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Treatment of Recurrent Hepatitis C in Liver Transplant Recipients

2005; Elsevier BV; Volume: 3; Linguagem: Inglês

10.1016/s1542-3565(05)00709-3

1542-7714

N.A. Terrault,

Liver Disease and Transplantation

The course of hepatitis C is accelerated after transplantation, with an average of 25% of patients developing cirrhosis within 5 years of transplantation. Consequently, the 5- and 10-year graft survival rates in hepatitis C virus (HCV)-infected patients are significantly lower than in HCV-uninfected patients. Therapeutic interventions to prevent HCV recurrence and/or alter the rate of disease progression after transplantation are desirable. Prophylactic therapy in the form of polyclonal HCV antibodies has not been effective at prevention of HCV re-infection, but one study suggests that higher-dose therapy may modify the severity of early disease recurrence. Pre-emptive antiviral therapy has modest efficacy and generally is poorly tolerated. Live donor liver transplant recipients and recipients with low model of end-stage liver disease scores pretransplantation may tolerate pre-emptive therapy best. The treatment of recurrent established disease with a combination of interferon and ribavirin has been the mainstay of management. Similar to pre-emptive therapy, tolerance is reduced and dose reductions are frequent. The sustained virologic response rates are less than 45% in studies to date. Histologic and biochemical improvements generally are more frequent than virologic responses. Overall, the treatment of HCV disease in transplant recipients leaves much to be desired and there is an urgent need of new HCV therapies in this patient population. The course of hepatitis C is accelerated after transplantation, with an average of 25% of patients developing cirrhosis within 5 years of transplantation. Consequently, the 5- and 10-year graft survival rates in hepatitis C virus (HCV)-infected patients are significantly lower than in HCV-uninfected patients. Therapeutic interventions to prevent HCV recurrence and/or alter the rate of disease progression after transplantation are desirable. Prophylactic therapy in the form of polyclonal HCV antibodies has not been effective at prevention of HCV re-infection, but one study suggests that higher-dose therapy may modify the severity of early disease recurrence. Pre-emptive antiviral therapy has modest efficacy and generally is poorly tolerated. Live donor liver transplant recipients and recipients with low model of end-stage liver disease scores pretransplantation may tolerate pre-emptive therapy best. The treatment of recurrent established disease with a combination of interferon and ribavirin has been the mainstay of management. Similar to pre-emptive therapy, tolerance is reduced and dose reductions are frequent. The sustained virologic response rates are less than 45% in studies to date. Histologic and biochemical improvements generally are more frequent than virologic responses. Overall, the treatment of HCV disease in transplant recipients leaves much to be desired and there is an urgent need of new HCV therapies in this patient population. If hepatitis C virus (HCV) infection is not eradicated before transplantation, re-infection occurs in essentially 100% of patients. In follow-up studies of 5 or more years, the outcomes of HCV-positive transplant recipients are worse than HCV-negative recipients, with a significant reduction in both patient and graft survival rates.1Forman L.M. Lewis J.D. Berlin J.A. et al.The association between hepatitis C infection and survival after orthotopic liver transplantation.Gastroenterology. 2002; 122: 889-896Abstract Full Text Full Text PDF PubMed Scopus (944) Google Scholar The risk for graft loss at 5 years is 30% higher in HCV-positive patients compared with HCV-negative patients.1Forman L.M. Lewis J.D. Berlin J.A. et al.The association between hepatitis C infection and survival after orthotopic liver transplantation.Gastroenterology. 