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Antiviral prophylaxis during chemotherapy or immunosuppressive drug therapy to prevent HBV reactivation in patients with resolved HBV infection: a systematic review and meta-analysis

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Abstract

Background

Until recently, the role of antiviral prophylaxis in preventing hepatitis B virus (HBV) reactivation during immunosuppressive therapy or chemotherapy in patients with resolved HBV infection was unclear. The aim of the study reported here was to compare the efficacy of antiviral prophylaxis versus that of non-prophylaxis in resolved HBV-infected patients undergoing chemotherapy or immunosuppressive therapy.

Methods

PubMed, the Cochrane library, and the ClinicalTrials.gov website were searched from inception until December 2017. Studies comparing reactivation in prophylaxis versus non-prophylaxis in patients undergoing immunosuppressive therapy or chemotherapy were included. The meta-analysis was performed to calculate the relative risk (RR) and the pooled estimates.

Results

A meta-analysis was conducted of 13 studies (2 randomized controlled trials [RCTs] and 11 cohort studies). The summary RR for HBV reactivation was 0.47 (95% confidence interval [CI] 0.13–1.69) for antiviral prophylaxis versus non-prophylaxis. Both of the RCTs included in the meta-analysis enrolled patients treated with rituximab. Subgroup analyses showed that the two RCTs ± high-quality cohort studies showed a decreased risk of HBV reactivation among the antiviral prophylaxis groups (RCT 1: RR 0.13, 95% CI 0.02–0.70; P = 0.02; RCT 2: 0.28, 95% CI 0.08–0.98; P = 0.05). Subgroup analyses further showed that the cohort studies did not support an association between the antiviral prophylaxis groups and HBV reactivation (RR 0.62, 95% CI 0.14–2.83; P = 0.54); adjusting for confounding factors, such as detectable anti-HBs antibodies, failed to produce a significant association (RR,0.29, 95% CI 0.07-1.28; P = 0.10).

Conclusion

Our meta-analyses did not show an association between antiviral prophylaxis use and risk of HBV reactivation. As using only the RCTs ± high-quality cohort studies data rendered this association significant, clinicians can consider providing antiviral prophylaxis to patients with resolved HBV infection who are undergoing rituximab-based therapy.

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References

  1. Paul S, Saxena A, Terrin N et al (2016) Hepatitis B virus reactivation and prophylaxis during solid tumor chemotherapy: a systematic review and meta-analysis. Ann Intern Med 164(1):30–40

    Article  PubMed  Google Scholar 

  2. Perrillo RP, Gish R, Falck-Ytter YT (2015) American Gastroenterological Association Institute technical review on prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy. Gastroenterology 148(1):221–244 e3

    Article  PubMed  Google Scholar 

  3. Yeo W, Chan HL (2013) Hepatitis B virus reactivation associated with anti-neoplastic therapy. J Gastroenterol Hepatol 28:31–37

    Article  PubMed  CAS  Google Scholar 

  4. Liaw YF, Kao JH, Piratvisuth T et al (2012) Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2012 update. Hepatol Int 6:531–561

    Article  PubMed  Google Scholar 

  5. Loomba R, Rowley A, Wesley R et al (2008) Systematic review: the effect of preventive lamivudine on hepatitis B reactivation during chemotherapy. Ann Intern Med 148(7):519–528

    Article  PubMed  PubMed Central  Google Scholar 

  6. Perrillo RP, Martin P, Lok AS (2015) Preventing hepatitis B reactivation due to immunosuppressive drug treatments. JAMA 313(16):1617–1618

    Article  PubMed  Google Scholar 

  7. Sarin SK, Kumar M, Lau GK et al (2016) Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int 10(1):1–98

    Article  PubMed  CAS  Google Scholar 

  8. Barone M, Notarnicola A, Lopalco G et al (2015) Safety of long-term biologic therapy in rheumatologic patients with a previously resolved hepatitis B viral infection. Hepatology 62(1):40–46

