Currently, the leading indication for liver transplantation

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1 ORIGINAL ARTICLES Severe Recurrent Hepatitis C After Liver Retransplantation for Hepatitis C Virus Related Graft Cirrhosis Marina Berenguer, * Martín Prieto, * Antonio Palau, * José M. Rayón, Domingo Carrasco, * Fernando San Juan, F-Xavier López-Labrador, Rosalba Moreno, * José Mir, and Joaquín Berenguer * An increase in the number of hepatitis C virus (HCV)- infected transplant recipients at need for repeated liver transplantation is anticipated. To date, there is a certain reluctance to accept these patients because of an increased organ shortage, early reports suggesting a poor outcome, and uncertainty regarding the natural history of recurrent hepatitis C in the second graft. The aim of this study is to determine the outcome of patients undergoing retransplantation for HCV-related graft cirrhosis. Of 49 transplant recipients with HCV-related allograft cirrhosis, 31 patients developed decompensation with criteria for retransplantation. Thirteen patients were denied this option. Of the 18 patients accepted, 6 patients died while on the waiting list (5 patients died of graft cirrhosis at a median of 3.2 months of listing), and 12 patients have undergone retransplantation (median, 10 months since HCV cirrhosis). After retransplantation, 8 patients (67%) died at a median of 8 months, and 4 patients (33%) remain alive after 1.9 years of follow-up. Causes and times of death from retransplantation were: surgical complications, n 3 (perioperative period); HCV cirrhosis of the second graft, n 2 (at 9 and 54 months); fibrosing cholestatic hepatitis, n 1 (at 2 years); lymphoproliferative disorder, n 1 (at 7 months); and endocarditis, n 1 (at 3.5 years, with underlying cirrhosis). Of the 4 patients alive, fibrosis stages in the last specimens are stage 1(n 1), stage 3 (n 1), and stage 4 or cirrhosis (n 1; one patient has not undergone ), despite antiviral therapy. The outcome of retransplantation for HCV cirrhosis of the first graft is very poor because of multiple complications. The severity of recurrent HCV disease in the second graft seems to be related to that observed in the first graft. (Liver Transpl 2003;9: ) From the *HepatoGastroenterology Service, Pathology Service, Liver Transplantation and Surgery Unit, and Microbiology Service, Hospital Universitari La Fe, Valencia, Spain. Supported in part by contract no. 99/3101 from the Fondo de Investigación Sanitaria. Instituto de Salud Carlos III (F-X.L-L.). Address reprint requests to Marina Berenguer, MD, Servicio de Medicina Digestiva, Hospital Universitario La Fe, Avda Campanar 21, Valencia 46009, Spain. Telephone: ; FAX: ; mbhaym@teleline.es Copyright 2003 by the American Association for the Study of Liver Diseases /03/ $30.00/0 doi: /jlts Currently, the leading indication for liver transplantation is hepatitis C virus (HCV)-related endstage liver disease. Unfortunately, infection recurs in virtually all patients. Although short-term survival after liver transplantation for HCV infection is similar to that obtained with other indications, emerging data show that the longterm outcome is not as benign as previously believed. 1,2 Infection of the graft leads to the development of histological hepatitis in the vast majority of patients, with progression to cirrhosis in 10% to 30% of patients at 5 years posttransplantation. 1,3-9 In addition, recent data have shown that disease progression has a median time to reach the stage of graft cirrhosis estimated at only 9 to 12 years and is more aggressive and accelerated compared with the natural history of primary chronic HCV infection observed in immunocompetent patients. 9 The high aggressiveness of hepatitis C in the transplant setting also is evident after cirrhosis is established, shown by a shortened clinical course of clinically compensated HCV-related graft cirrhosis. In one recent study from our group, the 1-year actuarial risk for decompensation was 42%, significantly greater than the 28% at 10 years in nontransplantation cirrhotic patients with HCV infection. 10 Finally, in a small number of patients ( 5%), an accelerated course of liver injury leading to rapid development of liver failure has been observed, 11 reminiscent of that previously described in hepatitis B virus infected transplant recipients with fibrosing cholestatic hepatitis. Unfortunately, effective prophylactic therapies to prevent recurrence are lacking, and current antiviral therapies have shown only limited efficacy in the treatment of posttransplantation HCV disease. 12 Together, these data explain the reduced graft and patient survival compared with patients who undergo transplantation for nonviral causes that recently was reported 1,2 and are evidenced by the progressive increase in number of patients infected with HCV in need of retransplantation. 13 With the prospect of this 228 Liver Transplantation, Vol 9, No 3 (March), 2003: pp

