Treatment of Recurrent Hepatitis C in Liver Transplant Recipients

CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2005;3:S125–S131

Treatment of Recurrent Hepatitis C in Liver Transplant Recipients NORAH A. TERRAULT Division of Gastroenterology, University of California at San Francisco, San Francisco, California

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 higherdose 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.

f 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.1 The risk for graft loss at 5 years is 30% higher in HCV-positive patients compared with HCV-negative patients.1 The rate of disease progression is variable, but approximately 25% (range, 8%– 44%) will develop recurrent cirrhosis within 5–7 years of transplantation.2– 6 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%

I

within the next year.7 A worsening of graft and patient survival rates over time has been identified. The use of newer and more potent immunosuppressive agents,8 and the increasing use of older donors, particularly those over 40 years of age, are possible explanations for this cohort effect.5,9,10 Given 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).2,5,11–13 Whether recipients of live donor allografts are at risk for earlier and more severe HCV recurrence than deceased donor transplant recipients is unclear.14 –18 In the only 2 studies using protocol biopsy procedures to assess disease severity and progression, widely disparate results were reported.14,15 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,19 with 1-year patient survival rates of as low as 50% in some series.20 Consequently, retransplantation for recurrent HCV disease is an increasingly controversial indication.21

Management of Hepatitis C Virus in the Liver Transplant Setting Given 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 Abbreviations used in this paper: ALT, alanine transaminase; HCIG, hepatitis C immune globulin; HCV, hepatitis C virus; SVR, sustained virologic response. © 2005 by the American Gastroenterological Association 1542-3565/05/$30.00 PII: 10.1053/S1542-3565(05)00709-3

S126

NORAH A. TERRAULT

CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 3, No. 10

Table 1. Factors Associated With Increased Risk for Fibrosis Progression or Cirrhosis Donor

Recipient

Disease-specific

External

Age ⬎40 y Age

Pretransplant viral Treated acute load rejection Non-Caucasian race High HAI score at 3 CMV infection and 12 mo Female sex Presence of fibrosis at 1 year after liver transplantation

HAI, histologic activity index; CMV, cytomegalovirus.

suggests that HCV transplant recipients would benefit from younger donors (age ⬍50 y) but the current donororgan 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.22 Because 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 disease23 or the treatment is ineffective in achieving viral eradication.24 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 HCVinfected transplant patients are as follows: (1) prophylactic therapy (starting at time of transplantation); (2) preemptive 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. 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.22 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.25 Prophylactic Therapy Hepatitis 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.26 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.27–29 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 Table 2. Treatment Options for HCV-Infected Liver Transplant Recipients Timing/Type

Definition of Therapy

Pre-transplantation

Initiated 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. Initiated at the time of transplantation and continued posttransplantation with the goal of preventing recurrent infection. Initiated early in the posttransplant period (typically within the first 8 weeks) before the evidence of onset of biochemical and histologic disease. Initiated after biochemical and histological evidence of recurrent (and typically progressive) disease are evident.

Prophylactic

Pre-emptive

Posttransplantation (delayed)

SVR, sustained virologic response.

October Supplement 2005

remained normal during the period of infusions in treated chimpanzees compared with control chimpanzees given intravenous immune globulin infusions.29 After discontinuation of the HCIG infusions, 1 of the 2 chimpanzees developed acute hepatitis but infection was prevented in the other chimpanzee.29 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.30 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.31 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 Therapy Studies 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 can-

RECURRENT HCV TREATMENT

S127

didates 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.32 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,32–35 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 therapy32,36,37 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.36 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 ␮g/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).32 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.37

S128

NORAH A. TERRAULT

CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 3, No. 10

Table 3. Pre-emptive Treatment of HCV in Liver Transplant Recipients

Study Singh et al, 1998

34

Sheiner et al,33 1998

Study type

N

RCT

12 treated, 12 control

RCT

35 IFN, 46 no treatment

Time to treatment Treatment regimen (wk) IFN, 3 MU 3 times/ wk ⫻ 6 mo vs no treatment IFN 3 MU 3 times/ wk ⫻ 6 mo vs no treatment