    Article  PubMed  CAS  Google Scholar 

  9. Hui CK, Cheung WW, Zhang HY et al (2006) Kinetic and risk of de novo hepatitis B infection in HBsAg-negative patients undergoing cytotoxic chemotherapy. Gastroenterology 131:59–68

    Article  PubMed  CAS  Google Scholar 

  10. Yeo W, Chan TC, Leung NW et al (2009) Hepatitis B virus reactivation in lymphoma patients with prior resolved hepatitis B undergoing anticancer therapy with or without rituximab. J Clin Oncol 27:605–611

    Article  PubMed  CAS  Google Scholar 

  11. Higgins JPT, Green S (eds) Cochrane handbook for systematic reviews of interventions version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available at: www.cochrane-handbook.org (accessed15 June 2014)

  12. Liberati A, Altman DG, Tetzlaff J et al (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 339:b2700

    Article  PubMed  PubMed Central  Google Scholar 

  13. Higgins JPT, Altman DG, Sterne JAC (eds) Chapter 8: assessing risk of bias in included studies. In: Higgins JPT, Green S (eds) Cochrane handbook for systematic reviews of interventions version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available at: www.cochranehandbook.org Accessed 8 Aug 2014

  14. Wells GASB, O’Connell D, Peterson J et al The Newcastle–Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in metaanalyses. Available at: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed 8 Aug 2014

  15. Suurmond R, van Rhee H, Hak T (2017) Introduction, comparison and validation of meta-essentials: a free and simple tool for meta-analysis. Res Synth Methods 8(4):537–553

    Article  PubMed  PubMed Central  Google Scholar 

  16. Egger M, Davey Smith G, Schneider M et al (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315(7109):629–634

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Kohrt HE, Ouyang DL, Keeffe EB (2006) Systematic review: lamivuidine prophylaxis for chemotherapy-induced reactivation of chronic hepatitis B virus infection. Aliment Pharmacol Ther 24(7):1003–1016

    Article  PubMed  CAS  Google Scholar 

  18. Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327:557–560

    Article  PubMed  PubMed Central  Google Scholar 

  19. The Nordic Cochrane Centre (2012) Review Manager (RevMan) [Computer program], version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration

  20. Huang YH, Hsiao LT, Hong YC et al (2013) Randomized controlled trial of entecavir prophylaxis for rituximab-associated hepatitis B virus reactivation in patients with lymphoma and resolved hepatitis B. J Clin Oncol 31(22):2765–2772

    Article  PubMed  CAS  Google Scholar 

  21. Huang Y-H, Hong Y-C, Hsiao L-T et al (2012) Randomized controlled trial of prophylactic entecavir in HBsAg-negative/anti-HBC-positive lymphoma patients undergoing rituximab-based chemotherapy: preliminary report. J Hepatol 56[Suppl 2]:S204

    Article  Google Scholar 

  22. Buti M, Manzano ML, Morillas RM et al (2017) Randomized prospective study evaluating tenofovir disoproxil fumarate prophylaxis against hepatitis B virus reactivation in anti-HBc-positive patients with rituximab-based regimens to treat hematologic malignancies: the Preblin study. PLoS One 12(9):e0184550

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Buti M, Manzano ML, Morillas RM et al (2016) Prevents HBV reactivation with tenofovir in anti-HBC positive patients with hematologic malignancies treated with rituximab. Results final visit 18-months (PREBLIN study). J Hepatol 64(2 Suppl):S369

    Article  Google Scholar 

  24. Buti M, Manzano ML, Morillas RM et al (2014) Tenofovir DF prevents HBV reactivation in anti-HBc positive patients with hematologic malignancies treated with Rituximab: 12-months results of a randomized study (PREBLIN study). In: 65th Annual Meeting of the American Association for the Study of Liver Diseases: The Liver Meeting 2014 Boston. 60:997A

  25. Buti M, Morillas R, Manzano ML et al (2014) Tenofovir for the prophylaxis of HBV reactivation in anti-HBC-positive patients with hematologic malignancies treated with rituximab: Preliminary results of a randomized study (preblin study). In: 49th Annual Meeting of the European Association for the Study of the Liver, International Liver Congress 2014. London. 60(1 Suppl 1):S421–S422

