Viral Hepatitis and Liver Transplantation

ABSTRACT

Hepatitis C is the one of the most common indications for liver transplantation. Infection of the allograft after transplantation is universal, and recurrent hepatitis C progresses at an accelerated rate. Antiviral therapy in selected patients on the transplant waiting list may reduce the rate of hepatitis C virus reinfection. Preemptive antiviral therapy after transplantation has been disappointing. However, treatment of established histological disease with a combination of pegylated interferon and ribavirin is associated with sustained virologic response rates of 25 to 40%. Significant advances have been made in the prevention of hepatitis B reinfection after transplantation. Results are now excellent, with graft infection rates less than 10%. The challenges for the future include designing strategies to optimize the use of antiviral agents to prevent the need for transplantation and to avoid antiviral resistance and to determine the dose and duration of hepatitis B immunoglobulin needed in the era of multiple nucleoside analogs.

Hepatitis C - hepatitis B - interferon - hepatitis B immunoglobulin - antiviral therapy

REFERENCES

• 1 Gane E J, Portmann B C, Naoumov N V et al.. Long-term outcome of hepatitis C infection after liver transplantation.  N Engl J Med. 1996;  334 815-820
• 2 Pelletier S J, Iezzoni J C, Crabtree T D, Hahn Y S, Sawyer R G, Pruett T L. Prediction of liver allograft fibrosis after transplantation for hepatitis C virus: persistent elevation of serum transaminase levels versus necroinflammatory activity.  Liver Transpl. 2000;  6 44-53
• 3 Berenguer M, Prieto M, San Juan F et al.. Contribution of donor age to the recent decrease in patient survival among HCV-infected liver transplant recipients.  Hepatology. 2002;  36 202-210
• 4 Feray C, Caccamo L, Alexander G J et al.. European collaborative study on factors influencing outcome after liver transplantation for hepatitis C. European Concerted Action on Viral Hepatitis (EUROHEP) Group.  Gastroenterology. 1999;  117 619-625
• 5 Gane E J, Naoumov N V, Qian K P et al.. A longitudinal analysis of hepatitis C virus replication following liver transplantation.  Gastroenterology. 1996;  110 167-177
• 6 Firpi R J, Abdelmalek M F, Soldevila-Pico C et al.. One-year protocol liver biopsy can stratify fibrosis progression in liver transplant recipients with recurrent hepatitis C infection.  Liver Transpl. 2004;  10 1240-1247
• 7 Berenguer M, Ferrell L, Watson J et al.. HCV-related fibrosis progression following liver transplantation: increase in recent years.  J Hepatol. 2000;  32 673-684
• 8 Boker K H, Dalley G, Bahr M J et al.. Long-term outcome of hepatitis C virus infection after liver transplantation.  Hepatology. 1997;  25 203-210
• 9 Ghobrial R M, Steadman R, Gornbein J et al.. A 10-year experience of liver transplantation for hepatitis C: analysis of factors determining outcome in over 500 patients.  Ann Surg. 2001;  234 384-393 discussion 393-384
• 10 Forman L M, Lewis J D, Berlin J A, Feldman H I, Lucey M R. The association between hepatitis C infection and survival after orthotopic liver transplantation.  Gastroenterology. 2002;  122 889-896
• 11 Wiesner R H, Sorrell M, Villamil F. Report of the first International Liver Transplantation Society expert panel consensus conference on liver transplantation and hepatitis C.  Liver Transpl. 2003;  9 S1-S9
• 12 Schluger L K, Sheiner P A, Thung S N et al.. Severe recurrent cholestatic hepatitis C following orthotopic liver transplantation.  Hepatology. 1996;  23 971-976
• 13 Levy G, Villamil F, Samuel D et al.. Results of lis2t, a multicenter, randomized study comparing cyclosporine microemulsion with C2 monitoring and tacrolimus with C0 monitoring in de novo liver transplantation.  Transplantation. 2004;  77 1632-1638
• 14 Wiesner R H, Shorr J S, Steffen B J, Chu A H, Gordon R D, Lake J R. Mycophenolate mofetil combination therapy improves long-term outcomes after liver transplantation in patients with and without hepatitis C.  Liver Transpl. 2005;  11 750-759
