Impact of direct-acting antivirals on the recurrence of hepatocellular carcinoma in chronic hepatitis C

Abstract

Chronic hepatitis C virus (HCV) infection is estimated to affect 56.8 million individuals globally and is a major and independent risk factor for the development of hepatocellular carcinoma (HCC). After the introduction of safe and potent direct-acting antivirals (DAAs), capable of curing HCV infection also in patients with advanced liver disease at high risk of HCC, the beneficial effect on a de novo HCC development after viral clearance has been established. However, studies addressing the relationship between DAA-induced eradication and risk of HCC recurrence (i.e., reappearance of HCC treated before starting antivirals) have produced contradictory data, suggesting either an increase or a decrease of HCC recurrence rate, while some report no effect of these treatments. Thus, there seems to be an unclear benefit of viral clearance in patients with a history of HCC curative treatment, where the recurrence rate remains worryingly high. This short review aims to summarize current evidence on the impact of DAAs on HCC recurrence rates, the pathogenic mechanisms and characteristics of HCC recurrence after DAA treatment, the predictors of tumor recurrence, and the impact of DAAs on overall survival.

Keywords

Hepatitis C virus / hepatocellular carcinoma / liver oncogenesis / direct-acting antivirals / tumor recurrence

References

[1] Villanueva A.Hepatocellular carcinoma.N Engl J Med2019;380:1450-62

[2] Organisation WH. Projections of mortality and causes of death, 2016 to 2060.

[3] Jemal A,Johnson CJ.Annual report to the nation on the status of cancer, 1975-2014, featuring survival.J Natl Cancer Inst2017;109 PMCID:PMC5409140

[4] Cabibbo G,Cammà C.Should we cure hepatitis C virus in patients with hepatocellular carcinoma while treating cancer?.Liver Int2018;38:2108-16

[5] Blach S,Tacke F.Global change in hepatitis C virus prevalence and cascade of care between 2015 and 2020: a modelling study.2022;7:396-415

[6] Tampaki M,Cholongitas E.Intrahepatic recurrence of hepatocellular carcinoma after resection: an update.Clin J Gastroenterol2021;14:699-713

[7] Sahakyan Y,Bremner KE,Krahn MD.Impact of direct-acting antiviral regimens on mortality and morbidity outcomes in patients with chronic hepatitis c: Systematic review and meta-analysis.J Viral Hepat2021;28:739-54

[8] Morgan RL,Smith BD,Pitasi M.Eradication of hepatitis C virus infection and the development of hepatocellular carcinoma: a meta-analysis of observational studies.Ann Intern Med2013;158:329-37

[9] Spârchez Z.Hepatocellular carcinoma occurrence and recurrence after antiviral treatment in HCV-related cirrhosis. Are outcomes different after direct antiviral agents?.J Gastrointestin Liver Dis2017;26:403-10

[10] Shiha G,Soliman R,Adel Elbasiony M.Incidence of HCC in chronic hepatitis C patients with advanced hepatic fibrosis who achieved SVR following DAAs: a prospective study.J Viral Hepat2020;27:671-9

[11] AASLD-IDSA HCV Guidance Panel.Hepatitis C guidance 2018 update: AASLD-IDSA recommendations for testing, managing, and treating hepatitis C virus infection.Clin Infect Dis2018;67:1477-92 PMCID:PMC7190892

[12] Reig M,Perelló C.Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon-free therapy.J Hepatol2016;65:719-26

[13] Conti F,Scuteri A.Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with direct-acting antivirals.J Hepatol2016;65:727-33

[14] Nagata H,Asahina Y.Ochanomizu Liver Conference Study Group. Effect of interferon-based and -free therapy on early occurrence and recurrence of hepatocellular carcinoma in chronic hepatitis C.J Hepatol2017;67:933-9

[15] Ikeda K,Kobayashi M.Direct-acting antivirals decreased tumor recurrence after initial treatment of hepatitis C virus-related hepatocellular carcinoma.Dig Dis Sci2017;62:2932-42

[16] Celsa C,Giuffrida P.Direct-acting antiviral agents and risk of Hepatocellular carcinoma: critical appraisal of the evidence.Ann Hepatol2022;27 Suppl 1:100568

