International Journal of Hepatology

International Journal of Hepatology / 2012 / Article
Special Issue

Hepatitis C and Metabolic Disorders: Genetics, Mechanism, and Therapies (Clinical and Experimental)

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Review Article | Open Access

Volume 2012 |Article ID 686135 | 22 pages | https://doi.org/10.1155/2012/686135

Liver Transplantation and Hepatitis C

Academic Editor: Mario Reis Alvares-da-Silva
Received09 Feb 2012
Accepted21 May 2012
Published26 Jul 2012

Abstract

Hepatitis-C-virus- (HCV-) related end-stage cirrhosis is the primary indication for liver transplantation in many countries. Unfortunately, however, HCV is not eliminated by transplantation and graft reinfection is universal, resulting in fibrosis, cirrhosis, and finally graft decompensation. The use of poor quality organs, particularly from older donors, has a highly negative impact on the severity of recurrence and patient/graft survival. Although immunosuppressive regimens have a considerable impact on the outcome, the optimal regimen after liver transplantation for HCV-infected patients remains unclear. Disease progression monitoring with protocol biopsy and new noninvasive methods is essential for predicting patient/graft outcome and starting antiviral treatment with the appropriate timing. Antiviral treatment with pegylated interferon and ribavirin is currently considered the most promising regimen with a sustained viral response rate of around 30% to 35%, although the survival benefit of this regimen remains to be investigated. Living-donor liver transplantation is now widely accepted as an established treatment for HCV cirrhosis and the results are equivalent to those of deceased donor liver transplantation.

1. Introduction

End-stage liver disease caused by chronic hepatitis C virus (HCV) infection is the leading cause of liver transplantation in developed countries [1, 2], including Japan [3]. Unfortunately, liver transplantation does not cure HCV-infected recipients, but reinfection of HCV universally occurs and disease progression is accelerated compared with that in the nontransplant population, resulting in poor outcomes for HCV-infected recipients. Although several studies have investigated the factors affecting the natural history of recurrent HCV, many aspects remain unclear and require further investigation [4]. For patients with progressive fibrosis, it is essential to monitor disease progression and the only strategy that is known to modify the outcome is antiviral therapy at an appropriate disease stage. In this paper, we address the issues that transplant physicians face in the management of patients with recurrent hepatitis C, review the results of antiviral treatments, and discuss on living donor liver transplantation (LDLT) for HCV cirrhosis.

2. Natural History of Hepatitis C after Liver Transplantation

HCV reinfection of liver allografts is universal, occurring just after reperfusion followed by a rapid increase in HCV ribonucleic acid (RNA) levels within 4 postoperative months [5]. Diagnosis of recurrent HCV infection is based on the detection of HCV RNA in the serum and/or liver graft, but diagnosis of recurrent disease requires histologic confirmation [6]. The histologic features of liver injury usually resemble those of nontransplant HCV hepatitis typically developing after 3 months, but the clinical presentation, severity, and outcome are extremely heterogeneous and more profound compared to those in immune competent patients [7]. The pattern of recurrence is worse over time compared with chronic hepatitis, and further cirrhosis, as well-described in the nontransplant population, develops with higher viremia and faster fibrosis progression. Progression to cirrhosis usually takes 9 to 12 years after liver transplantation with a linear progression of histologic fibrosis [7, 8]. A less common, but well-documented form of recurrence is called fibrosing cholestatic hepatitis (<10%), possibly mediated by a direct cytopathic mechanism under an extremely high viral load and immune-compromised condition. Graft failure occurs in 50% of recipients within a few months after fibrosing cholestatic hepatitis develops [9]. Some HCV-reinfected recipients, however, show no apparent disease progression for at least the first decade and their graft injury remains mild or even absent despite a high viral burden.

Overall, cirrhosis develops in approximately 25% of liver transplant recipients (range 8%–44%) after 5 to 10 years and this percentage is likely to increase with an increase in the follow-up period [7, 8]. Once cirrhosis is complete, survival time is severely decreased and decompensation is encountered with cumulative rates at 1 and 3 years of 40% and 60%, respectively, which finally results in graft failure [8, 10].

The development of decompensated cirrhosis due to recurrent hepatitis C is now the most frequent cause of graft failure, patient death, and the need for retransplantation in HCV-infected recipients [6, 8, 1013]. As a result, survival is significantly decreased compared with other indications, an overall 10% difference at 3 years. In the most recent United Network for Organ Sharing/Organ Procurement and Transplantation Network (UNOS/OPTN) study from the United States, 3-year survival is 78% among 7459 HCV-positive recipients compared with 82% among 20734 HCV-negative recipients ( ; http://www.unos.org/) [14].

The poor outcome of HCV-positive recipients has resulted in the divergence in transplant outcomes between HCV-positive recipients and HCV-negative recipients. Improvements in organ preservation, surgical techniques, and postoperative care have dramatically improved the survival of HCV-negative recipients over the last two decades, whereas this has not been the case in HCV-positive recipients for whom outcome has remained unchanged or even worsened over time [1417].

This background indicates the importance of identifying the factors related to severe recurrent hepatitis C and monitoring disease progression.

3. Factors Associated with the Outcome of HCV-Infected Recipients

In the transplant setting, many factors contribute to disease progression compared with nontransplant patients [10], including, in addition to viral-related factors, donor and recipient-related factors, graft and surgical factors, and immunosuppressive agents (Table 1). Although numerous studies have examined this issue, nearly all have, unfortunately, been retrospective, conducted in limited populations and at single centers, utilized immunosuppressive therapies in an uncontrolled manner, and failed to utilize protocol biopsy to evaluate histologic progression. Yet, investigation of the prognostic factors of severe recurrent disease is important for identifying potential factors for modifying disease outcome and improving organ allocation.


VariablesEffect on recurrent hepatitis C

Donor and graft factors
 AgeMore severe disease (>40, >50, >65)
 SteatosisFew studies
 Prolonged ischemic timeMore severe disease
 HCV+ graftNo influence
 Reduced size versus whole liver (LDLT versus DDLT)No difference
Pretransplant recipient factors
 Genotype 1bControversial
 Pre-LT higher viral loadUnclear
 AgeFew studies
 RaceFew studies
 SexFew studies
 HIV coinfectionNo influence
 IL-28B gene polymorphismMore severe disease in CT and TT genotype
Posttransplant recipient factors
 Post-LT higher viral loadMore severe disease
 CMV infectionUnclear More severe disease
 Diabetes mellitus (metabolic syndrome)More severe disease
Immunosuppression
 Steroid bolusMore severe disease
 OKT3More severe disease
 Maintenance steroidSevere disease when rapidly tapered
 Steroid free regimenNo influence
 Tacrolimus versus CyclosporineNo difference
 Anti-IL-2 receptor antibodiesControversial
 AzathioprineControversial
 Mycophenolate mofetilControversial
 mTOR inhibitorsFew studies

Abbreviations: CMV: cytomegalovirus; DDLT: deceased donor liver transplantation; HCV: hepatitis C virus; HIV: human immunodeficiency virus; LDLT: living-donor liver transplantation; LT: liver transplantation; mTOR: mammalian target of rapamycin.
3.1. Donor Age

The impact of donor age on outcome has gained increased attention due to the increased use of liver grafts from older donors, which reflects the absolute shortage of available organs. Accumulating data indicates that grafts from older donors are at greater risk for severe histologic findings, disease progression, and impaired graft/patient survival compared with those from younger donors [13, 15, 1825]. In addition, older donor age might hinder the efficacy of posttransplant antiviral treatment [2628]. Features of older grafts, such as telomere shortening, impaired hepatocyte proliferation, increased fibrogenesis, and immunologic problems, are thought to be the cause of the lower quality of grafts from aged donors [29]. Recently, Avolio et al. [30] reported that the model for end-stage liver disease (MELD) score adjusted by donor age (D-MELD; calculated as Donor age × MELD) could accurately predict the outcome of HCV-infected recipients.

