Considerations When Treating Hepatitis C in a Cirrhotic Transplant Candidate

  • Kimberly E. Daniel
  • Adnan Said
Liver (S Cotler and E Kallwitz, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Liver


Purpose of Review

This review examines the issues in determining the decision to treat a HCV-positive patient who is a liver transplant (LT) candidate with highly effective and well-tolerated direct-acting antiviral (DAA) therapies.

Recent Findings

Cure of HCV with DAA can improve liver function and allow delisting in some patients. Beyond a threshold of hepatic impairment (likely MELD score > 16 to 20), patients may experience a decline in MELD score with HCV cure without improvement in liver-related complications resulting in decreased opportunity to receive a LT. Eradicating HCV from patients who need LT regardless also deprives them of the option of receiving HCV-positive donor organs. Patients with MELD > 16 or Child-Pugh B/C may also have reduced cure rates of HCV, increased risk of hepatic decompensation, and adverse events with DAA pre-LT compared to post-LT DAA therapy. Preliminary data demonstrates increase risk of hepatocellular carcinoma (HCC) recurrence after treatment with DAA with subsequent studies raising doubts about this association.


Patients with HCV cirrhosis on the LT waiting list with MELD score > 16, CTP-B/C, and HCC are best treated after LT with better response, tolerability, and the ability to receive organs from a larger donor pool that includes HCV-positive donors. Larger, prospective studies are needed to assess whether increased HCC recurrence after DAA is a true effect.


Direct-acting antivirals (DAA) Hepatitis C (HCV) Liver transplant Cirrhosis Liver decompensation Hepatocellular carcinoma (HCC) Delisting 


Compliance with Ethical Standards

Conflict of Interest

Adnan Said and Kimberly Daniel declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