2002; 122: 889-896Abstract Full Text Full Text PDF PubMed Scopus (944) Google Scholar The rate of disease progression is variable, but approximately 25% (range, 8%–44%) will develop recurrent cirrhosis within 5–7 years of transplantation.2Berenguer M. Ferrell L. Watson J. et al.HCV-related fibrosis progression following liver transplantation increase in recent years.J Hepatol. 2000; 32: 673-684Abstract Full Text Full Text PDF PubMed Scopus (688) Google Scholar, 3Feray 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: 619-625Abstract Full Text Full Text PDF PubMed Scopus (345) Google Scholar, 4Gane E. Portmann B. Naoumov N. et al.Long-term outcome of hepatitis C infection after liver transplantation.N Engl J Med. 1996; 334: 815-820Crossref PubMed Scopus (943) Google Scholar, 5Neumann U. Berg T. Bahra M. et al.Fibrosis progression after liver transplantation in patients with recurrent hepatitis C.J Hepatol. 2004; 41: 830-836Abstract Full Text Full Text PDF PubMed Scopus (311) Google Scholar, 6Prieto M. Berenguer M. Rayon J. et al.High incidence of allograft cirrhosis in hepatitis C virus genotype 1b infection following transplantation relationship with rejection episodes.Hepatology. 1999; 29: 250-256Crossref PubMed Scopus (485) Google Scholar The estimated average time to cirrhosis is 8–12 years, based on cohort studies published to date and once cirrhosis occurs, the risk for decompensation is 40% within the next year.7Berenguer M. Prieto M. Rayon J.M. et al.Natural history of clinically compensated hepatitis C virus-related graft cirrhosis after liver transplantation.Hepatology. 2000; 32: 852-858Crossref PubMed Scopus (489) Google Scholar A worsening of graft and patient survival rates over time has been identified. The use of newer and more potent immunosuppressive agents,8Samonakis D.N. Triantos C.K. Thalheimer U. et al.Immunosuppression and donor age with respect to severity of HCV recurrence after liver transplantation.Liver Transpl. 2005; 11: 386-395Crossref PubMed Scopus (95) Google Scholar and the increasing use of older donors, particularly those over 40 years of age, are possible explanations for this cohort effect.5Neumann U. Berg T. Bahra M. et al.Fibrosis progression after liver transplantation in patients with recurrent hepatitis C.J Hepatol. 2004; 41: 830-836Abstract Full Text Full Text PDF PubMed Scopus (311) Google Scholar, 9Berenguer 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: 202-210Crossref PubMed Scopus (572) Google Scholar, 10Lake J.R. Shorr J.S. Steffen B.J. et al.Differential effects of donor age in liver transplant recipients infected with hepatitis B, hepatitis C and without viral hepatitis.Am J Transplant. 2005; 5: 549-557Crossref PubMed Scopus (160) Google ScholarGiven the variable natural history, there is a need to identify transplant recipients at greatest risk for graft loss caused by recurrent disease. The factors associated most consistently with risk for fibrosis progression and development of cirrhosis include donor age, female sex, fibrosis within 1 year posttransplantation, high pretransplant viral load, treated acute cellular rejection, presence of cytomegalovirus infection, non-Caucasian race, and recipient age (Table 1).2Berenguer M. Ferrell L. Watson J. et al.HCV-related fibrosis progression following liver transplantation increase in recent years.J Hepatol. 2000; 32: 673-684Abstract Full Text Full Text PDF PubMed Scopus (688) Google Scholar, 5Neumann U. Berg T. Bahra M. et al.Fibrosis progression after liver transplantation in patients with recurrent hepatitis C.J Hepatol. 2004; 41: 830-836Abstract Full Text Full Text PDF PubMed Scopus (311) Google Scholar, 11Rosen H. Shackleton C. Higa L. et al.Use of OKT3 is associated with early and severe recurrence of hepatitis C after liver transplantation.Am J Gastroenterol. 1997; 92: 1453-1457PubMed Google Scholar, 12Firpi 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: 1240-1247Crossref PubMed Scopus (148) Google Scholar, 13Charlton M. Seaberg E. Wiesner R. et al.Predictors of patient and graft survival following liver transplantation for hepatitis C.Hepatology. 