The impact of direct-acting antivirals on hepatitis C associated hepatocellular carcinoma

Abstract

The increased incidence of hepatocellular carcinoma (HCC) in the last several decades in the United States and worldwide has partly resulted from an increase in hepatitis C virus (HCV) infection. HCV carcinogenesis is speculated to be indirectly related to multiple steps from inflammation to fibrosis and advanced fibrosis/cirrhosis over 20 or more years. However, the direct carcinogenic potential from HCV may explain HCC occurring in non-cirrhotic HCV patients. Highly potent direct-acting antivirals (DAAs) in recent years have changed hepatitis C treatment significantly and have resulted in the sustained virologic response (SVR) rate exceeding 90%. Although initial reports concerned the increase in de novo and recurrent HCC associated with DAAs, more recent studies showed that DAA-induced SVR on the contrary reduced risk of HCV-associated HCC without increasing its recurrence. The International Consortium of Hepatitis C Therapeutic Registry and Research Network (HCV-TARGET) database and other resources of HCV patients treated with DAA collectively in the near future most likely will be able to show definitive evidence on the risk of HCC occurrence and recurrence after DAA with SVR. The long-term risk of HCC in chronic hepatitis C patients with advanced fibrosis or cirrhosis remains high after DAAs with SVR. Thus, HCC surveillance on this sub-group of patients is important for early detection and intervention of HCC.

Keywords

Direct-acting antivirals / hepatitis C virus infection / risk of hepatocellular carcinoma

References

[1] Bray F,Soerjomataram I,Torre LA.Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries..CA Cancer J Clin2018;68:394-424

[2] Akinyemiju T,Ahmed M,Alemayohu MA.The burden of primary liver cancer and underlying etiologies from 1990 to 2015 at the global, regional, and national level: results from the Global Burden of Disease Study 2015..JAMA Oncol2017;3:1683-91 PMCID:PMC5824275

[3] Islami F,Miller KD,Fedewa SA.Proportion and number of cancer cases and deaths attributable to potentially modifiable risk factors in the United States..CA Cancer J Clin2018;68:31-54

[4] Goossens N.Hepatitis C virus-induced hepatocellular carcinoma..Clin Mol Hepatol2015;21:105-14 PMCID:PMC4493352

[5] Tan A,Liu CJ,Chen PJ.Viral hepatocarcinogenesis: from infection to cancer..Liver Int2008;28:175-88

[6] Kamegaya Y,Zukerberg L,Blackard JT.Hepatitis C virus acts as a tumor accelerator by blocking apoptosis in a mouse model of hepatocarcinogenesis..Hepatology2005;41:660-7

[7] Lemon SM.Is hepatitis C carcinogenic?.Gastroenterology2012;142:1274-8 PMCID:PMC4422399

[8] Chen CL,Machida K.Oncogenic signaling pathways and origins of tumor-initiating stem –like cells of hepatocellular carcinomas induced by hepatitis C virus, alcohol and/or obesity..Hepatol Int2014;8:330-8

[9] Zhang Y.Detection of epigenetic aberrations in the development of hepatocellular carcinoma..Cancer Epigenetics2014;1238:709-31

[10] Yeh MM,Torbenson M.Hepatitis C associated hepatocellular carcinoma in non-cirrhotic livers..Mod Pathol2010;23:276-83 PMCID:PMC3037012

[11] Koike K.Hepatitis C virus contributes to hepatocarcinogenesis by modulating metabolic and intracellular signaling pathways..J Gastroenterol Hepatol2007;22:S108-11

[12] Hoshida Y,Bardeesy N,Chung RT.Pathogenesis and prevention of hepatitis C virus-induced hepatocellular carcinoma..J Hepatol2014;61:S79-90 PMCID:PMC4435677

[13] Axley P,Ravi S.Hepatitis C virus and hepatocellular carcinoma: a narrative review..J Clin Transl Hepatol2018;6:79-84 PMCID:PMC5863002

