Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Predicting the loss of hepatitis B surface antigen following haematopoietic stem cell transplantation in patients with chronic HBV infection

Abstract

Clearance of hepatitis B surface antigen (HBsAg) is an ideal therapeutic goal for patients with chronic hepatitis B virus (HBV) infection. Haematopoietic stem cell transplantation (HSCT) is the most effective therapy for a variety of haematological diseases. For patients with chronic HBV infection who received allo-HSCT, recipient hepatitis B serological status might change after allo-HSCT; however, data on the loss of HBsAg following allo-HSCT are relatively rare. We first reviewed patients with chronic HBV infection who received allo-HSCT in our centre from 2010 to 2020, and 125 patients were included in our study. A total of 62 patients (49.6%) with chronic HBV infection achieved HBsAg loss after allo-HSCT. Positivity for HBeAb and HBsAb in donors as well as no cytomegalovirus (CMV) infection were identified as independent risk factors for HBsAg loss after allo-HSCT. A predictive model including positivity for HBeAb and HBsAb in donors and no CMV infection was subsequently developed and performed well with effective discrimination and calibration. In addition, patients could benefit when this model is used in the clinic, as revealed via decision-curve analysis (DCA). However, multicentre prospective studies are required for validation.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Cumulative incidence of HBsAg loss according to recipient or donot viral status at allo-HSCT.

Similar content being viewed by others

Data availability

All data generated or analyzed during this study are included either in this article or in additional files.

References

  1. Ott JJ, Stevens GA, Groeger J, Wiersma ST. Global epidemiology of hepatitis B virus infection: new estimates of age-specific HBsAg seroprevalence and endemicity. Vaccine 2012;30:2212–9.

    Article  CAS  PubMed  Google Scholar 

  2. Schweitzer A, Horn J, Mikolajczyk RT, Krause G, Ott JJ. Estimations of worldwide prevalence of chronic hepatitis B virus infection: a systematic review of data published between 1965 and 2013. Lancet 2015;386:1546–55.

    Article  PubMed  Google Scholar 

  3. Ozakyol A. Global epidemiology of Hepatocellular Carcinoma (HCC Epidemiology). J Gastrointest Cancer 2017;48:238–40.

    Article  PubMed  Google Scholar 

  4. Chu CM, Liaw YF. HBsAg seroclearance in Asian patients: too high and too bad in Hong Kong. Gastroenterology 2009;136:1459–60. 1460-1.

    Article  PubMed  Google Scholar 

  5. Yip TC, Wong GL, Chan HL, Tse YK, Lam KL, Lui GC, et al. HBsAg seroclearance further reduces hepatocellular carcinoma risk after complete viral suppression with nucleos(t)ide analogues. J Hepatol. 2019;70:361–70.

    Article  CAS  PubMed  Google Scholar 

  6. Moucari R, Korevaar A, Lada O, Martinot-Peignoux M, Boyer N, Mackiewicz V, et al. High rates of HBsAg seroconversion in HBeAg-positive chronic hepatitis B patients responding to interferon: a long-term follow-up study. J Hepatol. 2009;50:1084–92.

    Article  CAS  PubMed  Google Scholar 

  7. EASL Clinical Practice Guidelines: Management of chronic hepatitis B virus infection. J Hepatol. 2012;57:167–85.

  8. Alawad AS, Auh S, Suarez D, Ghany MG. Durability of spontaneous and treatment-related loss of Hepatitis B s antigen. Clin Gastroenterol H 2020;18:700–9.

    Article  CAS  Google Scholar 

  9. Marcellin P, Wong DK, Sievert W, Buggisch P, Petersen J, Flisiak R, et al. Ten-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B virus infection. Liver Int. 2019;39:1868–75.

    Article  CAS  PubMed  Google Scholar 

  10. Marcellin P, Buti M, Krastev Z, de Man RA, Zeuzem S, Lou L, et al. Kinetics of hepatitis B surface antigen loss in patients with HBeAg-positive chronic hepatitis B treated with tenofovir disoproxil fumarate. J Hepatol. 2014;61:1228–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Yu C, Sun Y, Xu L, Zhang X, Liu K, Jin J, et al. Hepatitis B seropositive status in recipients or donors is not related to worse outcomes after haploidentical hematopoietic stem cell transplantation. Transpl Cell Ther 2021;27:661–8.