1998; 28: 823-830Crossref PubMed Scopus (510) Google Scholar Whether recipients of live donor allografts are at risk for earlier and more severe HCV recurrence than deceased donor transplant recipients is unclear.14Shiffman M. Stravitz R. Contos M. et al.Histologic recurrence of chronic hepatitis C virus in patients after living donor and deceased donor liver transplantation.Liver Transpl. 2004; 10: 1248-1255Crossref PubMed Scopus (123) Google Scholar, 15Garcia-Retortillo M. Forns X. Llovet J. et al.Hepatitis C recurrence is more severe after living donor compared to cadaveric liver transplantation.Hepatology. 2004; 40: 699-707Crossref PubMed Scopus (167) Google Scholar, 16Thuluvath P. Yoo H. Graft and patient survival after adult live donor liver transplantation compared to a matched cohort who received a deceased donor transplantation.Liver Transpl. 2004; 10: 1263-1268Crossref PubMed Scopus (122) Google Scholar, 17Russo M. Galanko J. Beavers K. et al.Patient and graft survival in hepatitis C recipients after adult living donor liver transplantation in the United States.Liver Transpl. 2004; 10: 340-346Crossref PubMed Scopus (99) Google Scholar, 18Gaglio P. Malireddy S. Levitt B. et al.Increased risk of cholestatic hepatitis C in recipients of grafts from living versus cadaveric liver donors.Liver Transpl. 2003; 9: 1028-1035Crossref PubMed Scopus (107) Google Scholar In the only 2 studies using protocol biopsy procedures to assess disease severity and progression, widely disparate results were reported.14Shiffman M. Stravitz R. Contos M. et al.Histologic recurrence of chronic hepatitis C virus in patients after living donor and deceased donor liver transplantation.Liver Transpl. 2004; 10: 1248-1255Crossref PubMed Scopus (123) Google Scholar, 15Garcia-Retortillo M. Forns X. Llovet J. et al.Hepatitis C recurrence is more severe after living donor compared to cadaveric liver transplantation.Hepatology. 2004; 40: 699-707Crossref PubMed Scopus (167) Google ScholarTable 1Factors Associated With Increased Risk for Fibrosis Progression or CirrhosisDonorRecipientDisease-specificExternalAge >40 yAgePretransplant viral loadTreated acute rejectionNon-Caucasian raceHigh HAI score at 3 and 12 moCMV infectionFemale sexPresence of fibrosis at 1 year after liver transplantationHAI, histologic activity index; CMV, cytomegalovirus. Open table in a new tab For those with recurrent cirrhosis, retransplantation may be the only option. The outcome of patients with HCV is worse than those transplanted for other indications,19Rosen H.R. Martin P. Hepatitis C infection in patients undergoing liver retransplantation.Transplantation. 1998; 66: 1612-1616Crossref PubMed Scopus (132) Google Scholar with 1-year patient survival rates of as low as 50% in some series.20Neff G. O'Brien C. Nery J. et al.Factors that identify survival after liver retransplantation for allograft failure caused by recurrent hepatitis C infection.Liver Transpl. 2004; 10: 1497-1503Crossref PubMed Scopus (62) Google Scholar Consequently, retransplantation for recurrent HCV disease is an increasingly controversial indication.21Biggins S. Terrault N. Should HCV-related cirrhosis be a contraindication for retransplantation?.Liver Transpl. 2003; 9: 236-238Crossref PubMed Scopus (26) Google ScholarManagement of Hepatitis C Virus in the Liver Transplant SettingGiven this accelerated natural history and heightened risk for graft loss caused by recurrent HCV cirrhosis, increased attention has been focused on interventions that can prolong graft survival. The association with older donor age and worse outcomes for HCV patients suggests that HCV transplant recipients would benefit from younger donors (age <50 y) but the current donor-organ shortage does not make this feasible. Much has been discussed regarding the importance of immunosuppression as a contributing factor for disease progression. However, despite numerous studies, no single immunosuppressive drug has been linked consistently with risk for progressive disease and the optimal immunosuppressive regime has not been defined. The use of corticosteroid boluses and