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Epstein–Barr virus reactivation correlates with worse outcomes for patients exposed to hepatitis B virus after haploidentical hematopoietic stem cell transplantation

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Abstract

Hepatitis B virus (HBV)has a high, chronic infection rate in Asian populations, but only few studies have analyzed the effect of Epstein–Barr virus (EBV) or Cytomegalovirus (CMV) reactivation in patients exposed to HBV after haploidentical hematopoietic stem cell transplantation (haplo-HSCT). This study aimed to assess the clinical outcomes of these patients. We conducted a retrospective research including 61 patients exposed to HBV after undergoing haplo-HSCT. The patients were classified into two groups: the CMV reactivation group and no CMV reactivation group. The results were compared between the two groups using the K-W test for continuous variables, Pearson's chi-square test for categorical variables, Kaplan–Meier curves to estimate overall survival (OS) and leukemia-free survival (LFS), and a Cox proportional hazards model to analyze multivariable influences. The 3-year cumulative HBV reactivation rate was 8.2%. The median duration of HBV reactivation was 16 months (16–22 months) after haplo-HSCT. The CMV reactivation group had a higher cumulative incidence of HBV reactivation than the group without CMV reactivation. The EBV reactivation was substantially higher in the CMV reactivation group compared to that in the no CMV reactivation group (37.0% vs.5.9% respectively; P = 0.002). Furthermore, EBV reactivation was a risk factor for 1-year LFS and 1-year OS. Based on our data, EBV reactivation was related to worse outcomes in patients exposed to HBV after haplo-HSCT, whereas CMV reactivation was not.

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The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

References

  1. Fung S, Choi HSJ, Gehring A, Janssen HLA (2022) Getting to HBV cure: The promising paths forward. Hepatology 76(1):233–250

    Article  CAS  PubMed  Google Scholar 

  2. Xu X, Wu C, Lou Z, Peng C, Jiang L, Wu T, Zeng T, Dong Y, Ruan B (2023) Changing incidence of hepatitis B and persistent infection risk in adults: a population-based follow-up study from 2011 in China. BMC Public Health 23(1):256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Yuen MF, Chen DS, Dusheiko GM, Janssen HLA, Lau DTY, Locarnini SA, Peters MG, Lai CL (2018) Hepatitis B virus infection. Nat Rev Dis Primers 4:18035

    Article  PubMed  Google Scholar 

  4. Shi Y, Zheng M (2020) Hepatitis B virus persistence and reactivation. BMJ 370:m2200

    Article  PubMed  Google Scholar 

  5. Lopez-Fernandez T, Vadillo IS, de la Guia AL, Barbier KH (2021) Cardiovascular issues in hematopoietic stem cell transplantation (HSCT). Curr Treat Options Oncol 22(6):51

    Article  PubMed  Google Scholar 

  6. Xu LP, Wu DP, Han MZ, Huang H, Liu QF, Liu DH, Sun ZM, Xia LH, Chen J, Wang HX, Wang C, Li CF, Lai YR, Wang JM, Zhou DB, Chen H, Song YP, Liu T, Liu KY, Huang XJ (2017) A review of hematopoietic cell transplantation in China: data and trends during 2008–2016. Bone Marrow Transplant 52(11):1512–1518

    Article  CAS  PubMed  Google Scholar 

  7. Nagler A, Labopin M, Houhou M, Aljurf M, Mousavi A, Hamladji RM, Al Zahrani M, Bondarenko S, Arat M, Angelucci E, Koc Y, Gulbas Z, Sica S, Bourhis JH, Canaani J, Brissot E, Giebel S, Mohty M (2021) Outcome of haploidentical versus matched sibling donors in hematopoietic stem cell transplantation for adult patients with acute lymphoblastic leukemia: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. J Hematol Oncol 14(1):53

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Wang Y, Wu DP, Liu QF, Xu LP, Liu KY, Zhang XH, Yu WJ, Xu Y, Huang F, Huang XJ (2019) Low-dose post-transplant cyclophosphamide and anti-thymocyte globulin as an effective strategy for GVHD prevention in haploidentical patients. J Hematol Oncol 12(1):88

    Article  PubMed  PubMed Central  Google Scholar 

  9. Stern A, Su Y, Dumke H, Fang J, Tamari R, Jakubowski A, Cho C, Giralt S, Perales MA, Papanicolaou GA (2021) Cytomegalovirus viral load kinetics predict cytomegalovirus end-organ disease and mortality after hematopoietic cell transplant. J Infect Dis 224(4):620–631

    Article  PubMed  PubMed Central  Google Scholar 

  10. Wu Y, Huang H, Luo Y (2020) Management of hepatitis B Virus in allogeneic hematopoietic stem cell transplantation. Front Immunol 11:610500

    Article  CAS  PubMed  Google Scholar 

  11. Li SS, Zhang N, Jia M, Su M (2022) Association between cytomegalovirus and Epstein-Barr virus Co-Reactivation and hematopoietic stem cell transplantation. Front Cell Infect Microbiol 12:818167

