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Comparing Predictability of Non-invasive Tools for Hepatocellular Carcinoma in Treated Chronic Hepatitis C Patients

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A Correction to this article was published on 17 October 2022

An Editorial to this article was published on 27 July 2022

This article has been updated

Abstract

Background

Non-invasive tools including liver stiffness measurement (LSM) or FIB-4, assessed before or after direct acting antivirals (DAA), have been suggested to predict hepatocellular carcinoma (HCC).

Aims

This study aims to compare predictability of HCC by these methods at different time points, to validate the HCC surveillance suggestion by guidelines, and to propose personalized strategy.

Methods

Chronic hepatitis C whose LSM and FIB-4 were available at pretherapy and after sustained virological response (SVR) were enrolled. Advanced chronic liver disease (ACLD) was defined as pretherapy LSM ≥ 10 kPa or FIB-4 index ≥ 3.25 or ultrasound signs of cirrhosis plus platelet count < 150,000/μL. The predictabilities were compared by area under ROC. The cumulative HCC incidences were calculated by Kaplan–Meier analysis.

Results

Among 466 ACLD patients, 40 patients developed HCC during a follow-up duration of 26.8 months. Comparable predictive performances for HCC between LSM and FIB-4 at pretherapy and SVR were noted. By guidelines suggestion using pretherapy LSM = 10 kPa (advanced fibrosis) and 13 kPa (cirrhosis) for risk stratification, the annual HCC incidences of those with LSM of < 10, 10–12.9 and ≥ 13 kPa were 1.1, 3.6, and 5.0%, respectively. Combination of baseline LSM < 12 kPa and SVR FIB-4 < 3.7 could further stratify relatively low risk of HCC in ACLD patients of annal incidence of 1.2%.

Conclusions

ACLD patients who met advanced fibrosis but not cirrhosis by guidelines’ cut-offs still posed high risk of HCC. Baseline LSM with SVR FIB-4 can be applied to stratify low, intermediate, and high risk of HCC for personalizing surveillance strategies after SVR.

Graphical Abstract

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Data availability

Data are available on request due to privacy or other restrictions by the IRB board committee of Chang Gung Memorial Hospital.

Change history

Abbreviations

ACLD:

Advanced chronic liver disease

AFP:

Alpha-fetoprotein

ALT:

Alanine aminotransferase

AUROC:

Area under receiver-operating characteristic

BMI:

Body mass index

CHC:

Chronic hepatitis C

CI:

Confidence interval

CT:

Computerized tomography

DAA:

Direct antiviral agents

EOT:

End of treatment

HR:

Hazard ratio

HbA1c:

Glycohemoglobin

HBV:

Hepatitis B virus

HCC:

Hepatocellular carcinoma

HCV:

Hepatitis C virus

HD:

Hepatic decompensation

HIV:

Human immunodeficiency virus

IFN:

Interferon

INR:

International normalized ratio

IQR:

Interquartile range

kPa:

Kilopascal

LSM:

Liver stiffness measurement

MELD:

Model for end-stage liver disease

MRI:

Magnetic resonance imaging

NPV:

Negative predictive value

PPV:

Positive predictive value

SVR:

Sustained virological response

TE:

Transient elastography

References

  1. European Association for The Study of The Liver. EASL recommendations on treatment of hepatitis C 2018. J Hepatol. 2018;69:461–511.

    Article  Google Scholar 

  2. Ghany MG, Morgan TR. AASLD-IDSA hepatitis C guidance panel. Hepatitis C guidance 2019 update: American Association for the Study of Liver Diseases-Infectious Diseases Society of America recommendations for testing, managing, and treating hepatitis C virus infection. Hepatology 2020;71:686–721.

    Article  Google Scholar 

  3. Ioannou GN, Green PK, Berry K. HCV eradication induced by direct-acting antiviral agents reduces the risk of hepatocellular carcinoma. J Hepatol. 2018;68:25–32.

    Article  Google Scholar 

  4. Thabut D, Bureau C, Layese R et al. Validation of Baveno VI criteria for screening and surveillance of esophageal varices in patients with compensated cirrhosis and a sustained response to antiviral therapy. Gastroenterology 2019;156:e1005.

    Google Scholar 

  5. McDonald SA, Pollock KG, Barclay ST et al. Real-world impact following initiation of interferon-free hepatitis C regimens on liver-related outcomes and all-cause mortality among patients with compensated cirrhosis. J Viral Hepatitis 2020;27:270–280.

    Article  CAS  Google Scholar 

  6. Moon AM, Green PK, Rockey DC, Berry K, Ioannou GN. Hepatitis C eradication with direct-acting anti-virals reduces the risk of variceal bleeding. Aliment Pharmacol Ther. 2020;51:364–373.

