Direct antiviral therapy for hepatitis C and hepatocellular carcinoma: facing the conundrum

Abstract

Direct antiviral therapy has dramatically changed our possibility to eradicate hepatitis C virus (HCV) infection in all stages of chronic liver disease, with sustained virological response rates well above 90%. HCV eradication should lead to a better prognosis even after cirrhosis has established, including a reduced risk of developing hepatocellular carcinoma (HCC). Unfortunately, during the last two years different reports have raised the concern about a possible increased risk of developing HCC in cirrhotic patients treated with direct antivirals. In this review, we have evaluated the principal published data and have reached a few conclusions: (1) direct antiviral therapy does not seem to increase the cumulative annual rate of HCC de novo occurrence or recurrence; (2) direct antiviral therapy seems to accelerate the development of HCC, soon after the end of treatment, in those patients at higher risk of HCC occurrence or recurrence; and (3) preliminary reports seem to indicate that HCC developed after direct antiviral therapy has more aggressive features. These findings clearly indicate the need for aggressive and close monitoring of cirrhotic patients during and after antiviral treatment, to detect and treat HCC at their earliest occurrence.

Keywords

Direct-acting antivirals / hepatocellular carcinoma / liver cirrhosis / risk / hepatitis C

References

[1] Jemal A,Center MM,Ward E.Global cancer statistics..CA Cancer J Clin2011;61:69-90

[2] Ryerson AB,Altekruse SF,Jemal A,Henley SJ,Lake A,Anderson RN,Ly KN,Penberthy L.Annual Report to the Nation on the Status of Cancer, 1975-2012, featuring the increasing incidence of liver cancer..Cancer2016;122:1312-37 PMCID:PMC4840031

[3] Seeff LB.Natural history of chronic hepatitis C..Hepatology2002;36:S35-46

[4] Sangiovanni A,Fasani P,Ronchi G,Morabito A,Colombo M.Increased survival of cirrhotic patients with a hepatocellular carcinoma detected during surveillance..Gastroenterology2004;126:1005-14

[5] Lok AS,Morgan TR,Sterling RK,Everson GT,Lee WM,Dienstag JL,Morishima C.Incidence of hepatocellular carcinoma and associated risk factors in hepatitis C-related advanced liver disease..Gastroenterology2009;136:138-48 PMCID:PMC3749922

[6] Pompili M,de Matthaeis N,Ardito F,Brunello F,Giorgio A,De Sio I,Fornari F,Guglielmi A,Aldrighetti L,Calise F,Rapaccini GL.Long-term effectiveness of resection and radiofrequency ablation for single hepatocellular carcinoma ≤3 cm. Results of a multicenter Italian survey..J Hepatol2013;59:89-97

[7] Petta S,Barbara M,Bucci L,Giannini EG,Ciccarese F,Di Marco M,Zoli M,Sacco R,Marra F,Morisco F,Gasbarrini A,Foschi FG,Masotto A,Colecchia A,Boccaccio V,Bruno S,Cammà C.Hepatocellular carcinoma recurrence in patients with curative resection or ablation: impact of HCV eradication does not depend on the use of interferon..Aliment Pharmacol Ther2017;45:160-8

[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] El-Serag HB,Richardson P.Risk of hepatocellular carcinoma after sustained virological response in Veterans with hepatitis C virus infection..Hepatology2016;64:130-7 PMCID:PMC4917456

[10] van der Meer AJ,Hofer H,Calvaruso V,Aleman S,D'Ambrosio R,Trapero-Marugan M,Moreno-Otero R,Hultcrantz R,Rutter K,Alonso S,Colombo M,Veldt BJ,Janssen HL.Risk of cirrhosis-related complications in patients with advanced fibrosis following hepatitis C virus eradication..J Hepatol2017;66:485-93

[11] Falade-Nwulia O,Nelson DR,Segal JB.Oral direct-acting agent therapy for hepatitis C virus infection: a systematic review..Ann Intern Med2017;166:637-48

[12] Sangiovanni A,Fasani P,Romeo R,Del Ninno E,Colombo M.The natural history of compensated cirrhosis due to hepatitis C virus: a 17-year cohort study of 214 patients..Hepatology2006;43:1303-10

[13] Reig M,Perelló C,Ribeiro A,Díaz A,Darnell A,Sangro B,Forns X.Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon-free therapy..J Hepatol2016;65:719-26

[14] Conti F,Scuteri A,Bolondi L,Foschi FG,Mazzella G,Andreone P.Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with direct-acting antivirals..J Hepatol2016;65:727-33

[15] Renzulli M,Conti F,Serio I,Caraceni P,Verucchi G,Andreone P.Imaging features of microvascular invasion in hepatocellular carcinoma developed after direct-acting antiviral therapy in HCV-related cirrhosis..Eur Radiol2018;28:506-13

[16] Kanwal F,Asch SM,Cao Y.Risk of hepatocellular cancer in HCV patients treated with direct acting antiviral agents..Gastroenterology2017;153:996-1005.e1

[17] Bielen R,Van Vlierberghe H,Mulkay JP,Verlinden W,Decaestecker J,Janssens F,Van Steenkiste C,Cool M,Nevens F.The risk of early occurrence and recurrence of hepatocellular carcinoma in hepatitis C-infected patients treated with direct-acting antivirals with and without pegylated interferon: a Belgian experience..J Viral Hepat2017;24:976-81

[18] Kolly P,Vermehren J,Vögeli I,Semela D,Dufour JF.Hepatocellular carcinoma recurrence after direct antiviral agent treatment: A European multicentre study..J Hepatol2017;67:876-8

[19] ANRS collaborative study group on hepatocellular carcinoma (ANRS CO22 HEPATHER, CO12 CirVir and CO23 CUPILT cohorts)..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

[20] Nault JC.Hepatocellular carcinoma and direct acting antiviral treatments: controversy after the revolution..J Hepatol2016;65:663-5

[21] Werner JM,Protzer U.Immune reconstitution after HCV clearance with direct antiviral agents: potential consequences for patients with HCC?.Transplantation2017;101:904-9

[22] Romano A,Piovesan S,Cavalletto L,Vincenzi V,Panese S,Gambato M,Bertin T,Carlotto A,Scroccaro G.Incidence and pattern of "de novo" hepatocellular carcinoma in HCV patients treated with oral DAAs..Hepatology2016;64:10A

[23] Reig M,Perello C,Lens S,Vilana R,Varela M,Calleja JL,Bruix J.Tumour recurrence after interferon-free treatment for hepatitis C in patients with previously treated hepatocellular carcinoma discloses a more aggressive pattern and faster tumour growth..J Hepatol2017;66:PS-031

[24] Nakao Y,Abiru S,Yamasaki K,Saeki A,Kugiyama Y,Ito M,Yatsuhashi H.Rapidly growing, moderately differentiated HCC: a clinicopathological characteristic of HCC occurrence after IFN-free DAA therapy?.J Hepatol2017;