    Article  Google Scholar 

  12. Buzo BF, Ramos JF, Marques Rossetti RA, Salles N, Mendrone Júnior A, Rocha V, et al. Hepatitis B virus among hematopoietic stem cell transplant recipients: Antiviral impact in seroconversion, engraftment, and mortality in a Latin American center. Transpl Infect Dis. 2020;22:e13243.

  13. Francisci D, Aversa F, Coricelli V, Carotti A, Canovari B, Falcinelli F, et al. Prevalence, incidence and clinical outcome of hepatitis B virus and hepatitis C virus hepatitis in patients undergoing allogeneic hematopoietic stem cell transplantation between 2001 and 2004. Haematologica. 2006;91:980–2.

    PubMed  Google Scholar 

  14. 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 Transpl. 2011;17:1630–7.

    Article  Google Scholar 

  15. Lau GK, Lok AS, Liang RH, Lai CL, Chiu EK, Lau YL, et al. Clearance of hepatitis B surface antigen after bone marrow transplantation: role of adoptive immunity transfer. Hepatology 1997;25:1497–501.

    Article  CAS  PubMed  Google Scholar 

  16. Chang YJ, Huang XJ. Use of G-CSF-stimulated marrow in allogeneic hematopoietic stem cell transplantation settings: a comprehensive review. Clin Transpl. 2011;25:13–23.

    Article  CAS  Google Scholar 

  17. Wang Y, Liu DH, Liu KY, Xu LP, Zhang XH, Han W, et al. Long-term follow-up of haploidentical hematopoietic stem cell transplantation without in vitro T cell depletion for the treatment of leukemia: nine years of experience at a single center. Cancer-Am Cancer Soc. 2013;119:978–85.

    Google Scholar 

  18. Huang XJ, Liu DH, Liu KY, Xu LP, Chen H, Han W, et al. Haploidentical hematopoietic stem cell transplantation without in vitro T-cell depletion for the treatment of hematological malignancies. Bone Marrow Transpl. 2006;38:291–7.

    Article  Google Scholar 

  19. Yan CH, Xu LP, Wang FR, Chen H, Han W, Wang Y, et al. Causes of mortality after haploidentical hematopoietic stem cell transplantation and the comparison with HLA-identical sibling hematopoietic stem cell transplantation. Bone Marrow Transpl. 2016;51:391–7.

    Article  CAS  Google Scholar 

  20. Lok AS, Zoulim F, Dusheiko G, Chan HLY, Buti M, Ghany MG, et al. Durability of Hepatitis B surface antigen loss with nucleotide analogue and peginterferon therapy in patients with chronic Hepatitis B. Hepatol Commun 2020;4:8–20.

    Article  CAS  PubMed  Google Scholar 

  21. Li M, Zhang L, Lu Y, Chen Q, Lu H, Sun F, et al. Early serum HBsAg kinetics as predictor of HBsAg loss in patients with HBeAg-negative chronic Hepatitis B after treatment with Pegylated Interferonα-2a. Virol Sin. 2021;36:311–20.

    Article  PubMed  Google Scholar 

  22. Terrault NA, Lok ASF, McMahon BJ, Chang K, Hwang JP, Jonas MM, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology 2018;67:1560–99.

    Article  PubMed  Google Scholar 

  23. Yang Y, Huang A, Zhao Y. Spontaneous loss of chronic HBV infection markers in treatment-naïve children: a systematic review and pooled meta-analyses. Expert Rev Anti-Infe. 2021;19:649–60.

    Article  CAS  Google Scholar 

  24. Cao Z, Li Z, Wang Y, Liu Y, Mo R, Ren P, et al. Assessment of serum Golgi protein 73 as a biomarker for the diagnosis of significant fibrosis in patients with chronic HBV infection. J Viral Hepat. 2017;24(Suppl 1):57–65.

    Article  CAS  PubMed  Google Scholar 

  25. Shi Y, Zheng M. Hepatitis B virus persistence and reactivation. BMJ. 2020;370:m2200.

    Article  PubMed  Google Scholar 

  26. Hui CK, Lie A, Au WY, Leung YH, Ma SY, Cheung WW, et al. A long-term follow-up study on hepatitis B surface antigen-positive patients undergoing allogeneic hematopoietic stem cell transplantation. Blood 2005;106:464–9.

    Article  CAS  PubMed  Google Scholar 

  27. Wu Y, Shi J, Tan Y, Zhao Y, Yu J, Lai X, et al. A novel strategy for the prevention of Hepatitis B virus-related hepatitis following allogeneic hematopoietic stem cell transplantation from Hepatitis B surface antigen-positive donors. Biol Blood Marrow Transpl. 2020;26:1719–28.