3.2. Graft Characteristics

The use of extended criteria for the donors is especially important for HCV-positive recipients, although studies evaluating long-term outcomes in HCV-positive recipients are lacking. Several studies revealed that grafts from HCV-positive donors could be used as safely as those from HCV-negative donors for hepatitis C cirrhosis [2, 17, 22, 3134]. Considering superinfection and the impaired response of genotype 1 to antiviral treatment, it is recommended that HCV-positive grafts be used only in HCV genotype 1-positive recipients.

On the other hand, ischemic injury to the graft seems to have a serious impact on patient/graft survival and disease progression [3539]. An increased risk of severe recurrence of hepatitis C is reported with cardiac death allografts [40], but the most recent analysis of the UNOS/OPTN database revealed the opposite results, and concluded that the use of liver grafts from cardiac death donors is a valuable option for HCV-positive recipients [41].

As for steatosis of graft, despite early studies associating graft steatosis with poor function [42, 43], the impact of allograft steatosis for fibrosis progression and outcome in HCV-positive recipients is unclear [33, 44]. The most recent study by Subramanian et al. [45] indicated that fatty grafts might contribute to fibrosis and poor outcome in HCV-infected recipients. Another recent study by Brandman et al. [23] associated graft steatosis with severe fibrosis at 1 year.

Additionally, several experienced centers reported that LDLT could be performed as safely as deceased donor liver transplantation (DDLT) with an equivalent outcome for HCV-positive recipients [21, 4650].

3.3. Pretransplant Recipient Characteristics

Studies evaluating the association between the severity of HCV recurrence and HCV genotype are conflicting. Some studies suggest that genotype 1b is associated with a poorer outcome [21, 26, 5153], but other recent studies have not confirmed this finding. Several studies demonstrated that pretransplant HCV RNA in the serum is associated with increased mortality and graft loss [16, 5456]. It has been also suggested that a less complex quasispecies composition before transplantation is associated with a more severe recurrence [5658]. Older recipient age [51, 59, 60], race (white donor/black recipient) [6163], and sex (male [64]/female [15, 65] recipient) are also reported to be associated with impaired outcome. Recent studies suggest that polymorphisms close to the interleukin (IL)-28B gene, both in the recipient and the donor, can affect not only the course of recurrent HCV hepatitis but also the response to antiviral therapy after liver transplantation with a poorer outcome in the CT and TT genotypes than in the CC genotype [6669], which could be useful for selecting a suitable donor for HCV-infected recipients.

The coexistence of hepatocellular carcinoma is reported to have a negative impact on HCV-positive recipient survival [21, 51, 7076].

Coinfection of the human immunodeficiency virus (HIV) in patients with HCV cirrhosis, once considered to be a contraindication for liver transplantation, has now gained wider acceptance for liver transplantation, with the introduction of highly active antiretroviral therapy that increases survival of HIV/HCV coinfected patients and makes end-stage HCV cirrhosis the leading cause of death [77]. Studies suggest that liver transplantation in HIV/HCV coinfected patients is safe and that HIV coinfection does not influence the outcome [7883]. UNOS no longer considers HIV an absolute contraindication for liver transplantation (http://www.hivtransplant.com/) [84].

3.4. Posttransplant Recipient Characteristics

Early high viral loads at 7 days [7, 85], 4 months [55, 86], and 12 months posttransplantation [87, 88] are associated with lower patient and graft survival. A recent study by Shackel et al. [88] demonstrated a linear association between viral titers at 12 months and patient survival.

Postoperative infection with cytomegalovirus (CMV) is associated with more severe HCV disease, increased progression to cirrhosis, and a higher rate of graft failure compared to those without CMV infection [17, 51, 86, 8992].

Metabolic syndrome occurs in half of HCV-infected recipients within the first 12 months after transplantation and is associated with a greater progression of fibrosis [86]. Several studies demonstrated that posttransplant diabetes in HCV-infected recipients increases the risk of fibrosis/cirrhosis [9396], but conflicting results have been reported [97]. A causal relationship rather than an association between HCV and diabetes was strongly suggested by a study of 28,942 kidney transplant recipients [98], and accumulating evidence indicates that HCV induces insulin resistance by a variety of mechanisms, which should alert clinicians to the importance of minimizing diabetogenic drugs in the transplant population together with aggressive diabetic control [96]. A recent study by Veldt et al. [99] revealed that increased insulin resistance is associated with a higher rate of advanced fibrosis/cirrhosis in HCV-infected recipients.

4. Immunosuppression and Recurrent Hepatitis C

It is generally accepted that over-immunosuppression, such as steroid bolus and OKT3 as rejection therapy, and maintenance immunosuppression with triple-quadruple therapies at full dose are risk factors for HCV liver injury and are associated with a poorer outcome. The optimal immunosuppressive regimen for HCV-infected patients after liver transplantation remains unclear, however, despite several advances in our knowledge regarding the impact of various medications on HCV recurrence in parallel with the development of promising new drugs.

4.1. Steroid Boluses and OKT3

Numerous early studies clearly demonstrated that steroid boluses and/or OKT3 administered for graft rejection in HCV-positive patients accelerate recurrent hepatitis C [2, 16, 17, 76, 100103].

4.1.1. Steroid Maintenance

Based on early perceptions that a steroid bolus for acute rejection accelerates hepatitis C progression, steroids were believed to increase HCV injury. Considering liver injury and the long-term side effects of steroids, steroids were routinely discontinued by 3 months in most liver transplant programs until 2002 [104]. Another option to avoid the negative effects of steroids is to use a steroid-free immunosuppressive regimen.

In addition to early reports [53, 76], two recent retrospective studies [105, 106] revealed that slow steroid tapering (over 6 months) might be associated with less severe recurrent disease. The most compelling data supporting the beneficial effects of low-dose steroids is from Vivarelli et al. [107], who reported the results of a randomized study of rapid (3 months) versus slow (25 months) steroid tapering in conjunction with tacrolimus. The rates of histologic recurrence at the 1-year followup and of advanced fibrosis at the 2-year followup were significantly higher in the rapid tapering group. This important finding might resolve the controversy about the impact of low-dose steroids on the natural history of recurrent hepatitis C.

Several studies, including a meta-analysis, have demonstrated that steroid-free protocols are not significantly different from other protocols with regard to viremia, patient survival, or fibrosis progression [108114]. Manousou et al. [115] reported significantly more severe fibrosis in a group receiving tacrolimus monotherapy compared to those receiving triple immunosuppression with azathioprine and short-term steroids, but a recent randomized multicenter study reported that although steroid-free immunosuppression is safe and effective for liver transplant recipients with hepatitis C, steroid-free protocols have no advantage over traditional immunosuppression [116]. Considering the well-known diabetogenic complications of steroids, especially when tacrolimus is the primary immunosuppressive agent, the role of long-term steroid administration remains an important and difficult problem that requires further investigation. Current opinion regarding steroid use in HCV-positive recipients is that steroid boluses should be avoided in cases of mild rejection, steroid-free regimens are safe, and, when steroids are used, withdrawal should be extended with complete discontinuation not before 6 months.

