International Journal of Clinical Pharmacy

, Volume 38, Issue 5, pp 1035–1043 | Cite as

Comparison of entecavir and lamivudine in preventing HBV reactivation in lymphoma patients undergoing chemotherapy: a meta-analysis

  • Sisi Yu
  • Huaichao Luo
  • Meiling Pan
  • Angel Palomino Luis
  • Zhujuan Xiong
  • Pin Shuai
  • Zhihui ZhangEmail author
Review Article


Background Multiple studies have compared the efficacy of entecavir with lamivudine in preventing hepatitis B virus (HBV) reactivation among HBV-carrying lymphoma patients with chemotherapy treatment. However, the results were slightly varied. Aim of the review to combine the findings of independent studies assessing the clinical efficacy of the two drugs using a systematic review and meta-analysis. Methods PubMed, China National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature Database (CBM), Chongqing VIP and WanFang Data were retrieved. Two independent reviewers evaluated the study eligibility and extracted eight studies, with 770 patients in total. The meta-analysis was conducted using RevMan 5.3 and STATA software. Results HBV-carrying lymphoma patients receiving lamivudine during chemotherapy had a statistically significantly higher odds of HBV reactivation compared to those receiving entecavir (OR 5.0, 95 % CI 2.85–8.78, P < 0.001). The odds of hepatitis, HBV-Reactivation caused hepatitis and chemotherapy disruption was statistically significantly elevated in the patient group receiving lamivudine compared to the entecavir group (OR 4.12, 95 % CI 1.70–9.98, P = 0.002; OR 11.44, 95 % CI 2.70–48.52, P < 0.001; OR 6.71, 95 % CI 2.34–19.26, P < 0.001, respectively). Furthermore, the HBV reactivation rate in Ann Arbor stages I - II patient group was statistically significantly lower than the one in Ann Arbor stages III–IV group, with an overall pooled value of 0.37 (95 % CI 0.17–0.82, P = 0.01). Conclusion The metaanalysis result suggested that among HBV-carrying lymphoma patients undergoing chemotherapy, entecavir is more effective than lamivudine in preventing HBV reactivation.


Entecavir Lamivudine Lymphoma Meta-analysis Review 



We thank Pan ML and Luis AP from the University of Texas Health Science Center for its linguistic assistance during the preparation of this manuscript and the reviewers for their intellectual support.


No special funding was received for this review.

Conflicts of interest

There is no conflict of interests.

Supplementary material

11096_2016_358_MOESM1_ESM.tif (280 kb)
Supplementary Fig. 1 Funnel plot analysis for publication bias (A) Funnel plot for HBV reactivation rate (the lamivudine prophylaxis group vs. entecavir prophylaxis group) with all 8 studies, P for publication bias is 0.108; (B) Funnel plot for the incidence of hepatitis (the lamivudine prophylaxis group vs. entecavir prophylaxis group), P for publication bias is 1.00; (C) Funnel plot for the incidence of hepatitis due to HBV reactivation (the lamivudine prophylaxis group vs. entecavir prophylaxis group), P for publication bias is 0.296 (TIFF 280 kb)
11096_2016_358_MOESM2_ESM.tif (20 mb)
Supplementary Fig. 2 Funnel plot analysis for publication bias (A) Funnel plot for the incidence of chemotherapy disruption (the lamivudine prophylaxis group vs. entecavir prophylaxis group), P for publication bias is 0.296; (B) Funnel plot for HBV reactivation rate (Ann Arbor stage I–II group vs. Ann Arbor stage III–IV group), P for publication bias is 0.734 (TIFF 20526 kb)


