Skip to main content

Advertisement

SpringerLink
Log in

Serum soluble programmed death-1 levels predict the spontaneous HBeAg seroclearance in chronic hepatitis B

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Background and aims

In chronic hepatitis B virus (HBV) infection, earlier seroclearance of hepatitis B e antigen (HBeAg) is associated with more favorable outcomes. Soluble programmed cell death 1 (sPD-1) has been implicated in higher viral load and hepatocellular carcinoma. We investigated the association between sPD-1 levels and spontaneous HBeAg seroclearance.

Methods

Baseline serum samples from 488 HBeAg-seropositive patients in the REVEAL-HBV cohort were tested for sPD-1 levels. Among them, 329 with available follow-up serum samples were further assayed. Multivariate Cox regression analysis was used to estimate the adjusted rate ratio (aRR) and 95% confidence interval (CI) with adjustment of host and viral factors. The 66th percentile and an annual reduction of ≥ 10% were used as the cut-off point for baseline sPD-1 levels (high/low) and sPD-1 trajectory (decline/no decline), respectively.

Results

Lower baseline sPD-1 levels [aRR (95% CI): 2.19 (1.47–3.27)] and long-term decline in sPD-1 levels [aRR (95% CI): 4.08 (2.79–5.97)] were both independent predictors for HBeAg seroclearance. However, further stratification analysis by HBV genotype showed that lower baseline sPD-1 levels were significantly associated with HBeAg seroclearance only in genotype C infection [aRR (95% CI): 4.47 (2.38–8.37)] but not in genotype B infection. On the other hand, long-term decline in sPD-1 levels was predictive for HBeAg seroclearance regardless of HBV genotype with aRR (95% CI) of 4.62 (2.71–7.88) and 2.95 (1.68–5.17), respectively, for genotypes B and C.

Conclusion

Serum sPD-1 levels may serve as a novel immunological predictor for spontaneous HBeAg seroclearance in patients with chronic hepatitis B.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

ALT:

Alanine aminotransferase

Anti-HBe:

Anti-HBe antibody

CHB:

Chronic hepatitis B

HBV:

Hepatitis B virus

HBeAg:

Hepatitis B e antigen

HCC:

Hepatocellular carcinoma

LOESS:

Locally weighted regression

qHBsAg:

Hepatitis B surface antigen quantification

REVEAL-HBV:

Risk evaluation of viral load elevation and associated liver disease/cancer-hepatitis B virus

RR:

Rate ratio

sPD-1:

Soluble programmed-death 1

References

  1. Chen CJ, Yang HI. Natural history of chronic hepatitis B REVEALed. J Gastroenterol Hepatol. 2011;26:628–38.

    Article  Google Scholar 

  2. Keeffe EB, Dieterich DT, Han SH, et al. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States: 2008 update. Clin Gastroenterol Hepatol. 2008;6:1315–41; quiz 1286.

  3. Liaw YF, Kao JH, Piratvisuth T, et al. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2012 update. Hepatol Int. 2012;6:531–61.

    Article  Google Scholar 

  4. Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2007;45:507–39.

    Article  CAS  Google Scholar 

  5. Chu CM, Liaw YF. Chronic hepatitis B virus infection acquired in childhood: special emphasis on prognostic and therapeutic implication of delayed HBeAg seroconversion. J Viral Hepat. 2007;14:147–52.

    Article  Google Scholar 

  6. Yang HI, Lu SN, Liaw YF, et al. Hepatitis B e antigen and the risk of hepatocellular carcinoma. N Engl J Med. 2002;347:168–74.

    Article  CAS  Google Scholar 

  7. Yang HI, Hung HL, Lee MH, et al. Incidence and determinants of spontaneous seroclearance of hepatitis B e antigen and DNA in patients with chronic hepatitis B. Clin Gastroenterol Hepatol. 2012;10(527–34):e1-2.

    Google Scholar 

  8. Sharpe AH, Pauken KE. The diverse functions of the PD1 inhibitory pathway. Nat Rev Immunol. 2018;18:153–67.

    Article  CAS  Google Scholar 

  9. Sun C, Mezzadra R, Schumacher TN. Regulation and Function of the PD-L1 Checkpoint. Immunity. 2018;48:434–52.

    Article  CAS  Google Scholar 

  10. Barber DL, Wherry EJ, Masopust D, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature. 2006;439:682–7.

    Article  CAS  Google Scholar 

  11. Hirano F, Kaneko K, Tamura H, et al. Blockade of B7–H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res. 2005;65:1089–96.