2 Hepatitis C After Retransplantation 229 Figure 1. Follow-up of patients with HCV-related graft cirrhosis (WL, waiting list.) increase, it has become imperative to determine whether all patients with graft failure caused by recurrent HCV disease are candidates for further transplantation. To date, there is a certain reluctance to accept these patients for retransplantation, particularly those who have developed aggressive recurrent disease leading to graft failure in a short period. The reluctance to perform retransplantation on these patients is related to four major issues: (1) earlier reports suggesting worse outcome after retransplantation in HCV-infected transplant recipients than in those not infected, (2) uncertainty regarding the natural history of recurrent hepatitis C in the second graft, (3) advanced age of the recipient because most received their first transplant in their late 50s and early 60s, and (4) increased organ shortage. However, more recent data have shown improved outcome when retransplantation is performed before the development of infectious and renal complications. 13,16,17 One remaining concern is whether the severity of recurrent HCV disease in the second graft is related to that observed in the first graft. Clarification of this issue will be helpful for the development of a consensus regarding retransplantation for patients with graft failure caused by recurrent HCV. The aim of this study is to determine the outcome of HCV-infected transplant recipients undergoing retransplantation for HCV graft cirrhosis. Because we routinely perform protocol annual liver biopsies in HCV-infected transplant recipients, we are interested in evaluating histological outcome in these patients. Patients and Methods Patients Between January 5, 1991, and December 1999, a total of 557 patients underwent 598 orthotopic liver transplantations at our institution. Two hundred eighty-five of these patients underwent transplantation for cirrhosis secondary to chronic HCV infection, defined by the presence of antibody to HCV by enzyme immunoassay (EIA)-II and confirmed by recombinant immunoblot assay (RIBA)-II assay. Using annual protocol biopsies, cirrhosis of the graft caused by recurrent hepatitis C was detected in 49 patients. 5 These patients were included in a previous study aimed at describing the natural history of posttransplantation clinically compensated HCV graft cirrhosis. 5 Figure 1 shows the clinical course of these 49 patients (27 men, 22 women; median age at transplantation, 56 years; range, 25 to 66 years). Overall, 18 patients (37%) continued to have compensated cirrhosis after a median of 3.5 years from diagnosis, of whom only 2 patients have died (11%; hepatocellular carcinoma recurrence, n 1; compli-

3 230 Berenguer et al cations from renal failure, n 1). The clinical course of the 31 patients with decompensated cirrhosis and, more specifically, that of the18 patients listed for retransplantation, is reviewed, whereas the other 13 patients were not considered suitable for relisting. Follow-Up All patients undergoing retransplantation were evaluated clinically and biochemically monthly and histologically at yearly intervals or when considered necessary. Follow-up was terminated at the time of either death of the patient or end of the observation period (May 2002). Criteria applied for placement on the waitlist for retransplantation were similar to those for the original listing. However, patients with aggressive disease requiring retransplantation within less than 1 year after the original transplantation (excluding those with fibrosing cholestatic hepatitis) were not considered suitable for retransplantation based on arbitrarily established guidelines. Antiviral Therapy Before 1999, preemptive therapy after retransplantation was not considered a therapeutic option. After that date, attempts were made in all cases to introduce antiviral therapy as soon as possible after retransplantation. In all cases, interferon alfa-2b was administered in combination with ribavirin at doses tolerated by the patient. If possible, standard doses of interferon alfa-2b (3 million units thrice weekly) and ribavirin (1,000 mg/d) were used. Both erythropoietin and granulocyte-stimulating growth factor were administered at the discretion of the hepatologist in charge. Histological Assessment Protocol liver biopsies were performed yearly after retransplantation. Additional liver biopsies were performed for unexplained abnormalities in liver test results (serum aminotransferase values at least 1.5 times the upper limit of normal) and when otherwise clinically indicated. All specimens were reviewed by a single pathologist (J.M.R.) in a blinded fashion. Specimens were scored as previously described, differentiating histological grade (activity) from histological stage (fibrosis). 