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Prediction of liver-related events in patients with compensated HBV-induced cirrhosis receiving antiviral therapy

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Abstract

Background and aims

Many models have been developed to predict liver-related events (LRE) in chronic hepatitis B, few focused on compensated HBV-induced cirrhosis. We aimed to describe the incidence of LRE and to determine independent risk predictors of LRE in compensated HBV-induced cirrhosis patients receiving antiviral therapy using routinely available parameters.

Methods

Prospective cohorts of treatment-naïve adults with compensated HBV-induced cirrhosis were enrolled. Patients were treated with entecavir (ETV) or ETV + thymosin-alpha1 (Thy-α1) or lamivudine (LAM) + adefovir (ADV). Data were collected at baseline and every 6 months. LRE was defined as development of decompensation, HCC or death.

Results

Totally 937 patients were included, 608 patients treated with ETV, 252 with ETV + Thy-α1, and 77 with LAM + ADV. After a median follow-up of 4.5 years, 88 patients developed LRE including 48 with HCC. The cumulative incidence of LRE at year 1, 3, and 5 was 2.1%, 7.0%, and 12.7%, respectively, and was similar for three treatment groups. All models using variables at month 6 or 12 had better fit than models using baseline values. The best model for prediction of LRE used PLT, GGT, and AFP at month 6 [AUC: 0.762 (0.678–0.814)], for hepatic decompensation—PLT, LSM and GGT at month 12 (AUC: 0.834 (0.675–0.919)), and for HCC—AFP and GGT at month 6 [AUC 0.763 (0.691–0.828)]. All models had negative predictive values of 94.0–98.8%.

Conclusion

Models using on-treatment variables are more accurate than models using baseline variables in predicting LRE in patient with compensated HBV-induced cirrhosis receiving antiviral therapy. ClincialTrials.gov number NCT01943617, NCT01720238, NCT03366571, NCT02849132.

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Abbreviations

ADV:

Adefovir

ALT:

Alanine transaminase

ALB:

Albumin

AFP:

Alpha-fetoprotein

AST:

Aspartate aminotransferase

CTP:

Child-Turcotte-Pugh

Cr:

Creatine

ETV:

Entecavir

GGT:

Gamma-glutamyl transferase

HCC:

Hepatocellular carcinoma

HE:

Hepatoencephalopathy

INR:

International normalized ratio

LAM:

Lamivudine

LRE:

Liver-related event

LSM:

Liver stiffness measurement

MELD:

Model for end-stage liver disease

PLT:

Platelet

RCT:

Randomized controlled trial

Thy-α1:

Thymosin-alpha1

TB:

Total bilirubin

VB:

Variceal bleeding

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Acknowledgements

I would like to give special thanks to Dr. Anna Suk-Fong, Lok for her numerous advice on data analysis and review of the manuscript. I am grateful for your instruction on being a good doctor, for your guidance me on becoming an excellent clinical researcher, for your warm support through tough times, and for your strong encouragement. It is an unbelievable and precious experience in my life to have had the opportunity to work with you this past year.

Funding

This study was funded by the National Major Science and Technology Project (2018ZX10302204-004, 2018ZX09201016, 2017ZX10203202-003), the Project of Beijing Municipal Commission of Science and Technology (D161100002716003), and the Project of the Digestive Medical Coordinated Development Center of Beijing Hospitals Authority (XXZ0405).

Author information

Authors and Affiliations

  1. Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yong-an Road, Xi-Cheng District, Beijing, 100050, China

    Xiaoning Wu, Jialing Zhou, Yameng Sun, Tongtong Meng, Bingqiong Wang, Shuyan Chen, Yiwen Shi, Xiaojuan Ou, Hong You & Jidong Jia

  2. Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis, Beijing, China

    Xiaoning Wu, Jialing Zhou, Yameng Sun, Tongtong Meng, Bingqiong Wang, Shuyan Chen, Yiwen Shi, Xiaojuan Ou, Hong You & Jidong Jia

  3. National Clinical Research Center of Digestive Disease, Beijing, China

    Xiaoning Wu, Jialing Zhou, Yameng Sun, Tongtong Meng, Bingqiong Wang, Shuyan Chen, Yiwen Shi, Yuanyuan Kong, Xiaojuan Ou, Hong You & Jidong Jia

  4. Department of Gastroenterology, Beijing Youan Hospital, Capital Medical University, Beijing, China

    Huiguo Ding

  5. Division of Liver Fibrosis, The Fifth Medical Center, General Hospital of the People’s Liberation Army, Beijing, China

