Annals of Hematology

, Volume 83, Issue 5, pp 270–275

Preemptive use of interferon or lamivudine for hepatitis B reactivation in patients with aggressive lymphoma receiving chemotherapy

  • Shiang Jiin Leaw
  • Chia Jui Yen
  • Wen Tsung Huang
  • Tsai Yun Chen
  • Wu Chou Su
  • Chao Jung Tsao
Original Article


The hepatitis B virus (HBV) reactivation rate among hepatitis B virus surface antigen (HBsAg)-positive patients undergoing chemotherapy ranges from 21 to 35% with a mortality rate of 4–41%. The risk is significantly evident in patients with aggressive lymphoma, which is highly responsive to standard chemotherapy with cyclophosphamide, hydroxydaunomycin, vincristine, and prednisone (CHOP) achieving a complete response rate of 60–80% and 5-year survival rate of 30–50% with only 1% of treatment-related mortality. α-Interferon and lamivudine were given as preemptive treatment for HBV reactivation in HBsAg-positive patients treated for aggressive lymphoma consecutively from 1994 to 1997 and 1998 to 2001, respectively, in our institution. The outcome of 77 HBsAg-positive patients treated for aggressive lymphoma at our institution from 1990 to 2001 was studied. Of these patients, 53 did not receive prophylaxis while 13 received subcutaneous α-interferon 3×106 U thrice weekly and 11 received oral lamivudine 100 mg/day simultaneously with chemotherapy. Seventeen patients in the non-prophylactic group experienced HBV reactivation (32%), seven of whom progressed to fatal fulminant hepatitis (41%), which is associated with 13.2% of the mortality rate among the non-prophylactic patients. None of the 24 patients in the prophylactic group had grade III or IV toxicity or elevated ALT level greater than fivefold exceeding 200 IU/l suggestive of clinical hepatitis that required dose reduction or delayed chemotherapy. Thus, preemptive use of α-interferon or lamivudine in HBsAg-positive lymphoma patients undergoing chemotherapy may be a promising approach to prevent HBV reactivation that carries a risk of delayed treatment or even fatal outcome.