4 Grade was determined by combining histological activity index scores for periportal necrosis, scored 0 to 6 (0, none; 1, mild piecemeal necrosis; 3, moderate piecemeal necrosis; 4, marked piecemeal necrosis; 5, moderate piecemeal necrosis plus bridging necrosis; 6, marked piecemeal necrosis plus bridging necrosis), lobular degeneration and necrosis (0 to 4), and portal inflammation (0 to 4) and is defined as follows: 1 to 2, minimal; 3 to 6, mild; 7 to 10, moderate; 11 to 14, severe. Serological and Virological Assays Antibody to HCV testing, HCV RNA detection, and genotyping were determined as previously described. 4 HCV RNA quantitation was performed when a well-preserved sample was available using the Amplicor HCV Monitor 2.0 tes t (Roche Diagnostics, Indianapolis, IN). To avoid underestimation of viral loads in the high end of the dynamic range of the assay ( 700,000 IU/mL), samples were diluted 1:10 or 1:100 before testing. When diluted samples gave negative values, the assay was repeated without dilution. Results Evolution of Decompensated Cirrhotic Patients Of 31 patients with decompensated cirrhosis, 13 patients were not found suitable for retransplantation for the following reasons: extremely aggressive course of recurrent hepatitis C (n 4), age older than 65 years (n 2), severe associated comorbidities (n 3), and stabilization (n 4). Only the latter 4 patients are alive after a median of 33 months (range, 14 to 40 months) since decompensation (39 months [range, 30 to 51 months] since diagnosis of cirrhosis). The other 9 patients died of complications of their graft cirrhosis (n 7; 78%), sepsis (n 1; 11%), and other problems (n 1; 11%). Of the 18 patients placed on the waiting list, 12 patients have undergone retransplantation at a median of 10 months (range, 7 days to 56 months) since diagnosis of recurrent HCV cirrhosis in the graft. The 6 patients on the waiting list who did not receive a second graft died of complications from the graft cirrhosis. Characteristics of Patients Undergoing Retransplantation Main characteristics of the 12 patients undergoing liver retransplantation are listed in Table 1. In all patients, genotype was HCV 1b. In 6 of these 12 patients, adequate samples were available to determine viral load at the time of retransplantation, which ranged from 184,655 to 6,908,824 IU/mL. Immunosuppression consisted of: (1) dual therapy with cyclosporine and methylprednisolone administered intravenously, with tapering of the dose from 200 to 20 mg at day 6, at which time steroids were switched to oral prednisone (n 5); (2) dual therapy with tacrolimus and methylprednisolone (n 4); (3) standard triple therapy with cyclosporine, azathioprine (1 to 2 mg/kg/d), and methylprednisolone (n 1); or (4) triple therapy with cyclosporine, basiliximab, and methylprednisolone (n 2). Two of the 12 patients (16%) had creatinine levels greater than 2 mg/dl, whereas 4 patients (33%) had bilirubin levels greater than 10 mg/dl, levels associated with poor survival at the time of retransplantation. 17

4 Hepatitis C After Retransplantation 231 Table 1. Liver Retransplantation for End-Stage HCV-Related Graft Disease: Patient Baseline Features Patient No. Age at re- (yr) Sex Date at Re- Time Between and Re- (mo) Time Between Listing and Re- (d) Child- Pugh at Listing/ Re- Diagnosis at Re- Donor Age (yr) Creatinine at Re- (mg/dl) Bilirubin at Re- (mg/dl) MELD Score at Re- Viral Load at re- (IU/mL) 1 51 M 03/20/ /11 Cirrhosis , F 01/29/ /8 FCH NA 3 57 F 08/18/ /14 Cirrhosis NA 4 42 M 08/28/ /9 Cirrhosis ,908, M 12/30/ /11 Cirrhosis , M 10/25/ /12 Cirrhosis NA 7 58 M 11/17/ /9 Cirrhosis NA 8 57 M 09/17/ /9 Cirrhosis ,100, F 11/28/ /11 Cirrhosis , F 01/27/ /13 Cirrhosis NA M 06/13/ /10 Cirrhosis ,895, M 09/13/ /13 Cirrhosis NA Abbreviations:, orthotopic liver transplantation; FCH, fibrosing cholestatic hepatitis; NA, not available. Clinical Evolution After Retransplantation After