  26. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (USA). 2000 Feb 29 -. Identifier NCT01907230, Entecavir for biological agents associated HBV reactivation in inflammatory arthritis patients; 2013 Jul 24. Available from: https://clinicaltrials.gov/show/NCT01907230 Cited: 25 Dec 2017

  27. Maekawa H, Yazawa M, Koitabashi K et al (2016) Safety of monitoring viral and liver function markers in patients with prior resolved hepatitis B infection after kidney transplantation. Transplant Proc 48(6):2046–2049

    Article  PubMed  CAS  Google Scholar 

  28. Padovan M, Filippini M, Tincani A et al (2016) Safety of abatacept in rheumatoid arthritis with serologic evidence of past or present hepatitis B virus infection. Arthritis Care Res (Hoboken) 68(6):738–743

    Article  CAS  Google Scholar 

  29. Papadopoulos N, Deutsch M, Manolakopoulos S et al (2017) Efficacy of prophylactic antiviral therapy and outcomes in HBsAg-negative, anti-HBc-positive patients receiving chemotherapy: a real-life experience. Eur J Gastroenterol Hepatol 29(1):56–60

    Article  PubMed  CAS  Google Scholar 

  30. Cho Y, Yu SJ, Cho EJ et al (2016) High titers of anti-HBs prevent rituximab-related viral reactivation in resolved hepatitis B patient with non-Hodgkin’s lymphoma. J Med Virol 88(6):1010–1017

    Article  PubMed  CAS  Google Scholar 

  31. Moses SE, Lim ZY, Sudhanva M et al (2006) Lamivudine prophylaxis and treatment of hepatitis B virus-exposed recipients receiving reduced intensity conditioning hematopoietic stem cell transplants with alemtuzumab. J Med Virol 78(12):1560–1563

    Article  PubMed  CAS  Google Scholar 

  32. Liu HL, Zhao Z, Yang H et al (2013) The effects of nucleoside analogue prophylactic treatment on HBV activation in HBcAb+ patients undergoing immunosuppressive therapy. J Viral Hepat 20(9):645–649

    Article  PubMed  Google Scholar 

  33. Guarino M, Picardi M, Vitello A et al (2017) Viral outcome in patients with occult HBV infection or HCV-ab positivity treated for lymphoma. Ann Hepatol 16(2):198–206

    Article  PubMed  CAS  Google Scholar 

  34. Koo YX, Tan DS, Tan IB, Tao M, Chow WC, Lim ST (2010) Hepatitis B virus reactivation and role of antiviral prophylaxis in lymphoma patients with past hepatitis B virus infection who are receiving chemoimmunotherapy. Cancer 116(1):115–121

    PubMed  CAS  Google Scholar 

  35. Kim SJ, Hsu C, Song YQ et al (2013) Hepatitis B virus reactivation in B-cell lymphoma patients treated with rituximab: analysis from the Asia lymphoma study group. Eur J Cancer 49(16):3486–3496

    Article  PubMed  CAS  Google Scholar 

  36. Yoo JJ, Cho EJ, Cho YY et al (2015) Efficacy of antiviral prophylaxis in HBsAg-negative, anti-HBc positive patients undergoing hematopoietic stem cell transplantation. Liver Int 35(12):2530–2536

    Article  PubMed  CAS  Google Scholar 

  37. Lu S, Xu Y, Mu Q et al (2015) The risk of hepatitis B virus reactivation and the role of antiviral prophylaxis in hepatitis B surface antigen negative/hepatitis B core antibody positive patients with diffuse large B-cell lymphoma receiving rituximab-based chemotherapy. Leuk Lymphoma 56(4):1027–1032

    Article  PubMed  CAS  Google Scholar 

  38. Hsu C, Tsou HH, Lin SJ et al (2014) Chemotherapy-induced hepatitis B reactivation in lymphoma patients with resolved HBV infection: a prospective study. Hepatology 59(6):2092–2100