4.2. Calcineurin Inhibitors

In vitro series revealed that cyclosporine inhibits HCV replication in a cell-based replicon model [117119]. Several studies with small populations have confirmed this in vivo series [26, 120123]. Recently, Spanish groups performing a multicenter retrospective analysis reported that the use of cyclosporine-based immunosuppression regimens and longer treatment duration may protect patients against viral relapse after antiviral treatment [124]. Larger studies reported comparable, even improved results, in a tacrolimus group. Martin et al. [125] found a significantly increased viral load in patients receiving cyclosporine, without any difference in fibrosis or patient/graft survival. In two large prospective studies comparing cyclosporine and tacrolimus, no difference was observed in HCV-positive patients [126, 127]. Berenguer et al. [128] studied the relationship between calcineurin inhibitors and the development of acute hepatitis, fibrosing cholestatic hepatitis, and severe recurrence by protocol biopsies among 136 cyclosporine and 117 tacrolimus patients, which revealed no difference in any of the evaluated variables or in survival. The same authors performed a meta-analysis comprising 366 HCV-positive recipients (183 with tacrolimus, and 183 with cyclosporine) from 5 studies, which revealed no difference in patient or graft survival [129]. The most recent large retrospective study based on the UNOS/OPTN database by Irish et al. [130] analyzed patient death, graft failure, failure due to recurrent disease, and acute cellular rejection among 8092 tacrolimus patients and 717 cyclosporine patients. The findings revealed an increased risk of patient death, graft failure, and acute rejection in the cyclosporine group while the 3-year unadjusted patient and graft survival were comparable, and concluded that the targeted administration of cyclosporine in HCV-infected recipients should be reconsidered. To date, the use of specific calcineurin inhibitors cannot be recommended based on existing data indicating there are no differences in graft/patient survival nor in the progression of recurrent hepatitis C.

4.3. Role of Other Immunosuppressive Agents: Antithymocyte Globulin, IL-2 Receptor Antibodies, Mycophenolate, Azathioprine, and Mammalian Target of Rapamycin (mTOR) Inhibitors

Because induction with OKT3 and alemtuzumab is strongly associated with severe recurrent HCV [131, 132], several alternative regimens have been proposed for induction. Among these regimens, the use of rabbit antithymocyte globulin (ATG) as part of a steroid-free protocol gained popularity because an early randomized controlled trial showed a reduced incidence of recurrent HCV in the ATG group compared with a steroid bolus group [109]. Subsequent studies, however, failed to show a positive impact of ATG induction [133, 134], and at present, there are no data that conclusively show that ATG has a positive impact on HCV recurrence compared with steroid induction. Only a few studies have evaluated the impact of the anti-IL-2-receptor monoclonal antibodies baxiliximab and daclizumab for induction in HCV-positive recipients [113, 116, 135137]. Three prospective studies [116, 136, 137] evaluating induction with IL-2 receptor antibodies failed to show a positive impact on recurrent disease and patient/graft survival. On the other hand, a retrospective study by Nelson et al. [138] reported more severe hepatitis C recurrence in patients with anti-IL-2 receptor antibody induction with mycophenolate mofetil (MMF) when compared to standard therapy based on tacrolimus and steroids. Until adequately powered randomized controlled trials are performed, the use of monoclonal antibodies in HCV-positive liver transplant should be applied with caution and under the rigor of clinical trials.

Azathioprine and MMF are other immunosuppression maintenance drugs associated with disease progression in HCV-infected recipients. An early prospective study showed no effect of MMF in HCV-infected recipients [139]. Recently, however, several studies have reported favorable results for either adding MMF or substituting MMF for azathioprine for graft/patient survival and fibrosis progression [140145], while other authors found improved or equal effects of azathioprine on disease progression and patient outcome when compared with MMF [64, 115, 146, 147]. A recent review also advocated reappraisal of azathioprine based on several studies that obtained better results with azathioprine [147]. Thus, the overall intensity of immunosuppression rather than the independent action of either drug may have greater impact on HCV recurrence, as shown in recent randomized studies of triple agents [115, 116].

Although mTOR inhibitors have gained widespread use in selected transplant programs as maintenance agents because of their renal-sparing properties, few studies have evaluated the effect of those drugs on the course of recurrent hepatitis C [148150]. While findings of a few retrospective studies [149, 150] suggested a beneficial effect, there is little evidence to support its widespread use in recurrent HCV patients until results from well-designed, randomized trials are available.

5. Posttransplant Followup and Monitoring of HCV Hepatitis Disease Progression

The risk of progression to cirrhosis can be predicted by the biochemical and histologic recurrence pattern. Aminotransferase peak, bilirubin level, and the presence of biochemical cholestasis are associated with a higher rate of progression to graft cirrhosis [151153]. Histologic findings from liver biopsies performed in the first 12 months after transplantation are useful for predicting the risk of developing cirrhosis, severity of fibrosis, and graft loss [14, 21, 60, 76, 103, 151, 154, 155]. The presence of histologic recurrence, including cholestasis and hepatocellular ballooning, at an early stage is associated with higher rates of progression to cirrhosis [151]. Moderate-to-severe inflammation in liver biopsies performed within the first 12 months is also predictive of progression to cirrhosis and graft loss [21, 60, 103, 154].

In this background, posttransplant monitoring with reliable methods is crucial for predicting patient/graft outcome, to make an early diagnosis of disease progression, and to start antiviral treatment at the appropriate time. There are two types of prevalent diagnostic methods for monitoring recurrent hepatitis C after liver transplantation; invasive (liver biopsy and measurement of hepatic venous pressure gradient) and noninvasive (elastography, biochemical serum, and fibrogenesis markers, and predictive mathematical models of fibrosis).

Liver biopsy remains the gold standard and the key diagnostic criterion with which other tests are compared in assessing fibrosis. As discussed above, early studies demonstrated the prognostic value of liver biopsy at the time of recurrence and for monitoring disease progression within the first 12 months. With respect to antiviral treatment, a biopsy is essential not only to assess the severity of hepatitis but also to rule out rejection, and initiating treatment in earlier stages of fibrosis results in improved sustained viral response (SVR) rates [2628]. Consequently, consecutive follow-up protocol biopsies are now widely accepted and recommended by different transplant teams and societies [1, 2, 17, 156, 157]. In contrast, some clinicians object to sequential protocol biopsy given the known limitations of treatment and difficulty in predicting the future of this unpredictable disease [104]. Recently, measuring hepatic venous pressure gradients during transjugular liver biopsies was reported to have a good correlation with fibrosis progression obtained from liver biopsies [158160]. Hepatic venous pressure gradients greater than 6 mmHg at 12 months are even better for predicting the future development of hepatic decompensation than liver biopsy (sensitivity/specificity; 92%/88% versus 69%/88%) [158].

The estimation of liver stiffness (measured in kilopascals, kPa) with transient elastography (Fibroscan) has been aggressively investigated and is reported to correlate well with the fibrosis progression of HCV-infected grafts after liver transplantation [161166]. The best cut-off values for detecting patients with graft fibrosis (stage ≥2 for METAVIR or Scheuer scores and ≥3 for Ishak score) vary among studies between 7.9 and 10.1 kPa, with high positive predictive values (65%–85%), negative predictive values (88%–94%), and good discrimination for significant fibrosis (area under the receiver operating characteristics [ROC] curve: 0.81–0.94). For diagnosis of graft cirrhosis, the cut-off values range from 10.5 to 12.5 kPa with 50% to 74% positive predictive values, 99% to 100% negative predictive values, and 0.87 to 0.99 area under the ROC curve [162166]. Recently, further evaluation by Carrion et al. [167] indicated that repeated measurements of HCV-infected graft stiffness allow for discrimination between slow and rapid fibrosis progression, and that simple scores, including bilirubin and elastography, or donor age and elastography at 6 months, can accurately predict the risk to develop significant fibrosis or portal hypertension in these patients. Elastography using magnetic resonance imaging was also recently reported to be effective [168].