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Xu L, Chen H, Chen J, Han M, Huang H, Lai Y, Liu D, Liu Q, Liu T, Jiang M, Ren H, Song Y, Sun Z, Wang J, Wu D, Zhou D, Zou P, Liu K, Huang X (2018) The consensus on indications, conditioning regimen, and donor selection of allogeneic hematopoietic cell transplantation for hematological diseases in China-recommendations from the Chinese Society of Hematology. J Hematol Oncol 11(1):33

    Article  PubMed  PubMed Central  Google Scholar 

  13. Wang Y, Fu HX, Liu DH, Xu LP, Zhang XH, Chang YJ, Chen YH, Wang FR, Sun YQ, Tang FF, Liu KY, Huang XJ (2014) Influence of two different doses of antithymocyte globulin in patients with standard-risk disease following haploidentical transplantation: a randomized trial. Bone Marrow Transplant 49(3):426–433

    Article  CAS  PubMed  Google Scholar 

  14. Demirtas D, Cagdas D, TurulOzgur T, Kuskonmaz B, UckanCetinkaya D, Sanal O, Tezcan I (2022) Long term follow-up of the patients with severe combined immunodeficiency after hematopoietic stem cell transplantation: a single-center study. Immunol Invest 51(4):739–747

    Article  CAS  PubMed  Google Scholar 

  15. Huang XJ, Liu DH, Liu KY, Xu LP, Chen H, Han W, Chen YH, Zhang XH, Lu DP (2009) Treatment of acute leukemia with unmanipulated HLA-mismatched/haploidentical blood and bone marrow transplantation. Biol Blood Marrow Transplant 15(2):257–265

    Article  CAS  PubMed  Google Scholar 

  16. Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, Brown RS Jr, Bzowej NH, Wong JB (2018) Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology 67(4):1560–1599

    Article  PubMed  Google Scholar 

  17. Yang Y, Huang A, Zhao Y (2021) Spontaneous loss of chronic HBV infection markers in treatment-naive children: a systematic review and pooled meta-analyses. Expert Rev Anti Infect Ther 19(5):649–660

    Article  CAS  PubMed  Google Scholar 

  18. Yu S, Huang F, Wang Y, Xu Y, Yang T, Fan Z, Lin R, Xu N, Xuan L, Ye J, Yu W, Sun J, Huang X, Liu Q (2020) Haploidentical transplantation might have superior graft-versus-leukemia effect than HLA-matched sibling transplantation for high-risk acute myeloid leukemia in first complete remission: a prospective multicentre cohort study. Leukemia 34(5):1433–1443

    Article  CAS  PubMed  Google Scholar 

  19. Lu Y, Zhao YL, Zhang JP, Xiong M, Cao XY, Liu DY, Sun RJ, Wei ZJ, Zhou JR, Lu DP (2021) Comparable outcomes among unmanipulated haploidentical, matched unrelated, and matched sibling donors in BU-based myeloablative hematopoietic stem cell transplantation for intermediate and adverse risk acute myeloid leukemia in complete remission: a single-center study. Ann Hematol 100(6):1579–1591

    Article  CAS  PubMed  Google Scholar 

  20. Shih CA, Chen WC (2021) Prevention of hepatitis B reactivation in patients requiring chemotherapy and immunosuppressive therapy. World J Clin Cases 9(21):5769–5781

    Article  PubMed  PubMed Central  Google Scholar 

  21. Yuan C, Peng J, Xia R, He J, Qiu T, Yao Y (2022) Reactivation of occult hepatitis b virus infection during long-term Entecavir antiviral therapy. Front Microbiol 13:865124

    Article  PubMed  PubMed Central  Google Scholar 

  22. Marchesi F, Pimpinelli F, Gumenyuk S, Renzi D, Palombi F, Pisani F, Romano A, Spadea A, Papa E, Canfora M, Ensoli F, Mengarelli A (2015) Cytomegalovirus reactivation after autologous stem cell transplantation in myeloma and lymphoma patients: A single-center study. World J Transplant 5(3):129–136

    Article  PubMed  PubMed Central  Google Scholar 

  23. Zuo W, Zhao X (2021) Natural killer cells play an important role in virus infection control: Antiviral mechanism, subset expansion and clinical application. Clin Immunol 227:108727

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Lam JKP, Azzi T, Hui KF, Wong AMG, McHugh D, Caduff N, Chan KH, Munz C, Chiang AKS (2020) Co-infection of cytomegalovirus and Epstein-Barr virus diminishes the frequency of CD56(dim)NKG2A(+)KIR(-) NK cells and contributes to suboptimal control of EBV in immunosuppressed children with post-transplant lymphoproliferative disorder. Front Immunol 11:1231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Seto WK, Chan TS, Hwang YY, Wong DK, Fung J, Liu KS, Gill H, Lam YF, Lau EHY, Cheung KS, Lie AKW, Lai CL, Kwong YL, Yuen MF (2017) Hepatitis B reactivation in occult viral carriers undergoing hematopoietic stem cell transplantation: A prospective study. Hepatology 65(5):1451–1461