    CAS  PubMed  Google Scholar 

  12. Ferrando-Martinez S, Huang K, Bennett AS, et al. HBeAg seroconversion is associated with a more effective PD-L1 blockade during chronic hepatitis B infection. JHEP Rep. 2019;1:170–8.

    Article  Google Scholar 

  13. Zhu X, Lang J. Soluble PD-1 and PD-L1: predictive and prognostic significance in cancer. Oncotarget. 2017;8:97671–82.

    Article  Google Scholar 

  14. Nielsen C, Ohm-Laursen L, Barington T, et al. Alternative splice variants of the human PD-1 gene. Cell Immunol. 2005;235:109–16.

    Article  CAS  Google Scholar 

  15. He YF, Zhang GM, Wang XH, et al. Blocking programmed death-1 ligand-PD-1 interactions by local gene therapy results in enhancement of antitumor effect of secondary lymphoid tissue chemokine. J Immunol. 2004;173:4919–28.

    Article  CAS  Google Scholar 

  16. Pen JJ, Keersmaecker BD, Heirman C, et al. Interference with PD-L1/PD-1 co-stimulation during antigen presentation enhances the multifunctionality of antigen-specific T cells. Gene Ther. 2014;21:262–71.

    Article  CAS  Google Scholar 

  17. Zhou L, Li X, Huang X, et al. Soluble programmed death-1 is a useful indicator for inflammatory and fibrosis severity in chronic hepatitis B. J Viral Hepat. 2019;26:795–802.

    Article  CAS  Google Scholar 

  18. Cheng HY, Kang PJ, Chuang YH, et al. Circulating programmed death-1 as a marker for sustained high hepatitis B viral load and risk of hepatocellular carcinoma. PLoS One. 2014;9:e95870.

  19. Chen CJ, Yang HI, Su J, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA, J Am Med Assoc. 2006;295:65–73.

    Article  CAS  Google Scholar 

  20. Yeh SH, Tsai CY, Kao JH, et al. Quantification and genotyping of hepatitis B virus in a single reaction by real-time PCR and melting curve analysis. J Hepatol. 2004;41:659–66.

    Article  CAS  Google Scholar 

  21. Xia J, Huang R, Chen Y, et al. Profiles of serum soluble programmed death-1 and programmed death-ligand 1 levels in chronic hepatitis B virus-infected patients with different disease phases and after anti-viral treatment. Aliment Pharmacol Ther. 2020;51:1180–7.

    Article  CAS  Google Scholar 

  22. Li N, Zhou Z, Li F, et al. Circulating soluble programmed death-1 levels may differentiate immune-tolerant phase from other phases and hepatocellular carcinoma from other clinical diseases in chronic hepatitis B virus infection. Oncotarget. 2017;8:46020–33.

    Article  Google Scholar 

  23. Rajoriya N, Combet C, Zoulim F, et al. How viral genetic variants and genotypes influence disease and treatment outcome of chronic hepatitis B. Time for an individualised approach? J Hepatol. 2017;67:1281–1297.

  24. Yuen MF, Wong DK, Zheng BJ, et al. Difference in T helper responses during hepatitis flares in hepatitis B e antigen (HBeAg)-positive patients with genotypes B and C: implication for early HBeAg seroconversion. J Viral Hepat. 2007;14:269–75.

    Article  Google Scholar 

  25. Lindh M, Hannoun C, Dhillon AP, et al. Core promoter mutations and genotypes in relation to viral replication and liver damage in East Asian hepatitis B virus carriers. J Infect Dis. 1999;179:775–82.

    Article  CAS  Google Scholar 

  26. Orito E, Mizokami M, Sakugawa H, et al. A case-control study for clinical and molecular biological differences between hepatitis B viruses of genotypes B and C. Jpn HBV Genotype Res Group Hepatol. 2001;33:218–23.

    CAS  Google Scholar 

  27. Wu JF, Chang KC, Ni YH, et al. Impacts of the percentage of basal core promoter mutation on the progression of liver fibrosis after HBeAg-seroconversion. J Infect Dis. 2020;

  28. Watanabe K, Takahashi T, Takahashi S, et al. Comparative study of genotype B and C hepatitis B virus-induced chronic hepatitis in relation to the basic core promoter and precore mutations. J Gastroenterol Hepatol. 2005;20:441–9.