Other noninvasive methods utilizing biochemical markers and predictive mathematical models of fibrosis have also been investigated [161, 169175]. These include alanine aminotransferase/aspartate aminotransferase ratio index, aspartate aminotransferase/platelets ratio index, Forns index, Fibrotest, hyaluronic acid, procollagen type IV, YKL-40, and mathematical predictive models utilizing some of aforementioned biomarkers with other serum markers [165, 166, 170175]. The diagnostic accuracies of these studies are reported to have 40% to 75% positive predictive values, 42% to 93% negative predictive values, and 0.56 to 0.82 area under the ROC curve, none of which seems to improve nor surpass the diagnostic efficacy of elastography.

6. Antiviral Treatment

Strategies to improve the outcomes of liver transplantation in HCV-infected recipients include eradication of the HCV virus before transplantation with the use of pretransplant antiviral treatment, eradication of HCV virus early after transplantation preemptively to prevent graft damage, and treatment for established recurrent hepatitis C in the acute, or more commonly, chronic phase. Regardless of the antiviral treatment timing, interferon (INF), especially pegylated-INF (PEG-INF), in conjunction with ribavirin (RBV) are currently accepted as a standard key drugs according to the perspectives obtained in nontransplant populations.

6.1. Pretransplantation Antiviral Therapy

Antiviral treatment before transplantation is aimed at suppressing HCV viremia in liver transplant candidates, which may reduce or eliminate the risk of recurrent infection and disease progression, but this approach is severely limited by poor liver function, a high prevalence of nonresponders, severe cytopenia, and complications, including life-threatening infections [176]. To date, only five studies [177181] have been published in this phase with differences in the treatment duration (6–14 months versus 2-3 months) and in regimens used (INF only, INF/RBV, or PEG-INF/RBV). Regardless of the approach used, the results are similar, resulting in the prevention of HCV reinfection in about 20% of treated patients with high discontinuation rate and high-dose reduction rate [176]. Based on these five studies, the best candidates for pretransplant antiviral therapy remain Child-Pugh class A whose virologic response rate is high and in whom the risk of side effects is almost identical to controls. Antiviral therapy is contraindicated for Child-Pugh class C patients considering the high risk of severe infections and low SVR rate. In Child-Pugh class B patients, treatment should be discussed on a case-by-case basis considering factors for a potential response. The combination of PEG-INF and RBV at a standard dose in conjunction with growth factors is recommended, and can be discontinued after 1 to 3 months if there is no response.

6.2. Posttransplantation Prophylactic and Preemptive Therapy

Viral kinetic studies demonstrated that viremia is minimal in the anheptic phase and immediately after surgery, but the viral load increases as early as the second posttransplant week, reaching its maximal level between the first and third posttransplant month, with even higher levels than those observed at pretransplant period [5]. Therefore, several studies have reported that “prophylactic” or “preemptive” antiviral treatment should be started during this time to suppress viral replication and disease progression, but the results seem less effective [182, 183]. Studies of hepatitis C antibody therapy in the form of hepatitis C immune globulin or monoclonal antibodies against the E2 region motivated by the success of antihepatitis B immune globulins have been disappointing, with only a transient decrease in liver HCV RNA and serum aminotransferase levels [176, 184, 185]. Thus, prophylactic or preemptive antiviral treatment generally means antiviral treatment with INF/PEG-INF and RBV started at early posttransplant period, without requiring evidence of recurrent hepatitis C. The main drawbacks of this therapy are low applicability due to the existence of cytopenia, renal dysfunction, rejection, or extrahepatic complications, high levels of immunosuppression in this time window, and subsequent high frequency of dose reduction and drug discontinuation. In published studies [186191] of preemptive antiviral therapy, SVR rates are reported to range from 8% to 34% (5% to 43% for genotype 1 and 14% to 100% for genotypes 2 or 3). The rates of dose reduction and drug discontinuation are approximately 70% and 30%, respectively. The most recently published prospective, multicenter, randomized study (PHOENIX study) by Bzowej et al. [192] was designed to compare the efficacy, tolerability, and safety of an escalating dose regimen of PEG-INF alpha 2a/RBV for 48 weeks for preemptive antiviral treatment versus no treatment; 55 received preemptive treatment and 60 patients underwent observation only. The primary endpoint was the proportion of patients with significant histologic recurrence 120 weeks postrandomization. Enrollment into the study ended early because of the slow inclusion of patients, indicating the difficulties of initiating antiviral treatment in the early posttransplant period. The median delay from transplantation to initiation of therapy was 111 and 121 days in the prophylaxis and observation arms, respectively, which was significantly longer than in other preemptive antiviral studies. SVR was achieved in 22% of the prophylaxis patients. The rate of marked HCV recurrence at 120 weeks (62% in prophylaxis patients versus 65% in observation patients), the time until the first recurrence of HCV, histologic recurrence grades, and the progression of fibrosis at 120 weeks, as well as patient/graft survival were similar in both study arms in this intention-to-treat analysis. Dose reduction and discontinuation were required in 70% and 28%, respectively, in the preemptive antiviral treatment group. Based on these results, European and United States transplant societies do not support the routine use of preemptive antiviral therapy.

6.3. Antiviral Treatment for Established Recurrent Hepatitis C

The most widely accepted and used strategy is initiating antiviral therapy once recurrent hepatitis C in the graft is established by liver biopsies. Initial studies of monotherapy with IFN-alpha yielded poor results, with SVR rates lower than 5% [193]. With the addition of RBV to IFN-alpha treatment, there is a noticeable improvement in treatment outcomes with an SVR rate of 17% to 30% [194]. More recently, several centers reported that PEG-INF/RBV treatment with an improved SVR rate which has now become an established treatment for recurrent hepatitis in HCV-positive recipients [194198].

The recent reports of PEG-INF/RBV treatment are summarized in Table 2 [2628, 199223]. Most of the data come from uncontrolled studies with different designs regarding time to start treatment, regimen used, and followup, but treatment duration is generally 48 to 52 weeks. Therefore, the results were also very different, with SVR rates ranging 0% to 56% (median: 33%). These results are lower than those obtained in nontransplant populations, possibly due to the immunosuppressive status, high prevalence of genotype 1, high viral load, the difficulty in maintaining adequate antiviral doses (especially RBV), and the difficulty in maintaining therapy for the ideal duration.


AuthorYearIncluded patients ( )Genotype 1 (%)FCHPEG-INF alpha (dose)RBV dose (mg/day)Time since LTTreatment duration (months)Growth factorSVR,
(%)
Discontinuation (%)Dose reductions (%)

