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Sequential combination therapy with interferon, interleukin-2 and therapeutic vaccine in entecavir-suppressed chronic hepatitis B patients: the Endeavor study

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Abstract

Background

Switching from nucleos(t)ide analogues to interferon (IFN) improves hepatitis B surface antigen (HBsAg) loss. We aimed to evaluate whether combining immunomodulators such as interleukin-2 (IL-2) and therapeutic vaccine with IFN enhances HBsAg loss in entecavir (ETV)-suppressed patients.

Methods

Ninety-four patients exhibiting virological suppression and hepatitis B e antigen (HBeAg) loss following ETV treatment were randomized 1:1:1 to receive ETV (group I) or IFN (group II) for 48 weeks, or IFN and vaccine for 48 weeks plus IL-2 for 12 weeks (group III). The primary endpoint was HBsAg loss at week 48. Peripheral natural killer (NK) cells and regulatory T cells (Treg) were measured as immune checkpoint indicators.

Results

Mean HBsAg decline at week 48 was significantly greater in group III (0.85 log 10 IU/mL) and group II (0.74 log 10 IU/mL), than in group I (0.13 log 10 IU/mL). At week 48, 9.38%, 3.03%, and 3.70% of subjects in group III, II, and I, respectively, achieved HBsAg loss. Among patients with baseline HBsAg titers ranging from 100 to 1500 IU/mL, HBsAg loss rate was 27.3, 7.1, and 0% in group III, II, and I, respectively. Responders in group III showed a significantly higher increase in CD56bright CD16−NK cells from week 24 to 36, and a significant decline in Treg from week 12 to 24 than non-responders.

Conclusion

For ETV-suppressed patients, particularly those with low baseline HBsAg levels, combination therapy with IFN and other immunomodulators may enhance HBsAg loss, while successful response correlates with partial restoration of NK cells and Tregs.

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Abbreviations

ALT:

Alanine aminotransferase

CHB:

Chronic hepatitis B

cccDNA:

Covalently closed circular DNA

ETV:

Entecavir

HBeAg:

Hepatitis B e antigen

HBsAg:

Hepatitis B surface antigen

HBV:

Hepatitis B virus

HCC:

Hepatocellular carcinoma

ITT:

Intention-to-treat

IFN:

Interferon

IL-2:

Interleukin-2

LAM:

Lamivudine

mITT:

Modified intention-to-treat

NK cell:

Natural killer cell

NA:

Nucleos(t)ide analogue

Peg-IFN:

Pegylated Interferon

ROC:

Receiver-operating characteristic

Treg:

Regulatory T cell

ULN:

Upper limit of normal

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Acknowledgements

The authors would like to thank all the patients in this study, and the nurses who assisted in the patient management and the collection of serum samples. Data management and clinical trial monitoring were provided by Hangzhou Tigermed Consulting Co., Ltd.

Funding

This work was supported by grants from the Chinese National Twelfth Five Years Project in Science and Technology (2013ZX10002003), the Chinese National Thirteenth Five Years Project in Science and Technology (2017ZX10202201) and Hubei Provincial Natural Science Foundation of China (2018CFB206).

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Authors and Affiliations

  1. Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095, Jiefang Avenue, Wuhan, 430030, China

    Di Wu, Peng Wang, Meifang Han, Weiming Yan, Xiaoyang Wan & Qin Ning

  2. Department of Infectious Disease, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China

    Yongping Chen

  3. International Medical Department, Beijing You’an Hospital, Capital Medical University, Beijing, China

    Xinyue Chen

  4. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China

    Qi Xia

  5. Department of Infectious Disease, Anhui Provincial Hospital, Anhui Medical University, Hefei, Anhui, China

    Chuanlong Zhu

  6. Department of Infectious Diseases, Shanghai Ruijin Hospital, Jiaotong University School of Medicine, Shanghai, China

    Qing Xie

  7. Liver Research Center, First Affiliated Hospital of Fujian Medical University, Fuzhou, China

    Jiaji Jiang

  8. Department of Hepatology, Peking University People’s Hospital, Beijing, China

    Lai Wei

  9. Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, China

    Deming Tan

  10. Department of Infectious Disease, Shengjing Hospital of China Medical University, Shenyang, China

    Xiaoguang Dou

  11. Department of Infectious Diseases, Peking University First Hospital, Beijing, China

    Yanyan Yu

  12. Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China

    Jinlin Hou

  13. Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Xiaoping Luo

Authors
  1. Di Wu
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  2. Peng Wang
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  3. Meifang Han
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  6. Qi Xia
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  7. Weiming Yan
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  8. Xiaoyang Wan
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  9. Chuanlong Zhu
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  10. Qing Xie
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  16. Jinlin Hou
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  17. Xiaoping Luo
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  18. Qin Ning
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Contributions

QN, DW, and MH developed the concepts and designed the experiments. DW, and PW analyzed and interpreted the data. DW drafted the manuscript. YC, XC, QX, WY, CZ, QX, JJ, LW, DT, XD, YY, and JH were involved in patient recruitment, and data collection. QN, DW, XL, MH, and XW revised the manuscript.

Corresponding author

Correspondence to Qin Ning.

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Conflict of interest

The authors declare no conflict of interest.

Ethical approval

The study was performed in accordance with Good Clinical Practice and the Declaration of Helsinki principles for ethical research. The study protocol was approved by the independent central ethics committee of Tongji Medical College at Wuhan. Written informed consent was obtained from each participant. ClinicalTrials.gov Identifier: NCT02360592. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008 (5).

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Informed consent was obtained from all patients for being included in the study.

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Wu, D., Wang, P., Han, M. et al. Sequential combination therapy with interferon, interleukin-2 and therapeutic vaccine in entecavir-suppressed chronic hepatitis B patients: the Endeavor study. Hepatol Int 13, 573–586 (2019). https://doi.org/10.1007/s12072-019-09956-1

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