    Article  CAS  Google Scholar 

  29. Gane E, Verdon DJ, Brooks AE, et al. Anti-PD-1 blockade with nivolumab with and without therapeutic vaccination for virally suppressed chronic hepatitis B: a pilot study. J Hepatol. 2019;71:900–7.

    Article  CAS  Google Scholar 

  30. Onlamoon N, Rogers K, Mayne AE, et al. Soluble PD-1 rescues the proliferative response of simian immunodeficiency virus-specific CD4 and CD8 T cells during chronic infection. Immunology. 2008;124:277–93.

    Article  CAS  Google Scholar 

  31. Song MY, Park SH, Nam HJ, et al. Enhancement of vaccine-induced primary and memory CD8(+) T-cell responses by soluble PD-1. J Immunother. 2011;34:297–306.

    Article  CAS  Google Scholar 

  32. Amancha PK, Hong JJ, Rogers K, et al. In vivo blockade of the programmed cell death-1 pathway using soluble recombinant PD-1-Fc enhances CD4+ and CD8+ T cell responses but has limited clinical benefit. J Immunol. 2013;191:6060–70.

    Article  CAS  Google Scholar 

  33. Liaw YF, Chu CM, Su IJ, et al. Clinical and histological events preceding hepatitis B e antigen seroconversion in chronic type B hepatitis. Gastroenterology. 1983;84:216–9.

    Article  CAS  Google Scholar 

  34. Liaw YF, Pao CC, Chu CM, et al. Changes of serum hepatitis B virus DNA in two types of clinical events preceding spontaneous hepatitis B e antigen seroconversion in chronic type B hepatitis. Hepatology. 1987;7:1–3.

    Article  CAS  Google Scholar 

Download references

Funding

This study is financially supported by Academia Sinica, Taipei, Taiwan (AS-TP-108-L09-3).

Author information

Author notes

  1. Yu-Ju Chu and Wen-Juei Jeng contributed to this work equally.

Authors and Affiliations

  1. Genomics Research Center, Academia Sinica, Taipei, Taiwan

    Yu-Ju Chu, Mei-Hung Pan, Hui-Han Hu, Wen-Sheng Luo, Chien-Yu Su, Chen-Tse Chiang, Chin-Lan Jen, Chien-Jen Chen & Hwai-I Yang

  2. Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou, Taiwan

    Wen-Juei Jeng

  3. College of Medicine, Chang Gung University, Taoyuan, Taiwan

    Wen-Juei Jeng

  4. Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan

    Wen-Juei Jeng & Hwai-I Yang

  5. School of Public Health, National Defense Medical Center, Taipei, Taiwan

    Hui-Han Hu

  6. Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

    Hwai-I Yang

  7. Biomedical Translation Research Center, Academia Sinica, Taipei, Taiwan

    Hwai-I Yang

Authors
  1. Yu-Ju Chu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wen-Juei Jeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mei-Hung Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hui-Han Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wen-Sheng Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Chien-Yu Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Chen-Tse Chiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Chin-Lan Jen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Chien-Jen Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hwai-I Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Guarantor of article: H-IY. Specific author contributions: Y-JC: Conceptualization; formal analysis; methodology; writing—original draft, revision. W-JJ: conceptualization; methodology; writing—original draft, revision, review & editing. M-HP: data curation; formal analysis. H-HH: Investigation; methodology; resources. W-SL: Investigation; resources. C-YS: resources. C-TC: resources. C-LJ: Resources. C-JC: resources. H-IY: conceptualization; funding acquisition; methodology; project administration; analysis; resources; supervision; writing—revision, review & editing. We declare that we all have seen and approved the final version.

Corresponding author

Correspondence to Hwai-I Yang.

Ethics declarations

Conflict of interest

No potential conflicts of interest were disclosed.

Additional information

Publisher's Note

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

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 34 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chu, YJ., Jeng, WJ., Pan, MH. et al. Serum soluble programmed death-1 levels predict the spontaneous HBeAg seroclearance in chronic hepatitis B. J Gastroenterol 57, 423–432 (2022). https://doi.org/10.1007/s00535-022-01874-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00535-022-01874-8

Keywords

Search

Navigation