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

  1. 1.
    Denniston MM, Jiles RB, Drobeniuc J, Klevens RM, Ward JW, McQuillan G, et al. Chronic hepatitis C virus infection in the United States, National Health and Nutrition Examination Survey 2003 to 2010. Ann Intern Med. 2014;160(5):293–300.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Davis GL, Alter MJ, El-Serag H, Poynard T, Jennings LW. Aging of hepatitis C virus (HCV)-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression. Gastroenterology. 2010;138:513–21.CrossRefPubMedGoogle Scholar
  3. 3.
    Ly KN, Hughes EM, Jiles RB, Holmberg SD. Rising mortality associated with hepatitis C virus in the United States, 2003-2013. Clin Infect Dis. 2016;62(10):1287–8.CrossRefPubMedGoogle Scholar
  4. 4.
    • Chhatwal J, Wang X, Ayer T, Kabiri M, Chung RT, et al. Hepatitis C disease burden in the United States in the era of oral direct-acting antivirals. Hepatology. 2016;64(5):1442–50. A data-derived modeling of HCV-related burden in the USA in the era of DAA that predicts a significant number of decompensated cirrhosis and HCC. Increased screening and treatment capacity will be needed to further reduce burden of HCV disease. CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Kim WR, Lake JR, Smith JM, Skeans MA, Schladt DP, Edwards EB, et al. Liver. Am J Transplant. 2016;16 Suppl 2:69–98.CrossRefPubMedGoogle Scholar
  6. 6.
    Forman LM, Lewis JD, Berlin JA, Feldman HI, Lucey MR. The association between hepatitis C infection and survival after orthotopic liver transplantation. Gastroenterology. 2002;122(4):889–96.CrossRefPubMedGoogle Scholar
  7. 7.
    Fortune BE, Martinez-Camacho A, Kriedler S, Gralla J, Everson GT. Post-transplant survival is improved for hepatitis C recipients who are RNA negative at the time of liver transplantation. Transpl Int. 2015;28:980–9.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Gonzalez SA and Trotter JF. The rise of the opioid epidemic and hepatitis C positive organs: a new era in liver transplantation. Hepatology 2017; accepted 10 October 2017.Google Scholar
  9. 9.
    • van der Meer AJ, Veldt BJ, Feld JJ, WedemeyerH DJF, 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;308:2584–93. A long-term follow-up (median follow-up 8.4 years) of a multicenter treatment study of HCV patients with advanced fibrosis or cirrhosis that demonstrated reduced liver mortality, transplantation, HCC development, and liver failure in patients that developed SVR after IFN-based therapies. CrossRefPubMedGoogle Scholar
  10. 10.
    •• Backus LI, Belperio PS, Shahoumian TA, Mole LA. Impact of sustained virologic response with direct-acting antiviral treatment on mortality in patients with advanced liver disease. Hepatology. 2017; A national Veterans Affairs database study of DAA showing that SVR with DAA, even after short-term follow-up of approx. 1.6 years was associated with significant reduction in mortality and HCC incidence.
  11. 11.
    • Lens S, Alvarado-Tapias E, Marino Z, Londono MC, Lop E, Marinez J, et al. Effects of all-oral antiviral therapy on HVPG and systemic hemodynamics in patients with hepatitis C virus-associated cirrhosis. Gastroenterology. 2017;153:1273–83. A multicenter prospective study or all oral HCV therapy in cirrhosis that showed that despite improvement in portal hypertension (measured by HVPG) with SVR, clinically significant portal hypertension (HVPG > 10 mmHg) can persist in the majority (78%) who still remain at risk of liver decompensation. It raises the question of what threshold of liver disease is too much for clinically significant improvement in portal hypertension to occur after SVR. CrossRefPubMedGoogle Scholar
  12. 12.
    Mandorfer M, Kozbial K, Schwabl P, Freissmuth C, Schwarzer R, Stern R, et al. Sustained virologic response to interferon-free therapies ameliorates HCV-induced portal hypertension. J Hepatol. 2016;65(4):692–9.CrossRefPubMedGoogle Scholar
  13. 13.
    Cheung MCM, Walker AJ, Hudson BE, Verma S, McLauchlan J, Mutimer DJ, et al. Outcomes after successful direct-acting antiviral therapy for patients with chronic hepatitis C and decompensated cirrhosis. J Hepatol. 2016;65(4):741–7.CrossRefPubMedGoogle Scholar
  14. 14.
    Foster GR, Irving WL, Cheung MCM, Walker AJ, Hudson BE, Verma S, et al. Impact of direct acting antiviral therapy in patients with chronic hepatitis C and decompensated cirrhosis. J Hepatol. 2016;64(6):1224–31.CrossRefPubMedGoogle Scholar
  15. 15.
    Pascasio JM, Vinaixa C, Ferrer MT, Colmenero J, Rubin A, Castells L, et al. Clinical outcomes of patients undergoing antiviral therapy while awaiting liver transplantation. J Hepatol. 2017;67(6):1168–76.CrossRefPubMedGoogle Scholar
  16. 16.