  1. 1.
    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(16):3486–96.CrossRefPubMedGoogle Scholar
  2. 2.
    Li H, Zhang HM, Chen LF, Chen YQ, Chen L, Ren H, et al. Prophylactic lamivudine to improve the outcome of HBsAg-positive lymphoma patients during chemotherapy: a systematic review and meta-analysis. Clin Res Hepatol Gastroenterol. 2015;39(1):80–92.CrossRefPubMedGoogle Scholar
  3. 3.
    Park SC, Jeong SH, Kim J, Han CJ, Kim YC, Choi KS, et al. High prevalence of hepatitis B virus infection in patients with B-cell non-Hodgkin’s lymphoma in Korea. J Med Virol. 2008;80(6):960–6.CrossRefPubMedGoogle Scholar
  4. 4.
    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(3):299–307.CrossRefPubMedGoogle Scholar
  5. 5.
    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(7):1306–11.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Hwang J, Barbo A, Perrillo R. Hepatitis B reactivation during cancer chemotherapy: an international survey of the membership of the American Association for the Study of Liver Diseases. J Viral Hepat. 2015;22(3):346–52.CrossRefPubMedGoogle Scholar
  7. 7.
    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(6):1742–9.CrossRefPubMedGoogle Scholar
  8. 8.
    Dong HJ, Ni LN, Sheng GF, Song HL, Xu JZ, Ling Y. Risk of hepatitis B virus (HBV) reactivation in non-Hodgkin lymphoma patients receiving rituximab-chemotherapy: a meta-analysis. J Clin Virol. 2013;57(3):209–14.CrossRefPubMedGoogle Scholar
  9. 9.
    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(1):59–68.CrossRefPubMedGoogle Scholar
  10. 10.
    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(7):519–28.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Jarvis B, Faulds D. Lamivudine. A review of its therapeutic potential in chronic hepatitis B. Drugs. 1999;58(1):101–41.CrossRefPubMedGoogle Scholar
  12. 12.
    Dienstag JL, Goldin RD, Heathcote EJ, Hann HW, Woessner M, Stephenson SL, et al. Histological outcome during long-term lamivudine therapy. Gastroenterology. 2003;124(1):105–17.CrossRefPubMedGoogle Scholar
  13. 13.
    Lai CL, Chien RN, Leung NW, Chang TT, Guan R, Tai DI, et al. A one-year trial of lamivudine for chronic hepatitis B. Asia Hepatitis Lamivudine Study Group. N Engl J Med. 1998;339(2):61–8.CrossRefPubMedGoogle Scholar
  14. 14.
    Law JK, Ali JA, Harrigan PR, Sherlock CH, Savage KJ, Yoshida EM. Fatal postlymphoma chemotherapy hepatitis B reactivation secondary to the emergence of a YMDD mutant strain with lamivudine resistance in a noncirrhotic patient. Am J Hematol. 2006;81(12):969–72.CrossRefPubMedGoogle Scholar
  15. 15.
    Liaw YF. Management of YMDD mutations during lamivudine therapy in patients with chronic hepatitis B. J Gastroenterol Hepatol. 2002;17(s3):S333–7.CrossRefPubMedGoogle Scholar
  16. 16.
    Innaimo SF, Seifer M, Bisacchi GS, Standring DN, Zahler R, Colonno RJ. Identification of BMS-200475 as a potent and selective inhibitor of hepatitis B virus. Antimicrob Agents Chemother. 1997;41(7):1444–8.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Gish RG, Lok AS, Chang TT, de Man RA, Gadano A, Sollano J, et al. Entecavir therapy for up to 96 weeks in patients with HBeAg-positive chronic hepatitis B. Gastroenterology. 2007;133(5):1437–44.CrossRefPubMedGoogle Scholar
  18. 18.
    Li HR, Huang JJ, Guo HQ, Zhang X, Xie Y, Zhu HL, et al. Comparison of entecavir and lamivudine in preventing hepatitis B reactivation in lymphoma patients during chemotherapy. J Viral Hepat. 2011;18(12):877–83.CrossRefPubMedGoogle Scholar
  19. 19.
    Huang J, Chen XP, Chen XF, Chen WL. Clinical observation of preventing and treating HBV reactivation by lamivudine and entecavirin patients with non-Hodgkin lymphoma. J Prac Med. 2011;27(12):2225–7.Google Scholar
  20. 20.
    Lok AS, Liang RH, Chiu EK, Wong KL, Chan TK, Todd D. Reactivation of hepatitis B virus replication in patients receiving cytotoxic therapy. Rep Prospect Stud. Gastroenterol. 1991;100(1):182–8.Google Scholar