    Article  PubMed  CAS  Google Scholar 

  39. Seto WK, Chan TS, Hwang YY et al (2014) Hepatitis B reactivation in patients with previous hepatitis B virus exposure undergoing rituximab-containing chemotherapy for lymphoma: a prospective study. J Clin Oncol 32(33):3736–3743

    Article  PubMed  CAS  Google Scholar 

  40. Seto WK, Chan TS, Hwang YY et al (2017) Hepatitis B reactivation in occult viral carriers undergoing hematopoietic stem cell transplantation: a prospective study. Hepatology 65(5):1451–1461

    Article  PubMed  CAS  Google Scholar 

  41. Di Bisceglie AM, Lok AS, Martin P et al (2015) Recent US Food and Drug Administration warnings on hepatitis B reactivation with immune-suppressing and anticancer drugs: just the tip of the iceberg? Hepatology 61(2):703–711

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Seto WK (2015) Hepatitis B virus reactivation during immunosuppressive therapy: appropriate risk stratification. World J Hepatol 7(6):825–830

    Article  PubMed  PubMed Central  Google Scholar 

  43. Law MF, Ho R, Cheung CK et al (2016) Prevention and management of hepatitis B virus reactivation in patients with hematological malignancies treated with anticancer therapy. World J Gastroenterol 22(28):6484–6500

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Braun-Moscovici Y, Braun M, Saadi T et al (2016) Safety of corticosteroid treatment in rheumatologic patients with markers of hepatitis B viral infection: pilot evaluation study. J Clin Rheumatol 22(7):364–368

    Article  PubMed  Google Scholar 

  45. Reddy KR, Beavers KL, Hammond SP, Lim JK, Falck-Ytter YT, American Gastroenterological Association Institute (2015) American gastroenterological association institute guideline on the prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy. Gastroenterology 148(1):215–219

    Article  PubMed  CAS  Google Scholar 

  46. Di Bisceglie AM, Lok AS, Martin P, Terrault N, Perrillo RP, Hoofnagle JH (2015) Recent US food and drug administration warnings on hepatitis B reactivation with immune-suppressing and anticancer drugs: just the tip of the iceberg? Hepatology 61(2):703–711

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Lok AS, McMahon BJ, Brown RS Jr et al (2016) Antiviral therapy for chronic hepatitis B viral infection in adults: a systematic review and meta-analysis. Hepatology 63(1):284–306

    Article  PubMed  CAS  Google Scholar 

  48. Huang H, Li X, Zhu J et al (2014) 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 312(23):2521–2530

    Article  PubMed  CAS  Google Scholar 

  49. Zhang MY, Zhu GQ, Zheng JN et al (2017) Nucleos(t)ide analogues for preventing HBV reactivation in immunosuppressed patients with hematological malignancies: a network meta-analysis. Expert Rev Anti-Infect Ther 15(5):503–513

    Article  PubMed  CAS  Google Scholar 

  50. Germanidis G, Hytiroglou P, Zakalka M, Settas L (2012) Reactivation of occult hepatitis B virus infection, following treatment of refractory rheumatoid arthritis with abatacept. J Hepatol 56(6):1420–1421

    Article  PubMed  Google Scholar 

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Acknowledgements

This study was sponsored by the grants from Kaohsiung Veterans General Hospital (VGHKS106-185).

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Author notes

  1. Yi-Chia Su and Pei-Chin Lin contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacy, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan

    Yi-Chia Su & Pei-Chin Lin

  2. Department of Pharmacy, School of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan

    Pei-Chin Lin

  3. Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan

    Hsien-Chung Yu

  4. Division of Colorectal Surgery, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan

    Chih-Chien Wu

  5. Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan

    Chih-Chien Wu

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  1. Yi-Chia Su
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Correspondence to Chih-Chien Wu.

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Su, YC., Lin, PC., Yu, HC. et al. Antiviral prophylaxis during chemotherapy or immunosuppressive drug therapy to prevent HBV reactivation in patients with resolved HBV infection: a systematic review and meta-analysis. Eur J Clin Pharmacol 74, 1111–1119 (2018). https://doi.org/10.1007/s00228-018-2487-4

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