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©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
Dynamics of cytokines predicts risk of hepatocellular carcinoma among chronic hepatitis C patients after viral eradication
Ming-Ying Lu, Ming-Lun Yeh, Ching-I Huang, Shu-Chi Wang, Yi-Shan Tsai, Pei-Chien Tsai, Yu-Min Ko, Ching-Chih Lin, Kuan-Yu Chen, Yu-Ju Wei, Po-Yao Hsu, Cheng-Ting Hsu, Tyng-Yuan Jang, Ta-Wei Liu, Po-Cheng Liang, Ming-Yen Hsieh, Zu-Yau Lin, Shinn-Cherng Chen, Chung-Feng Huang, Jee-Fu Huang, Chia-Yen Dai, Wan-Long Chuang, Ming-Lung Yu
Ming-Ying Lu, Ming-Lun Yeh, Ching-I Huang, Yi-Shan Tsai, Pei-Chien Tsai, Yu-Min Ko, Ching-Chih Lin, Kuan-Yu Chen, Yu-Ju Wei, Po-Yao Hsu, Cheng-Ting Hsu, Tyng-Yuan Jang, Ta-Wei Liu, Po-Cheng Liang, Ming-Yen Hsieh, Zu-Yau Lin, Shinn-Cherng Chen, Chung-Feng Huang, Jee-Fu Huang, Chia-Yen Dai, Wan-Long Chuang, Ming-Lung Yu, Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
Ming-Lun Yeh, Ching-I Huang, Zu-Yau Lin, Shinn-Cherng Chen, Chung-Feng Huang, Jee-Fu Huang, Chia-Yen Dai, Wan-Long Chuang, Ming-Lung Yu, School of Medicine and Hepatitis Research Center, College of Medicine, Center for Cancer Research and Center for Liquid Biopsy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
Shu-Chi Wang, Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
Chia-Yen Dai, Health Management Center, Department of Community Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
Ming-Lung Yu, Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 80708, Taiwan
Author contributions: Lu MY analyzed the data and wrote the manuscript; Tsai PC confirmed the statistical analysis; Wang SC, Tsai YS, Ko YM, Lin CC, and Chen KY performed the experiments; Yeh ML, Huang CI, Wei YJ, Hsu PY, Hsu CT, Jang TY, Liu TW, Liang PC, Hsieh MY, Lin ZY, Chen SC, Huang CF, Huang JF, and Dai CY collected the clinical data; Yu ML and Chuang WL designed the study, interpreted data, and supervised the manuscript; all authors had read and approved the final manuscript.
Supported by Kaohsiung Medical University and Kaohsiung Medical University Hospital (KMU-KMUH Co-Project of Key Research), No. KMU-DK107004.
Institutional review board statement: This study was reviewed and approved by the Institutional Review Board of Kaohsiung Medical University Hospital [No. KMUHIRB-E(I)-20180307&KMUHIRB-G(II)-20170020].
Informed consent statement: All study participants provided informed written consent prior to study enrollment.
Conflict-of-interest statement: The authors declare that they have no competing interests.
Data sharing statement: Technical appendix, statistical code, and dataset available from the corresponding author at
fish6069@gmail.com. Participants gave informed consent for data sharing.
STROBE statement: The authors have read the STROBE Statement - checklist of items, and the manuscript was prepared and revised according to the STROBE Statement -checklist of items.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
http://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Ming-Lung Yu, MD, PhD, Chief Doctor, Full Professor, Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, No. 100 Shih-Chuan 1
st Road, Sanmin District, Kaohsiung 80708, Taiwan.
fish6069@gmail.com
Received: September 8, 2021
Peer-review started: September 8, 2021
First decision: October 16, 2021
Revised: October 27, 2021
Accepted: December 23, 2021
Article in press: December 23, 2021
Published online: January 7, 2022
Processing time: 113 Days and 19.3 Hours
BACKGROUND
Chronic hepatitis C virus (HCV) infection induces profound alterations in the cytokine and chemokine signatures in peripheral blood. Clearance of HCV by antivirals results in host immune modification, which may interfere with immune-mediated cancer surveillance. Identifying HCV patients who remain at risk of hepatocellular carcinoma (HCC) following HCV eradication remains an unmet need. We hypothesized that antiviral therapy-induced immune reconstruction may be relevant to HCC development.
AIM
To investigate the impact of differential dynamics of cytokine expression on the development of HCC following successful antiviral therapy.
METHODS
One hundred treatment-naïve HCV patients with advanced fibrosis (F3/4) treated with direct-acting antivirals (DAAs) or peginterferon/ribavirin who achieved sustained virologic response [SVR, defined as undetectable HCV RNA throughout 12 wk (SVR12) for the DAA group or 24 wk (SVR24) for the interferon group after completion of antiviral therapy] were enrolled since 2003. The primary endpoint was the development of new-onset HCC. Standard HCC surveillance (abdominal ultrasound and α-fetoprotein) was performed every six months during the follow-up. Overall, 64 serum cytokines were detected by the multiplex immunoassay at baseline and 24 wk after end-of-treatment.
RESULTS
HCC developed in 12 of the 97 patients over 459 person-years after HCV eradication. In univariate analysis, the Fibrosis-4 index (FIB-4), hemoglobin A1c (HbA1c), the dynamics of tumor necrosis factor-α (TNF-α), and TNF-like weak inducer of apoptosis (TWEAK) after antiviral therapy were significant HCC predictors. The multivariate Cox regression model showed that ΔTNF-α (≤ -5.7 pg/mL) was the most important risk factor for HCC (HR = 11.54, 95%CI: 2.27-58.72, P = 0.003 in overall cases; HR = 9.98, 95%CI: 1.88-52.87, P = 0.007 in the interferon group). An HCC predictive model comprising FIB-4, HbA1c, ΔTNF-α, and ΔTWEAK had excellent performance, with 3-, 5-, 10-, and 13-year areas under the curve of 0.882, 0.864, 0.903, and 1.000, respectively. The 5-year accumulative risks of HCC were 0%, 16.9%, and 40.0% in the low-, intermediate-, and high-risk groups, respectively.
CONCLUSION
Downregulation of serum TNF-α significantly increases the risk of HCC after HCV eradication. A predictive model consisting of cytokine kinetics could ameliorate personalized HCC surveillance strategies for post-SVR HCV patients.
Core Tip: Successful hepatitis C virus (HCV) eradication does not eliminate hepatocellular carcinoma (HCC) development. Clearance of HCV by antiviral agents results in host immune modification, which might interfere with immune-mediated cancer surveillance. We attempted to identify immune biomarkers to predict HCC occurrence after antiviral therapy. The dynamics of serum tumor necrosis factor-α (TNF-α) and TNF-like weak inducer of apoptosis were associated with HCC occurrence after HCV clearance. We established a predictive model to assess the risk of HCC among HCV patients after HCV eradication. Our findings provide a clue for the pathogenesis of hepatocarcinogenesis and a strategy for HCC surveillance based on risk stratification.
