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Hepatocellular Carcinoma in the Era of Direct Antiviral Agents Against Hepatitis C Virus

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Abstract

Purpose of Review

The hepatitis C virus (HCV) is a major cause of liver-related morbidity and mortality, and a major risk factor of hepatocellular carcinoma (HCC) around the world. Early detection, continued prevention of transmission, and antiviral treatment of chronically infected persons are the pillars to decrease incidence and mortality of HCV. The widespread access to safe and effective direct acting anti-viral agents (DAA) has allowed the elimination of the infection possible in almost all treated patients, thus leading to a significant reduction of liver-related and overall mortality due to HCV in the cured population. Treatment of HCV does not completely eradicate HCC risk in populations with advanced liver disease and those with cofactors known to promote liver carcinogenesis such as diabetes, obesity, and excessive alcohol consumption.

Recent Findings

Molecular-based biomarkers  are expected to overcome the limits of liver disease severity, thus improving  the identification of screening candidates.

Summary

The implementation of risk-stratified surveillance programs coupled with the identification of biomarkers to predict HCC in HCV cured patents is deemed necessary for implementing the cost-effective management of these patients.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Tan DJH, Setiawan VW, Ng CH, Lim WH, Muthiah MD, Tan EX, et al. Global burden of liver cancer in males and females: changing etiological basis and the growing contribution of NASH. Hepatology. 2023;77:1150–63.

    Article  PubMed  Google Scholar 

  2. Blach S, Terrault NA, Tacke F, Gamkrelidze I, Craxi A, Tanaka J, et al. Global change in hepatitis C virus prevalence and cascade of care between 2015 and 2020: a modelling study. Lancet Gastroenterol Hepatol. 2022;7:396–415.

    Article  Google Scholar 

  3. Global progress report on HIV, viral hepatitis and sexually transmitted infections, 2021. Accountability for the global health sector strategies 2016–2021: actions for impact. Geneva: World Health Organization; 2021. Licence: CC BY-NC-SA 3.0 IGO.

    Google Scholar 

  4. Toh MR, Wong EYT, Wong SH, Ng AWT, Loo L-H, Chow PK-H, et al. Global epidemiology and genetics of hepatocellular carcinoma. Gastroenterology. 2023;164:766–82.

    Article  PubMed  Google Scholar 

  5. Rumgay H, Arnold M, Ferlay J, Lesi O, Cabasag CJ, Vignat J, et al. Global burden of primary liver cancer in 2020 and predictions to 2040. J Hepatol. 2022;77:1598–606.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Global health sector strategies on, respectively, HIV, viral hepatitis and sexually transmitted infections for the period 2022-2030. Geneva: World Health Organization; 2022. Licence: CC BY-NC-SA 3.0 IGO. Accessed 5 June 2022.

  7. Karlsen TH, Sheron N, Zelber-Sagi S, Carrieri P, Dusheiko G, Bugianesi E, et al. The EASL–Lancet Liver Commission: protecting the next generation of Europeans against liver disease complications and premature mortality. Lancet. 2022;399:61–116.

    Article  PubMed  Google Scholar 

  8. Galle PR, Forner A, Llovet JM, Mazzaferro V, Piscaglia F, Raoul J-L, et al. EASL Clinical Practice Guidelines: management of hepatocellular carcinoma. J Hepatol. 2018;69:182–236.

    Article  Google Scholar 

  9. Lockart I, Yeo MGH, Hajarizadeh B, Dore GJ, Danta M. HCC incidence after hepatitis C cure among patients with advanced fibrosis or cirrhosis: a meta-analysis. Hepatology. 2022;76:139–54.

    Article  PubMed  Google Scholar 

  10. Hsu CC, Gopalakrishna H, Mironova M, Lee M-H, Chen C-J, Yang H-I, et al. Risk of hepatocellular carcinoma after spontaneous clearance of hepatitis C virus and in noncirrhosis chronic hepatitis C patients with sustained virological response: a systematic review. Clin Infect Dis. 2023;77:S245–56.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Hamdane N, Jühling F, Crouchet E, El Saghire H, Thumann C, Oudot MA, et al. HCV-induced epigenetic changes associated with liver cancer risk persist after sustained virologic response. Gastroenterology. 2019;156:2313–2329.e7.

    Article  PubMed  Google Scholar 

  12. Nahon P, Vo Quang E, Ganne-Carrié N. Stratification of hepatocellular carcinoma risk following HCV eradication or HBV control. J Clin Med. 2021;10:353.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021;7:6.

    Article  PubMed  Google Scholar 

  14. Lemon SM, McGivern DR. Is hepatitis C virus carcinogenic? Gastroenterology. 2012;142:1274–8.

    Article  PubMed  Google Scholar 

  15. Bandiera S, Billie Bian C, Hoshida Y, Baumert TF, Zeisel MB. Chronic hepatitis C virus infection and pathogenesis of hepatocellular carcinoma. Curr Opin Virol. 2016;20:99–105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. D’souza S, Lau KC, Coffin CS, Patel TR. Molecular mechanisms of viral hepatitis induced hepatocellular carcinoma. World J Gastroenterol. 2020;26:5759–83.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Wölfl M, Rutebemberwa A, Mosbruger T, Mao Q, Li H, Netski D, et al. Hepatitis C virus immune escape via exploitation of a hole in the T cell repertoire. J Immunol. 2008;181:6435–46.

    Article  PubMed  Google Scholar 

  18. Li J-T, Liao Z-X, Ping J, Xu D, Wang H. Molecular mechanism of hepatic stellate cell activation and antifibrotic therapeutic strategies. J Gastroenterol. 2008;43:419–28.

    Article  ADS  CAS  PubMed  Google Scholar 

  19. Kanda T, Goto T, Hirotsu Y, Moriyama M, Omata M. Molecular mechanisms driving progression of liver cirrhosis towards hepatocellular carcinoma in chronic hepatitis B and C infections: a review. Int J Mol Sci. 2019;20:1358.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Quan H, Zhou F, Nie D, Chen Q, Cai X, Shan X, et al. Hepatitis C virus core protein epigenetically silences SFRP1 and enhances HCC aggressiveness by inducing epithelial–mesenchymal transition. Oncogene. 2014;33:2826–35.

    Article  CAS  PubMed  Google Scholar 

  21. Iida N, Mizukoshi E, Yamashita T, Yutani M, Seishima J, Wang Z, et al. Chronic liver disease enables gut Enterococcus faecalis colonization to promote liver carcinogenesis. Nat Can. 2021;2:1039–54.

    Article  CAS  Google Scholar 

  22. 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;153:996–1005.e1.

    Article  CAS  PubMed  Google Scholar 

  23. Ioannou GN, Beste LA, Green PK, Singal AG, Tapper EB, Waljee AK, 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;157:1264–1278.e4.

    Article  CAS  PubMed  Google Scholar 

  24. Calvaruso V, Cabibbo G, Cacciola I, Petta S, Madonia S, Bellia A, et al. Incidence of hepatocellular carcinoma in patients with HCV-associated cirrhosis treated with direct-acting antiviral agents. Gastroenterology. 2018;155:411–421.e4.

    Article  CAS  PubMed  Google Scholar 

  25. Degasperi E, D’Ambrosio R, Iavarone M, Sangiovanni A, Aghemo A, Soffredini R, 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;17:1183–1191.e7.

    Article  CAS  PubMed  Google Scholar 

  26. Chen Q, Ayer T, Adee MG, Wang X, Kanwal F, Chhatwal J. Assessment of incidence of and surveillance burden for hepatocellular carcinoma among patients with hepatitis C in the era of direct-acting antiviral agents. JAMA Netw Open. 2020;3:e2021173.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Ciancio A, Ribaldone DG, Spertino M, Risso A, Ferrarotti D, Caviglia GP, et al. Who should not be surveilled for HCC development after successful therapy with DAAS in advanced chronic hepatitis C? Results of a long-term prospective study. Biomedicines. 2023;11:166.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Pons M, Rodríguez-Tajes S, Esteban JI, Mariño Z, Vargas V, Lens S, 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;72:472–80.

    Article  PubMed  Google Scholar 

  29. Tahata Y, Sakamori R, Yamada R, Kodama T, Hikita H, Nozaki Y, et al. Risk of hepatocellular carcinoma after sustained virologic response in hepatitis C virus patients without advanced liver fibrosis. Hepatol Res. 2022;52:824–32.

    Article  CAS  PubMed  Google Scholar 

  30. Pawlotsky J-M, Negro F, Aghemo A, Berenguer M, Dalgard O, Dusheiko G, et al. EASL recommendations on treatment of hepatitis C 2018. J Hepatol. 2018;69:461–511.

    Article  Google Scholar 

  31. Singal AG, Llovet JM, Yarchoan M, Mehta N, Heimbach JK, Dawson LA, et al. AASLD Practice Guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma. Hepatology. 2023;78:1922–65.

    Article  PubMed  Google Scholar 

  32. Ioannou GN. HCC surveillance after SVR in patients with F3/F4 fibrosis. J Hepatol. 2021;74:458–65.

    Article  PubMed  Google Scholar 

  33. Kim NJ, Vutien P, Berry K, Ioannou GN. Hepatocellular carcinoma risk declines but remains high enough for screening in the first 7 years after hepatitis C virus cure with direct-acting antivirals in patients with cirrhosis or high fibrosis-4 score. Gastroenterology. 2022;163:1104–1106.e3. Findings from this study suggest that all patients following SVR should undergo HCC screening, except those with low Fib-4 and no pre-treatment cirrhosis.

    Article  CAS  PubMed  Google Scholar 

  34. Nahon P, Bamba-Funck J, Layese R, Trépo E, Zucman-Rossi J, Cagnot C, et al. Integrating genetic variants into clinical models for hepatocellular carcinoma risk stratification in cirrhosis. J Hepatol. 2023;78:584–95.

    Article  CAS  PubMed  Google Scholar 

  35. Huntley C, Torr B, Sud A, Rowlands CF, Way R, Snape K, et al. Utility of polygenic risk scores in UK cancer screening: a modelling analysis. Lancet Oncol. 2023;24:658–68.

    Article  PubMed  Google Scholar 

  36. Omata M, Cheng A-L, Kokudo N, Kudo M, Lee JM, Jia J, et al. Asia–Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update. Hepatol Int. 2017;11:317–70.

    Article  PubMed  Google Scholar 

  37. Allaire M, Bruix J, Korenjak M, Manes S, Maravic Z, Reeves H, et al. What to do about hepatocellular carcinoma: recommendations for health authorities from the International Liver Cancer Association. JHEP Rep. 2022;4:100578.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Tayob N, Kanwal F, Alsarraj A, Hernaez R, El-Serag HB. The Performance of AFP, AFP-3, DCP as Biomarkers For Detection Of Hepatocellular Carcinoma (HCC): A Phase 3 Biomarker Study in the United States. Clin Gastroenterol Hepatol. 2023;21:415–423.e4.

    Article  CAS  PubMed  Google Scholar 

  39. Singal AG, Zhang E, Narasimman M, Rich NE, Waljee AK, Hoshida Y, et al. HCC surveillance improves early detection, curative treatment receipt, and survival in patients with cirrhosis: A meta-analysis. J Hepatol. 2022;77:128–39.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Tzartzeva K, Obi J, Rich NE, Parikh ND, Marrero JA, Yopp A, et al. Surveillance Imaging And Alpha Fetoprotein For Early Detection Of Hepatocellular Carcinoma In Patients With Cirrhosis: A Meta-Analysis. Gastroenterology. 2018;154:1706–1718.e1.

    Article  CAS  PubMed  Google Scholar 

  41. Santi V, Trevisani F, Gramenzi A, Grignaschi A, Mirici-Cappa F, Del PP, et al. Semiannual surveillance is superior to annual surveillance for the detection of early hepatocellular carcinoma and patient survival. J Hepatol. 2010;53:291–7.

    Article  PubMed  Google Scholar 

  42. Trinchet J-C, Chaffaut C, Bourcier V, Degos F, Henrion J, Fontaine H, et al. Ultrasonographic surveillance of hepatocellular carcinoma in cirrhosis: A randomized trial comparing 3- and 6-month periodicities. Hepatology. 2011;54:1987–97.

    Article  PubMed  Google Scholar 

  43. Omata M, Kanda T, Wei L, Yu M-L, Chuang W-L, Ibrahim A, et al. APASL consensus statements and recommendations for hepatitis C prevention, epidemiology, and laboratory testing. Hepatol Int. 2016;10:681–701.

    Article  PubMed  Google Scholar 

  44. Mueller PP, Chen Q, Ayer T, Nemutlu GS, Hajjar A, Bethea ED, et al. Duration and cost-effectiveness of hepatocellular carcinoma surveillance in hepatitis C patients after viral eradication. J Hepatol. 2022;77:55–62.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Cabibbo G, Celsa C, Calvaruso V, Petta S, Cacciola I, Cannavò MR, et al. Direct-acting antivirals after successful treatment of early hepatocellular carcinoma improve survival in HCV-cirrhotic patients. J Hepatol. 2019;71:265–73.

    Article  CAS  PubMed  Google Scholar 

  46. Singal AG, Reddy S, Radadiya aka Patel H, Villarreal D, Khan A, Liu Y, et al. Multicenter Randomized Clinical Trial Of A Mailed Outreach Strategy For Hepatocellular Carcinoma Surveillance. Clin Gastroenterol Hepatol. 2022;20:2818–2825.e1.

    Article  PubMed  Google Scholar 

  47. Yoon JH, Lee JM, Lee DH, Joo I, Jeon JH, Ahn SJ, et al. A Comparison Of Biannual Two-Phase Low-Dose Liver CT and US for HCC Surveillance In A Group At High Risk of HCC Development. Liver Cancer. 2020;9:503–17.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Kim SY, An J, Lim Y-S, Han S, Lee J-Y, Byun JH, et al. MRI With Liver-Specific Contrast For Surveillance Of Patients With Cirrhosis At High Risk Of Hepatocellular Carcinoma. JAMA Oncol. 2017;3:456.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Berhane S, Toyoda H, Tada T, Kumada T, Kagebayashi C, Satomura S, et al. Role of the GALAD and BALAD-2 serologic models in diagnosis of hepatocellular carcinoma and prediction of survival in patients. Clin Gastroenterol Hepatol. 2016;14:875–886.e6.

    Article  CAS  PubMed  Google Scholar 

  50. Kim DH, Choi SH, Shim JH, Kim SY, Lee SS, Byun JH, et al. Meta-analysis of the accuracy of abbreviated magnetic resonance imaging for hepatocellular carcinoma surveillance: non-contrast versus hepatobiliary phase-abbreviated magnetic resonance imaging. Cancers (Basel). 2021;13:2975.

    Article  PubMed  Google Scholar 

  51. Lin N, Lin Y, Xu J, Liu D, Li D, Meng H, et al. A multi-analyte cell-free DNA–based blood test for early detection of hepatocellular carcinoma. Hepatol Commun. 2022;6:1753–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kim AK, Hamilton JP, Lin SY, Chang T-T, Hann H-W, Hu C-T, et al. Urine DNA biomarkers for hepatocellular carcinoma screening. Br J Cancer. 2022;126:1432–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Gupta P, Soundararajan R, Patel A, Kumar-M P, Sharma V, Kalra N. Abbreviated MRI for hepatocellular carcinoma screening: A systematic review and meta-analysis. J Hepatol. 2021;75:108–19. Findings from this study suggest that AMRI might be superior than US in certain subgroups of patients, including obese individuals, patients with nonalcoholic steatohepatitis, and those with Child Pugh B or C cirrhosis.

    Article  PubMed  Google Scholar 

  54. Lee JY, Huo EJ, Weinstein S, Santos C, Monto A, Corvera CU, et al. Evaluation of an abbreviated screening MRI protocol for patients at risk for hepatocellular carcinoma. Abdom Radiol. 2018;43:1627–33.

    Article  Google Scholar 

  55. Yokoo T, Masaki N, Parikh ND, Lane BF, Feng Z, Mendiratta-Lala M, et al. Multicenter validation of abbreviated MRI for detecting early-stage hepatocellular carcinoma. Radiology. 2023;307.  https://doi.org/10.1148/radiol.220917.

  56. Nguyen MH, Roberts LR, Engel-Nitz NM, Bancroft T, Ozbay AB, Singal AG. Gaps in hepatocellular carcinoma surveillance in a United States cohort of insured patients with cirrhosis. Curr Med Res Opin. 2022;38:2163–73.

    Article  PubMed  Google Scholar 

  57. CHAI and The Hepatitis Fund announce pricing breakthrough to reduce cost of viral hepatitis treatment by over 90 percent. The Clinton Health Access Initiative (CHAI). 2023 [Cited 2023 Dec 19]. [Internet]. Available from: https://www.clintonhealthaccess.org/news/chai-and-the-hepatitis-fund-announce-pricing-breakthrough-to-reduce-cost-of-viral-hepatitis-treatment-by-over-90-percent/

  58. Parikh ND, Tayob N, Singal AG. Blood-based biomarkers for hepatocellular carcinoma screening: approaching the end of the ultrasound era? J Hepatol. 2023;78:207–16.

    Article  CAS  PubMed  Google Scholar 

  59. Yeo YH, Samaan JS, Ng WH, Ting P-S, Trivedi H, Vipani A, et al. Assessing the performance of ChatGPT in answering questions regarding cirrhosis and hepatocellular carcinoma. Clin Mol Hepatol. 2023;29:721–32.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Page K, Melia MT, Veenhuis RT, Winter M, Rousseau KE, Massaccesi G, et al. Randomized trial of a vaccine regimen to prevent chronic HCV infection. N Engl J Med. 2021;384:541–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, MI, Italy

    Alessio Aghemo & Davide Polverini

  2. Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, MI, Italy

    Alessio Aghemo & Davide Polverini

  3. EASL International Liver Foundation, 7 rue Daubin, 1203, Geneva, Switzerland

    Massimo Colombo

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  1. Alessio Aghemo
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Correspondence to Massimo Colombo.

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Author AA is part of the advisory board of Abbvie, Gilead, MSD, and Intercept. Author AA has received speaker honorarium from Abbvie, Gilead, and Mylan. Authors MC and DP declare that have no conflict of interest.

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Aghemo, A., Polverini, D. & Colombo, M. Hepatocellular Carcinoma in the Era of Direct Antiviral Agents Against Hepatitis C Virus. Curr Hepatology Rep (2024). https://doi.org/10.1007/s11901-024-00664-5

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