Is there increased risk of hepatocellular carcinoma recurrence in liver transplant patients with direct-acting antiviral therapy?

  • Ashokkumar JainEmail author
  • Danielle Miller
  • Ian Schreibman
  • Thomas R. RileyIII
  • Karen L. Krok
  • Takehiko Dohi
  • Rajeev Sharma
  • Zakiyah Kadry
Original Article



Recently, a controversy has emerged: is the rate of recurrence of hepatocellular carcinoma (HCC) higher following treatment of hepatitis C virus (HCV) with direct-acting antiviral (DAA) therapy? However, the risk of HCC recurrence has not been studied in liver transplant (LTx) recipients who received DAA therapy. The aim of the present study is to compare the rate of HCC recurrence in LTx recipients who did or did not receive DAA therapy.

Patients and methods

Sixty-three patients received LTx with HCC. Twenty-seven (42.9%) with HCV received DAA therapy (Group A), 20 (31.7%) with HCV did not receive DAA therapy (Group B), and 16 (25.4%) did not have HCV (Group C).


In group A, three (11%), in group B, one (5%), and in group C, none had recurrence of HCC. Actuarial 4-year recurrence-free survival was 88.9, 95, and 100% in group A, B, and C, respectively (p = 0.37). Group A was subdivided into two groups for comparison with Group B: A1 included five patients who had end of treatment response (ETR) without sustained virological response (SVR), and A2 included 20 patients who achieved SVR. Three patients from A1 had HCC recurrence and no patients from A2 had HCC recurrence. (p = 0.0038; group A1, A2, and B).


The rate of HCC recurrence in LTx patients with DAA therapy was significantly higher with ETR, without SVR, after DAA therapy compared to patients with SVR or patients who did not receive DAA therapy. LTx recipients with HCC receiving DAA therapy requires further studies.


Immunosuppression Metastatic disease Chemoembolization Hepatitis C 



Nancy Sabb, provided the accuracy on clinical details on the transplant recipients. Michelle Carraher, for identifying the study population and for providing demographic details from the transplant data base. Jenna Weller, for typing and proofreading.

Authors’ contributions

Research design: AJ, ZK. Acquisition and analysis of data: AJ, ZK, DM, TR, RS. Interpretation of data: all authors. Drafting of the manuscript: all authors. Critical revision of the manuscript for important intellectual content: all authors. Study supervision: AJ, ZK.

Compliance with ethical standards

Conflicts of interest

Ashokkumar Jain, Danielle Miller, Ian Schreibman, Thomas R. Riley III, Karen L. Krok, Takehiko Dohi, Rajeev Sharma, and Zakiyah Kadry have no conflicts of interest.

Ethical standards

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008. As this was a retrospective study, the requirement for informed consent was waived by the institutional review board.


  1. 1.
    Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334:693–699CrossRefGoogle Scholar
  2. 2.
    Ghany MG, Strader DB, Thomas DL, Seeff LB, American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology 2009;49:1335–1374CrossRefGoogle Scholar
  3. 3.
    Ghobrial RM, Farmer DG, Baquerizo A, Colquhoun S, Rosen HR, Yersiz H, et al. Orthotopic liver transplantation for hepatitis C: outcome, effect of immunosuppression, and causes of retransplantation during an 8-year single-center experience. Ann Surg 1999;229:824–831 (discussion 831-833) CrossRefGoogle Scholar
  4. 4.
    Serti E, Chepa-Lotrea X, Kim YJ, Keane M, Fryzek N, Liang TJ, et al. successful interferon-free therapy of chronic hepatitis C virus infection normalizes natural killer cell function. Gastroenterology 2015;149(190–200):e192Google Scholar
  5. 5.
    Charlton M, Gane E, Manns MP, Brown RS Jr, Curry MP, Kwo PY, et al. Sofosbuvir and ribavirin for treatment of compensated recurrent hepatitis C virus infection after liver transplantation. Gastroenterology 2015;148:108–117CrossRefGoogle Scholar
  6. 6.
    Gutierrez JA, Carrion AF, Avalos D, O’Brien C, Martin P, Bhamidimarri KR, et al. Sofosbuvir and simeprevir for treatment of hepatitis C virus infection in liver transplant recipients. Liver Transpl 2015;21:823–830CrossRefGoogle Scholar
  7. 7.
    Jothimani D, Govil S, Rela M. Management of post liver transplantation recurrent hepatitis C infection with directly acting antiviral drugs: a review. Hepatol Int 2016;10:749–761CrossRefGoogle Scholar
  8. 8.
    Conti F, Buonfiglioli F, Scuteri A, Crespi C, Bolondi L, Caraceni P, et al. Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with direct-acting antivirals. J Hepatol 2016;65:727–733CrossRefGoogle Scholar
  9. 9.
    Kozbial K, Moser S, Schwarzer R, Laferl H, Al-Zoairy R, Stauber R, et al. Unexpected high incidence of hepatocellular carcinoma in cirrhotic patients with sustained virologic response following interferon-free direct-acting antiviral treatment. J Hepatol 2016;65:856–858CrossRefGoogle Scholar
  10. 10.
    Reig M, Marino Z, Perello C, Inarrairaegui M, Ribeiro A, Lens S, et al. Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon-free therapy. J Hepatol 2016;65:719–726CrossRefGoogle Scholar
  11. 11.
    Toyoda H, Kumada T, Tada T. Changes in patient backgrounds may increase the incidence of HCC after SVR in the era of IFN-free therapy for HCV. Hepatology 2016;64:1818–1889CrossRefGoogle Scholar
  12. 12.
    An C, Rakhmonova G, Choi JY, Kim MJ. Liver imaging reporting and data system (LI-RADS) version 2014: understanding and application of the diagnostic algorithm. Clin Mol Hepatol 2016;22:296–307CrossRefGoogle Scholar
  13. 13.
    Idee JM, Guiu B. Use of Lipiodol as a drug-delivery system for transcatheter arterial chemoembolization of hepatocellular carcinoma: a review. Crit Rev Oncol Hematol 2013;88:530–549CrossRefGoogle Scholar
  14. 14.
    Ioannou GN, Perkins JD, Carithers RL Jr. Liver transplantation for hepatocellular carcinoma: impact of the MELD allocation system and predictors of survival. Gastroenterology 2008;134:1342–1351CrossRefGoogle Scholar
  15. 15.
    Sharma P, Balan V, Hernandez JL, Harper AM, Edwards EB, Rodriguez-Luna H, et al. Liver transplantation for hepatocellular carcinoma: the MELD impact. Liver Transpl 2004;10:36–41CrossRefGoogle Scholar
  16. 16.
    Crippin JS, McCashland T, Terrault N, Sheiner P, Charlton MR. A pilot study of the tolerability and efficacy of antiviral therapy in hepatitis C virus-infected patients awaiting liver transplantation. Liver Transpl 2002;8:350–355CrossRefGoogle Scholar
  17. 17.
    Feray C, Samuel D, Gigou M, Paradis V, David MF, Lemonnier C, Reynes M, Bismuth H. An open trial of interferon alfa recombinant for hepatitis C after liver transplantation: antiviral effects and risk of rejection. Hepatology 1995;22:1084–1089CrossRefGoogle Scholar
  18. 18.
    Jain A, Demetris AJ, Manez R, Tsamanadas AC, Van Thiel D, Rakela J, et al. Incidence and severity of acute allograft rejection in liver transplant recipients treated with alfa interferon. Liver Transpl Surg 1998;4:197–203CrossRefGoogle Scholar
  19. 19.
    Shiratori Y, Ito Y, Yokosuka O, Imazeki F, Nakata R, Tanaka N, Tokyo-Chiba Hepatitis Research Group, et al. Antiviral therapy for cirrhotic hepatitis C: association with reduced hepatocellular carcinoma development and improved survival. Ann Intern Med 2005;142:105–114CrossRefGoogle Scholar
  20. 20.
    van der Meer AJ, Veldt BJ, Feld JJ, Wedemeyer H, Dufour JF, Lammert F, et al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA 2012;308:2584–2593CrossRefGoogle Scholar
  21. 21.
    Makiyama A, Itoh Y, Kasahara A, Imai Y, Kawata S, Yoshioka K, et al. Characteristics of patients with chronic hepatitis C who develop hepatocellular carcinoma after a sustained response to interferon therapy. Cancer 2004;101:1616–1622CrossRefGoogle Scholar
  22. 22.
    Cheung MC, Walker AJ, Hudson BE, Verma S, McLauchlan J, Mutimer DJ, HCV Research UK, et al. Outcomes after successful direct-acting antiviral therapy for patients with chronic hepatitis C and decompensated cirrhosis. J Hepatol 2016;65:741–747CrossRefGoogle Scholar
  23. 23.
    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 Hepatol 2016;65:734–740Google Scholar
  24. 24.
    Nault JC, Colombo M. Hepatocellular carcinoma and direct acting antiviral treatments: controversy after the revolution. J Hepatol 2016;65:663–665CrossRefGoogle Scholar
  25. 25.
    Zeng QL, Li ZQ, Liang HX, Xu GH, Li CX, Zhang DW, et al. Unexpected high incidence of hepatocellular carcinoma in patients with hepatitis C in the era of DAAs: Too alarming? J Hepatol 2016;65:1068–1069CrossRefGoogle Scholar
  26. 26.
    Kolly P, Dufour JF. A strong message is needed to address the issue of HCC recurrence after DAA therapy. J Hepatol 2016;65:1268–1269CrossRefGoogle Scholar
  27. 27.
    Ioannou G, Green P, Berry K. Eradication of HCV induced by direct antiviral is associated with 79% reduction in HCC risk. Hepatology 2017;66(1):82A–83AGoogle Scholar
  28. 28.
    Mangia A, Piazzolla V, Santoro V, Palmieri V, Copetti M. Risk of developing “de novo” liver cancer after achieving sustained virologic response (SVR) after direct antiviral (DAA) regimens in patients with chronic hepatitis C virus (HCV) infection: a 21,4 months follow up study cohort. Hepatology 2017;66(66):597–598Google Scholar
  29. 29.
    Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, SHARP Investigators Study Group, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378–390CrossRefGoogle Scholar
  30. 30.
    Ono A, Goossens N, Finn RS, Schmidt WN, Thung SN, Im GY, Precision Liver Cancer Prevention Consortium, et al. Persisting risk of hepatocellular carcinoma after hepatitis C virus cure monitored by a liver transcriptome signature. Hepatology 2017;66:1344–1346CrossRefGoogle Scholar

Copyright information

© Asian Pacific Association for the Study of the Liver 2019

Authors and Affiliations

  1. 1.Division of Transplantation, Department of Surgery, College of MedicinePennsylvania State UniversityHersheyUSA
  2. 2.Division of Gastroenterology, Department of Medicine, College of MedicinePennsylvania State UniversityHersheyUSA
  3. 3.CSL BehringKing of PrussiaUSA

Personalised recommendations