Considerations When Treating Hepatitis C in a Cirrhotic Transplant Candidate
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.
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.
KeywordsDirect-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
- 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
- 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.• 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.•• 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; https://doi.org/10.1002/hep.29408. 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.• 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
- 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.• 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.•• 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
- 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
- 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
- 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. https://www.hcvguidelines.org/ (accessed March 2018).
- 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
- 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.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.•• 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
- 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
- 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