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Entecavir combining Chinese herbal medicine for HBeAg-positive chronic hepatitis B patients: a randomized, controlled trial

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Abstract

Background and aim

Traditional Chinese medicine (TCM) is widely accepted and prescribed in China alongside Nucleoside analogs (NAs). In this double-blind, placebo-controlled, randomized, multi-center trial, we evaluated whether entecavir (ETV) plus TCM formulas Tiao-Gan-Yi-Pi granule (TGYP) and Tiao-Gan-Jian-Pi-Jie-Du granule (TGJPJD) increase the rate of hepatitis B e antigen (HBeAg) loss in Chinese patients.

Methods

596 eligible participants were randomly assigned, in a 1:1 ratio, to two study groups in this 108-week trial: The experiment group was assigned ETV plus the TCM formula. The control group was assigned ETV plus a TCM placebo. We compared the rate of HBeAg loss by the end of week 108 between the two arms as the primary outcome. Secondary outcomes included hepatitis B surface antigen (HBsAg) level, proportion of undetectable HBV-DNA, and liver enzymes (ALT, AST, GGT) at week 108.

Results

The combination therapy achieved superior HBeAg loss at 108 weeks, without additional adverse events. The rate of HBeAg loss at week 108 was 37.54% (95% CI 31.9–43.2%) in the experiment group and 27.21% (95% CI 22.0–32.4%) in the control group. There was a statistically significant difference between the two arms of 10.33% (95% CI 8.4–12.3%, p = 0.008). The DNA loss rate, serum HBsAg level, and liver enzymes were similar between the groups by the end of 108th week.

Conclusion

Combining the Chinese herbal formula with ETV therapy demonstrated superior HBeAg clearance compared with ETV monotherapy. This finding indicates that this combined therapy could produce an improved therapeutic effect and safety profile.

Clinical trial number

ChiCTR-TRC-12002784 (Chinese Clinical Trial Registry).

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Acknowledgements

We thank the patients for participating in the trial. We want to give thanks to Professor Yan Liu and Doctor Xiaobin Zao (Dongzhimen Hospital, BUCM), Professor Yiming Zhao, and Professor Nan Li (Research Center of Clinical Epidemiology, Peking University Third Hospital) for their advice on statistical analysis.

Funding

This study is funded by China National Science and Technology major projects 12th 5-year plan, No. 2012ZX10005004.

Author information

Authors and Affiliations

  1. Department of Gastroenterology, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine (BUCM), Institute of Liver Diseases, BUCM, No. 5 Haiyuncang road, Dongcheng District, Beijing, 100700, China

    Xiaoke Li, Feng Jiang, Zhiguo Li, Xianzhao Yang, Danan Gan, Ludan Zhang, Hongbo Du & Yong’an Ye

  2. Department of Hepatology, Shenzhen TCM Hospital, No. 1 Fuhua Road, Futian District, Shenzhen, 518033, China

    Daqiao Zhou

  3. Department of Hepatology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Dade Road 111, Guangzhou, 510120, Guangdong, China

    Xiaoling Chi

  4. Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, No. 312 Xihong road, Gulou District, Fujian, 350025, Fuzhou, China

    Qin Li

  5. Department of Hepatology, Public Health Clinical Center of Chengdu, No. 377 Jingming Road, Jinjiang District, Chengdu, 610066, Sichuan, China

    Li Wang

  6. Department of Hepatology, Liaoning Hospital of TCM, Huanggu District, No. 33, Beiling Street, Shenyang, 110032, Liaoning, China

    Bingjiu Lu

  7. Department of Hepatology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, No. 89-9, Dongge road, Nanning, 530023, Guangxi, China

    Dewen Mao

  8. Department of Hepatology, The Third People’s Hospital of Shenzhen, No. 29 Bujibulan Road, Longgang District, Shenzhen, 518112, China

    Qikai Wu

  9. Department of Hepatology, Beijing Ditan Hospital, No. 8 Jingshun East Road, Chaoyang District, Beijing, 100015, China

    Xianbo Wang

  10. Department of Hepatology, The Sixth People’s Hospital of Shenyang, No. 85 Heping south road, Heping District, Shenyang, 110006, Liaoning, China

    Mingxiang Zhang

  11. Department of Hepatology, Shaanxi Hospital of TCM, No. 4 Xihuamen, Lianhu District, Xi’an, 710003, Shaanxi, China

    Jingdong Xue

  12. Department of Hepatology, The Affiliated Hospital of Shandong University of TCM, No. 42 Wenhua West Road, Jinan, 250011, Shandong, China

    Yong Li

  13. Department of Hepatology, Tianjin Second People’s Hospital, No.7 Sudi South Road, Nankai District, Tianjin, 300192, China

    Wei Lu

  14. Department of Hepatology, Xixi Hospital of Hangzhou, No. 2 Hengbu road, Liuxiazhen, Xihu District, Hangzhou, 310023, Zhejiang, China

    Jianchun Guo

  15. Department of Liver Disease, Fifth Medical Center of Chinese PLA General Hospital, No.100 West Fourth Ring Road, Beijing, 100039, China

    Xinwei Zhang

  16. Department of Hepatology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, No. 314 An Shan Xi Road, Nan Kai District, Tianjin, 300193, China

    Hui Guo

  17. Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medicine Sciences, No. 16, Dongzhimen South Street, Dongcheng District, Beijing, 100700, China

    Liyun He & Lin Luo

Authors
  1. Xiaoke Li
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  4. Qin Li
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  5. Li Wang
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  6. Bingjiu Lu
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  15. Feng Jiang
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Contributions

XKL is the academic secretary of the project, and he drafted the manuscript. DQZ, XLC, QL, WL, BJL, DWM, QKW, XBW, MXZ, JDX, YL, WL, JCG, FJ, XWZ, HG are PIs of subcenters. ZGL, XZY, DNG, LYH, LL, LDZ participated in the program and helped with polishing the manuscript. HBD is the vice PI of the project, and YAY is the PI of the project.

Corresponding authors

Correspondence to Hongbo Du or Yong’an Ye.

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The authors declare that they have no competing interests.

Ethical approval

All procedures performed in the study (involving human participants) were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Li, X., Zhou, D., Chi, X. et al. Entecavir combining Chinese herbal medicine for HBeAg-positive chronic hepatitis B patients: a randomized, controlled trial. Hepatol Int 14, 985–996 (2020). https://doi.org/10.1007/s12072-020-10097-z

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  • DOI: https://doi.org/10.1007/s12072-020-10097-z

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