2

0% both groups No difference in severity

3

17% IFN vs 5% no treatment

IFN 3 MU 3 times/ wk ⫹ RBV 10 mg/kg/day for 12 mo IFN (3 MU ¡ 6 MU 3 times/wk) ⫹ RBV (600 mg/ day) ⫻ ⱖ72 mo

3

33%

4

39%

Mazzaferro et al,36 Uncontrolled 2001

36

Sugawara et al,37 2004

RCT (2 different treatment protocols) LDLT recipients only RCT (2 different treatment arms)

23

47

IFN/PEG-IFN alone vs IFN/PEG-IFN ⫹ RBV ⫻ 48 wk

ⱕ6wk

RCT

26 treated, 28 control

PEG-IFN a-2a 180 ug ⫻ 48 wk

ⱕ3wk

Shergill et al,32 2005

Chalasani et al,35 2005

SVR

Histologic response

Fewer with recurrence at 1 and 2 years in IFN group Normal histology in virologic responders Scores lower in responders

9% overall NA (18% combination, vs 5% IFN monotherapy) 8% vs 0% No statistical difference

Dose reduction or discontinuation 50%

28% treatment discontinuation

47%

57%

85% dose reductions 37% treatment discontinuation 32% treatment discontinuation

RCT, randomized controlled trial; IFN, interferon; RBV, ribavirin; PEG-IFN, peginterferon; SVR, sustained virologic response; LDLT, live donor liver transplant.

In summary, pre-emptive therapy cannot be recommended universally because the response rates with combination therapy are modest (18%–39%) and not clearly superior to those achieved with treatment started after recurrence is evident histologically. A study comparing the pre-emptive strategy vs the strategy of waiting and treating progressive disease is underway, but results likely will not be available for a few years. In the interim, pre-emptive therapy may be useful in these patients predicted to be at risk for rapidly progressive disease. However, the latter approach of targeting pre-emptive therapy to those at risk for progressive recurrent disease requires accurate models to predict posttransplant disease severity. Treatment of Recurrent Hepatitis C Virus Disease The potential advantages of initiating treatment when recurrent disease is clinically or histologically apparent rather than as pre-emptive treatment include the presence of lower doses of immunosuppression, which may enhance responses to antiviral therapy, improved performance status, which may increase tolerability of treatment, a potentially lower risk for acute rejection as

the risk of rejection is lower after the first 6 months posttransplantation, and cost savings because only those with progressive disease are treated. Potential disadvantages of the “wait and treat progressive disease” approach are a higher viral load and the presence of fibrosis at the time of treatment initiation, which reduces the likelihood of virologic responses in nontransplant patients. Because recurrent disease typically becomes apparent clinically and histologically at 3– 6 months after transplantation, most of the studies of antiviral therapy for those with recurrent disease have initiated treatment between 6 and 24 months after transplantation. The majority of the studies evaluating antiviral therapy for established recurrent HCV disease have been uncontrolled and of small sample size, and with variable interferon/ribavirin doses and treatment duration. Reported SVR rates in interferon monotherapy studies (including peginterferon monotherapy) are less than 20%.23,35 Combination interferon and ribavirin therapy is associated with slightly higher rates of response, with a median SVR rate of 23% (range, 5%–35%) in studies including 20 patients or more.38 – 48 Data using peginterferon plus ribavirin report very divergent SVR results (range, 0%– 45%),49 –53 but in

October Supplement 2005

RECURRENT HCV TREATMENT

S129

Table 4. Controlled Studies of Treatment of Established Recurrent HCV Disease in Liver Transplant Recipients

Study

Treatment

Interferon and ribavirin Samuel et al,47 IFN 3 MU 3 times/wk 2003 ⫹ RBV 1000–1200 mg/day ⫻ 48 wk (N ⫽ 28), vs untreated controls (N ⫽ 27) PegInterferon Chalasani et al,35 PEG-IFN alfa-2a 180 ug 2005 ⫻ 48 wk (N ⫽ 33), vs untreated controls (N ⫽ 32)