  21. 21.
    Huang H, Li X, Zhu J, Ye S, Zhang H, Wang W, et al. Entecavir versus 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(23):2521–30.CrossRefPubMedGoogle Scholar
  22. 22.
    Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 2010;25(9):603–5.CrossRefPubMedGoogle Scholar
  23. 23.
    Chen YM, Qian SX, Xie YP, Yang F. Comparison of lamivudine and entecavir in preventing hepatitis B reactivation in B-cell non-Hodgkin’S lymphoma patients during chemotherapy and the risk factors of hepatitis B occurrence. Zhejiang Med J. 2014;36(11):941–4.Google Scholar
  24. 24.
    Ziakas PD, Karsaliakos P, Mylonakis E. Effect of prophylactic lamivudine for chemotherapy-associated hepatitis B reactivation in lymphoma: a meta-analysis of published clinical trials and a decision tree addressing prolonged prophylaxis and maintenance. Haematologica. 2009;94(7):998–1005.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Alagozlu H, Ozdemir O, Koksal B, Yilmaz A, Coskun M. Prevelance of common YMDD motif mutations in long term treated chronic HBV infections in a Turkish population. Asian Pac J Cancer Prev. 2013;14(9):5489–94.CrossRefPubMedGoogle Scholar
  26. 26.
    Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009;50(3):661–2.CrossRefPubMedGoogle Scholar
  27. 27.
    Ni CB, Long B. Clinical comparison of preventive and therapeutic effects of lamivudine and entecavir on HBV reactivation among patients with non-Hodgkin lymphoma. J Clin Hepatol. 2014;30(4):363–6.Google Scholar
  28. 28.
    Tan Y, Wu HF, Zou ML, Pan HC, Hu ZP, Wu JY. Comparison study of entecavir and lamivudine in treating hepatitis B reactivation in Non-Hodgkin lymphoma patients. Jiangxi Med J. 2014;49(9):854-67.Google Scholar
  29. 29.
    Chang TT, Gish RG, de Man R, Gadano A, Sollano J, Chao YC, et al. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med. 2006;354(10):1001–10.CrossRefPubMedGoogle Scholar
  30. 30.
    Lai CL, Shouval D, Lok AS, Chang TT, Cheinquer H, Goodman Z, et al. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N. Engl. J. Med. 2006;354(10):1011–20.CrossRefPubMedGoogle Scholar
  31. 31.
    Rivkin A. Entecavir: a new nucleoside analogue for the treatment of chronic hepatitis B. Drugs Today. 2007;43(4):201–20.PubMedGoogle Scholar
  32. 32.
    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(5):1503–14.CrossRefPubMedGoogle Scholar
  33. 33.
    Sherman M, Yurdaydin C, Sollano J, Silva M, Liaw YF, Cianciara J, et al. Entecavir for treatment of lamivudine-refractory, HBeAg-positive chronic hepatitis B. Gastroenterology. 2006;130(7):2039–49.CrossRefPubMedGoogle Scholar
  34. 34.
    Sherman M, Yurdaydin C, Simsek H, Silva M, Liaw YF, Rustgi VK, et al. Entecavir therapy for lamivudine-refractory chronic hepatitis B: improved virologic, biochemical, and serology outcomes through 96 weeks. Hepatology. 2008;48(1):99–108.CrossRefPubMedGoogle Scholar
  35. 35.
    Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50(4):1088–101.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing 2016

Authors and Affiliations

  • Sisi Yu
    • 1
  • Huaichao Luo
    • 2
  • Meiling Pan
    • 3
  • Angel Palomino Luis
    • 4
  • Zhujuan Xiong
    • 1
  • Pin Shuai
    • 5
  • Zhihui Zhang
    • 1
    Email author
  1. 1.Department of Medical OncologySichuan Cancer Hospital and InstituteChengduPeople’s Republic of China
  2. 2.Department of Clinical LaboratorySichuan Cancer Hospital and InstituteChengduPeople’s Republic of China
  3. 3.Department of BiostatisticsThe University of Texas Health Science Center at HoustonHoustonUSA
  4. 4.McGovern Medical SchoolThe University of Texas Health Science Center at HoustonHoustonUSA
  5. 5.Health Management CenterHospital of University of Electronic Science and Technology of China and Sichuan Provincial People’s HospitalChengduPeople’s Republic of China

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