    Article  CAS  Google Scholar 

  7. Ioannou GN. HCC surveillance after SVR in patients with F3/F4 fibrosis. J Hepatol. 2020;74:458–465.

    Article  Google Scholar 

  8. Pons M, Rodríguez-Tajes S, Esteban JI et al. Non-invasive prediction of liver-related events in patients with HCV-associated compensated advanced chronic liver disease after oral antivirals. J Hepatol. 2020;72:472–480.

    Article  Google Scholar 

  9. Alonso López S, Manzano ML, Gea F et al. A model based on noninvasive markers predicts very low hepatocellular carcinoma risk after viral response in hepatitis C virus-advanced fibrosis. Hepatology 2020;72:1924–1934.

    Article  Google Scholar 

  10. Semmler G, Binter T, Kozbial K et al. Non-invasive risk stratification after HCV-eradication in patients with advanced chronic liver disease. Hepatology 2020;73:1275–1289.

    Article  Google Scholar 

  11. Butt AA, Ren Y, Lo Re H III, Taddei TH, Kaplan DE. Comparing child-Pugh, MELD, and FIB-4 to predict clinical outcomes in hepatitis C virus-infected persons: results from ERCHIVES. Clin Infect Dis. 2017;65:64–72.

    Article  Google Scholar 

  12. Hézode C, Castéra L, Roudot-Thoraval F et al. Liver stiffness diminishes with antiviral response in chronic hepatitis C. Aliment Pharmacol Ther. 2011;34:656–663.

    Article  Google Scholar 

  13. Anrs C. Regression of liver stiffness after sustained hepatitis C virus (HCV) virological responses among HIV/HCV-coinfected patients. AIDS (London, England) 2015;29:1821.

    Article  Google Scholar 

  14. De Franchis R. Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension. J Hepatol. 2015;63:743–752.

    Article  Google Scholar 

  15. Narita Y, Genda T, Tsuzura H et al. Prediction of liver stiffness hepatocellular carcinoma in chronic hepatitis C patients on interferon-based anti-viral therapy. J Gastroenterol Hepatol. 2014;29:137–143.

    Article  CAS  Google Scholar 

  16. Wang JH, Yen YH, Yao CC et al. Liver stiffness-based score in hepatoma risk assessment for chronic hepatitis C patients after successful antiviral therapy. Liver Int. 2016;36:1793–1799.

    Article  CAS  Google Scholar 

  17. Lee HW, Chon YE, Kim SU et al. Predicting liver-related events using transient elastography in chronic hepatitis C patients with sustained virological response. Gut Liver 2016;10:429.

    Article  Google Scholar 

  18. Degasperi E, D’Ambrosio R, Iavarone M et al. Factors associated with increased risk of de novo or recurrent hepatocellular carcinoma in patients with cirrhosis treated with direct-acting antivirals for HCV infection. Clin Gastroenterol Hepatol 2019;17:e1187.

    Google Scholar 

  19. Rinaldi L, Guarino M, Perrella A et al. Role of liver stiffness measurement in predicting HCC occurrence in direct-acting antivirals setting: a real-life experience. Dig Dis Sci. 2019;64:3013–3019.

    Article  Google Scholar 

  20. Peleg N, Issachar A, Sneh Arbib O et al. Liver steatosis is a major predictor of poor outcomes in chronic hepatitis C patients with sustained virological response. J Viral Hepatitis 2019;26:1257–1265.

    Article  CAS  Google Scholar 

  21. Søholm J, Hansen JF, Mössner B et al. Low incidence of HCC in chronic hepatitis C patients with pretreatment liver stiffness measurements below 17.5 kilopascal who achieve SVR following DAAs. PLoS ONE 2020;15:0243725.

    Article  Google Scholar 

  22. Lim JK, Flamm SL, Singh S et al. American Gastroenterological Association Institute guideline on the role of elastography in the evaluation of liver fibrosis. Gastroenterology 2017;152:1536–1543.

    Article  Google Scholar 

  23. Degos F, Perez P, Roche B et al. Diagnostic accuracy of FibroScan and comparison to liver fibrosis biomarkers in chronic viral hepatitis: a multicenter prospective study (the FIBROSTIC study). J Hepatol. 2010;53:1013–1021.

    Article  Google Scholar 

  24. Afdhal NH, Bacon BR, Patel K et al. Accuracy of fibroscan, compared with histology, in analysis of liver fibrosis in patients with hepatitis B or C: a United States multicenter study. Clin Gastroenterol Hepatol. 2015;13:e773.

    Google Scholar 

  25. Ravaioli F, Conti F, Brillanti S et al. Hepatocellular carcinoma risk assessment by the measurement of liver stiffness variations in HCV cirrhotics treated with direct acting antivirals. Digest Liver Dis. 2018;50:573–579.