[14] Singal AG,Kanwal F.AGA clinical practice update on interaction between oral direct-acting antivirals for chronic hepatitis C infection and hepatocellular carcinoma: expert review..Gastroenterology2019;156:2149-57 PMCID:PMC6529246

[15] Yu ML,Chuang WL,Wang JH.A sustained virological response to interferon or interferon/ribavirin reduces hepatocellular carcinoma and improves survival in chronic hepatitis C: a nationwide, multicenter study in Taiwan..Antivir Ther2006;11:985-94

[16] Singal AG,Jensen D,Schoenfeld PS.A sustained viral response is associated with reduced liver-related morbidity and mortality in patients with hepatitis C virus..Clin Gastroenterol Hepatol2010;8:280-8,288.e1

[17] Ogawa E,Kajiwara E,Nomura H.Efficacy of pegylated interferon alpha-2b and ribavirin treatment on the risk of hepatocellular carcinoma in patients with chronic hepatitis C: a prospective, multicenter study..J Hepatol2013;58:495-501

[18] Moon C,Kim DY,Park JY.Lower incidence of hepatocellular carcinoma and cirrhosis in hepatitis C patients with sustained virological response by pegylated interferon and ribavirin..Dig Dis Sci2015;60:573-81

[19] 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 Inter Med2013;158:329-37

[20] van der Meer AJ,Feld JJ,Dufour JF.Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis..JAMA2012;308:2584-93

[21] Janjua NZ,Kuo M,Wong J.Long-term effect of sustained virological response on hepatocellular carcinoma in patients with hepatitis C in Canada..J Hepatol2017;66:504-13

[22] 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

[23] Chung RT.Curing chronic hepatitis C-the arc of a medical triumph..N Engl J Med2014;370:1576-8

[24] McGlynn EA,Kramer J,Silverberg MJ.Assessing the safety of direct-acting antiviral agents for hepatitis C..JAMA Network Open2019;2:e194765 PMCID:PMC6563580

[25] American Association for the Study of Liver Diseases and Infectious Diseases Society of America. Recommendations for testing, managing, and treating hepatitis C. Available from: http://www.hcvguidelines.org [Last accessed on 14 Apr 2020]

[26] Kohli A,Sherman A.Treatment of hepatitis C: a systematic review..JAMA2014;312:631-40

[27] Wyles DL,Dieterich D.Management of hepatitis C/HIV coinfection in the era of highly effective hepatitis C virus direct-acting antiviral therapy..Clin Infect Dis.2016;63 Suppl 1:S3-11 PMCID:PMC4928450

[28] Kohli A,Georgie F,Gish RG.Direct-acting antivirals for the treatment of chronic hepatitis C in patients with chronic kidney disease..Therap Adv Gastroenterol2016;9:887-97 PMCID:PMC5076774

[29] 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 PMCID:PMC5486987

[30] Cheung MCM,Hudson BE,McLauchlan J.Outcomes after successful direct-acting antiviral therapy for patients with chronic hepatitis C and decompensated cirrhosis..J Hepatol2016;65:741-7

[31] Nahon P,Layese R,Cagnot C.Eradication of hepatitis C virus infection in patients with cirrhosis reduces risk of liver and non-liver complications..Gastroenterology2017;152:142-6

[32] Su F.Hepatocellular carcinoma risk after direct-acting antiviral therapy..Clin Liver Dis (Hoboken)2019;13:6-12 PMCID:PMC6465785

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

[34] Ioannou GN,Berry K.HCV eradication induced by direct-acting antiviral agents reduces the risk of hepatocellular carcinoma..J Hepatol2017;Epub ahead of print. doi: 10.1016/j.jhep.2017.08.030 PMCID:PMC5837901