lymphocyte-depleting drugs to treat acute rejection has been associated with a higher risk for cirrhosis. Excessive immunosuppressive or rapid changes in immunosuppression, as seen with treatment of acute rejection, appear to be of importance. The International Liver Transplantation Society consensus report emphasized the need for sufficient immunosuppression to prevent acute and chronic rejection but to minimize the use of excessive immunosuppression that may be detrimental to HCV disease.22Wiesner R. Sorrell M. Villamil F. International Liver Transplantation Society Expert PanelReport of the first International Liver Transplantation Society expert panel consensus conference on liver transplantation and hepatitis C.Liver Transpl. 2003; 9: S1-S9Crossref PubMed Scopus (402) Google ScholarBecause the majority of the donor, recipient, and external factors linked with an increased risk for cirrhosis are not modifiable (Table 1), therapies to prevent HCV recurrence or to modify the rate of disease progression are essential. There has been increasing interest in undertaking treatment of HCV infection in patients awaiting transplantation as eradication of HCV before transplantation eliminates the problem of recurrent disease posttransplantation. However, for the majority of cirrhotic patients awaiting transplantation, antiviral therapy is not an option because of the advanced nature of their liver disease23Crippin J.S. McCashland T. Terrault N. et al.A pilot study of the tolerability and efficacy of antiviral therapy in hepatitis C virus-infected patients awaiting liver transplantation.Liver Transpl. 2002; 8: 350-355Crossref PubMed Scopus (310) Google Scholar or the treatment is ineffective in achieving viral eradication.24Everson G. Treatment of patients with hepatitis C virus on the waiting list.Liver Transpl. 2003; 9: S90-S94Crossref PubMed Scopus (62) Google Scholar For viremtic individuals, recurrent infection will develop in essentially all individuals after transplantation and alternative management strategies are needed. The potential time points to prevent or modify the risk for recurrent HCV disease among these HCV-infected transplant patients are as follows: (1) prophylactic therapy (starting at time of transplantation); (2) pre-emptive therapy (started in the early posttransplant period); and (3) treatment of recurrent histologic disease (Table 2). The latter approach has been the most frequent method of managing HCV-infected transplant recipients.Table 2Treatment Options for HCV-Infected Liver Transplant RecipientsTiming/TypeDefinition of TherapyPre-transplantationInitiated before transplantation with goal of achieving an SVR before transplantation. Whether a reduced HCV RNA level on treatment and at time of transplantation can reduce the risk for recurrent disease is unknown.ProphylacticInitiated at the time of transplantation and continued posttransplantation with the goal of preventing recurrent infection.Pre-emptiveInitiated early in the posttransplant period (typically within the first 8 weeks) before the evidence of onset of biochemical and histologic disease.Posttransplantation (delayed)Initiated after biochemical and histological evidence of recurrent (and typically progressive) disease are evident.SVR, sustained virologic response. Open table in a new tab The International Liver Transplantation Society consensus statement recommended that, at a minimum, HCV-infected transplant recipients with stage 2 higher fibrosis be considered for treatment with interferon and ribavirin.22Wiesner R. Sorrell M. Villamil F. International Liver Transplantation Society Expert PanelReport of the first International Liver Transplantation Society expert panel consensus conference on liver transplantation and hepatitis C.Liver Transpl. 2003; 9: S1-S9Crossref PubMed Scopus (402) Google Scholar Surveys of clinical practices regarding management of chronic HCV in transplant recipients show a trend toward earlier initiation of antiviral therapy after transplantation, with an increasing number of programs starting treatment once recurrent HCV disease is documented.25Khalili M. Vardanian A. Hamerski C. et al.Clinical management of hepatitis C-infected transplant recipients in North American transplant centers changes in recent years.Clin Transpl. 