    Guofeng Chen

  6. Liver Research Center, Beijing Ditan Hospital, Capital Medical University, Beijing, China

    Wen Xie

  7. Office of Clinical Trials, Affiliated Hospital of Yanbian University, Yanji, Jilin, China

    Hongxin Piao

  8. Division of Infectious Diseases, Peking University First Hospital, Beijing, China

    Xiaoyuan Xu

  9. Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China

    Wei Jiang

  10. Liver Research Center, Peking University People’s Hospital, Beijing, China

    Hui Ma

  11. Division of Infectious Diseases, China-Japan Friendship Hospital, Beijing, China

    Anlin Ma

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

    Yongpeng Chen

  13. Department of Gastroenterology and Hepatology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

    Mingyi Xu

  14. Department of Gastroenterology, Shanghai Public Health Clinical Center, Shanghai, China

    Jilin Cheng

  15. Department of Gastroenterology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China

    Youqing Xu

Authors
  1. Xiaoning Wu
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  2. Jialing Zhou
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  3. Yameng Sun
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  4. Huiguo Ding
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  5. Guofeng Chen
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  6. Wen Xie
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  7. Hongxin Piao
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  8. Xiaoyuan Xu
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  9. Wei Jiang
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  10. Hui Ma
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  11. Anlin Ma
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  14. Jilin Cheng
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  16. Tongtong Meng
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  17. Bingqiong Wang
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  18. Shuyan Chen
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  19. Yiwen Shi
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  20. Yuanyuan Kong
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  21. Xiaojuan Ou
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  22. Hong You
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  23. Jidong Jia
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Corresponding authors

Correspondence to Xiaojuan Ou, Hong You or Jidong Jia.

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Conflict of interest

Xiaoning Wu, Jialing Zhou, Yameng Sun, Huiguo Ding, Guofeng Chen, Wen Xie,Hongxin Piao, Xiaoyuan Xu, Wei Jiang, Hui Ma, Anlin Ma, Yongpeng Chen, Mingyi Xu, Jilin Cheng, Youqing Xu, Tongtong Meng, Bingqiong Wang, Shuyan Chen, Yiwen Shi, Yuanyuan Kong, Xiaojuan Ou, Hong You, Jidong Jia authors have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The protocol, patient information sheets, and consent forms were approved by the Medical Ethics Committee of Beijing Friendship Hospital, Capital Medical University (BJFH-EC/2013-029, BJFH-EC/2013-067, 2016-P2-021-01, 2016-P2-022-01) and the other 33 participating centers. The studies were registered with the ClinicalTrials.gov identifier NCT01943617, NCT01720238, NCT03366571, NCT02849132.

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

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12072_2020_10114_MOESM1_ESM.tif

Supplementary file1 Supplementary figure 1. Cumulative incidence of LRE, decompensation and HCC had no statistical differences among three treatment groups. LRE, liver related events; HCC, hepatocellular carcinoma (TIF 58 kb)

12072_2020_10114_MOESM2_ESM.tif

Supplementary file1 Supplementary figure 2. Long-term virological response and biochemical response in patients with and without LRE. A. HBV DNA decreased rapidly after initiation of antiviral treatment and maintained. B. More than 90% of patients achieved HBV DNA< 200 IU/mL after 1 year antiviral treatment and maintained. C, E,F. AST, ALB, GGT improved rapidly during the first 6 months (all P <0.01), and then continued to improve slowly but significantly to 2 years in LRE group and to 3 years in non-LRE group, and remained stable thereafter. D. TB had no significant change because most patients were within normal range. AST, alanine aminotransferase; TB, total bilirubin; ALB, albumin; GGT, Gamma-glutamyl transferase (TIF 117 kb)

12072_2020_10114_MOESM3_ESM.tif

Supplementary file1 Supplementary figure 3. On-treatment change of PLT, AFP and liver cirrhosis related indices. PLT increased significantly from baseline to year 5 in both LRE group (median 78 to 124 ×109/L, P<0.01) and non-LRE group (median 96 to 140 ×109/L, P<0.01), but the increase was slower in LRE group and stabilized after 2 years, while progressive increase was observed in non-LRE group. AFP in LRE group decreased from baseline to year 2 (P < 0.001) and then kept stable, it continually improved from baseline to year 5 significantly in non-LRE group. LSM improved rapidly during the first 6 months (all P <0.01), and then continued to improve slowly but significantly to 2 years in LRE group and to 3 years in non-LRE group, and remained stable thereafter. INR in LRE group decreased during the first year and then increased, it continually improved from baseline to year 5 significantly in non-LRE group. APRI and FIB-4 decreased rapidly during 6 months and decreased slowly to year 2 and maintained. LRE, liver related event; PLT, platelet; AFP, alpha-fetoprotein; LSM, liver stiffness measurement; INR, international normalized ratio; APRI, AST to PLT ratio index; FIB-4, fibrosis-4 (TIF 101 kb)

12072_2020_10114_MOESM4_ESM.tif

Supplementary file1 Supplementary figure 4. On-treatment changes of CTP, MELD ALBI. CTP and MELD showed no significant change after initiation of antiviral therapy. ALBI decreased gradually as albumin increased. CTP, Child-Turcotte-Pugh; MELD, model for end-stage liver disease; ALBI, albumin-bilirubin(TIF 48 kb)

Supplementary file1 (DOCX 38 kb)

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Wu, X., Zhou, J., Sun, Y. et al. Prediction of liver-related events in patients with compensated HBV-induced cirrhosis receiving antiviral therapy. Hepatol Int 15, 82–92 (2021). https://doi.org/10.1007/s12072-020-10114-1

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