• 15 Jain A, Kashyap R, Demetris A J, Eghstesad B, Pokharna R, Fung J J. A prospective randomized trial of mycophenolate mofetil in liver transplant recipients with hepatitis C.  Liver Transpl. 2002;  8 40-46
• 16 Firpi R J, Nelson D R, Davis G L. Lack of antiviral effect of a short course of mycophenolate mofetil in patients with chronic hepatitis C virus infection.  Liver Transpl. 2003;  9 57-61
• 17 Calmus Y, Scheele J R, Gonzalez-Pinto I et al.. Immunoprophylaxis with basiliximab, a chimeric anti-interleukin-2 receptor monoclonal antibody, in combination with azathioprine-containing triple therapy in liver transplant recipients.  Liver Transpl. 2002;  8 123-131
• 18 Neuhaus P, Clavien P A, Kittur D et al.. Improved treatment response with basiliximab immunoprophylaxis after liver transplantation: results from a double-blind randomized placebo-controlled trial.  Liver Transpl. 2002;  8 132-142
• 19 Charlton M, Seaberg E, Wiesner R et al.. Predictors of patient and graft survival following liver transplantation for hepatitis C.  Hepatology. 1998;  28 823-830
• 20 Russo M W, Galanko J, Beavers K, Fried M W, Shrestha R. Patient and graft survival in hepatitis C recipients after adult living donor liver transplantation in the United States.  Liver Transpl. 2004;  10 340-346
• 21 Shiffman M L, Stravitz R T, Contos M J et al.. Histologic recurrence of chronic hepatitis C virus in patients after living donor and deceased donor liver transplantation.  Liver Transpl. 2004;  10 1248-1255
• 22 Garcia-Retortillo M, Forns X, Llovet J M et al.. Hepatitis C recurrence is more severe after living donor compared to cadaveric liver transplantation.  Hepatology. 2004;  40 699-707
• 23 Olthoff K M, Merion R M, Ghobrial R M et al.. Outcomes of 385 adult-to-adult living donor liver transplant recipients: a report from the A2ALL Consortium.  Ann Surg. 2005;  242 314-323 discussion 323-315
• 24 Crippin J S, McCashland T, Terrault N, Sheiner P, Charlton M R. A pilot study of the tolerability and efficacy of antiviral therapy in hepatitis C virus-infected patients awaiting liver transplantation.  Liver Transpl. 2002;  8 350-355
• 25 Everson G T, Trotter J, Forman L et al.. Treatment of advanced hepatitis C with a low accelerating dosage regimen of antiviral therapy.  Hepatology. 2005;  42 255-262
• 26 Forns X, Garcia-Retortillo M, Serrano T et al.. Antiviral therapy of patients with decompensated cirrhosis to prevent recurrence of hepatitis C after liver transplantation.  J Hepatol. 2003;  39 389-396
• 27 Feray C, Gigou M, Samuel D et al.. Incidence of hepatitis C in patients receiving different preparations of hepatitis B immunoglobulins after liver transplantation.  Ann Intern Med. 1998;  128 810-816
• 28 Willems B, Ede M, Marotta P et al.. Anti HCV immunoglobulins for prevention of experimental HCV infection [abstract].  J Hepatol. 2002;  36(suppl 1) S96
• 29 Davis G L, Nelson D R, Terrault N et al.. A randomized, open-label study to evaluate the safety and pharmacokinetics of human hepatitis C immune globulin (Civacir) in liver transplant recipients.  Liver Transpl. 2005;  11 941-949
• 30 Sheiner P A, Boros P, Klion F M et al.. The efficacy of prophylactic interferon alfa-2b in preventing recurrent hepatitis C after liver transplantation.  Hepatology. 1998;  28 831-838
• 31 Mazzaferro V, Regalia E, Pulvirenti A et al.. Prophylaxis against HCV recurrence after liver transplantation: effect of interferon and ribavirin combination.  Transplant Proc. 1997;  29 519-521
• 32 Mazzaferro V, Tagger A, Schiavo M et al.. Prevention of recurrent hepatitis C after liver transplantation with early interferon and ribavirin treatment.  Transplant Proc. 2001;  33 1355-1357
• 33 Terrault N A. Prophylactic and preemptive therapies for hepatitis C virus-infected patients undergoing liver transplantation.  Liver Transpl. 2003;  9 S95-S100
• 34 Chalasani N, Manzarbeitia C, Ferenci P et al.. Peginterferon alfa-2a for hepatitis C after liver transplantation: two randomized, controlled trials.  Hepatology. 2005;  41 289-298