2005Google ScholarProphylactic TherapyHepatitis B immune globulin has been an effective means of preventing hepatitis B virus re-infection after liver transplantation. A similar approach has been examined for HCV. There are indirect data from a cohort study of hepatitis B virus–HCV co-infected patients that receipt of hepatitis B immune globulin before screening of HCV in blood donors was associated with lower rates of recurrent HCV.26Feray 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: 810-816Crossref PubMed Scopus (129) Google Scholar This suggested the polyclonal immunoglobulins contained HCV antibodies that could prevent HCV infection. Neutralizing HCV antibodies have been associated with reduced frequency of acute infection in chimpanzees and human beings.27Yu M.Y. Bartosch B. Zhang P. et al.Neutralizing antibodies to hepatitis C virus (HCV) in immune globulins derived from anti-HCV-positive plasma.Proc Natl Acad Sci U S A. 2004; 101: 7705-7710Crossref PubMed Scopus (134) Google Scholar, 28Lavillette D. Morice Y. Germanidis G. et al.Human serum facilitates hepatitis C virus infection, and neutralizing responses inversely correlate with viral replication kinetics at the acute phase of hepatitis C virus infection.J Virol. 2005; 79: 6023-6034Crossref PubMed Scopus (236) Google Scholar, 29Krawczynski K. Alter M. Tankersley D. et al.Effect of immune globulin on the prevention of experimental hepatitis C virus infection.J Infect Dis. 1996; 173: 822-828Crossref PubMed Scopus (173) Google Scholar In a model of acute hepatitis C, chimpanzees (N = 2) treated with hepatitis C immune globulin (HCIG) at doses of 100 mg/kg at 1 or 24 hours after HCV inoculation and twice weekly infusions for 13 weeks, had delayed detection of HCV RNA and alanine transaminase (ALT) levels remained normal during the period of infusions in treated chimpanzees compared with control chimpanzees given intravenous immune globulin infusions.29Krawczynski K. Alter M. Tankersley D. et al.Effect of immune globulin on the prevention of experimental hepatitis C virus infection.J Infect Dis. 1996; 173: 822-828Crossref PubMed Scopus (173) Google Scholar After discontinuation of the HCIG infusions, 1 of the 2 chimpanzees developed acute hepatitis but infection was prevented in the other chimpanzee.29Krawczynski K. Alter M. Tankersley D. et al.Effect of immune globulin on the prevention of experimental hepatitis C virus infection.J Infect Dis. 1996; 173: 822-828Crossref PubMed Scopus (173) Google Scholar These studies provided the rationale for testing the efficacy of HCV antibodies in preventing HCV re-infection after transplantation.To date, 2 studies using HCIG have been completed and a third study using fully humanized monoclonal antibodies (HepeX-C; XTL Biopharmaceuticals, Rhovet, Israel) is underway. The first study from Canada, using HCIG (Cangene Corp, Winnipeg, Canada) at two different doses 500 mg anhepatic phase, 250 mg daily for 10 days, 75 mg every 2 weeks for a total of 48 weeks and (1500 mg anhepatic phase, 750 mg daily for 10 days, and 250 mg every 2 weeks for a total of 48 weeks) found no protective effects. All 16 treated patients developed recurrent HCV infection and there was no difference in the time-course of viremia between treated patients and untreated controls.30Willems B. Marotta P. Greig P.D. et al.Anti-HCV immunoglobulins for the prevention of graft infection in HCV-related liver transplantation.J Hepatol. 2002; 36: S96AAbstract Full Text PDF Google Scholar A second study from the United States used higher doses (200 mg/kg and 75 mg/kg) of HCIG (Civacir, NABI Inc, Boca Raton, FL) and treated patients for 14 weeks posttransplantation. Similar to the Canadian study, all transplant recipients developed recurrent HCV posttransplantation and there was no demonstrable effect of treatment on HCV RNA levels in serum.31Davis G. 