Rodriguez-Luna et al. [199]20041963NA2b: 0.5–1.5 μg/kg per week ( )400 then escalated to 800–10004.2 (1–16.2)12Yes5 (26)7 (38)NA
Neff et al. [200]20045798NA2b: 1.5 μg/kg per week ( )400–60023.5 (1.6–84.7)12Yes8 (14)18 (32)INF 38 (67), RBV 22 (39)
Ross et al. [201]2004166922b: 1.5 μg/kg per week ( )800–12009.512Yes0 (0)8 (50)INF 12 (75), RBV 13 (81)
Dumortier et al. [202]2004208002b: 0.5–1 μg/kg per week ( )40028 (3–103)12No9 (45)4 (20)INF 13 (65), RBV 6 (30)
Babatin et al. [203]2005134602b: 0.9 μg/kg per week ( )60024 (6–73)12Yes4 (31)7 (54)9 (72)
Toniutto et al. [204]20051210002b: 0.5 μg/kg per week ( )600–80014 (0.6–60.8)12No1 (8)7 (58)11 (92)
Castells et al. [205]2005241002b: 1.5 μg/kg per week ( )6003.8 ± 2.212Yes8 (35)3 (13)INF 6 (25), RBV 14 (58)
Biselli et al. [206]2006208002b: 1 μg/kg per week ( )60056.5 (13–157)12Yes9 (45)1 (5)RBV 7 (35)
Berenguer et al. [207]20063689NA2b: 1.5 μg/kg per week ( ),
2a: 180 μg/week ( )
600–120016.6 (2.7–132.6)12Yes18 (50)17 (47)19 (53)
Oton et al. [208]2006559102b: 1.5 μg/kg per week ( ),
2a: 180 μg/week ( )
800–120063.3 ± 45.5G1/4: 12, G2/3: 6Yes24 (44)16 (29)INF 17 (31), RBV 17 (31)
Mukherjee and Lyden [209]20063275NA2a: 180 μg/week ( )800 then escalated to 1000–120016 (2–70)G1/4: 12, G2/3: 6Yes11 (34)5 (16)NA
Mukherjee and Lyden [210]20063979NA2b: 1.5 μg/kg per week ( )80020 (2–168)G1/4: 12, G2/3: 6No13 (33)17 (44)NA
Fernández et al. [211]20064794102b: 1.5 μg/kg per week ( )600–80032 ± 2512Yes11 (23)10 (21)RBV 15 (32)
Neumann et al. [212]2006258002b: 1 μg/kg per week ( )60038 (2–108)12Yes9 (36)1 (4)INF 15 (52), RBV 9 (36)
Neumann et al. [212] 2006618702b: 1 μg/kg per week ( )600–80025 (3–131)G1/4: 12, G2/3: 6No17 (28)9 (15)48 (79)
Angelico et al. [214]2007428102a: 180 μg/week ( )200 then escalated to 1200 until tolerated48 ± 2912No7 (33)7 (33)INF 8 (38), RBV 21 (100)
Carrión et al. [215]2007819342b: 1.5 μg/kg per week ( )400–1200 adjusted for renal function14.5 (2–38)12Yes18 (33)21 (39)INF 13 (24), RBV 36 (67)
Sharma et al. [216]2007357712b: 1.5 μg/kg per week,
2a: 180 μg/week, (no of patients not stated)
80016 (1.5–129)12Yes13 (37)15 (43)NA
Zimmermann et al. [217]2007268802a: 90 μg/week for 4 weeks then escalated to 135–180 μg/week ( )600 then escalated to 800–12009.4 ± 3.612Yes5 (19)3 (12)17 (65)
Dinges et al. [218] 20091968NA2a: 180 μg/week ( )10 mg/kg/day23 (6–162)12Yes9 (47)5 (26)INF 8 (50), RBV 7 (37)
Lodato et al. [219]20085310002b: 1.0 μg/kg per week ( )8–10 mg/kg/day14 (3–151)12Yes14 (26)24 (45)INF 3 (6), RBV 21 (40)
Roche et al. [27]2008133 (29: INF)75NA2b: 0.6–1.5 μg/kg per week ( ), 2a: 90–180 μg/week ( )1.8–16.9 mg/kg/day86 (5–231)12Yes58 (44)41 (38)INF 41 (38), RBV 80 (60)
Hanouneh et al. [220]2008537902b: 1.5 μg/kg per week,
2a: 180 μg/week, (no. of patients not stated)
1000–120015 (7–39)12Yes19 (35)14 (26)31 (58)
Berenguer et al. [28]200910786112b: 1.5 μg/kg per week ( ),
2a: 180 μg/week ( )
600–120021 (2–133)12Yes39 (37)INF 37 (35), RBV 43 (40)
Selzner et al. [26]2009172 (36: INF)6862b: 1.5 μg/kg per week,
2a: 180 μg/week, (no. of patients not stated)
800–100019 (1–149)12Yes86 (50)29 (17)80 (47%)
Schmidt et al. [221]20108388NA2b: 1.0 μg/kg per week ( ),
2a: 180 μg/week ( )
400–100041 (0.6–144)12Yes31 (26)24 (29)49 (51)
Jain et al. [222]20106093NA2b: 1–1.5 μg/kg per week ( ),
2a: 180 μg/week ( )
80029 ± 2812Yes21 (35)24 (40)INF 21 (35), RBV 16 (27)
Al-Hamoudi et al. [223]2011250 (All genotype 4)NA2a: 180 μg/week ( )400–120014 (1–72)12Yes14 (56)1 (4)INF 0 (0), RBV 7 (28)

Abbreviations: FCH: fibrosing cholestatic hepatitis; INF: interferon; LT: liver transplantation; NA: not available; PEG-INF: pegylated-interferon; RBV: ribavirin; SVR: sustained viral response.

Factors affecting SVR rates after PEG-INF/RBV therapy have been aggressively investigated in these studies. Non-1 genotype [26, 27, 199, 202, 213, 218, 220, 234, 235], absence of prior antiviral therapy [194], early virologic response (evaluated after 3 months) [27, 28, 202, 205, 207210, 214, 215, 217221, 223, 235], rapid virologic response (evaluated after 1 month) [206, 208, 220], adherence to therapy [27, 202, 207, 211, 213, 216218], low baseline viral load [27, 208, 211213, 216, 221, 222], low pretreatment fibrosis stage [26, 28, 204], younger donor age [26, 28, 221, 234], polymorphisms close to the IL-28B gene [6669], and cyclosporine-based immunosuppression [26, 234, 236] are associated with an improved SVR. Most studies demonstrated improved biochemical and histologic findings, even in virologic nonresponders [222, 237], but whether antiviral therapy slows disease progression in nonresponders has not yet been demonstrated. In addition, several recent retrospective studies with a considerable follow-up period revealed improved patient/graft survival in patients with an SVR [26, 73, 238, 239].

In the absence of controlled studies comparing different treatment regimens, it is not currently possible to determine whether to begin treatment with full or reduced doses and increase as tolerated, or whether individualized treatment is beneficial according to viral response kinetics. Therefore, the rules set out for the nontransplant population should be followed, but adherence to treatment is a major issue for posttransplant recipients. Dose reductions of RBV and/or PEG-INF are necessary in approximately 70% of patients and treatment discontinuation in approximately 30% (Table 2). Dose-dependent hemolytic anemia due to RBV is the major cause of dose reduction and treatment discontinuation in transplant recipients. Several authors have initiated RBV at low doses and then escalated according to tolerance in relation to hemoglobin levels and renal function. To avoid dose reduction, and thus achieve improved SVR, many authors used adjunctive therapy with erythropoietin or granulocyte colony stimulating factor (Table 2). While these drugs improve tolerability to antiviral treatment, there are no data confirming that they result in higher efficacy.

An increased risk of acute rejection in patients treated with PEG-INF/RBV (5%-6%) compared with those with INF/RBV (1%–3%) was suggested by recent systematic reviews [194197], although controlled studies did not detect any differences in the rejection rate between treated patients and untreated controls [190, 215, 240]. Whether PEG-INF/RBV therapy increases the risk of rejection remains to be investigated, but acute or chronic rejection seems to be frequently associated with concomitant low or negative serum HCV RNA, leading to an improvement in hepatic function after viral clearance, and resulting in lower serum immunosuppressant levels [241244]. Thus, close monitoring of calcineurin inhibitor levels is necessary during antiviral treatment. Several authors reported cases with immune-mediated hepatitis observed during or shortly after antiviral treatment (mainly after viral clearance) that responded well to increased immunosuppression [245247]. In patients under antiviral treatment, particularly in those with undetectable HCV RNA, any flare-up in liver enzymes would suggest rejection or “autoimmune hepatitis” and a liver biopsy should be performed.