Lymphoma Lamivudine Interferon HBV 


  1. 1.
    Ahmed A, Keefe EB (1999) Lamivudine therapy for chemotherapy-induced reactivation of hepatitis B virus infection. Am J Gastroenterol 94:249–251PubMedGoogle Scholar
  2. 2.
    Al-Taie OH, Mörk H, Gassel AM, Wilhelm M, Weissbrich B, Scheurlen M (1999) Prevention of hepatitis B flare-up during chemotherapy using lamivudine: case report and review of literature. Ann Hematol 78:247–249PubMedGoogle Scholar
  3. 3.
    Armitage JO (1993) Treatment of non-Hodgkin’s lymphoma. N Engl J Med 328:1023–1030CrossRefPubMedGoogle Scholar
  4. 4.
    Bird GL, Smith H, Portmann B, Alexander GJ, Williams R (1989) Acute liver decompensation on withdrawal of cytotoxic chemotherapy and immunosuppressive therapy in hepatitis B carriers. Q J Med 73:895–902PubMedGoogle Scholar
  5. 5.
    Beasley RP, HwangLY, Lin CC, Leu ML, Stevens CE, Szmuness W, et al. (1982) Incidence of hepatitis B infection in preschool children in Taiwan. J Infect Dis 146:198–204PubMedGoogle Scholar
  6. 6.
    Cheng AL (1996) Steroid-free chemotherapy decreases the risk of hepatitis flare-up in hepatitis B virus carriers with non-Hodgkin’s lymphoma. Blood 87:1202Google Scholar
  7. 7.
    Cheng AL, Chao AH, Su IJ, Chen PJ, Chang MC, Tsao CJ, Kao WY, Yen WC, Hsu CH, Tien HF, Chao TY, Chen LT, Jacqueline WP, representing the Lymphoma Committee of Taiwan Cooperative Oncology Group (TCOG) (2003) Steroid-free chemotherapy decreases risk of hepatitis B virus reactivation in HBV-carriers with lymphoma. Hepatology 37:1320–1328CrossRefPubMedGoogle Scholar
  8. 8.
    Clark FL, Drummond MW, Chambers S, Chapman BA, Patton WN (1998) Successful treatment with lamivudine for fulminant reactivated hepatitis B infection following intensive therapy for high-grade non-Hodgkin’s lymphoma. Ann Oncol 9:385–387PubMedGoogle Scholar
  9. 9.
    Dai MS, Lu JJ, Chen YC, Perng CL, Chao TY (2001) Reactivation of precore mutant hepatitis B virus in chemotherapy-treated patients. Cancer 92:2927–2932PubMedGoogle Scholar
  10. 10.
    Dienstag JL, Schiff ER, Wright TL, Perrillo RP, Hann HW, Goodman Z, Crowther L, Condreay LD, Woessner M, Rubin M, Brown NA (1999) Lamivudine as initial treatment for chronic hepatitis B in the United States. N Engl J Med 341:1256–1263PubMedGoogle Scholar
  11. 11.
    Di Bisceglie AM, Fong TL, Fried MW, Swain MG, Baker B, Korenman J, Bergasa NV, Waggoner JG, Park Y, Hoofnagle JH (1993) A randomized, controlled trial of recombinant alpha-interferon therapy for chronic hepatitis B. Am J Gastroenterol 88:1887–1892PubMedGoogle Scholar
  12. 12.
    Endo T, Sakai T, Fujimoto K, Yamamoto S, Takashima H, Haseyama Y, Nishio M, Koizumi K, Koike T, Sawada K (2001) A possible role for lamivudine as prophylaxis against hepatitis B reactivation in carriers of hepatitis B who undergo chemotherapy and autologous peripheral blood stem cell transplantation for non-Hodgkin’s lymphoma. Bone Marrow Transplant 27:433–436CrossRefPubMedGoogle Scholar
  13. 13.
    Fattovich G, Farci P, Rugge M, Brollo L, Mandas A, Pontisso P, Giustina G, Lai ME, Belussi F, Busatto G, et al. (1992) A randomized controlled trial of lymphoblastoid interferon-alpha in patients with chronic hepatitis B lacking HBeAg. Hepatology 15:584–589PubMedGoogle Scholar
  14. 14.
    Fisher RI, Gaynor ER, Dahlberg S, Oken MM, Grogan TM, Mize EM, Glick JH, Coltman CA Jr, Miller TP (1993) Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma. N Engl J Med 328:1002–1006PubMedGoogle Scholar
  15. 15.
    Galbraith RM, Eddleston AL, Williams R, Zuckerman AJ (1975) Fulminant hepatic failure in leukaemia and choriocarcinoma related to withdrawal of cytotoxic drug therapy. Lancet 2:528-530CrossRefPubMedGoogle Scholar
  16. 16.
    Gordon LI, Harrington D, Anderson J, et al. (1992) Comparison of a second generation combination chemotherapeutic regimen (m-BACOD) with a standard regimen (CHOP) for advanced diffuse non-Hodgkin’s lymphoma. N Engl J Med 327:1342–1349PubMedGoogle Scholar
  17. 17.
    Haanen JB, Bieger R, van’t Wout JW (1996) Acute hepatic injury after discontinuation of chemotherapy in a patient with non-Hodgkin’s lymphoma and chronic hepatitis B virus infection. Neth J Med 49:239–43CrossRefPubMedGoogle Scholar
  18. 18.
    Hoofnagle JH, Dusheiko GM, Schafer DF, Jones EA, Micetich KC, Young RC, Costa J (1982) Reactivation of chronic hepatitis B virus infection by cancer chemotherapy. Ann Intern Med 96:447–449PubMedGoogle Scholar
  19. 19.
    Janssen HL, Gerken G, Carreno V, Marcellin P, Naoumov NV, Craxi A, Ring-Larsen H, Kitis G, van Hattum J, de Vries RA, Michielsen PP, ten Kate FJ, Hop WC, Heijtink RA, Honkoop P, Schalm SW (1999) Interferon alfa for chronic hepatitis B infection: increased efficacy of prolonged treatment. The European Concerted Action on Viral Hepatitis (EUROHEP). Hepatology 30:238–243PubMedGoogle Scholar
  20. 20.
    Kumagai K, Takagi T, Nakamura S, Sawada U, Kura Y, Kodama F, Shimano S, Kudoh I, Nakamura H, Sawada K, Ohnosi T (1997) Hepatitis B virus carriers in the treatment of malignant lymphoma: an epidemiological study in Japan. Ann Oncol 8:107–109CrossRefPubMedGoogle Scholar
  21. 21.
    Lai CL, Chien RN, Leung NW, Chang TT, Guan R, Tai DI, Ng KY, Wu PC, Dent JC, Barber J, Stephenson SL, Gray DF (1998) A one-year trial of lamivudine for chronic hepatitis B. Asia Hepatitis Lamivudine Study Group. N Engl J Med 339:61–68PubMedGoogle Scholar
  22. 22.
    Lam KC, Ching LL, Mg RP, Trepo C, Wu PC (1981) Deleterious effect of prednisolone in HBsAg-positive chronic active hepatitis. N Engl J Med 304:380–386PubMedGoogle Scholar
  23. 23.
    Lampertico P, Del Ninno E, Vigano M, Romeo R, Donato MF, Sablon E, Morabito A, Colombo M (2003) Long-term suppression of hepatitis B e antigen-negative chronic hepatitis B by 24-month interferon therapy. Hepatology 37:756–763CrossRefPubMedGoogle Scholar
  24. 24.
    Lau JY, Lai CL, Lin HJ, Lok AS, Liang RH, Wu PC, Chan TK, Todd D (1989) Fatal reactivation of chronic hepatitis B virus infection following withdrawal of chemotherapy in lymphoma patients. Q J Med 73:911–917PubMedGoogle Scholar
  25. 25.
    Lau GK, Leung YH, Fong DY, Au WY, Kwong YL, Lie A, Hou JL, Wen YM, Nanj A, Liang R (2002) 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 99:2324–2330PubMedGoogle Scholar
  26. 26.
    Lewin S, Walters T, Locarnini S (2002) Hepatitis B treatment: rational combination chemotherapy based on viral kinetic and animal model studies. Antiviral Res 55:381–396CrossRefPubMedGoogle Scholar
  27. 27.
    Lim LL, Wai CT, Lee YM, Kong HL, Koay E, Lim SG (2002) Prophylactic lamivudine prevents hepatitis B reactivation in chemotherapy patients. Aliment Pharmacol Ther 16:1939–1944CrossRefPubMedGoogle Scholar
  28. 28.
    Lin SM, Sheen IS, Chien RN, Chu CM, Liaw YF (1999) Long-term beneficial effect of interferon therapy in patients with chronic hepatitis B virus infection. Hepatology 29:971–975PubMedGoogle Scholar
  29. 29.
    Liao CA, Lee CM, Wu HC, Wang MC, Lu SN, Eng HL (2002) Lamivudine for the treatment of hepatitis B virus reactivation following chemotherapy for non-Hodgkin’s lymphoma. Br J Haematol 116:166–169PubMedGoogle Scholar
  30. 30.
    Lok SF, Liang HS, Chiu KW, Wong KL, Chan TK, Todd D. (1991) Reactivation of hepatitis B virus replication in patients receiving cytotoxic therapy. Gastroenterology 100:182–188Google Scholar
  31. 31.
    Lok AS, Heathcote EJ, Hoofnagle JH (2001) Management of hepatitis B: 2000—summary of a workshop. Gastroenterology 120:1828–1853PubMedGoogle Scholar
  32. 32.
    Markovic S, Drozina G, Vovk M, Fidler-Jenko M (1999) Reactivation of hepatitis B but not hepatitis C in patients with malignant lymphoma and immunosuppressive therapy. A prospective study in 305 patients. Hepatogastroenterology 46:2925–2930PubMedGoogle Scholar
  33. 33.
    Nakamura Y, Motokura T, Fujita A, Yamashita T, Ogata E (1996) Severe hepatitis related to chemotherapy in hepatitis B virus carriers with hematologic malignancies. Survey in Japan, 1987–1991. Cancer 78:2210–2215CrossRefPubMedGoogle Scholar