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: 941-949Crossref PubMed Scopus (154) Google Scholar However, patients receiving HCIG therapy had lower mean ALT levels throughout the first 6–10 weeks compared with untreated controls. In the higher-dose HCIG group, the ALT levels were in the normal range throughout the treatment period and correlated with less necroinflammation on biopsy examination. These results suggest that HCIG may reduce hepatic inflammation, possibly by masking viral antigens and thereby reducing host-mediated cell damage.Based on results to date, HCIG does not appear to be effective in preventing HCV re-infection. The US HCIG study found that higher doses of HCIG were associated with lower ALT levels and less necroinflammation on biopsy examination, suggesting that HCIG may modify the severity of HCV recurrence. These findings require confirmation. The results of the ongoing HCV monoclonal antibody study (HepeX-C) are awaited.Pre-emptive Antiviral TherapyStudies have shown that pre-emptive antiviral therapy can lead to eradication of HCV infection posttransplantation, but tolerability of therapy has been limiting. Additionally, not all transplant recipients are candidates for pre-emptive therapy. In a University of California San Francisco study of 110 consecutive patients transplanted for HCV, only 60% were candidates for pre-emptive antiviral therapy by the 8th week posttransplantation and patients with a low pretransplant model of end-stage liver disease (MELD) and Child–Pugh–Turcotte scores and those who were live donor recipients were most suitable for early initiation of therapy.32Shergill A. Khalili M. Straley S. et al.Applicability, tolerability and efficacy of preemptive anviral therapy in hepatitis C infected patients undergoing liver transplantation.Am J Transplant. 2005; 5: 118-124Crossref PubMed Scopus (171) Google Scholar Finally, whether pre-emptive antiviral therapy offers advantages over treatment initiated later after transplantation when recurrent disease is established is unclear.Clinical trials using pre-emptive interferon monotherapy,32Shergill A. Khalili M. Straley S. et al.Applicability, tolerability and efficacy of preemptive anviral therapy in hepatitis C infected patients undergoing liver transplantation.Am J Transplant. 2005; 5: 118-124Crossref PubMed Scopus (171) Google Scholar, 33Sheiner P. Boros P. Klion F. et al.The efficacy of prophylactic interferon alfa-2b in preventing recurrent hepatitis C after liver transplantation.Hepatology. 1998; 28: 831-838Crossref PubMed Scopus (197) Google Scholar, 34Singh 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: 82-86Crossref PubMed Scopus (154) Google Scholar, 35Chalasani N. Manzarbeitia C. Ferenci P. et al.Peginterferon alfa-2a for hepatitis C after liver transplantation two randomized, controlled trials.Hepatology. 2005; 41: 289-298Crossref PubMed Scopus (256) Google Scholar although generally positive, show a modest benefit with sustained virologic responses obtained in less than 20% (Table 3). Rates of response generally are higher with combination therapy32Shergill A. Khalili M. Straley S. et al.Applicability, tolerability and efficacy of preemptive anviral therapy in hepatitis C infected patients undergoing liver transplantation.Am J Transplant. 2005; 5: 118-124Crossref PubMed Scopus (171) Google Scholar, 36Mazzaferro 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: 1355-1357Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar, 37Sugawara Y. Makuuchi M. Matsui Y. et al.Preemptive therapy for hepatitis C virus after living-donor liver transplantation.Transplantation. 