Based on the present perspectives, it is compelling to conclude that there is currently no evidence to support the recommendation of antiviral treatment for recurrent graft hepatitis C due to the lack of clinical benefit and frequent adverse effects, as concluded by the recent Cochrane meta-analysis [198]. Recent retrospective cohort studies with a considerable follow-up duration found improved patient/graft survival in patients who obtained an SVR after antiviral treatment [26, 73, 238, 239]. Further randomized clinical trials with adequate trial methodology and adequate follow-up duration are necessary to confirm an actual survival benefit of antiviral treatment. At the same time, direct-acting antivirals such as protease, polymerase, or other nonstructural protein inhibitors should be investigated [248250].

7. Living Donor Liver Transplantation in Patients with HCV Cirrhosis

In areas with low deceased donor organ availability like Japan, the indication of LDLT for HCV cirrhosis is similar to that of DDLT [3], whereas in Western countries, LDLT is conducted in an attempt to alleviate the shortage of donor organs and decrease the mortality among patients awaiting transplants. Early studies raised some concerns, however, regarding the outcomes of LDLT in HCV patients, such as a poorer graft outcome and earlier and more aggressive HCV recurrence after LDLT compared with DDLT [224, 225, 227]. Several theories have been proposed to explain the differences in HCV recurrence between LDLT and DDLT recipients. One possible explanation is that the intense hepatocyte proliferation that occurs in partial liver grafts may lead to increased viral translation and replication [225, 251253]. Genetic donor-recipient similarity is another proposed mechanism for more severe HCV recurrence [254, 255]. Recent studies however, comparing outcomes of LDLT and DDLT in HCV-infected patients have not only failed to identify LDLT as a risk factor for more intense viral recurrence with impaired outcome, but also revealed improved results in LDLT recipients [21, 4650, 226, 228233], which do not support the aforementioned speculations. Alternatively, recent studies favored the theory that outcomes of LDLT for HCV cirrhosis could be better than those of DDLT due to the younger donor age and shorter ischemic time of LDLT grafts. The studies comparing outcomes between LDLT and DDLT in HCV-infected recipients are summarized in Table 3. While several studies demonstrated impaired patient/graft survival and severe histologic findings in LDLT [224, 225, 227], the majority of studies reported equal or even improved outcomes both in patient/graft survival and in fibrosis progression in LDLT [21, 4650, 226, 228233]. These data should be interpreted with caution, however, because of the important clinical distinction between LDLT and DDLT. At the time of transplantation, DDLT recipients are far sicker than LDLT recipients as represented by a significantly higher MELD score, donor age is higher, and graft ischemic time is longer, as shown in Table 3. All these factors, as discussed earlier, are considered independent prognostic factors for severe HCV recurrence and impaired patient/graft outcome. Additionally, as Terrault et al. [50] reported, the learning curve for the LDLT procedure may have a considerable impact on the outcome of LDLT for HCV cirrhosis. Jain et al. [233], who recently reported that both patient/graft survival and histologic findings are better in LDLT, found in a sub-analysis of the study that adjusting for MELD score (<25) and donor age (<50) resulted in similar outcomes.


AuthorYear (LDLT/DDLT)MELD score (LDLT/DDLT)Donor age (LDLT/DDLT)Cold ischemia time (h) (LDLT/DDLT)Follow up (mo)Histologic progressionPatient survival LDLT/DDLT (%)Graft survival LDLT/DDLT (%)Comments

Gaglio et al. [224]200368 (23/45)12.6/28*NANA24NA87/8987/85No difference in outcomes, increased risk of cholestatic hepatitis in LDLT
Shiffman et al. [46]200476 (23/53)13.5 ± 1.1/16.2 ± 1.047.6 ± 2/47.8 ± 0.8NA36No difference79/8276/82No difference in outcomes
Humar et al. [48] 200551 (12/39)17 (14–27)/24 (17–40)*37.7 ± 9.2/42.8 ± 16.210.2 ± 4.2/<128.3Significantly severe in DDLT92/90NALDLT may be at a low risk for HCV recurrence
Garcia-Retortillo et al. [225]2004117 (22/95)11 (5–24)/11 (2–28)31 (19–58)/47 (13–86)NA22Significantly severe in LDLTNANASevere hepatitis C recurrence in LDLT
Maluf et al. [226] 2005126 (29/97)13.2 ± 1.1/21 ± 0.8*NA0.6 ± 0.2/7.5 ± 2.872NA67/7064/69No difference in survival, more rejection in DDLT and biliary complications in LDLT
Thuluvath and Yoo [227]2004619 (207/412)NA35.8 ± 0.4/38.9 ± 18.13.9 ± 7.3/8.4 ± 4.524NA79/8174/73Lower graft survival in LDLT
Russo et al. [228]20044234 (279/3955)NA (TB, PT and Cre were significantly worse in DDLT)37/408.1/2.624NA83/8172/75No difference in outcomes
Bozorgzadeh et al. [229]2004100 (35/65)14.9 ± 4/15.9 ± 5.334.6 ± 9.7/49.2 ± 20.4NA39No difference89/7583/64No difference in outcomes
Van Vlierberghe et al. [230]200443 (17/26)15 ± 9/15 ± 831 ± 8/48 ± 173.1 ± 1.3/11.1 ± 2.612No differenceNo difference (Presented with only figure)No difference (Presented with only figure)No difference in outcomes in short-term
Schiano et al. [231]200526 (11/15)14 (9–19)/18 (10–31) 33 (20–54)/47 (13–73)0.6 (0.3–1.0)/10 (4.4–20)24NA73/8073/80No difference in survival, accelerated viral load increase in LDLT
Guo et al. [49]200667 (15/52)16.9 ± 6.9/19.0 ± 8.3NANA24No difference93/9687/94No difference in outcomes
Terrault et al. [50]2007275 (181/94)14 (6–40)/18 (7–40)*38 (19–57)/41 (9–72)0.8 (0.1–8)/6.7 (0.2–10)36No difference74/8268/80 fNo significant difference in patient/graft survival in experienced LDLT centers
Schmeding et al. [47]2007289 (20/269)NA38.6 ± 15.2/44.2 ± 12NA60No differenceBetter in DDLT ( )Better in DDLT ( )LDLT does not increase the risk and severity of HCV recurrence, No difference in patient/graft survival when HCC beyond Milan excluded.
Selzner et al. [232]2008201 (46/155)14 (7–39)/17 (6–40)38 (19–59)/46 (11–79)1.5 (0.5–4.9)/7.5 (1.1–16)60Significantly severe in DDLT84/7876/74Donor age, rather than transplant approach affects the progression of HCV
Gallegos-Orozco et al. [21]2009200 (32/168)14.6 ± 4.7/25.5 ± 5.9*35 ± 12/40 ± 16
NA60No difference81/81NALDLT is a good option for HCV cirrhosis
Jain et al. [233]2011100 (35/65)14.5 ± 3.9/16.8 ± 7.3*34.3 ± 9.3/47.2 ± 19.811 ± 3.1 in DDLT84Significantly severe in DDLT at all time points77/6571/46Both patient/graft survival and histologic findings were better in LDLT

*MELD score is significantly higher in DDLT.
Donor age is significantly higher in DDLT.
Cold ischemia time is significantly longer in DDLT.
Abbreviations: Cre: creatinine; DDLT: deceased donor liver transplantation; LDLT: living donor liver transplantation; MELD: model for end-stage liver disease; NA: not available; PT: prothombin-time; TB: total bilirubin.

Based on accumulating reports comparing LDLT and DDLT for HCV cirrhosis, hepatitis C recurrence by itself does not seem to explain the differences in patient/graft survival between LDLT and DDLT, and even improved outcomes could be achieved in LDLT due to the better quality of the graft and less sick recipient condition at the time of transplantation. Thus, LDLT could be strongly recommended for HCV-positive patients whenever it is available.