retransplantation, 8 of the 12 patients (67%) died at a median of 8 months (range, 2 days to 55.5 months), and 4 patients (35%) were alive after 1.9 years of follow-up (range, 7 to 39.5 months; Fig. 1; Table 2). Causes and times of death after retransplantation were: surgical complications, n 3 (perioperative period); lymphoproliferative disorder, n 1 (at 7 months); spontaneous bacterial peritonitis (with a high likelihood of underlying severe HCV-related graft disease), Table 2. Clinical Outcome of Patients Undergoing Retransplantation for Recurrent Hepatitis C Patient No. Induction IS Therapy Biopsy-Proven Rejection Rejection Treatment Status Follow-Up Cause of Death 1 CyA P No No Dead 9 d Perioperative 2 CyA Aza P No No Dead 54 mo Cirrhosis 3 CyA P Yes No Dead 24 mo Fibrosing cholestatic hepatitis 4 ATGAM followed by Tac P No No Dead 43 mo Infection (endocarditis with underlying cirrhosis) 5 Tac P No No Alive 42 mo 6 Tac P No No Alive 32 mo 7 Tac P No No Dead 19 d Multiorgan failure 8 CyA P No No Dead 9 mo Infection (spontaneous bacterial peritonitis with underlying cirrhosis) 9 Tac P No 2 MP boluses Alive 19 mo (empiric treatment) 10 Basiliximab P No No Dead 1 d Abdominal hemorrhage 11 CyA P No No Dead 7 mo Posttransplantation lymphoproliferative disorder 12 CyA P Yes No Alive 11 mo Abbreviations: Aza, azathioprine; CyA, cyclosporine Neoral; IS, immunosuppression; MP, methylprednisolone; P, prednisone; Tac, tacrolimus; ATGAM, antithymocyte globulin.

5 232 Berenguer et al Table 3. Histological Evolution of Recurrent Hepatitis C After the First and Second Liver Transplantation Patient No. Histological Evolution in the Initial Graft First Biopsy First-Year Protocol Biopsy 2 Fibrosis 4 in year-1 liver (with FCH) 3 Fibrosis 4 in year-4 liver 4 Fibrosis 4 in year-1 liver 5 Fibrosis 4 in year-1 liver 6 Fibrosis 4 in year-1 liver Second-Year Protocol Biopsy Minimal changes Activity: Activity: Piecemeal necrosis: 4 Piecemeal necrosis: 5 Lobular degeneration: 1 Lobular degeneration: 3 Portal inflammation: 4 Portal inflammation: 4 Fibrosis: 3 Fibrosis: 4 Acute hepatitis*; fibrosis 1 Activity*: NA Piecemeal necrosis: 4 Lobular degeneration: 3 Portal inflammation: 4 Fibrosis: 4 Minimal changes Activity: Activity: Piecemeal necrosis: 3 Piecemeal necrosis: 5 Lobular degeneration: 3 Lobular degeneration: 4 Portal inflammation: 3 Portal inflammation: 3 Fibrosis: 1 Fibrosis: 4 Acute hepatitis Activity: Activity: Piecemeal necrosis: 1 Piecemeal necrosis: 1 Lobular degeneration: 1 Lobular degeneration: 1 Portal inflammation: 1 Portal inflammation: 1 Fibrosis: 1 Fibrosis: 1 Acute hepatitis Activity: Activity: Piecemeal necrosis: 3 Piecemeal necrosis: 3 Lobular degeneration: 3 Lobular degeneration: 4 Portal inflammation: 3 Portal inflammation: 3 Fibrosis: 1 Fibrosis: 4 Acute hepatitis NA NA 8 Fibrosis 4 in year-2 liver 9 Fibrosis 4 in year-1 liver Acute hepatitis Not done (patient refusal) NA 11 Not available PTLD NA NA 12 Fibrosis 4 in year-3 liver Cholestatic hepatitis Activity: NA signs of rejection Piecemeal necrosis: 3 Lobular degeneration: 1 Portal inflammation: 3 Fibrosis: 3 Abbreviations: FCH, fibrosing cholestatic hepatitis; NA, not applicable; PTLD, posttransplantation lymphoproliferative disorder. *Findings in subsequent liver biopsies were compatible with FCH. n 1 (at 9 months); fibrosing cholestatic hepatitis, n 1 (at 24 months); HCV cirrhosis of the second graft, n 1 (at 54 months); and endocarditis (with underlying cirrhosis, n 1, at 43 months). Histological Evolution After Retransplantation Histological findings in post-retransplantation biopsies of the nine patients who survived beyond the perioperative period are listed in Table 3. In the last protocol liver performed at either 1 or 2 years after retransplantation, a new cirrhosis was diagnosed in three patients (33%), with stage 3 fibrosis, stage 1 fibrosis, fibrosing cholestatic hepatitis, and acute hepatitis in one patient each (11% each). Three patients lacked protocol liver biopsies because of refusal to undergo that (n 1) or lack of follow-up (n 2). Comparison of the natural history of recurrent hepatitis C after the first and second transplantation is shown in Table 3. Overall, the severity of recurrent hepatitis C after retransplantation tended to mirror that observed after the first transplantation. Although in all instances, an effort to use antiviral therapy was made, complete treatment of 12 months