2004; 78: 1308-1311Crossref PubMed Scopus (102) Google Scholar than with interferon monotherapy, so the former would be the treatment of choice for pre-emptive therapy. Both response rates and tolerability of combination antiviral therapy vary from study to study. In an uncontrolled study from Italy, 36 patients (83% genotype 1b) were treated with combination standard interferon alfa 2b 3 MU 3 times weekly and ribavirin 10 mg/kg/day, with treatment initiated within 3 weeks after transplantation and continued for 52 weeks.36Mazzaferro 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: 1355-1357Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar The overall sustained virologic response (SVR) was 33% with normalization of serum transaminase levels and histology in responders. Viral clearance was more frequent in patients with non-1 HCV genotypes (100%) compared with those with genotype 1b (20%). In contrast to the Italian experience, a US study of pre-emptive therapy using interferon or peginterferon alfa-2b, 3 million units 3 times weekly or 1.5 μg/kg per week, as monotherapy or in combination with ribavirin, 600 mg daily increasing to 1.0–1.2 g daily, for a total of 48 weeks, reported a SVR rate of only 9% (18% with combination therapy vs 5% with monotherapy).32Shergill A. Khalili M. Straley S. et al.Applicability, tolerability and efficacy of preemptive anviral therapy in hepatitis C infected patients undergoing liver transplantation.Am J Transplant. 2005; 5: 118-124Crossref PubMed Scopus (171) Google Scholar Dose reductions and discontinuations were required in 85% and 37% of patients, respectively. Tolerability of pre-emptive therapy will be influenced by the clinical status of the patients in the early posttransplant period. Sicker patients and those with postoperative complications will be less likely to tolerate early initiation of posttransplant antiviral therapy. Live donor liver transplant recipients because they are generally less sick prior to transplantation may be good candidates for pre-emptive treatment. A recent Japanese study of 23 live donor liver transplant recipients treated with pre-emptive interferon plus ribavirin found a 39% SVR rate; however, drug discontinuation or dose reductions were required in 57% of patients.37Sugawara Y. Makuuchi M. Matsui Y. et al.Preemptive therapy for hepatitis C virus after living-donor liver transplantation.Transplantation. 2004; 78: 1308-1311Crossref PubMed Scopus (102) Google ScholarTable 3Pre-emptive Treatment of HCV in Liver Transplant RecipientsStudyStudy typeNTreatment regimenTime to treatment (wk)SVRHistologic responseDose reduction or discontinuationSingh et al,34Singh 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: 82-86Crossref PubMed Scopus (154) Google Scholar 1998RCT12 treated, 12 controlIFN, 3 MU 3 times/ wk × 6 mo vs no treatment20% both groupsNo difference in severity50%Sheiner et al,33Sheiner P. Boros P. Klion F. et al.The efficacy of prophylactic interferon alfa-2b in preventing recurrent hepatitis C after liver transplantation.Hepatology. 1998; 28: 831-838Crossref PubMed Scopus (197) Google Scholar 1998RCT35 IFN, 46 no treatmentIFN 3 MU 3 times/wk × 6 mo vs no treatment317% IFN vs 5% no treatmentFewer with recurrence at 1 and 2 years in IFN group28% treatment discontinuationMazzaferro et al,36Mazzaferro 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: 1355-1357Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar 2001Uncontrolled36IFN 3 MU 3 times/wk + RBV 10 mg/kg/day for 12 mo333%Normal histology in virologic responders47%Sugawara et al,37Sugawara Y. Makuuchi M. Matsui Y. et al.Preemptive therapy for hepatitis C virus after living-donor liver transplantation.Transplantation. 2004; 78: 1308-1311Crossref PubMed Scopus (102) Google Scholar 2004RCT (2 different treatment protocols) LDLT recipients only23IFN (3 MU → 6 MU 3 times/wk) + RBV (600 mg/day) × ≥72 mo439%Scores lower in responders57%Shergill et al,32Shergill A. Khalili M. Straley S. et al.Applicability, tolerability and efficacy of preemptive anviral therapy in hepatitis C infected patients undergoing liver transplantation.Am J Transplant. 2005; 5: 118-124Crossref PubMed Scopus (171) Google Scholar 2005RCT (2 different treatment arms)47IFN/PEG-IFN alone vs IFN/PEG-IFN + RBV × 48 wk≤6 wk9% overall (18% combination, vs 5% IFN monotherapy)NA85% dose reductions 37% treatment discontinuationChalasani et al,35Chalasani N. Manzarbeitia C. Ferenci P. et al.Peginterferon alfa-2a for hepatitis C after liver transplantation two randomized, controlled trials.