    Article  CAS  Google Scholar 

  28. Sullivan LM, Massaro JM, D’Agostino RS. Presentation of multivariate data for clinical use: The Framingham Study risk score functions. Stat Med. 2004;23:1631–60.

    Article  PubMed  Google Scholar 

  29. Ren X, Huang Q, Qu Q, Cai X, Fu H, Mo X, et al. Predicting mortality from intracranial hemorrhage in patients who undergo allogeneic hematopoietic stem cell transplantation. Blood Adv. 2021;5:4910–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Deng RX, Wu YJ, Xu LP, Liu KY, Huang XJ, Zhang XH. Clinical risk factors and prognostic model for idiopathic inflammatory demyelinating diseases after haploidentical hematopoietic stem cell transplantation in patients with hematological malignancies. Am J Hematol. 2021;96:1407–19.

    Article  CAS  PubMed  Google Scholar 

  31. Gui RY, Huang QS, Cai X, Wu J, Liu HX, Liu Y, et al. Development and validation of a prediction model (AHC) for early identification of refractory thrombotic thrombocytopenic purpura using nationally representative data. Br J Haematol. 2020;191:269–81.

    Article  CAS  PubMed  Google Scholar 

  32. Pabinger I, van Es N, Heinze G, Posch F, Riedl J, Reitter EM, et al. A clinical prediction model for cancer-associated venous thromboembolism: a development and validation study in two independent prospective cohorts. Lancet Haematol 2018;5:e289–98.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Wu YJ, Hou M, Liu HX, Peng J, Ma LM, Yang LH, et al. A risk score for predicting hospitalization for community-acquired pneumonia in ITP using nationally representative data. Blood Adv. 2020;4:5846–57.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Vickers AJ, Elkin EB. Decision curve analysis: a novel method for evaluating prediction models. Med Decis Making. 2006;26:565–74.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Vickers AJ, van Calster B, Steyerberg EW. A simple, step-by-step guide to interpreting decision curve analysis. Diagn Progn Res 2019;3:18.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Lavezzi M, Donati A, Davi D, Carpanelli MC, Farinelli S, Soracco E. [Response to vaccination against the etiologic agent of viral hepatitis B (HBV) in a population at risk]. Quad Sclavo Diagn. 1987;23:164–8.

    CAS  PubMed  Google Scholar 

  37. McMahon BJ. The natural history of chronic hepatitis B virus infection. Hepatology 2009;49(5 Suppl):S45–55.

    Article  CAS  PubMed  Google Scholar 

  38. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392:1736–88.

  39. Liu JH, Liao XW, Chen CH, Yao M, Li CC, Lin CT, et al. Adoptive donor immunity protects against resolved hepatitis B virus reactivation after allogeneic haematopoietic stem cell transplantation in the world’s largest retrospective cohort study. Brit J Haematol. 2019;186:72–85.

    Article  CAS  Google Scholar 

  40. Mikulska M, Nicolini L, Signori A, Rivoli G, Del BV, 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. 2014;20:O694–701.

    Article  CAS  PubMed  Google Scholar 

  41. Marcellin P, Ahn SH, Ma X, Caruntu FA, Tak WY, Elkashab M, et al. Combination of Tenofovir Disoproxil Fumarate and Peginterferon α-2a increases loss of Hepatitis B surface antigen in patients with chronic hepatitis B. Gastroenterology 2016;150:134–44.

    Article  CAS  PubMed  Google Scholar 

  42. Lok AS, Zoulim F, Dusheiko G, Ghany MG. Hepatitis B cure: From discovery to regulatory approval. Hepatology 2017;66:1296–313.

    Article  PubMed  Google Scholar 

  43. Cornberg M, Wong VW, Locarnini S, Brunetto M, Janssen HLA, Chan HL. The role of quantitative hepatitis B surface antigen revisited. J Hepatol. 2016;66:398–411.

    Article  PubMed  Google Scholar 

  44. Liu J, Yang HI, Lee MH, Lu SN, Jen CL, Wang LY, et al. Incidence and determinants of spontaneous hepatitis B surface antigen seroclearance: a community-based follow-up study. Gastroenterology 2010;139:474–82.

    Article  PubMed  Google Scholar 

  45. Hosaka T, Suzuki F, Kobayashi M, Seko Y, Kawamura Y, Sezaki H, et al. Clearance of hepatitis B surface antigen during long-term nucleot(s)ide analog treatment in chronic hepatitis B: results from a nine-year longitudinal study. J Gastroenterol. 2013;48:930–41.