[35] Piñero F,Ridruejo E,Ameigeiras B.Treatment with direct-acting antivirals for HCV decreases but does not eliminate the risk of hepatocellular carcinoma..Liver Int2019;39:1033-43

[36] Davis GL,El-Serag H,Jennings LW.Aging of hepatitis C virus (HCV)-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression..Gastroenterology2010;138:513-21

[37] Lazo M,Daya NR,Mehta SH.Confluence of epidemics of hepatitis C, diabetes, obesity, and chronic kidney disease in the United States Population..Clin Gastroenterol Hepatol2017;15:1957-64 PMCID:PMC5693729

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

[39] Singer AW,Telep LE,Brainard DM.Direct-acting antiviral treatment for hepatitis C virus infection and risk of incident liver cancer: a retrospective cohort study..Aliment Pharmacol Ther2018;47:1278-87

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

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

[42] Kozbial K,Schwarzer R,Al-Zoairy R.Unexpected high incidence of hepatocellular carcinoma in cirrhotic patients with sustained virologic response following interferon-free direct-acting antiviral treatment..J Hepatol2016;65:856-8

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

[44] Mariño Z,Lens S,Díaz A.Time association between HCV therapy and hepatocellular carcinoma emergence in patients with cirrhosis. The relevance of non-characterized nodules..J Hepatol2019;70:874-84

[45] Nahon P,Bourcier V,Marcellin P.Incidence of hepatocellular carcinoma after direct antiviral therapy for HCV in patients with cirrhosis Included in surveillance programs..Gastroenterology2018;155:1436-50

[46] Ogawa E,Nomura H,Higashi N.Short-term risk of hepatocellular carcinoma after hepatitis C virus eradication following direct-acting anti-viral treatment..Aliment Pharmacol Ther2018;47:104-13

[47] Ioannou GN,Green PK,Tapper EB.Increased risk for hepatocellular carcinoma persists up to 10 years after HCV eradication in patients with baseline cirrhosis or high FIB-4 Scores..Gastroenterology2019;157:1264-78 PMCID:PMC6815714

[48] Kanwal F,Asch SM,Li L.Long-term risk of hepatocellular carcinoma in HCV patients treated with direct acting antiviral agents..Hepatology2020;71:44-55

[49] Llovet JM.Liver cancer: effect of HCV clearance with direct-acting antiviral agents on HCC..Nat Rev Gastroenterol Hepatol2016;13:561-2

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

[51] Debes JD,Groothuismink ZMA,Schulze Zur Wiesch J.Levels of cytokines in serum associate with development of hepatocellular carcinoma in patients with HCV infection treated with direct-acting antivirals..Gastroenterology2018;154:515-7.e3

[52] Sanduzzi-Zamparelli M,Leal C.Hepatocellular carcinoma recurrence in HCV patients treated with direct antiviral agents..Viruses2019;11:406 PMCID:PMC6563506

[53] Villani R,Serviddio G.Molecular Mechanisms Involved in HCC Recurrence after direct-acting antiviral therapy..Int J Mol Sci2019;20:49 PMCID:PMC6337751

[54] Singal AK,Anand BS.Meta-analysis: interferon improves outcomes following ablation or resection of hepatocellular carcinoma..Aliment Pharmacol Ther2010;32:851-8

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

[56] Colombo M.HCV therapy and risk of liver cancer recurrence: who to treat?.Nat Rev Gastroenterol Hepatol2018;15:392-3

[57] Reig M,Bruix J.The impact of direct antiviral agents on the development and recurrence of hepatocellular carcinoma..Liver Int2017;37:136-9

[58] Guarino M,Ponziani FR,Lai Q.Recurrence of hepatocellular carcinoma after direct acting antiviral treatment for hepatitis C virus infection: literature review and risk analysis..Dig Liver Dis2018;50:1105-14

[59] Guarino M,Cossiga V,Caporaso N.Direct-acting antivirals and hepatocellular carcinoma in chronic hepatitis C: a few lights and many shadows..World J Gastroenterol2018;24:2582-95 PMCID:PMC6021774