Time from liver transplant to treatment (mo)

Drug discontinuation (N%) Dose reduction N (%)

EOTR N (%)

SVR N (%)

54 (mean)

12 (43) Not reported

9 (32) treated vs 0% controls

6 (21) treated vs 0% control

6–60 (range)

10 (30) 20 (61)

9 (27) treated vs 0% controls

4 (12) treated vs 0% controls

IFN, interferon; RBV, ribavirin; PEG-IFN, peginterferon; EOTR, end-of-treatment response.

the studies of 20 or more patients the SVR rates were 31%– 45%.49 –51 Thus, combination therapy is the treatment of choice and, based on results in the nontransplant setting, peginterferon plus ribavirin would be predicted to be the best therapy. However, the retrospective studies published to date suggest poorer tolerability of peginterferon than conventional interferon and this, in turn, may limit the success of therapy.52,53 Prospective head-to-head trials comparing interferon plus ribavirin vs peginterferon plus ribavirin have not been conducted. Two randomized controlled studies of posttransplant antiviral therapy have been reported (Table 4). In a study of 28 patients treated with conventional interferon (3 MU 3 times weekly) plus ribavirin (1–1.2 g/day), an SVR was achieved in 21% of treated patients vs 0% of 24 untreated controls (P ⫽ .04).47 The second study compared 33 HCV-infected transplant recipients treated with peginterferon alfa-2a 180 ug weekly with 32 untreated controls.35 An SVR was obtained in 12% of treated patients and none of the untreated controls (P ⫽ .03). Treated patients also had a higher biochemical response, with 28% of treated patients with a normal ALT level at the end of 48 weeks of treatment vs 9% of untreated controls (P ⫽ .048). Patients with non-1 genotypes had higher SVR rates than those with genotype 1. In both studies, histologic improvements were seen in treated patients but differences between treated and untreated patients did not achieve statistical significance.35,47 The rate of treatment discontinuation was high in both studies (30% and 43%) and cytopenias were the most commonly cited reason for treatment discontinuation or reduction in drug doses.35,47 Growth factors were not used to manage cytopenias, which may have limited tolerability, and, ultimately, the SVR rates.

All the studies using interferon (conventional or pegylated) plus ribavirin reported drug discontinuation rates higher than those reported in nontransplant patients. Interferon dose reductions were required in 40%– 60% (higher if pegylated interferon was used) and ribavirin dose reductions were required in 50%–90%. The use of growth factors may be predicted to reduce the frequency of dose reductions and thereby enhance the rates of virologic response. The optimal duration of treatment for recurrent HCV disease is unknown. In an immunosuppressed population of liver transplant recipients, longer treatment periods may be necessary to enhance SVRs. Prolonged low-dose maintenance interferon is being evaluated for histologic and clinical benefits in patients who fail to clear HCV after combination interferon and ribavirin therapy in several clinical trials (HALT-C, EPIC, and CO-PILOT). The risk-benefit of this strategy needs to be evaluated in the transplant setting. Because interferon has immune modulatory properties, there are concerns regarding the risk for acute or chronic rejection with antiviral therapy. In uncontrolled studies, the rate of acute rejection has ranged from 0% to 33% (median, 1%). Potential biases in these uncontrolled reports are related to the difficulty in interpreting the diagnosis of acute rejection in the setting of recurrent HCV disease,54 the heightened surveillance of patients during treatment making the finding of acute rejection more likely, and the unmeasured changes in immunosuppression that may have occurred before or during antiviral therapy. In the only 2 controlled studies of antiviral therapy in posttransplant recipients, no significant differences in the rate of acute or chronic rejection were found between treated and untreated controls,35,47

S130

NORAH A. TERRAULT

CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 3, No. 10

although the studies were of limited size and underpowered to detect small differences in rejection risk. 10.