    Article  CAS  PubMed  Google Scholar 

  46. Seto W, Chan TS, Hwang Y, Wong DK, Fung J, Liu KS, et al. Hepatitis B reactivation in occult viral carriers undergoing hematopoietic stem cell transplantation: A prospective study. Hepatology 2017;65:1451–61.

    Article  CAS  PubMed  Google Scholar 

  47. Gentile G, Antonelli G. HBV Reactivation in patients undergoing hematopoietic stem cell transplantation: a narrative review. Viruses. 2019;11.

  48. Ljungman P, de la Camara R, Robin C, Crocchiolo R, Einsele H, Hill JA, et al. Guidelines for the management of cytomegalovirus infection in patients with haematological malignancies and after stem cell transplantation from the 2017 European Conference on Infections in Leukaemia (ECIL 7). Lancet Infect Dis 2019;19:e260–72.

    Article  PubMed  Google Scholar 

  49. Harvala H, Stewart C, Muller K, Burns S, Marson L, MacGilchrist A, et al. High risk of cytomegalovirus infection following solid organ transplantation despite prophylactic therapy. J Med Virol. 2013;85:893–8.

    Article  CAS  PubMed  Google Scholar 

  50. Camargo JF, Komanduri KV. Emerging concepts in cytomegalovirus infection following hematopoietic stem cell transplantation. Hematol/Oncol Stem Cell Ther 2017;10:233–8.

    Article  CAS  PubMed  Google Scholar 

  51. Meesing A, Razonable RR. New developments in the management of cytomegalovirus infection after transplantation. DRUGS 2018;78:1085–103.

    Article  CAS  PubMed  Google Scholar 

  52. Styczynski J, van der Velden W, Fox CP, Engelhard D, de la Camara R, Cordonnier C, et al. Management of Epstein-Barr Virus infections and post-transplant lymphoproliferative disorders in patients after allogeneic hematopoietic stem cell transplantation: Sixth European Conference on Infections in Leukemia (ECIL-6) guidelines. Haematologica 2016;101:803–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Ocheni S, Kroeger N, Zabelina T, Sobottka I, Ayuk F, Wolschke C, et al. EBV reactivation and post transplant lymphoproliferative disorders following allogeneic SCT. Bone Marrow Transpl. 2008;42:181–6.

    Article  CAS  Google Scholar 

  54. Jackson SE, Redeker A, Arens R, van Baarle D, van den Berg S, Benedict CA, et al. CMV immune evasion and manipulation of the immune system with aging. Geroscience 2017;39:273–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Ljungman P, Hakki M, Boeckh M. Cytomegalovirus in hematopoietic stem cell transplant recipients. Infect Dis Clin North Am. 2010;24:319–37.

    Article  PubMed  Google Scholar 

  56. Chaichotjinda K, Anurathapan U, Boonsathorn S, Chaisavaneeyakorn S, Treepongkaruna S, Techasaensiri C, et al. Immune responses to hepatitis B vaccination after hematopoietic stem cell transplantation in pediatric and young adult patients. Clin Transpl. 2020;34:e14024.

    Article  Google Scholar 

  57. Sun X, Su Y, Liu X, Zhang Y, He Y, Han W, et al. Overt gastrointestinal bleeding following haploidentical haematopoietic stem cell transplantation: incidence, outcomes and predictive models. Bone Marrow Transpl. 2021;56:1341–51.

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Key Research and Development Program of China. (Nos. 2017YFA0105500 and 2017YFA0105503), the National Natural Science Foundation of China (No. 81970113), the Key Program of National Natural Science Foundation of China (No. 81730004) and the Beijing Natural Science Foundation (No. H2018206423).

Author information

Authors and Affiliations

Authors

Contributions

X-HZ, X-JH, K-YL, and L-PX designed the study. X-YS, H-XF, C-CW, Y-YZ, WH, HC, YW, QC, YH, and Q-SH collected the data. YC, C-HYT-TH, ML, X-DM, J-ZW, F-RW, Y-HC, and X-LZ analyzed the results. X-YS and H-XF wrote the manuscript. All authors critically revised, reviewed, and approved the final version of this manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Xiaohui Zhang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sun, X., Fu, H., Wang, C. et al. Predicting the loss of hepatitis B surface antigen following haematopoietic stem cell transplantation in patients with chronic HBV infection. Bone Marrow Transplant 58, 265–272 (2023). https://doi.org/10.1038/s41409-022-01880-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41409-022-01880-7

Search

Quick links