• 35 Sugawara Y, Makuuchi M, Matsui Y et al.. Preemptive therapy for hepatitis C virus after living-donor liver transplantation.  Transplantation. 2004;  78 1308-1311
• 36 Gane E J, Tibbs C J, Ramage J K, Portmann B C, Williams R. Ribavirin therapy for hepatitis C infection following liver transplantation.  Transpl Int. 1995;  8 61-64
• 37 Cattral M S, Hemming A W, Wanless I R et al.. Outcome of long-term ribavirin therapy for recurrent hepatitis C after liver transplantation.  Transplantation. 1999;  67 1277-1280
• 38 Bizollon T, Palazzo U, Ducerf C et al.. Pilot study of the combination of interferon alfa and ribavirin as therapy of recurrent hepatitis C after liver transplantation.  Hepatology. 1997;  26 500-504
• 39 Lavezzo B, Rizzetto M. Treatment of recurrent hepatitis C virus infection after liver transplantation.  J Hepatol. 1999;  31(suppl 1) 222-226
• 40 Giostra E, Kullak-Ublick G, Keller W et al.. Ribavirin/interferon alfa sequential treatment of recurrent hepatitis C after liver transplantation [abstract].  Hepatology. 2001;  34 641A
• 41 Samuel D, Bizollon T, Feray C et al.. Interferon-alpha 2b plus ribavirin in patients with chronic hepatitis C after liver transplantation: a randomized study.  Gastroenterology. 2003;  124 642-650
• 42 Dumortier J, Scoazec J Y, Chevallier P, Boillot O. Treatment of recurrent hepatitis C after liver transplantation: a pilot study of peginterferon alfa-2b and ribavirin combination.  J Hepatol. 2004;  40 669-674
• 43 Castells L, Vargas V, Allende H et al.. Combined treatment with pegylated interferon (alpha-2b) and ribavirin in the acute phase of hepatitis C virus recurrence after liver transplantation.  J Hepatol. 2005;  43 53-59
• 44 Rodriguez-Luna H, Khatib A, Sharma P et al.. Treatment of recurrent hepatitis C infection after liver transplantation with combination of pegylated interferon alpha2b and ribavirin: an open-label series.  Transplantation. 2004;  77 190-194
• 45 Neff G W, Montalbano M, O'Brien C B et al.. Treatment of established recurrent hepatitis C in liver-transplant recipients with pegylated interferon-alfa-2b and ribavirin therapy.  Transplantation. 2004;  78 1303-1307
• 46 Saab S, Kalmaz D, Gajjar N A et al.. Outcomes of acute rejection after interferon therapy in liver transplant recipients.  Liver Transpl. 2004;  10 859-867
• 47 Watt K D, Lyden E R, McCashland T M. Poor survival after liver retransplantation: is hepatitis C to blame?.  Liver Transpl. 2003;  9 1019-1024
• 48 Ghobrial R M. Retransplantation for recurrent hepatitis C.  Liver Transpl. 2002;  8(suppl 1) S38-S43
• 49 Sheiner P A, Schluger L K, Emre S et al.. Retransplantation for recurrent hepatitis C.  Liver Transpl Surg. 1997;  3 130-136
• 50 Doyle H R, Morelli F, McMichael J et al.. Hepatic retransplantation: an analysis of risk factors associated with outcome.  Transplantation. 1996;  61 1499-1505
• 51 Rosen H R, Martin P. Hepatitis C infection in patients undergoing liver retransplantation.  Transplantation. 1998;  66 1612-1616
• 52 Kim W R, Poterucha J J, Kremers W K, Ishitani M B, Dickson E R. Outcome of liver transplantation for hepatitis B in the United States.  Liver Transpl. 2004;  10 968-974
• 53 Roche B, Feray C, Gigou M et al.. HBV DNA persistence 10 years after liver transplantation despite successful anti-HBS passive immunoprophylaxis.  Hepatology. 2003;  38 86-95
• 54 Steinmuller T, Seehofer D, Rayes N et al.. Increasing applicability of liver transplantation for patients with hepatitis B-related liver disease.  Hepatology. 2002;  35 1528-1535
• 55 Todo S, Demetris A J, Van Thiel D, Teperman L, Fung J J, Starzl T E. Orthotopic liver transplantation for patients with hepatitis B virus-related liver disease.  Hepatology. 1991;  13 619-626
• 56 O'Grady J G, Smith H M, Davies S E et al.. Hepatitis B virus reinfection after orthotopic liver transplantation: serological and clinical implications.  J Hepatol. 1992;  14 104-111