    Article  CAS  PubMed  Google Scholar 

  26. Hammond SP, Borchelt AM, Ukomadu C, Ho VT, Baden LR, Marty FM (2009) Hepatitis B virus reactivation following allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 15(9):1049–1059

    Article  PubMed  Google Scholar 

  27. Mikulska M, Nicolini L, Signori A, Rivoli G, Del Bono V, Raiola AM, Di Grazia C, Dominietto A, Varaldo R, Ghiso A, Bacigalupo A, Viscoli C (2014) Hepatitis B reactivation in HBsAg-negative/HBcAb-positive allogeneic haematopoietic stem cell transplant recipients: risk factors and outcome. Clin Microbiol Infect 20(10):O694-701

    Article  CAS  PubMed  Google Scholar 

  28. Zhang A, Wu Y, Tan Y, Shi J, Zhao Y, Hu Y, Yu J, Zheng W, Lai X, Zhang M, Zhu Y, Ye Y, Huang Y, Fu S, Huang H, Luo Y (2020) Determining whether prophylactic antiviral treatment is necessary in HBsAg-Negative/HBcAb-Positive patients receiving allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 26(5):956–964

    Article  CAS  PubMed  Google Scholar 

  29. Seto WK, Wong DK, Chan TS, Hwang YY, Fung J, Liu KS, Gill H, Lam YF, Cheung KS, Lie AK, Lai CL, Kwong YL, Yuen MF (2016) Association of hepatitis B core-related antigen with hepatitis B virus reactivation in occult viral carriers undergoing high-risk immunosuppressive therapy. Am J Gastroenterol 111(12):1788–1795

    Article  CAS  PubMed  Google Scholar 

  30. Zapatka M, Borozan I, Brewer DS, Iskar M, Grundhoff A, Alawi M, Desai N, Sultmann H, Moch H, Pathogens P, Cooper CS, Eils R, Ferretti V, Lichter P, Consortium P (2020) The landscape of viral associations in human cancers. Nat Genet 52(3):320–330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Xu M, Zhang WL, Zhu Q, Zhang S, Yao YY, Xiang T, Feng QS, Zhang Z, Peng RJ, Jia WH, He GP, Feng L, Zeng ZL, Luo B, Xu RH, Zeng MS, Zhao WL, Chen SJ, Zeng YX, Jiao Y (2019) Genome-wide profiling of Epstein-Barr virus integration by targeted sequencing in Epstein-Barr virus associated malignancies. Theranostics 9(4):1115–1124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wu YX, Zhang WL, Wang TM, Liao Y, Zhang YJ, Xiao RW, Jia YJ, Wu ZY, Deng CM, Yang DW, Xue WQ, He YQ, Zheng XH, Li XZ, Zhou T, Zhang PF, Zhang SD, Hu YZ, Zhang JB, Jia WH (2022) Genomic landscapes of Epstein-Barr virus in pulmonary Lymphoepithelioma-like carcinoma. J Virol 96(4):e0169321

    Article  PubMed  Google Scholar 

  33. Tian R, Wang Y, Li W, Cui Z, Pan T, Jin Z, Huang Z, Li L, Lang B, Wu J, Xie H, Lu Y, Tian X, Hu Z (2022) Genome-wide virus-integration analysis reveals a common insertional mechanism of HPV, HBV and EBV. Clin Transl Med 12(8):e971

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This study were approved by the Beijing Natural Science Foundation of China to Mei Jia (Grant No. 7222194) and the National Natural Science Foundation of China to Ming Su(Grant No. 81870196).

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  1. Jiajia Hu and Shanshan Li contributed equally to work and share first authorship.

Authors and Affiliations

  1. Department of Clinical Laboratory, Peking University People’s Hospital, No. 11 Xizhimen South Street, Xicheng District, Beijing, 100044, People’s Republic of China

    Jiajia Hu, Jie Zhao, Chunyan Wang, Mei Jia, Ming Su & Shanshan Li

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  1. Jiajia Hu
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  2. Jie Zhao
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  4. Mei Jia
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Contributions

Shanshan Li and Ming Su: design of the study; Jiajia Hu and Shanshan Li: data acquisition, analysis, and interpretation; Jie Zhao and Chuanyan Wang: drafted the article and critically revised the manuscript; Shanshan Li and Ming Su: gave final approval for the version to be submitted.

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Correspondence to Ming Su or Shanshan Li.

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The studies involving human participants were reviewed and approved by the Ethics Committee of the Peking University People’s Hospital. The patients/participants provided their written informed consent to participate in this study.

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Hu, J., Zhao, J., Wang, C. et al. Epstein–Barr virus reactivation correlates with worse outcomes for patients exposed to hepatitis B virus after haploidentical hematopoietic stem cell transplantation. Ann Hematol 102, 3593–3601 (2023). https://doi.org/10.1007/s00277-023-05492-z

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