    Goldberg D, Ditah IC, Saeian K, Lalehzari M, Aronsohn A, Gorospe EC, et al. Changes in the prevalence of hepatitis C virus infection, nonalcoholic steatohepatitis, and alcoholic liver disease among patients with cirrhosis or liver failure on the waitlist for liver transplantation. Gastroenterology. 2017;152:1090–9.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    • Flemming JA, Kim WR, Brosgart CL, Terrault NA. Reduction in liver transplant wait-listing in the era of direct-acting antiviral therapy. Hepatology. 2017;65:804–12. A SRTR database study that showed that over 2003–2015 listing for HCV-related decompensated liver disease declined by 32% compared to the IFN era. CrossRefPubMedGoogle Scholar
  18. 18.
    •• Belli LS, Berenguer M, Cortesi PA, Strazzabosco M, Rockenschaub SR, Martini S, et al. Delisting of liver transplant candidates with chronic hepatitis C after viral eradication: a European study. J Hepatol. 2016;65(3):524–31. An 11 center study that looked at DAA treatment on the waiting list and showed inactivation and delisting was 33 and 19%, respectively, 60 weeks after SVR with DAA. Baseline MELD score 16–20 was associated with higher chances of delisting than higher MELD score as was decline in MELD and improvement in albumin with DAA . CrossRefPubMedGoogle Scholar
  19. 19.
    Curry MP, O’Leary JG, Bzowej N, Muir AJ, Korenblat KM, et al. Sofosbuvir and velpatasvir for HCV in patients with decompensated cirrhosis. N Engl J Med. 2015;373(27):2618–28.CrossRefPubMedGoogle Scholar
  20. 20.
    Poordad F, Schiff ER, Vierling JM, Landis C, Fontana RJ, Yang R, et al. Daclatasvir with sofosbuvir and ribavirin for hepatitis C virus infection with advanced cirrhosis or post-liver transplantation recurrence. Hepatology. 2016;63(5):1493–505.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    •• Carrillo C, Lens S, Llop E, Pascasio JM, Crespo J, Arenas J, et al. Treatment of hepatitis C virus infection in patients with cirrhosis and predictive value of model for end-stage liver disease: analysis of data from the Hepa-C Registry. Hepatology. 2017;65(6):1810–22. Spanish multicenter real-world study that demonstrated DAA use in decompensated cirrhosis. Significant differences in SVR12 and relapse rates were observed between CTP class A and CTP class B/C patients (94 versus 78%, and 4 versus 14%, respectively; both P< 0.001). Serious adverse events (SAEs) were more common in CTP class B/C versus CTP class A patients (50% versus 12%, respectively; P< 0.001 ). Baseline MELD score alone (cut-off 18) was the best predictor of survival. CrossRefGoogle Scholar
  22. 22.
    Verna E. The dynamic landscape of liver transplant in the era of effective hepatitis c virus therapy. Hepatology. 2017;65:763–6.CrossRefPubMedGoogle Scholar
  23. 23.
    Cholankeril G, Joseph-Talreja M, Perumpail BJ, Liu A, Yoo ER, Ahmed A, et al. Timing of hepatitis C virus treatment in liver transplant candidates in the era of direct-acting antiviral agents. J Clin Transl Hepatol. 2017;5(4):363–7.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Chen T, Terrault N. Perspectives on treating hepatitis C infection in the liver transplantation setting. Curr Opin Organ Transplant. 2016;21:111–9.CrossRefPubMedGoogle Scholar
  25. 25.
    • Goldberg DS, Blumberg E, McCauley M, Abt P, Levine M. Improving organ utilization to help overcome the tragedies of the opioid epidemic. Am J Transplant. 2016;16:2836–41. A concise review of OPTN showing increasing donors from opioid-related deaths and the low risk of disease transmission from such donors. CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Bowring MG, Kucirka LM, Massie AB, Luo X, Cameron A, Sulkowski M, et al. Changes in utilization and discard of hepatitis C-infected donor livers in the recent era. Am J Transplant. 2017;17:519–27.CrossRefPubMedGoogle Scholar
  27. 27.
    Ofosu A, Durand CM, Saberi B, Alqahtani S, Ucbilek E, Belden M, et al. Implications of treating hepatitis C virus infection among patients awaiting cadaveric liver transplant: a single-center experience. Exp Clin Transplant. 2015;13:7–10.PubMedGoogle Scholar
  28. 28.
    Abdelqader A, Kabacam G, Woreta TA, Hamilton JP, Luu H, Khalloufi K, et al. Pre-versus posttransplant treatment of hepatitis C virus with direct-acting antivirals in liver transplant recipients: more issues to be solved. Exp Clin Transplant. 2017;15(S1):1–5.PubMedGoogle Scholar
  29. 29.
    American Association for the Study of Liver Diseases (AASLD) and Infectious Diseases Society of America (IDSA). Recommendations for testing, managing and treating hepatitis C. (accessed March 2018).
  30. 30.
    Bunchorntavakul C, Reddy KR. Treat chronic hepatitis C virus infection in decompensated cirrhosis – pre- or post-liver transplantation? The ironic conundrum in the era of effective and well-tolerated therapy. J Viral Hepat. 2016;23:408–18.CrossRefPubMedGoogle Scholar
  31. 31.