• 57 Starzl T E, Demetris A J, Van Thiel D. Liver transplantation (2).  N Engl J Med. 1989;  321 1092-1099
• 58 Marcellin P, Samuel D, Areias J et al.. Pretransplantation interferon treatment and recurrence of hepatitis B virus infection after liver transplantation for hepatitis B-related end-stage liver disease.  Hepatology. 1994;  19 6-12
• 59 Perrillo R, Tamburro C, Regenstein F et al.. Low-dose, titratable interferon alfa in decompensated liver disease caused by chronic infection with hepatitis B virus.  Gastroenterology. 1995;  109 908-916
• 60 Fontana R J, Hann H W, Perrillo R P et al.. Determinants of early mortality in patients with decompensated chronic hepatitis B treated with antiviral therapy.  Gastroenterology. 2002;  123 719-727
• 61 Perrillo R P, Wright T, Rakela J et al.. A multicenter United States-Canadian trial to assess lamivudine monotherapy before and after liver transplantation for chronic hepatitis B.  Hepatology. 2001;  33 424-432
• 62 Villeneuve J P, Condreay L D, Willems B et al.. Lamivudine treatment for decompensated cirrhosis resulting from chronic hepatitis B.  Hepatology. 2000;  31 207-210
• 63 Yao F Y, Bass N M. Lamivudine treatment in patients with severely decompensated cirrhosis due to replicating hepatitis B infection.  J Hepatol. 2000;  33 301-307
• 64 Chang T T, Lai C L, Chien R N et al.. Four years of lamivudine treatment in Chinese patients with chronic hepatitis B.  J Gastroenterol Hepatol. 2004;  19 1276-1282
• 65 Marzano A, Lampertico P, Mazzaferro V et al.. Prophylaxis of hepatitis B virus recurrence after liver transplantation in carriers of lamivudine-resistant mutants.  Liver Transpl. 2005;  11 532-538
• 66 Schiff E R, Lai C L, Hadziyannis S et al.. Adefovir dipivoxil therapy for lamivudine-resistant hepatitis B in pre- and post-liver transplantation patients.  Hepatology. 2003;  38 1419-1427
• 67 Schiff E, Lai C L, Neuhaus P et al.. Adefovir dipivoxil provides significant clinical benefit, reduces MELD score and prevents transplantation in chronic hepatitis B patients wait-listed for liver transplantation with lamivudine resistance [abstract].  J Hepatol. 2005;  42(suppl 2) 5
• 68 Angus P, Vaughan R, Xiong S et al.. Resistance to adefovir dipivoxil therapy associated with the selection of a novel mutation in the HBV polymerase.  Gastroenterology. 2003;  125 292-297
• 69 Barcena R, Del Campo S, Moraleda G et al.. Study on the efficacy and safety of adefovir dipivoxil treatment in post-liver transplant patients with hepatitis B virus infection and lamivudine-resistant hepatitis B virus.  Transplant Proc. 2005;  37 3960-3962
• 70 Lai C L, Shouval D, Lok A S et al.. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B.  N Engl J Med. 2006;  354 1011-1020
• 71 Gish R G, Chang T T, Hadziyannis S et al.. 428 Lamivudine-refractory hepatitis B patients can be safely switched directly to entecavir 1 mg daily therapy [abstract].  J Hepatol. 2004;  40(suppl 1) 127
• 72 Colonno R J, Rose R, Levine S et al.. Entecavir two year resistance update observed in nucleoside naive patients and low frequency resistance emergence in lamivudine refractory patients.  Hepatology. 2005;  42(suppl 1) 573A
• 73 Fung S K, Chae H B, Fontana R J et al.. Virologic response and resistance to adefovir in patients with chronic hepatitis B.  J Hepatol. 2006;  44 283-290
• 74 Chang T T, Gish R G, Hadziyannis S J et al.. A dose-ranging study of the efficacy and tolerability of entecavir in lamivudine-refractory chronic hepatitis B patients.  Gastroenterology. 2005;  129 1198-1209
• 75 Samuel D, Bismuth A, Mathieu D et al.. Passive immunoprophylaxis after liver transplantation in HBsAg-positive patients.  Lancet. 1991;  337 813-815
• 76 McGory R W, Ishitani M B, Oliveira W M et al.. Improved outcome of orthotopic liver transplantation for chronic hepatitis B cirrhosis with aggressive passive immunization.  Transplantation. 1996;  61 1358-1364
• 77 Terrault N A, Zhou S, Combs C et al.. Prophylaxis in liver transplant recipients using a fixed dosing schedule of hepatitis B immunoglobulin.  Hepatology. 1996;  24 1327-1333