[60] Saraiya N,Rich NE,Parikh ND.Systematic review with meta-analysis: recurrence of hepatocellular carcinoma following direct-acting antiviral therapy..Aliment Pharmacol Ther2018;48:127-37 PMCID:PMC6019180

[61] Singal AG,Mehta N,Pillai A.Direct-acting antiviral therapy not associated with recurrence of hepatocellular carcinoma in a multicenter North American cohort study..Gastroenterology2019;156:1683-92 PMCID:PMC6598433

[62] Dang H,Yasuda S,Iio E.Cure with interferon free DAA is associated with increased survival in patients with HCV related HCC from both East and West..Hepatology2019;Epub ahead of print [PMID: 31610027 DOI: 10.1002/hep.30988]

[63] Saberi B,Durand CM,Cameron AM.Challenges in treatment of hepatitis C among patients with hepatocellular carcinoma..Hepatology2017;66:661-3

[64] Beste LA,Berry K,Allison SK.Effectiveness of hepatitis C antiviral treatment in a USA cohort of veteran patients with hepatocellular carcinoma..J Hepatol2017;67:32-9 PMCID:PMC6590903

[65] Prenner SB,Flamm SL,Lewandowski RJ.Hepatocellular carcinoma decreases the chance of successful hepatitis C virus therapy with direct-acting antivirals..J Hepatol2017;66:1173-81 PMCID:PMC5776681

[66] Chang CY,Le A,Ahmed A.Real-world experience with interferon -free, direct-acting antiial therapies in Asian Americans with chronic hepatitis C and advanced liver disease..Medicine (Baltimore)2017;96:e6128 PMCID:PMC5313031

[67] Soria A,Lapadula G.Unexpected viral relapses in hepatitis C virus-infected patients diagnosed with hepatocellular carcinoma during treatment with direct-acting antivirals..Hepatology2017;66:992-4

[68] Ji F,Wei MT,Dang S.Hepatocellular carcinoma decreases the effectiveness of hepatitis C antiviral treatment: do direct-acting antiviral regimens matter?.Hepatology2018;67:1180-2

[69] Harrod E,Gurakar A,Dieterich D.Management of concomitant hepatocellular carcinoma and chronic hepatitis C: a review..Hepatoma Res2019;5:28

[70] Ahmed A,Cholankeril G,McGinnis J.Treatment of patients waitlisted for liver transplant with all-oral direct-acting antivirals is a cost-effective treatment strategy in the United Status..Hepatology2017;66:46-56

[71] Radhakrishnan K,Reddy KR,Levitsky J.Treatment status of hepatocellular carcinoma does not influence rates of sustained virologic response: an HCV-TARGET analysis..Hepatol Commun2019;3:1388-99 PMCID:PMC6771159

[72] Roche B,Duclos-Vallee JC.The impact of treatment of hepatitis C with DAAs on the occurrence of HCC..Liver Int2018;38:139-45

[73] Belli LS,Cortesi PA,Rockenschaub SR.Delisting of liver transplant candidates with chronic hepatitis C after viral eradication: a European study..J Hepatol2016;65:524-31

[74] Gadiparthi C,Perumpail BJ,Satapathy SK.Use of direct-acting antiviral agents in hepatitis C virus- infected liver transplant candidates..World J Gastroenterol2018;24:315-22 PMCID:PMC5776393

[75] Pascasio JM,Ferrer MT,Rubin A.Clinical outcomes of patients undergoing antiviral therapy while awaiting liver transplantation..J Hepatol2017;67:1168-76

[76] Yang JD,Pungpapong S,Roberts LR.Direct acting antiviral therapy and tumor recurrence after liver transplantation for hepatitis C-associated hepatocellular carcinoma..J Hepatol2016;65:856-68

[77] Bigam D,Kneteman N.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