6 Hepatitis C After Retransplantation 233 Figure 2. Patient survival after retransplantation. Non HCV-infected transplant recipients (n 28) ( ); HCVinfected transplant recipients undergoing retransplantation for causes other than recurrent hepatitis C (n 15) ( ); HCV-infected transplant recipients undergoing retransplantation for HCV-related graft failure (n 12) ( ). was seldom achieved because of: (1) initial contraindications in the presence of associated comorbidities (three of nine patients; 33%), such as cardiological problems (n 1), general poor condition with neurological problems related to calcineurin-inhibitor toxicity (n 1), or multifactorial renal insufficiency with need for hemodialysis (n 1); or (2) the need for discontinuation of therapy because of lack of efficacy and/or the development of severe side effects (four of nine patients; 44%), including posttransplantation lymphoproliferative disorder (n 1), thyroid dysfunction (n 1); and worsening of liver disease (n 2). Patient Survival Cumulative patient survival was extremely poor after retransplantation. It was not significantly worse than that observed in: (1) HCV-infected patients who underwent retransplantation for other causes of graft failure (n 15), and (2) HCV-negative patients undergoing retransplantation (n 28; P.2, log-rank test; Fig. 2). Discussion In recent years, time on the waiting list for liver transplantation and number of deaths on the list have greatly increased because of the discrepancy between the number of donor organs and number of candidates for liver transplantation. This discrepancy mainly is related to the fact that the total number of donors remains unchanged, whereas the number of potential candidates for liver transplantation increases. 18 In addition, but to a lesser extent, the number of patients developing end-stage graft failure, and thus the need for retransplantation, also has increased. 13 Moreover, this number is expected to grow as primary transplant recipients survive long enough to develop graft failure from recurrent disease. Liver disease can recur for almost all indications. This is particularly true for HCV, which accounts for the majority of indications in most transplant centers. HCV recurs in virtually all patients and leads to graft failure in approximately one third of patients within the first 7 years posttransplantation. 12 Thus, if more effective antiviral

7 234 Berenguer et al therapies do not become available, one can predict that the number of HCV-infected transplant recipients in need of retransplantation will increase substantially in the next decade. With these considerations in mind and given the magnitude of the problem, it has become imperative to decide who should and should not be considered for retransplantation. Because each program currently follows its own criteria, consensus on this issue has become a priority for transplant centers. In general, most programs have chosen not to accept patients with recurrent HCV based on the poor results reported in early series However, more recent data from Rosen et al 17 suggested that better results may be achieved by better timing of retransplantation, advocating retransplantation before significant impairment in renal and liver function develops. A question that remains to be elucidated is that of the severity of recurrent hepatitis C after retransplantation. If this severity proves to be similar to that observed in the first graft, denial of retransplantation for these patients would be based on a more rational approach. The aim of this study is to determine whether an association exists between the aggressiveness of recurrent hepatitis C after the first and second transplantations. Results of this study can be summarized as follows. (1) Early posttransplantation mortality is a reality, probably because retransplantation is performed at a very late stage of disease when serious comorbid conditions have developed, particularly renal insufficiency. (2) Recurrent hepatitis C after retransplantation is extremely aggressive because more than two thirds of patients developed severe HCV-related graft disease in less than 2 years. The first result of this study is probably true and only confirms previous findings that associated urgency and severity of liver disease to poor survival. 13 Some considerations need to be made with regard to the second finding. HCV disease progression after transplantation recently was shown to be more aggressive in recent years. 