8. Retransplantation for Graft Failure Due to Recurrent Hepatitis C

Graft reinfection by HCV is universal with a faster progression to fibrosis and cirrhosis compared with nontransplanted patients, and in those with decompensated graft cirrhosis, retransplantation is the only potentially curative option, although HCV infection has been identified as a risk factor in previous studies [12, 256263]. Recipient and donor age, bilirubin and creatinine levels, UNOS status, MELD score, time to retransplantation (<1 year), and HCV infection have been identified as independent risk factors in these studies. The International Liver Transplantation Society Expert Panel established that bilirubin ≥ 10 mg/dl, creatinine ≥ 2.0 mg/dl, recipient age < 55, donor age > 40, and early HCV recurrence (cirrhosis within 1 year after transplant) are variables associated with a worse outcome after retransplantation [2].

Due to the lack of a clear consensus with a variety of reported factors, several models based on logistic regression analysis of donor and recipient factors have been developed in the decision-making process for elective retransplantation in HCV-infected patients. These models include the Rosen score [264], the MELD score [12, 262, 265], the Child-Turcotte-Pugh score [258, 262, 266], and the Donor Risk Index [267]. Among these, the Rosen score [264], calculated based on recipient age, bilirubin and creatinine levels, and retransplantation interval, is most widely used and validated. Patients with a Rosen score ≤ 16 had the best 1- and 3-year survival rates (75% and 70%, resp.), while patients with a Rosen score ≥ 20.5 had survival rates of only 42% and 38%, respectively. Two recent studies [263, 266] using the Rosen score as a screening tool revealed similar survival rates in HCV-infected patients and non-HCV-infected patient. Overall, liver retransplantation is not contraindicated in HCV-infected patients, yet in patients with a high risk of death after retransplantation (e.g., ≥20.5 in Rosen score) the use of a new organ seems unreasonable.

9. Conclusion

Hepatitis C is here to stay and will remain the most common indication for liver transplantation. Physicians treating HCV-infected candidates and recipients of liver transplantation must be aware of important issues that affect the natural history of recurrent HCV. At present, factors modifiable by clinicians include proper graft allocation, preservation injury, immunosuppression, and antiviral treatment, but many factors among these aspects remain to be determined in future well-designed prospective studies. LDLT can be performed as safely and effectively as DDLT for HCV-infected patients in experienced centers.

Abbreviations

ALT:Alanine aminotransferase;
AST: Aspartate aminotrasnsferase;
ATG: Antithymocyte globulin;
CMV: Cytomegarovirus;
DDLT: Deceased donor liver transplantation;
FCH: Fibrosing cholestatic hepatitis;
HCV: Hepatitis C virus;
HIV: Human immunodeficiency virus;
IL: Interleukin;
INF: Interferon;
LDLT: Living donor liver transplantation;
MELD: Model for end-stage liver disease;
MMF: Mycophenolate mofetil;
mTOR: Mammalian target of rapamycin;
PEG-INF: Pegylated interferon;
RBV: Ribavirin;
RNA: Ribonucleic acid;
ROC: Receiver operating characteristics;
SVR: Sustained viral response;
UNOS/OPTN: The United Network for Organ Sharing/Organ Procurement and Transplantation Network.

