  37. Yeo W, Johnson PJ. Diagnosis, prevention and management of hepatitis B virus reactivation during anticancer therapy. Hepatology. 2006;43:209–20.

    Article  CAS  PubMed  Google Scholar 

  38. Ostuni P, Botsios C, Punzi L, Sfriso P, Todesco S. Hepatitis B reactivation in a chronic hepatitis B surface antigen carrier with rheumatoid arthritis treated with infliximab and low dose methotrexate. Ann Rheum Dis. 2003;62:686–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Esteve M, Saro C, González-Huix F, Suarez F, Forné M, Viver JM. Chronic hepatitis B reactivation following infliximab therapy in Crohn’s disease patients: need for primary prophylaxis. Gut. 2004;53:1363–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Suwannalai P, Auethavekiat P, Udomsubpayakul U, Janvitayanujit S. The infectious profiles of anti-tumor necrosis factor agents in a Thai population: a retrospective study a the university-based hospital. Int J Rheum Dis. 2009;12:118–24.

    Article  PubMed  Google Scholar 

  41. 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.

    Article  PubMed  Google Scholar 

  42. Ohishi W, Chayama K. Current treatment for chronic hepatitis B in Japan. Clin J Gastroenterol. 2009;2:325–30.

    Article  PubMed  Google Scholar 

  43. Kumada H, Okanoue T, Onji M, Moriwaki H, Izumi N, Tanaka E, et al. Guidelines for the treatment of chronic hepatitis and cirrhosis due to hepatitis B virus infection for the fiscal year 2008 in Japan. Hepatol Res. 2010;40:1–7.

    Article  PubMed  Google Scholar 

  44. Lai CL, Dienstag J, Schiff E, Leung NW, Atkins M, Hunt C, et al. Prevalence and clinical correlates of YMDD variants during lamivudine therapy for patients with chronic hepatitis B. Clin Infect Dis. 2003;36:687–96.

    Article  CAS  PubMed  Google Scholar 

  45. 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-naïve patients is rare through 5 years of therapy. Hepatology. 2009;49:1503–14.

    Article  CAS  PubMed  Google Scholar 

  46. Ahmed A, Keeffe EB. Lamivudine therapy for chemotherapy-induced reactivation of hepatitis B virus infection. Am J Gastroenterol. 1999;94:249–51.

    Article  CAS  PubMed  Google Scholar 

  47. Yeo W, Steinberg JL, Tam JS, Chan PK, Leung NW, Lam KC, et al. Lamivudine in the treatment of hepatitis B virus reactivation during cytotoxic chemotherapy. J Med Virol. 1999;59:263–9.

    Article  CAS  PubMed  Google Scholar 

  48. Clark FL, Drummond MW, Chambers S, Chapman BA, Patton WN. Successful treatment with lamivudine for fulminant reactivated hepatitis B infection following intensive therapy for high-grade non-Hodgkin’s lymphoma. Ann Oncol. 1998;9:385–7.

    Article  CAS  PubMed  Google Scholar 

  49. Picardi M, Selleri C, De Rosa G, Raiola A, Pezzullo L, Rotoli B. Lamivudine treatment for chronic replicative hepatitis B virus infection after allogeneic bone marrow transplantation. Bone Marrow Transpl. 1998;21:1267–9.

    Article  CAS  Google Scholar 

  50. Colson P, Borentain P, Coso D, Chabannon C, Tamalet C, Gérolami R. Entecavir as a first-line treatment for HBV reactivation following polychemotherapy for lymphoma. Br J Haematol. 2008;143:148–50.

    Article  PubMed  Google Scholar 

  51. 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.

    Article  CAS  PubMed  Google Scholar 

  52. Rossi G, Pelizzari A, Motta M, Puoti M. Primary prophylaxis with lamivudine of hepatitis B virus reactivation in chronic HbsAg carriers with lymphoid malignancies treated with chemotherapy. Br J Haematol. 2001;115:58–62.

    Article  CAS  PubMed  Google Scholar 

  53. Shibolet O, Ilan Y, Gillis S, Hubert A, Shouval D, Safadi R. Lamivudine therapy for prevention of immunosuppressive-induced hepatitis B virus reactivation in hepatitis B surface antigen carriers. Blood. 2002;100:391–6.

    Article  CAS  PubMed  Google Scholar 

  54. 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.

    Article  CAS  PubMed  Google Scholar 

  55. Katz LH, Fraser A, Gafter-Gvili A, Leibovici L, Tur-Kaspa R. Lamivudine prevents reactivation of hepatitis B and reduces mortality in immunosuppressed patients: systematic review and meta-analysis. J Viral Hepat. 2008;15:89–102.

    CAS  PubMed  Google Scholar 

  56. 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 

  57. Okita R, Takahashi M, Narahara H, Sanada Y, Okada M, Kawakami Y, et al. Use of entecavir to prevent hepatitis B virus reactivation during cytotoxic chemotherapy for solid malignancy. Clin J Gastroenterol. 2009;2:214–7.

    Article  PubMed  Google Scholar 

  58. Watanabe M, Shibuya A, Takada J, Tanaka Y, Okuwaki Y, Minamino T, et al. Entecavir is an optional agent to prevent hepatitis B virus (HBV) reactivation: a review of 16 patients. Eur J Intern Med. 2010;21(4):333–7.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Clinical Studies, Radiation Effects Research Foundation, Hiroshima, Japan

    Waka Ohishi

  2. Department of Medicine and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan

    Kazuaki Chayama

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  1. Waka Ohishi
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Correspondence to Kazuaki Chayama.

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Ohishi, W., Chayama, K. Prevention of hepatitis B virus reactivation in immunosuppressive therapy or chemotherapy. Clin Exp Nephrol 15, 634–640 (2011). https://doi.org/10.1007/s10157-011-0464-7

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