1,9 Reasons for this trend have yet to be identified. The majority of patients included in this study underwent retransplantation in the last 3 years and thus belong to the so-called high-risk period. Given the small number of patients, it is difficult to assess whether the same outcome would be seen in a larger cohort. In addition, antiviral therapies were not used uniformly in these patients, and more importantly, in 77% of patients, a complete course of treatment could not be completed because of comorbidities, development of severe side effects, and/or lack of efficacy. Furthermore, this therapy generally was initiated after the diagnosis of recurrent hepatitis C was made, not in a preemptive manner. Preliminary data suggest that a preemptive strategy may be the best in reducing the rate of severe recurrent hepatitis C. 19 However, difficulty initiating this therapy early post-retransplantation was the main reason for delaying therapy. It is likely that this will hold true regardless of the sample size. Conversely, if patients were to undergo retransplantation at early stages of their disease, 10 preemptive therapy would become a more realistic approach. In conclusion, although this study is limited by the small sample size, performing annual protocol biopsies has allowed us to show that the severity of HCV-related disease after retransplantation probably is related to that observed after the first transplantation. Therefore, if retransplantation is to be considered in these patients, it should only be done in the setting of a more effective antiviral therapeutic strategy. References 1. Berenguer M, Prieto M, San Juan F, Rayón JM, Martinez F, Carrasco D, et al. Contribution of donor age to the recent decrease in patient survival among HCV-infected liver transplant recipients. Hepatology 2002;36: 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: Gane E, Portmann B, Naoumov N, Smith HM, Underhill JA, Donaldson PT, et al. Long-term outcome of hepatitis C infection after liver transplantation. N Engl J Med 1996;334: Prieto M, Berenguer M, Rayón M, Córdoba J, Arguello L, Carrasco D, et al. High incidence of allograft cirrhosis in hepatitis C virus genotype 1b infection following transplantation: Relationship with rejection episodes. Hepatology 1999;29: Berenguer M, Rayón M, Prieto M, Aguilera V, Nicolás D, Ortiz V, et al. Are posttransplantation protocol liver biopsies useful in the long-term? Liver Transpl 2001;7: Feray C, Caccamo L, Alexander GJM, Ducot B, Gugenheim J, Casanovas T, et al. European Collaborative Study on factors influencing the outcome after liver transplantation for hepatitis C. Gastroenterology 1999;117: Testa G, Crippin JS, Netto GJ, Goldstein RM, Jennings LW, Brkic BS, et al. Liver transplantation for hepatitis C: Recurrence and disease progression in 300 patients. Liver Transpl 2000;6: Sanchez-Fueyos A, Restrepo J-C, Quintó L, Bruguera M, Grande L, Sanchez-Tapias JM, et al. Impact of the recurrence of hepatitis C infection after liver transplantation on the long term viability of the graft. Transplantation 2002;73: Berenguer M, Ferrell L, Watson J, Prieto M, Kim M, RayónM, et al. HCV-related fibrosis progression following liver transplantation: Increase in recent years. J Hepatol 2000;32: Berenguer M, Prieto M, Rayón JM, Mora J, Pastor M, Ortiz V, et al. Natural history of clinically compensated HCV-related

8 Hepatitis C After Retransplantation 235 graft cirrhosis following liver transplantation. Hepatology 2000; 32: Schluger L, Sheiner P, Thung S, Lau JY, Min A, Wolf DC, et al. Severe recurrent cholestatic hepatitis C following orthotopic liver transplantation. Hepatology 1996;23: Berenguer M, Lopez-Labrador FX, Wright TL. Hepatitis C and liver transplantation. J Hepatol 2001;35: Biggins SW, Beldecos A, Rabkin JM, Rosen HR. Re-transplantation for hepatic allograft failure: Prognostic modeling and ethical considerations. Liver Transpl 2002;8: Sheiner PA, Schluger LK, Emre S, Thung SN, Lau JY, Guy SR, et al. Retransplantation for recurrent hepatitis C. Liver Transpl Surg 1997;3: Rosen H, O Reilly P, Shackleton C, McDiarmid S, Holt C, Busuttil RW, et al. Graft loss following liver transplantation in patients with chronic hepatitis C. Transplantation 1996;62: Facciuto M, Heidt D, Guarrera J, Bodian CA, Miller CM, Emre S, et al. Retransplantation for late liver graft failure: Predictors of mortality. Liver Transpl 2000;6: Rosen HR, Madden JP, Martin P. A model to predict survival following liver re-transplantation. Hepatology 1999;29: Keefe EB. Liver transplantation: Current status and novel approaches to liver replacement. Gastroenterology 2001;120: Mazzaferro V, Tagger A, Schiavo M, Regalia E, Pulvirenti A, Ribero ML, et al. Prevention of recurrent hepatitis C after liver transplantation with early interferon and ribavirin treatment. Transplant Proc 2001;33: