, Volume 47, Issue 1, pp 59–65 | Cite as

Efficacy of lamivudine prophylaxis in preventing hepatitis B virus reactivation in patients with resolved infection undergoing allogeneic SCT and receiving rituximab

  • Emanuela Zappulo
  • Laura Ambra Nicolini
  • Carmen Di Grazia
  • Alida Dominietto
  • Teresa Lamparelli
  • Francesca Gualandi
  • Patrizia Caligiuri
  • Bianca Bruzzone
  • Emanuele Angelucci
  • Claudio Viscoli
  • Malgorzata MikulskaEmail author
Original Paper



Hepatitis B virus (HBV) reactivation during immunosuppressive therapy is common in patients with hematological malignancies, even in case of resolved infection. Prophylaxis of HBV reactivation is universally recommended in stem cell transplant (SCT) recipients and patients treated with anti-CD20 agents (i.e., rituximab). Despite its well-established favorable safety profile, lamivudine (LAM) use in prophylaxis has been debated because of the possible emergence of resistant viral strains. The aim of this study was to investigate the efficacy of LAM in preventing HBV reactivation in allogeneic SCT recipients with a resolved HBV infection.


Patients who received first allogeneic SCT in years 2009–2016 were evaluated. Sixty-three patients with resolved infection received LAM prophylaxis and were included in the study. Baseline and post-SCT characteristics were recorded, including rituximab exposure, length of LAM prophylaxis, and time from transplant to the last clinical and virological follow-up.


Overall, 39 patients (62%) were male, 39 (62%) had acute myeloid leukemia, 38 (60%) received transplant from haploidentical donor, 29 (53%) received myeloablative conditioning, and 15 (24%) received rituximab post-transplant. Median clinical follow-up was 24 months after SCT (range 0.3–97); median virological follow-up 16 months (range 0.3–78), and median length of LAM prophylaxis of 14.5 months (range 0.3–78). No patient experienced HBV reactivation while on LAM prophylaxis. One patient experienced reactivation 8 months after discontinuing prophylaxis.


In this high-risk population, LAM prophylaxis was effective in preventing HBV reactivation in patients with resolved infection. It should be considered a reasonable first-line prophylactic agent to be administered in this setting.


LAM HBV Anti-CD20 Hematological HBcAb Transplant 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interest.