    Article  Google Scholar 

  26. Broquetas T, Herruzo-Pino P, Mariño Z et al. Elastography is unable to exclude cirrhosis after sustained virological response in HCV-infected patients with advanced chronic liver disease. Liver Int. 2021;41:2733–2746.

    Article  Google Scholar 

  27. Kanwal F, Kramer J, Asch SM, Chayanupatkul M, Cao Y, El-Serag HB. Risk of hepatocellular cancer in HCV patients treated with direct-acting antiviral agents. Gastroenterology 2017;153:e1001.

    Google Scholar 

  28. Ioannou GN, Beste LA, Green PK et al. Increased risk for hepatocellular carcinoma persists up to 10 years after HCV eradication in patients with baseline cirrhosis or high FIB-4 scores. Gastroenterology 2019;157:e1264.

    Article  Google Scholar 

  29. Facciorusso A, Del Prete V, Turco A, Buccino RV, Nacchiero MC, Muscatiello N. Long-term liver stiffness assessment in hepatitis C virus patients undergoing antiviral therapy: Results from a 5-year cohort study. J Gastroenterol Hepatol. 2018;33:942–949.

    Article  CAS  Google Scholar 

  30. Singh S, Facciorusso A, Loomba R, Falck-Ytter YT. Magnitude and kinetics of decrease in liver stiffness after antiviral therapy in patients with chronic hepatitis C: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2018;16:e24.

    Google Scholar 

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Acknowledgments

We have to thank Ms. Hui-Chuan Cheng, Ms. Yi-Meng Chiang, and Ms. Pei-Chueh Li for their assistance in database creation and maintenance.

Funding

This study was supported by grants from Chang Gung Medical Research Fund (CMRPG3I0271-2, CMRPG3K0891 and CMRPG3M1131).

Author information

Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Main Branch, No.5, Fuxing St., Guishan Dist, Taoyuan city, 333, Taiwan, ROC

    Yen-Chun Liu, Ya-Ting Cheng, Yi-Cheng Chen, Yi-Chung Hsieh, Wen-Juei Jeng, Chun-Yen Lin, Rong-Nan Chien, Dar-In Tai & I.-Shyan Sheen

  2. College of Medicine, Chang Gung University, Taoyuan, Taiwan, ROC

    Yen-Chun Liu, Ya-Ting Cheng, Yi-Cheng Chen, Yi-Chung Hsieh, Wen-Juei Jeng, Chun-Yen Lin, Rong-Nan Chien, Dar-In Tai & I.-Shyan Sheen

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  1. Yen-Chun Liu
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Contributions

Conceptualization: W-JJ, C-YL; Methodology: W-JJ, Y-CL, Y-TC, Y-CH, Y-CC, R-NC, D-IT, C-YL; Data recruitment: Y-CL, Y-TC, Y-CH, D-IT, I-SS; formal analysis and investigation: Y-CL, W-JJ; Writing—original draft preparation: Y-CL; Writing—review and editing: W-JJ and all the authors; Funding acquisition: W-JJ; Resources: C-YL, D-IT, I-SS; Supervision: W-JJeng.

Corresponding author

Correspondence to Wen-Juei Jeng.

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Conflict of interest

The authors have no financial or personal relationships with other people or organizations that could inappropriately influence (bias) their work.

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An editorial commenting on this article is available at https://doi.org/10.1007/s10620-022-07623-4.

The original online version of this article was revised: The following text was inadvertently included in the article title: ‘Characters: 102(<120)’. However, now the article title is corrected.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary figure 1. Flowchart of patient recruitment (TIF 109 kb)

10620_2022_7621_MOESM2_ESM.tif

Supplementary figure 2 Comparisons of predictive performance for HCC with AUROC curves between LSM/FIB-4 at different time points (a) baseline LSM and baseline FIB-4 (b) SVR LSM and SVR FIB-4 (c) baseline LSM and SVR LSM (TIF 138 kb)

10620_2022_7621_MOESM3_ESM.tif

Supplementary figure 3 Comparisons of predictive performance for hepatic decompensation with AUROC curves between LSM/FIB-4 at different time points (a) baseline LSM and baseline FIB-4 (b) SVR LSM and SVR FIB-4 (c) baseline LSM and SVR LSM (TIF 135 kb)

10620_2022_7621_MOESM4_ESM.tif

Supplementary figure 4 The cumulative hepatic decompensation incidences stratified by baseline LSM and SVR LSM (TIF 104 kb)

Supplementary file5 (DOCX 39 kb)

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Liu, YC., Cheng, YT., Chen, YC. et al. Comparing Predictability of Non-invasive Tools for Hepatocellular Carcinoma in Treated Chronic Hepatitis C Patients. Dig Dis Sci 68, 323–332 (2023). https://doi.org/10.1007/s10620-022-07621-6

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