Management of Hepatitis C Virus Infection in Liver Transplant Recipients in 2005 In summary, the treatment of recurrent HCV disease in 2005 is focused primarily on treatment of recurrent histologic disease. Although large-scale and controlled studies are lacking, the use of pegylated interferon plus ribavirin is the treatment of choice in most programs.25 Strategies to improve tolerability are needed as this would be predicted to increase response rates. Pre-emptive therapy does not have an established role in the management of HCV among transplant recipients, and future use is likely to be in selective patient groups. Patients at highest risk for recurrent and progressive disease may be best served by this treatment strategy. Prophylactic therapy using HCV antibody therapy has not yielded very impressive results to date and is unlikely to be effective as monotherapy long term. However, there may be a role of such therapies in delaying the onset of infection and bridging patients to other HCV therapies. Finally, because this is a patient population in whom nonresponse to current therapies is frequent, new antiviral agents with improved efficacy and tolerability are needed urgently.

11.

12.

13.

14.

15.

16.

17.

18.

19. 20.

References 1. Forman LM, Lewis JD, Berlin JA, et al. The association between hepatitis C infection and survival after orthotopic liver transplantation. Gastroenterology 2002;122:889 – 896. 2. 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. 3. Feray C, Caccamo L, Alexander GJ, 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. 4. Gane E, Portmann B, Naoumov N, et al. Long-term outcome of hepatitis C infection after liver transplantation. N Engl J Med 1996;334:815– 820. 5. Neumann U, Berg T, Bahra M, et al. Fibrosis progression after liver transplantation in patients with recurrent hepatitis C. J Hepatol 2004;41:830 – 836. 6. Prieto 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 –256. 7. Berenguer M, Prieto M, Rayon JM, et al. Natural history of clinically compensated hepatitis C virus-related graft cirrhosis after liver transplantation. Hepatology 2000;32:852– 858. 8. Samonakis DN, Triantos CK, Thalheimer U, et al. Immunosuppression and donor age with respect to severity of HCV recurrence after liver transplantation. Liver Transpl 2005;11:386 – 395. 9. Berenguer M, Prieto M, San Juan F, et al. Contribution of donor

21. 22.

23.

24. 25.

26.

27.

28.

age to the recent decrease in patient survival among HCV-infected liver transplant recipients. Hepatology 2002;36: 202–210. Lake JR, Shorr JS, Steffen BJ, 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 – 557. Rosen 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;92:1453–1457. Firpi RJ, Abdelmalek MF, 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. 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. Shiffman 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 –1255. Garcia-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 –707. Thuluvath 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; 10:1263–1268. Russo 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 –346. Gaglio 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 –1035. Rosen HR, Martin P. Hepatitis C infection in patients undergoing liver retransplantation. Transplantation 1998;66:1612–1616. Neff 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;10:1497–1503. Biggins S, Terrault N. Should HCV-related cirrhosis be a contraindication for retransplantation? Liver Transpl 2003;9:236 –238. Wiesner R, Sorrell M, Villamil F, International Liver Transplantation Society Expert Panel. Report of the first International Liver Transplantation Society expert panel consensus conference on liver transplantation and hepatitis C. Liver Transpl 2003;9:S1–S9. Crippin JS, McCashland T, Terrault N, et al. A pilot study of the tolerability and efficacy of antiviral therapy in hepatitis C virusinfected patients awaiting liver transplantation. Liver Transpl 2002;8:350 –355. Everson G. Treatment of patients with hepatitis C virus on the waiting list. Liver Transpl 2003;9:S90 –S94. Khalili 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 2005; (in press). 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. Yu MY, Bartosch B, Zhang P, et al. Neutralizing antibodies to hepatitis C virus (HCV) in immune globulins derived from antiHCV-positive plasma. Proc Natl Acad Sci U S A 2004;101:7705– 7710. Lavillette 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– 6034.