  1. 1.
    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.CrossRefGoogle Scholar
  2. 2.
    Chemin I, Jeantet D, Kay A, Trepo C. Role of silent hepatitis B virus in chronic hepatitis B surface antigen(−) liver disease. Antivir Res. 2001;52:117–23.CrossRefGoogle Scholar
  3. 3.
    Etzion O, Ghany MG. Screening for hepatitis B virus to prevent viral reactivation—who and when? Clin Liver Dis. 2015;5:47–50. Scholar
  4. 4.
    EASL. Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol. 2017;67:370–98. Scholar
  5. 5.
    Mallet V, van Bommel F, Doerig C, Pischke S, Hermine O, Locasciulli A, et al. Management of viral hepatitis in patients with haematological malignancy and in patients undergoing haemopoietic stem cell transplantation: recommendations of the 5th European Conference on Infections in Leukaemia (ECIL-5). Lancet Infect Dis. 2016;16:606–17. Scholar
  6. 6.
    Vigano M, Vener C, Lampertico P, Annaloro C, Pichoud C, Zoulim F, et al. Risk of hepatitis B surface antigen seroreversion after allogeneic hematopoietic SCT. Bone Marrow Transplant. 2011;46:125–31. Scholar
  7. 7.
    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 J Am Soc Blood Marrow Transplant. 2009;15:1049–59. Scholar
  8. 8.
    Nakamoto S, Kanda T, Nakaseko C, Sakaida E, Ohwada C, Takeuchi M, et al. Reactivation of hepatitis B virus in hematopoietic stem cell transplant recipients in Japan: efficacy of nucleos(t)ide analogues for prevention and treatment. Int J Mol Sci. 2014;15:21455–67. Scholar
  9. 9.
    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 Off Publ Eur Soc Clin Microbiol Infect Dis. 2014;20:O694–701. Scholar
  10. 10.
    Park S, Kim K, Kim DH, Jang JH, Kim SJ, Kim WS, et al. Changes of hepatitis B virus serologic status after allogeneic hematopoietic stem cell transplantation and impact of donor immunity on hepatitis B virus. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2011;17:1630–7. Scholar
  11. 11.
    Knoll A, Boehm S, Hahn J, Holler E, Jilg W. Long-term surveillance of haematopoietic stem cell recipients with resolved hepatitis B: high risk of viral reactivation even in a recipient with a vaccinated donor. J Viral Hepat. 2007;14:478–83. Scholar
  12. 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;32:3736–43. Scholar
  13. 13.
    Gentile G, Andreoni M, Antonelli G, Sarmati L. Screening, monitoring, prevention, prophylaxis and therapy for hepatitis B virus reactivation in patients with haematologic malignancies and patients who underwent haematologic stem cell transplantation: a systematic review. Clin Microbiol Infect. 2017;23:916–23.CrossRefGoogle Scholar
  14. 14.
    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;148:215–9. Scholar
  15. 15.
    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;312:2521–30. Scholar
  16. 16.
    Chen W-C, Cheng J-S, Chiang P-H, Tsay F-W, Chan H-H, Chang H-W, 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.CrossRefGoogle Scholar
  17. 17.
    Coppoletta S, Tedone E, Galano B, Soracco M, Raiola AM, Lamparelli T, et al. Rituximab treatment for Epstein–Barr virus DNAemia after alternative-donor hematopoietic stem cell transplantation. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2011;17:901–7. Scholar
  18. 18.
    Dominietto A, Tedone E, Soracco M, Bruno B, Raiola AM, Van Lint MT, et al. In vivo B-cell depletion with rituximab for alternative donor hemopoietic SCT. Bone Marrow Transplant. 2012;47:101–6.CrossRefGoogle Scholar
  19. 19.
    Frassoni F, Gualandi F, Podestà M, Raiola AM, Ibatici A, Piaggio G, et al. Direct intrabone transplant of unrelated cord-blood cells in acute leukaemia: a phase I/II study. Lancet Oncol. 2008;9:831–9.CrossRefGoogle Scholar
  20. 20.
    Raiola A, Dominietto A, Varaldo R, Ghiso A, Galaverna F, Bramanti S, et al. Unmanipulated haploidentical BMT following non-myeloablative conditioning and post-transplantation CY for advanced Hodgkin’s lymphoma. Bone Marrow Transplant. 2014;49:190.CrossRefGoogle Scholar
  21. 21.
    Cerva C, Colagrossi L, Maffongelli G, Salpini R, Di Carlo D, Malagnino V, et al. Persistent risk of HBV reactivation despite extensive lamivudine prophylaxis in haematopoietic stem cell transplant recipients who are anti-HBc-positive or HBV-negative recipients with an anti-HBc-positive donor. Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis. 2016;22:946 e1–e8. Scholar
  22. 22.
    Giaccone L, Festuccia M, Marengo A, Resta I, Sorasio R, Pittaluga F, et al. Hepatitis B virus reactivation and efficacy of prophylaxis with lamivudine in patients undergoing allogeneic stem cell transplantation. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2010;16:809–17. Scholar
  23. 23.
    Gupta A, Punatar S, Gawande J, Bagal B, Mathew L, Bhat V, et al. Hepatitis B-related serological events in hematopoietic stem cell transplant patients and efficacy of lamivudine prophylaxis against reactivation. Hematol Oncol. 2016;34:140–6. Scholar
  24. 24.
    Moses SE, Lim ZY, Sudhanva M, Devereux S, Ho AY, Pagliuca A, et al. Lamivudine prophylaxis and treatment of hepatitis B virus-exposed recipients receiving reduced intensity conditioning hematopoietic stem cell transplants with alemtuzumab. J Med Virol. 2006;78:1560–3. Scholar
  25. 25.
    Yoo J-J, Cho EJ, Cho YY, Lee M, Lee DH, Cho Y, et al. Efficacy of antiviral prophylaxis in HBsAg-negative, anti-HBc positive patients undergoing hematopoietic stem cell transplantation. Liver Int. 2015;35:2530–6. Scholar
  26. 26.
    Allen MI, Deslauriers M, Andrews CW, Tipples GA, Walters KA, Tyrrell DL, et al. Identification and characterization of mutations in hepatitis B virus resistant to lamivudine. Lamivudine Clinical Investigation Group. Hepatology (Baltim, MD). 1998;27:1670–7. Scholar
  27. 27.
    Wright TL. Clinical trial results and treatment resistance with lamivudine in hepatitis B. Semin Liver Dis. 2004;24:31–6. Scholar
  28. 28.
    Liaw YF. The current management of HBV drug resistance. J Clin Virol Off Publ Pan Am Soc Clin Virol. 2005;34:S143–6.CrossRefGoogle Scholar
  29. 29.
    Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology (Baltim, MD). 2007;45:507–39. Scholar
  30. 30.
    Hwang JP, Somerfield MR, Alston-Johnson DE, Cryer DR, Feld JJ, Kramer BS, et al. Hepatitis B virus screening for patients with cancer before therapy: American Society of Clinical Oncology provisional clinical opinion update. J Clin Oncol. 2015;33:2212–20. Scholar
  31. 31.
    Chen FW, Coyle L, Jones BE, Pattullo V. Entecavir versus lamivudine for hepatitis B prophylaxis in patients with haematological disease. Liver Int Off J Int Assoc Study Liver. 2013;33:1203–10. Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Emanuela Zappulo
    • 1
    • 2
    • 3
  • Laura Ambra Nicolini
    • 1
    • 2
  • Carmen Di Grazia
    • 4
  • Alida Dominietto
    • 4
  • Teresa Lamparelli
    • 4
  • Francesca Gualandi
    • 4
  • Patrizia Caligiuri
    • 5
  • Bianca Bruzzone
    • 6
  • Emanuele Angelucci
    • 4
  • Claudio Viscoli
    • 1
    • 2
  • Malgorzata Mikulska
    • 1
    • 2
    Email author
  1. 1.Division of Infectious Diseases, Department of Health SciencesUniversity of GenoaGenoaItaly
  2. 2.Ospedale Policlinico San Martino-IRCCS per l’OncologiaGenoaItaly
  3. 3.Section of Infectious Diseases, Department of Clinical Medicine and SurgeryUniversity of Naples “Federico II”NaplesItaly
  4. 4.Division of Hematology and Bone Marrow TransplantationOspedale Policlinico San Martino-IRCCS per l’OncologiaGenoaItaly
  5. 5.Department of Health SciencesUniversity of GenoaGenoaItaly
  6. 6.Hygiene UnitOspedale Policlinico San Martino-IRCCS per l’OncologiaGenoaItaly

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