    Manns M, Samuel D, Gane EJ, Mutimer D, McCaughan G, Buti M, et al. Ledipasvir and sofosbuvir plus ribavirin in patients with genotype 1 or 4 hepatitis C virus infection and advanced liver disease: a multicentre, open-label, randomised, phase 2 trial. Lancet Infect Dis. 2016;16:685–97.CrossRefPubMedGoogle Scholar
  32. 32.
    Tapper EB, Afdhal NH, Curry MP. Before or after transplantation? A review of the cost effectiveness of treating waitlisted patients with hepatitis C. Transplantation. 2017;101:933–7.CrossRefPubMedGoogle Scholar
  33. 33.
    Ahmed A, Gonzalez S, Cholankeril G, Perumpail RB, McGinnis J, et al. Treatment of patients waitlisted for liver transplant with all-oral direct-acting antivirals is a cost-effective treatment strategy in the United States. Hepatology. 2017;66(1):46–56.CrossRefPubMedGoogle Scholar
  34. 34.
    Maan R, van Tilborg M, Deterding K, Ramji A, van der Meer AJ, Wong F, et al. Safety and effectiveness of direct-acting antiviral agents for treatment of hepatitis C virus infection and cirrhosis. Clin Gastroenterol Hepatol. 2016;14(12):1821–30.CrossRefPubMedGoogle Scholar
  35. 35.
    Miyake Y, Takaki A, Iwasaki Y, Yamamoto K. Meta-analysis: interferon-alpha prevents the recurrence after curative treatment of hepatitis c virus-related hepatocellular carcinoma. J Viral Hepat. 2010;17(4):287–92.CrossRefPubMedGoogle Scholar
  36. 36.
    Grandhe S, Frenette CT. Occurence and recurrence of hepatocellular carcinoma after successful direct-acting antiviral therapy for patients with chronic hepatitis C virus infection. Gastroenterol Hepatol. 2017;13(7):421–5.Google Scholar
  37. 37.
    Sekyere SO, Falk CS, Aregay A, et al. IFN-free cure of HCV infection alters the soluble inflammatory milieu in patients with liver cirrhosis which could affect HCC surveillance by CD8+ T cells. Program and abstracts of the European Association for the Study of the Liver International Liver Congress; April 19–23, 2017; Amsterdam, The Netherlands. Abstract GS-003.Google Scholar
  38. 38.
    •• Reig M, Marino Z, Perello C, Inarrairaegui M, Ribeiro A, et al. Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon-free therapy. J Hepatol. 2016;65:719–26. The first report of significant recurrence of HCC after DAA treatment (27.6% after 5.7months) in 58 patients treated after HCC treatment. CrossRefPubMedGoogle Scholar
  39. 39.
    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;65:727–33.CrossRefPubMedGoogle Scholar
  40. 40.
    Yang JD, Aqel BA, Pungpapong S, Gores GJ, Roberts LR, Leise MD. Direct acting antiviral therapy and tumor recurrence after liver transplantation for hepatitis C-associated hepatocellular carcinoma. J Hepatol. 2016;65:859–60.CrossRefPubMedGoogle Scholar
  41. 41.
    Cabibbo G, Petta A, Barbara M, et al. A meta-analysis of single HCV-untreated arm of studies evaluating outcomes after curative treatments of HCV-related hepatocellular carcinoma. Liver Int. 2017;37(8):1157–66.CrossRefPubMedGoogle Scholar
  42. 42.
    ANRS collaborative study group on hepatocellular carcinoma. Lack of evidence of an effect of direct-acting antivirals on the recurrence of hepatocellular carcinoma: data from three ANRS cohorts. J Hepatol. 2016;65:734–40.CrossRefGoogle Scholar
  43. 43.
    Zanetto A, Shalaby S, Vitale A, Mescoli C, Ferrarese A, Gambato M, et al. 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 Transpl. 2017;23:1103–12.CrossRefPubMedGoogle Scholar
  44. 44.
    Zavaglia C, Okolicsanyi S, Cesarini L, Mazzarelli C, Pontecorvi V, Ciaccio A, et al. Is the risk of neoplastic recurrence increased after prescribing direct-acting antivirals to patients whose HCC was previously cured? J Hepatol. 2017;66(1):236–7.CrossRefPubMedGoogle Scholar
  45. 45.
    •• Waziry R, Hajarizadeh B, Grebely J, Amin J, Law M, Danta M, et al. Hepatocellular carcinoma risk following direct-acting antiviral HCV therapy: a systemic review, meta-analysis, and meta-regression. J Hepatol. 2017;67:1204–12. A meta-analysis of 41 studies on HCC recurrence after DAA versus IFN that showed that after adjusting for age and study follow-up. DAA was not associated with higher HCC recurrence than interferon-based therapies . CrossRefPubMedGoogle Scholar
  46. 46.
    Alberti A, Piovesan S. Increased incidence of liver cancer after successful DAA treatment of chronic hepatitis C: fact or fiction? Liver Int. 2017;37:802–8.CrossRefPubMedGoogle Scholar
  47. 47.
    Terrault NA, McCaughan GW, Curry MP, Gane E, Fagiuoli S, Fung JYY, et al. International Liver Transplantation Society Consensus Statement on hepatitis C management in liver transplant candidates. Transplantation. 2017;101:945–55.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Gastroenterology and Hepatology FellowMedical College of WisconsinMilwaukeeUSA
  2. 2.Gastroenterology and Hepatology, Department of MedicineUniversity of Wisconsin School of Medicine and Public Health and Madison VAMCMadisonUSA

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