October Supplement 2005

29. Krawczynski 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– 828. 30. Willems B, Marotta P, Greig PD, et al. Anti-HCV immunoglobulins for the prevention of graft infection in HCV-related liver transplantation. J Hepatol 2002;36:S96A. 31. Davis G, Nelson DR, 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. 32. Shergill 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 –124. 33. Sheiner 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– 838. 34. Singh N, Gayowski T, Wannstedt CF, 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. 35. 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. 36. 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. 37. Sugawara Y, Makuuchi M, Matsui Y, et al. Preemptive therapy for hepatitis C virus after living-donor liver transplantation. Transplantation 2004;78:1308 –1311. 38. Berenguer M, Prieto M, Palau A, et al. Recurrent hepatitis C genotype 1b following liver transplantation: treatment with combination interferon-ribavirin therapy. Eur J Gastroenterol Hepatol 2004;16:1207–1212. 39. Firpi R, Abdelmalek M, Soldevila-Pico C, et al. Combination of interferon alfa-2b and ribavirin in liver transplant recipients with histological recurrent hepatitis C. Liver Transpl 2002;8:1000 – 1006. 40. Lavezzo B, Franchello A, Smedile A, et al. Treatment of recurrent hepatitis C in liver transplants: efficacy of a six versus a twelve month course of interferon alfa 2b with ribavirin. J Hepatol 2002; 37:247–252. 41. Stravitz R, Shiffman M, Sanyal A, et al. Effects of interferon treatment on liver histology and allograft rejection in patients with recurrent hepatitis C following liver transplantation. Liver Transpl 2004;10:850 – 858. 42. 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. 43. Mukherjee S, Lyden E, McCashland TM, et al. Interferon alpha 2b and ribavirin for the treatment of recurrent hepatitis C after liver

RECURRENT HCV TREATMENT

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

S131

transplantation: cohort study of 38 patients. J Gastroenterol Hepatol 2005;20:198 –203. Giostra E, Kullak-Ublick GA, Keller W, et al. Ribavirin/interferonalpha sequential treatment of recurrent hepatitis C after liver transplantation. Transpl Int 2004;17:169 –176. Narayanan Menon KV, Poterucha JJ, El-Amin OM, et al. Treatment of posttransplantation recurrence of hepatitis C with interferon and ribavirin: lessons on tolerability and efficacy. Liver Transpl 2002;8:623– 629. Nair S, Khan S, Loss G, et al. Treatment of recurrent hepatitis C in liver transplant recipients: is there any histologic benefit? Liver Transpl 2003;9:354 –359. 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. Shakil AO, McGuire B, Crippin J, et al. A pilot study of interferon alfa and ribavirin combination in liver transplant recipients with recurrent hepatitis C. Hepatology 2002;36:1253–1258. 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. Dumortier J, Scoazec J, Chevallier P, et al. Treatment of recurrent hepatitis C after liver transplantation: a pilot study of peginterferon alfa-2b and ribavirin combination. J Hepatol 2004;40:669 – 674. Mukherjee S, Rogge J, Weaver L, et al. Pilot study of pegylated interferon alfa-2b and ribavirin for recurrent hepatitis C after liver transplantation. Transplant Proc 2003;35:3042–3044. Toniutto P, Fabris C, Fumo E, et al. Pegylated versus standard interferon-alpha in antiviral regimens for post-transplant recurrent hepatitis C: comparison of tolerability and efficacy. J Gastroenterol Hepatol 2005;20:577–582. Ross AS, Bhan AK, Pascual M, et al. Pegylated interferon alpha-2b plus ribavirin in the treatment of post-liver transplant recurrent hepatitis C. Clin Transplant 2004;18:166 –173. Regev A, Molina E, Moura R, et al. Reliability of histopathologic assessment for the differentiation of recurrent hepatitis C from acute rejection after liver transplantation. Liver Transpl 2004;10: 1233–1239.

Address requests for reprints to: Norah Terrault, MD, MPH, Division of Gastroenterology, University of California, San Francisco, S 357, 513 Parnassus Avenue, San Francisco, California 94143-0538. e-mail: [email protected]; fax: (415) 502-6714. Dr Terrault has received research support from Roche Pharmaceuticals, NABI Biopharmaceuticals, and XTL Biopharmaceuticals, and has been on the Speakers Bureau for Schering Plough.