  34. 34.
    Nagington J, Cossart YE, Cohen BJ (1977) Reactivation of hepatitis B after transplantation operations. Lancet 1:558–560CrossRefPubMedGoogle Scholar
  35. 35.
    Papatheodoridis GV, Dimou E, Papadimitropoulos V (2002) Nucleoside analogues for chronic hepatitis B: antiviral efficacy and viral resistance. Am J Gastroenterol 97:1618–1628CrossRefPubMedGoogle Scholar
  36. 36.
    Rossi G, Pelizzari A, Motta M, Puoti M (2001) Primary prophylaxis with lamivudine of hepatitis B virus reactivation in chronic HBsAg carriers with lymphoid malignancies treated with chemotherapy. Br J Haematol 115:58–62PubMedGoogle Scholar
  37. 37.
    Sagnelli E, Manzillo G, Mario G, Pasquale G, Felaco FM, Filippini P, Izzo CM, Piccinino F (1980) Serum levels of hepatitis B surface and core antigens during immunosuppressive treatment of HBsAg-positive chronic active hepatitis. Lancet 2:395–397CrossRefPubMedGoogle Scholar
  38. 38.
    Scullard GH, Smith CI, Merigan TC, Roinson WS, Gregory PB (1981) Effects of immunosuppressive therapy on viral markers in chronic active hepatitis B. Gastroenterology 81:987–991PubMedGoogle Scholar
  39. 39.
    Shibolet O, IIan Y, Gillis S, Hubert A, Shouval D, Safadi R (2002) Lamivudine therapy for prevention of immunosuppressive-induced hepatitis B virus reactivation in hepatitis B surface antigen carriers. Blood 100:391–396CrossRefPubMedGoogle Scholar
  40. 40.
    Silverstri F, Ermacora A, Sperotto A, Patriarca F, Zaja F, (2000) Lamivudine allows completion of chemotherapy in lymphoma patients with hepatitis B reactivation. Br J Haematol 108:394–396CrossRefPubMedGoogle Scholar
  41. 41.
    Simpson ND, Simpson PW, Ahmed AM, Nguyen MH, Garcia G, Keeffe EB, Ahmed A (2003) Prophylaxis against chemotherapy-induced reactivation of hepatitis B virus infection with lamivudine. J Clin Gastroenterol 37:68–71CrossRefPubMedGoogle Scholar
  42. 42.
    Tassopoulos NC, Koutelou MG, Polychronaki H, Paraloglou-Ioannides M, Hadziyannis SJ (1997) Recombinant interferon-alpha therapy for acute hepatitis B: a randomized, double-blind, placebo-controlled trial. J Viral Hepat 4:387–394CrossRefPubMedGoogle Scholar
  43. 43.
    Thung SN, Gerber MA, Klion F, Gilbert H (1985) Massive hepatic necrosis after chemotherapy withdrawal in a hepatitis B virus carrier. Arch Intern Med 145:1313–1314CrossRefPubMedGoogle Scholar
  44. 44.
    Tur-Kaspa R, Burk RD, Shaul Y, Shafritz DA (1986) Hepatitis B virus DNA contains a glucocorticoid-responsive element. Proc Natl Acad Sci U S A 83:1627–1631PubMedGoogle Scholar
  45. 45.
    Vendro S, Cainelli F, Longhi MS (2002) Reactivation of replication of hepatitis B and C viruses after immunosuppressive therapy: an unresolved issue. Lancet Oncol 3:333–340CrossRefPubMedGoogle Scholar
  46. 46.
    Wands JR (1975) Subacute and chronic active hepatitis after withdrawal of chemotherapy. Lancet 2:979Google Scholar
  47. 47.
    Wong GC, Tan P, Goh YT, Ng HS, Chong R, Lee LH (1996) Exacerbation of hepatitis in hepatitis B carriers following chemotherapy for haematological malignancies. Ann Acad Med Singapore 25:500–503PubMedGoogle Scholar
  48. 48.
    Yeo W, Steinberg JL, Tam JS, Chan PK, Leung NW, Lam KC, Mok TS, Johnson PJ (1999) Lamivudine in the treatment of hepatitis B virus reactivation during cytotoxic chemotherapy. J Med Virol 59:263–269PubMedGoogle Scholar
  49. 49.
    Yeo W, Chan KS, Zhong S, Ho WM, Steinberg JL, Tam S, Hui P, Leung WY, Zee B, Johnson PJ (2000) 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 62:299–307CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • Shiang Jiin Leaw
    • 1
  • Chia Jui Yen
    • 1
  • Wen Tsung Huang
    • 1
  • Tsai Yun Chen
    • 1
  • Wu Chou Su
    • 1
  • Chao Jung Tsao
    • 1
  1. 1.Division of Hematology and Oncology, Department of Internal MedicineNational Cheng-Kung University Hospital TainanTainanTaiwan ROC

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