[17] Cabibbo G,Barbàra M.ITALI.CA study group. A meta-analysis of single HCV-untreated arm of studies evaluating outcomes after curative treatments of HCV-related hepatocellular carcinoma.Liver Int2017;37:1157-66

[18] Gao X,Wang L,Niu J.Timing of DAA initiation after curative treatment and its relationship with the recurrence of HCV-related HCC.J Hepatocell Carcinoma2020;7:347-60 PMCID:PMC7720283

[19] Yamamoto Y,Morimura R.Optimal duration of the early and late recurrence of hepatocellular carcinoma after hepatectomy.World J Gastroenterol2015;21:1207-15 PMCID:PMC4306165

[20] Kolly P,Vermehren J.Hepatocellular carcinoma recurrence after direct antiviral agent treatment: a European multicentre study.J Hepatol2017;67:876-8

[21] El Kassas M,Salaheldin M.Increased recurrence rates of hepatocellular carcinoma after DAA therapy in a hepatitis C-infected Egyptian cohort: a comparative analysis.J Viral Hepat2018;25:623-30

[22] Mashiba T,Kurosaki M.Does interferon-free direct-acting antiviral therapy for hepatitis C after curative treatment for hepatocellular carcinoma lead to unexpected recurrences of HCC?.PLoS One2018;13:e0194704 PMCID:PMC5901785

[23] Singal AG,Mehta N.Direct-acting antiviral therapy for hepatitis c virus infection is associated with increased survival in patients with a history of hepatocellular carcinoma.Gastroenterology2019;157:1253-1263.e2 PMCID:PMC6815711

[24] Nakamura S,Okada H.Hepatocellular carcinoma recurrence in HCV patients treated with direct-acting antivirals after curative treatment.Hepatoma Res2019;5:16

[25] Zou WY,Kramer JR.Risk of hepatocellular cancer recurrence in hepatitis C virus + patients treated with direct-acting antiviral agents.Dig Dis Sci2019;64:3328-36 PMCID:PMC6819241

[26] Kuo YH,Chang KC.The influence of direct-acting antivirals in hepatitis C virus related hepatocellular carcinoma after curative treatment.Invest New Drugs2020;38:202-10

[27] Ogawa E,Furusyo N.Kyushu university liver disease study (KULDS) group. Long-term assessment of recurrence of hepatocellular carcinoma in patients with chronic hepatitis C after viral cure by direct-acting antivirals.J Gastroenterol Hepatol2022;37:190-9

[28] Elbaz T,El-Akel W.Impact of successful HCV treatment using direct acting antivirals on recurrence of well ablated hepatocellular carcinoma.Expert Rev Anti Infect Ther2022;20:307-14

[29] Watanabe T,Joko K.AFP and eGFR are related to early and late recurrence of HCC following antiviral therapy.BMC Cancer2021;21:699 PMCID:PMC8201700

[30] Tani J,Moriya A.Long-term outcomes and evaluation of hepatocellular carcinoma recurrence after hepatitis C virus eradication by direct-acting antiviral treatment: all kagawa liver disease group (AKLDG) study.Cancers (Basel)2021;13:2257 PMCID:PMC8125844

[31] Ochi H,Hirooka M.Direct-acting antivirals improve survival and recurrence rates after treatment of hepatocellular carcinoma within the Milan criteria.J Gastroenterol2021;56:90-100 PMCID:PMC7819935

[32] Ahn YH,Kim DY.Independent risk factors for hepatocellular carcinoma recurrence after direct-acting antiviral therapy in patients with chronic hepatitis C.Gut Liver2021;15:410-9 PMCID:PMC8129654

[33] collaborative study group on hepatocellular carcinoma (ANRS CO22 HEPATHER, CO12 CirVir and CO23 CUPILT cohorts). Electronic address: [e-mail]. Lack of evidence of an effect of direct-acting antivirals on the recurrence of hepatocellular carcinoma: Data from three ANRS cohorts.J Hepatol2016;65:734-40

[34] Cabibbo G,Calvaruso V.Rete Sicilia Selezione Terapia - HCV (RESIST-HCV). Is early recurrence of hepatocellular carcinoma in HCV cirrhotic patients affected by treatment with direct-acting antivirals?.Aliment Pharmacol Ther2017;46:688-95

[35] Ogawa E,Nomura H.Kyushu University Liver Disease Study (KULDS) Group. Short-term risk of hepatocellular carcinoma after hepatitis C virus eradication following direct-acting anti-viral treatment.Aliment Pharmacol Ther2018;47:104-13

[36] Lleo A,Aghemo A,Bruno S.collaborators. Predictors of hepatocellular carcinoma in HCV cirrhotic patients treated with direct acting antivirals.Dig Liver Dis2019;51:310-7

[37] Nakano M,Ide T.Predictors of hepatocellular carcinoma recurrence associated with the use of direct-acting antiviral agent therapy for hepatitis C virus after curative treatment: a prospective multicenter cohort study.Cancer Med2019;8:2646-53 PMCID:PMC6536965

[38] Cabibbo G,Calvaruso V.Rete Sicilia Selezione Terapia – HCV (RESIST-HCV) and Italian Liver Cancer (ITA.LI.CA.) Group. Direct-acting antivirals after successful treatment of early hepatocellular carcinoma improve survival in HCV-cirrhotic patients.J Hepatol2019;71:265-73

[39] Sangiovanni A,Gattai R.Undefined/non-malignant hepatic nodules are associated with early occurrence of HCC in DAA-treated patients with HCV-related cirrhosis.J Hepatol2020;73:593-602

[40] Chi CT,Su CW.Direct-acting antivirals for patients with chronic hepatitis C and hepatocellular carcinoma in Taiwan.J Microbiol Immunol Infect2021;54:385-95

[41] Nishibatake Kinoshita M,Tateishi R.Impact of direct-acting antivirals on early recurrence of HCV-related HCC: comparison with interferon-based therapy.J Hepatol2019;70:78-86

[42] Tahata Y,Urabe A.Clinical outcomes of direct-acting antiviral treatments for patients with hepatitis C after hepatocellular carcinoma are equivalent to interferon treatment.Hepatol Res2020;50:1118-27

[43] Adhoute X,Raoul JL.Hepatocellular carcinoma recurrence in hepatitis C virus-related cirrhosis treated with direct-acting antivirals: a case-control study.Eur J Gastroenterol Hepatol2018;30:368-75

[44] Waziry R,Grebely J.Hepatocellular carcinoma risk following direct-acting antiviral HCV therapy: a systematic review, meta-analyses, and meta-regression.J Hepatol2017;67:1204-12

[45] Sapena V,Torres F.Hepatocellular carcinoma recurrence after direct-acting antiviral therapy: an individual patient data meta-analysis.Gut2022;71:593-604

[46] Lui FH,Patel A.Decreased risk of hepatocellular carcinoma recurrence with direct-acting antivirals compared with no treatment for hepatitis C: a meta-analysis.Ann Gastroenterol2020;33:293-8 PMCID:PMC7196608

[47] Belli LS,Cortesi PA.European Liver and Intestine Association (ELITA). Delisting of liver transplant candidates with chronic hepatitis C after viral eradication: A European study.J Hepatol2016;65:524-31

[48] Ferrarese A,Gambato M.Hepatitis C virus related cirrhosis decreased as indication to liver transplantation since the introduction of direct-acting antivirals: a single-center study.World J Gastroenterol2018;24:4403-11 PMCID:PMC6189844

[49] Zanetto A,Vitale A.Dropout rate from the liver transplant waiting list because of hepatocellular carcinoma progression in hepatitis C virus-infected patients treated with direct-acting antivirals.Liver Transpl2017;23:1103-12

[50] Huang AC,Dodge JL,Terrault NA.Direct-acting antivirals do not increase the risk of hepatocellular carcinoma recurrence after local-regional therapy or liver transplant waitlist dropout.Hepatology2018;68:449-61 PMCID:PMC6097892

[51] Emamaullee JA,Meeberg G.HCV eradication with direct-acting antivirals does not impact HCC progression on the waiting list or HCC recurrence after liver transplantation.Can J Gastroenterol Hepatol2019;2019:2509059 PMCID:PMC6354133

[52] Lim N,Jackson S.Recurrence of hepatocellular carcinoma in hepatitis C virus (HCV) liver transplant recipients treated with pretransplant direct-acting antiviral (DAA) therapy.Gastrointest Tumors2020;7:134-43 PMCID:PMC7590751

[53] Turgeon MK,Delman AM.Optimal timing of administration of direct-acting antivirals for patients with hepatitis C-associated hepatocellular carcinoma undergoing liver transplantation.Ann Surg2021;274:613-20 PMCID:PMC8559662

[54] Warzyszyńska K,Wasiak D,Małkowski P.Accelerated hepatocellular carcinoma recurrence rate after postoperative direct-acting antivirals treatment - preliminary report.Clin Exp Hepatol2017;3:194-7 PMCID:PMC5731431

[55] Reig M,Mariño Z,Forns X.Liver cancer emergence associated with antiviral treatment: an immune surveillance failure?.Semin Liver Dis2017;37:109-18

[56] Sung PS.Immunological mechanisms for hepatocellular carcinoma risk after direct-acting antiviral treatment of hepatitis C virus infection.J Clin Med2021;10:221 PMCID:PMC7827927

[57] Sung PS.Natural killer cell dysfunction in hepatocellular carcinoma: pathogenesis and clinical implications.Int J Mol Sci2018;19:3648 PMCID:PMC6274919

[58] Easom NJW,Swadling L.IL-15 Overcomes hepatocellular carcinoma-induced NK cell dysfunction.Front Immunol2018;9:1009 PMCID:PMC5954038

[59] Chu PS,Taniki N.On-treatment decrease of NKG2D correlates to early emergence of clinically evident hepatocellular carcinoma after interferon-free therapy for chronic hepatitis C.PLoS One2017;12:e0179096 PMCID:PMC5472371

[60] Golden-Mason L,Kriss MS.Early and late changes in natural killer cells in response to ledipasvir/sofosbuvir treatment.Hepatol Commun2018;2:364-75 PMCID:PMC5880201

[61] Bolte FJ,Webb LM.Intra-Hepatic depletion of mucosal-associated invariant T cells in hepatitis C virus-induced liver inflammation.Gastroenterology2017;153:1392-1403.e2 PMCID:PMC5669813

[62] Hengst J,Deterding K.Nonreversible MAIT cell-dysfunction in chronic hepatitis C virus infection despite successful interferon-free therapy.Eur J Immunol2016;46:2204-10

[63] Villani R,Bellanti F.DAAs rapidly reduce inflammation but increase serum vegf level: a rationale for tumor risk during anti-HCV treatment.PLoS One2016;11:e0167934 PMCID:PMC5172554

[64] Faillaci F,Critelli R.Liver angiopoietin-2 Is a key predictor of de novo or recurrent hepatocellular cancer after hepatitis C virus direct-acting antivirals.Hepatology2018;68:1010-24 PMCID:PMC6175123

[65] Santangelo L,Montaldo C.Hepatitis C virus direct-acting antivirals therapy impacts on extracellular vesicles microRNAs content and on their immunomodulating properties.Liver Int2018;38:1741-50

[66] Giovannini C,Indio V.Direct antiviral treatments for hepatitis C virus have off-target effects of oncologic relevance in hepatocellular carcinoma.Cancers (Basel)2020;12:2674 PMCID:PMC7565876

[67] Bojkova D,Costa R.Sofosbuvir activates EGFR-dependent pathways in hepatoma cells with implications for liver-related pathological processes.Cells2020;9:1003 PMCID:PMC7225999

[68] Cabibbo G,Barbara M.Italian Liver Cancer (ITA.LI.CA) group. Hepatic decompensation is the major driver of death in HCV-infected cirrhotic patients with successfully treated early hepatocellular carcinoma.J Hepatol2017;67:65-71

[69] Kamp WM,Stein S,Kim HS.Impact of direct acting antivirals on survival in patients with chronic hepatitis c and hepatocellular carcinoma.Sci Rep2019;9:17081 PMCID:PMC6864088

[70] Association for the Study of the Liver. Electronic address: [e-mail]., Clinical Practice Guidelines Panel: Chair:., EASL Governing Board representative:., Panel members:. EASL recommendations on treatment of hepatitis C: final update of the series.J Hepatol2020;73:1170-218

[71] Marrero JA,Sirlin CB.Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the American association for the study of liver diseases.Hepatology2018;68:723-50

[72] Omata M,Kokudo N.Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update.Hepatol Int2017;11:317-70 PMCID:PMC5491694

[73] Kanda T,Wei L.APASL HCV guidelines of virus-eradicated patients by DAA on how to monitor HCC occurrence and HBV reactivation.Hepatol Int2019;13:649-61 PMCID:PMC6861433