• 78 Muller R, Gubernatis G, Farle M et al.. Liver transplantation in HBs antigen (HBsAg) carriers: prevention of hepatitis B virus (HBV) recurrence by passive immunization.  J Hepatol. 1991;  13 90-96
• 79 Shouval D, Samuel D. Hepatitis B immune globulin to prevent hepatitis B virus graft reinfection following liver transplantation: a concise review.  Hepatology. 2000;  32 1189-1195
• 80 Sawyer R G, McGory R W, Gaffey M J et al.. Improved clinical outcomes with liver transplantation for hepatitis B-induced chronic liver failure using passive immunization.  Ann Surg. 1998;  227 841-850
• 81 Mutimer D, Pillay D, Shields P et al.. Outcome of lamivudine resistant hepatitis B virus infection in the liver transplant recipient.  Gut. 2000;  46 107-113
• 82 Lo C M, Cheung S T, Lai C L et al.. Liver transplantation in Asian patients with chronic hepatitis B using lamivudine prophylaxis.  Ann Surg. 2001;  233 276-281
• 83 Wang R, Kim D, Yao F, Roberts J, Terrault N. Long term efficacy of different regimens of combination hepatitis B immunoglobulin and antivirals in preventing hepatitis B virus recurrence post transplantation.  Hepatology. 2005;  42 49A
• 84 Dickson R C, Terrault N A, Ishitani M et al.. Protective antibody levels and dose requirements for IV 5% Nabi hepatitis B immune globulin combined with lamivudine in liver transplantation for hepatitis B-induced end stage liver disease.  Liver Transpl. 2006;  12 124-133
• 85 Gane E, McCaughan G, Crawford D et al.. Combination lamivudine plus low dose intramuscular hepatitis B immunoglobulin prevents recurrent hepatitis B and may eradicate residual graft infection.  Hepatology. 2002;  36 221A
• 86 Naoumov N V, Lopes A R, Burra P et al.. Randomized trial of lamivudine versus hepatitis B immunoglobulin for long-term prophylaxis of hepatitis B recurrence after liver transplantation.  J Hepatol. 2001;  34 888-894
• 87 Buti M, Mas A, Prieto M et al.. Five year follow up of a randomized study comparing lamivudine vs. lamivudine + HBIg in the prevention of HBV recurrence after liver transplantation.  Hepatology. 2005;  42 492A
• 88 Sanchez-Fueyo A, Rimola A, Grande L et al.. Hepatitis B immunoglobulin discontinuation followed by hepatitis B virus vaccination: a new strategy in the prophylaxis of hepatitis B virus recurrence after liver transplantation.  Hepatology. 2000;  31 496-501
• 89 Sanchez-Fueyo A, Martinez-Bauer E, Rimola A. Hepatitis B vaccination after liver transplantation.  Hepatology. 2002;  36 257-258 author reply 258--259
• 90 Angelico M, Di Paolo D, Trinito M O et al.. Failure of a reinforced triple course of hepatitis B vaccination in patients transplanted for HBV-related cirrhosis.  Hepatology. 2002;  35 176-181
• 91 Bienzle U, Gunther M, Neuhaus R, Neuhaus P. Successful hepatitis B vaccination in patients who underwent transplantation for hepatitis B virus-related cirrhosis: preliminary results.  Liver Transpl. 2002;  8 562-564
• 92 Lo C M, Liu C L, Chan S C, Lau G K, Fan S T. Failure of hepatitis B vaccination in patients receiving lamivudine prophylaxis after liver transplantation for chronic hepatitis B.  J Hepatol. 2005;  43 283-287
• 93 Bock C T, Tillmann H L, Torresi J et al.. Selection of hepatitis B virus polymerase mutants with enhanced replication by lamivudine treatment after liver transplantation.  Gastroenterology. 2002;  122 264-273
• 94 Fung S K, Andreone P, Han S H et al.. Adefovir-resistant hepatitis B can be associated with viral rebound and hepatic decompensation.  J Hepatol. 2005;  43 937-943
• 95 Singh N, Gayowski T, Wannstedt C F et al.. Interferon-alpha for prophylaxis of recurrent viral hepatitis C in liver transplant recipients: a prospective, randomized, controlled trial.  Transplantation. 1998;  65 82-86
• 96 Shergill A K, Khalili M, Straley S et al.. Applicability, tolerability and efficacy of preemptive antiviral therapy in hepatitis C-infected patients undergoing liver transplantation.  Am J Transplant. 2005;  5 118-124