References

  1. R. Adam, P. McMaster, J. G. O'Grady et al., “Evolution of liver transplantation in Europe. Report of the European Liver Transplant Registry,” Liver Transplantation, vol. 9, no. 12, pp. 1231–1243, 2003. View at: Publisher Site | Google Scholar
  2. R. H. Wiesner, M. Sorrell, F. Villamil et al., “Report of the first international liver transplantation society expert panel consensus conference on liver transplantation and hepatitis C,” Liver Transplantation, vol. 9, no. 11, pp. S1–S9, 2003. View at: Publisher Site | Google Scholar
  3. Y. Sugawara and M. Makuuchi, “Living donor liver transplantation to patients with hepatitis C virus cirrhosis,” World Journal of Gastroenterology, vol. 12, no. 28, pp. 4461–4465, 2006. View at: Google Scholar
  4. M. Berenguer, R. Charco, J. Manuel Pascasio, and J. Ignacio Herrero, “Spanish society of liver transplantation (SETH) consensus recommendations on hepatitis C virus and liver transplantation,” Liver International, vol. 32, no. 5, pp. 712–731, 2012. View at: Publisher Site | Google Scholar
  5. M. Garcia-Retortillo, X. Forns, A. Feliu et al., “Hepatitis C virus kinetics during and immediately after liver transplantation,” Hepatology, vol. 35, no. 3, pp. 680–687, 2002. View at: Publisher Site | Google Scholar
  6. M. Berenguer, “Natural history of recurrent hepatitis C,” Liver Transplantation, vol. 8, no. 10, pp. S14–S18, 2002. View at: Publisher Site | Google Scholar
  7. E. J. Gane, B. G. Portmann, N. V. Naoumov et al., “Long-term outcome of hepatitis C infection after liver transplantation,” New England Journal of Medicine, vol. 334, no. 13, pp. 815–820, 1996. View at: Publisher Site | Google Scholar
  8. M. Berenguer, M. Prieto, J. M. Rayón et al., “Natural history of clinically compensated hepatitis C virus-related graft cirrhosis after liver transplantation,” Hepatology, vol. 32, no. 4 I, pp. 852–858, 2000. View at: Google Scholar
  9. T. K. Narang, W. Ahrens, and M. W. Russo, “Post-liver transplant cholestatic hepatitis C: a systematic review of clinical and pathological findings and application of consensus criteria,” Liver Transplantation, vol. 16, no. 11, pp. 1228–1235, 2010. View at: Publisher Site | Google Scholar
  10. B. Roche and D. Samuel, “Risk factors for hepatitis C recurrence after liver transplantation,” Journal of Viral Hepatitis, vol. 14, no. 1, supplement, pp. 89–96, 2007. View at: Publisher Site | Google Scholar
  11. L. M. Forman, J. D. Lewis, J. A. Berlin, H. I. Feldman, and M. R. Lucey, “The association between hepatitis C infection and survival after orthotopic liver transplantation,” Gastroenterology, vol. 122, no. 4, pp. 889–896, 2002. View at: Google Scholar
  12. M. Ghabril, R. Dickson, and R. Wiesner, “Improving outcomes of liver retransplantation: an analysis of trends and the impact of hepatitis C infection,” American Journal of Transplantation, vol. 8, no. 2, pp. 404–411, 2008. View at: Publisher Site | Google Scholar
  13. M. Berenguer, M. Prieto, F. S. Juan et al., “Contribution of donor age to the recent decrease in patient survival among HCV-infected liver transplant recipients,” Hepatology, vol. 36, no. 1, pp. 202–210, 2002. View at: Publisher Site | Google Scholar
  14. P. J. Thuluvath, K. L. Krok, D. L. Segev, and H. Y. Yoo, “Trends in post-liver transplant survival in patients with hepatitis C between 1991 and 2001 in the United States,” Liver Transplantation, vol. 13, no. 5, pp. 719–724, 2007. View at: Publisher Site | Google Scholar
  15. L. S. Belli, A. K. Burroughs, P. Burra et al., “Liver transplantation for HCV cirrhosis: improved survival in recent years and increased severity of recurrent disease in female recipients: results of a long term retrospective study,” Liver Transplantation, vol. 13, no. 5, pp. 733–740, 2007. View at: Publisher Site | Google Scholar
  16. M. Berenguer, L. Ferrell, J. Watson et al., “HCV-related fibrosis progression following liver transplantation: increase in recent years,” Journal of Hepatology, vol. 32, no. 4, pp. 673–684, 2000. View at: Publisher Site | Google Scholar
  17. D. Samuel, X. Forns, M. Berenguer et al., “Report of the monothematic EASL conference on liver transplantation for viral hepatitis. (Paris, France, January 12–14, 2006),” Journal of Hepatology, vol. 45, no. 1, pp. 127–143, 2006. View at: Publisher Site | Google Scholar
  18. D. G. Maluf, E. B. Edwards, R. T. Stravitz, and H. M. Kauftman, “Impact of the donor risk index on the outcome of hepatitis C virus-positive Liver transplant recipients,” Liver Transplantation, vol. 15, no. 6, pp. 592–599, 2009. View at: Publisher Site | Google Scholar
  19. M. Wali, R. F. Harrison, P. J. Gow, and D. Mutimer, “Advancing donor liver age and rapid fibrosis progression following transplantation for hepatitis C,” Gut, vol. 51, no. 2, pp. 248–252, 2002. View at: Publisher Site | Google Scholar
  20. K. Rifai, M. Sebagh, V. Karam et al., “Donor age influences 10-year liver graft histology independently of hepatitis C virus infection,” Journal of Hepatology, vol. 41, no. 3, pp. 446–453, 2004. View at: Publisher Site | Google Scholar
  21. J. F. Gallegos-Orozco, A. Yosephy, B. Noble et al., “Natural history of post-liver transplantation hepatitis C: a review of factors that may influence its course,” Liver Transplantation, vol. 15, no. 12, pp. 1872–1881, 2009. View at: Publisher Site | Google Scholar
  22. A. P. Khapra, K. Agarwal, M. I. Fiel et al., “Impact of donor age on survival and fibrosis progression in patients with hepatitis C undergoing liver transplantation using HCV+ allografts,” Liver Transplantation, vol. 12, no. 10, pp. 1496–1503, 2006. View at: Publisher Site | Google Scholar
  23. D. Brandman, A. Pingitore, J. C. Lai et al., “Hepatic steatosis at 1 year is an additional predictor of subsequent fibrosis severity in liver transplant recipients with recurrent hepatitis C virus,” Liver Transplantation, vol. 17, no. 12, pp. 1380–1386, 2011. View at: Publisher Site | Google Scholar
  24. S. C. Rayhill, Y. M. Wu, D. A. Katz et al., “Older donor livers show early severe histological activity, fibrosis, and graft failure after liver transplantation for hepatitis C,” Transplantation, vol. 84, no. 3, pp. 331–339, 2007. View at: Publisher Site | Google Scholar
  25. V. I. Machicao, H. Bonatti, M. Krishna et al., “Donor age affects fibrosis progression and graft survival after liver transplantation for hepatitis C,” Transplantation, vol. 77, no. 1, pp. 84–92, 2004. View at: Publisher Site | Google Scholar
  26. N. Selzner, E. L. Renner, M. Selzner et al., “Antiviral treatment of recurrent Hepatitis C after liver transplantation: predictors of response and long-term outcome,” Transplantation, vol. 88, no. 10, pp. 1214–1221, 2009. View at: Publisher Site | Google Scholar
  27. B. Roche, M. Sebagh, M. L. Canfora et al., “Hepatitis C virus therapy in liver transplant recipients: response predictors, effect on fibrosis progression, and importance of the initial stage of fibrosis,” Liver Transplantation, vol. 14, no. 12, pp. 1766–1777, 2008. View at: Publisher Site | Google Scholar
  28. M. Berenguer, V. Aguilera, M. Prieto et al., “Worse recent efficacy of antiviral therapy in liver transplant recipients with recurrent hepatitis C: impact of donor age and baseline cirrhosis,” Liver Transplantation, vol. 15, no. 7, pp. 738–746, 2009. View at: Publisher Site | Google Scholar
  29. M. Hoare, T. Das, and G. Alexander, “Ageing, telomeres, senescence, and liver injury,” Journal of Hepatology, vol. 53, no. 5, pp. 950–961, 2010. View at: Publisher Site | Google Scholar
  30. A. W. Avolio, U. Cillo, M. Salizzoni et al., “Balancing donor and recipient risk factors in liver transplantation: the value of D-MELD with particular reference to HCV recipients,” American Journal of Transplantation, vol. 11, no. 12, pp. 2724–2736, 2011. View at: Publisher Site | Google Scholar
  31. P. G. Northup, C. K. Argo, D. T. Nguyen et al., “Liver allografts from hepatitis c positive donors can offer good outcomes in hepatitis C positive recipients: a US national transplant registry analysis,” Transplant International, vol. 23, no. 10, pp. 1038–1044, 2010. View at: Publisher Site | Google Scholar
  32. J. I. Arenas, H. E. Vargas, and J. Rakela, “The use of hepatitis C-infected grafts in liver transplantation,” Liver Transplantation, vol. 9, no. 11, pp. S48–S51, 2003. View at: Publisher Site | Google Scholar
  33. M. Berenguer, “Risk of extended criteria donors in hepatitis C virus-positive recipients,” Liver Transplantation, vol. 14, pp. S45–S50, 2008. View at: Google Scholar
  34. R. Ballarin, A. Cucchetti, M. Spaggiari et al., “Long-term follow-up and outcome of liver transplantation from anti-hepatitis C virus-positive donors: a European multicentric case-control study,” Transplantation, vol. 91, no. 11, pp. 1265–1272, 2011. View at: Publisher Site | Google Scholar
  35. K. D. S. Watt, E. R. Lyden, J. M. Gulizia, and T. M. McCashland, “Recurrent hepatitis C posttransplant: early preservation injury may predict poor outcome,” Liver Transplantation, vol. 12, no. 1, pp. 134–139, 2006. View at: Publisher Site | Google Scholar
  36. P. W. Baron, D. Sindram, D. Higdon et al., “Prolonged rewarming time during allograft implantation predisposes to recurrent hepatitis C infection after liver transplantation,” Liver Transplantation, vol. 6, no. 4, pp. 407–412, 2000. View at: Google Scholar
  37. S. Feng, N. P. Goodrich, J. L. Bragg-Gresham et al., “Characteristics associated with liver graft failure: the concept of a donor risk index,” American Journal of Transplantation, vol. 6, no. 4, pp. 783–790, 2006. View at: Publisher Site | Google Scholar
  38. J. Briceño, R. Ciria, M. Pleguezuelo et al., “Contribution of marginal donors to liver transplantation for hepatitis C virus infection,” Transplantation Proceedings, vol. 39, no. 7, pp. 2297–2299, 2007. View at: Publisher Site | Google Scholar
  39. A. M. Cameron, R. M. Ghobrial, H. Yersiz et al., “Optimal utilization of donor grafts with extended criteria: a single-center experience in over 1000 liver transplants,” Annals of Surgery, vol. 243, no. 6, pp. 748–753, 2006. View at: Publisher Site | Google Scholar
  40. R. Hernandez-Alejandro, K. P. Croome, D. Quan et al., “Increased risk of severe recurrence of hepatitis C virus in liver transplant recipients of donation after cardiac death allografts,” Transplantation, vol. 92, no. 6, pp. 686–689, 2011. View at: Publisher Site | Google Scholar
  41. T. Uemura, V. Ramprasad, and C. S. Hollenbeak, “Liver transplantation for hepatitis C from donation after cardiac death donors: an analysis of OPTN/UNOS data,” American Journal of Transplantation, vol. 12, no. 4, pp. 984–991, 2012. View at: Google Scholar
  42. S. M. Strasberg, T. K. Howard, E. P. Molmenti, and M. Hertl, “Selecting the donor liver: risk factors for poor function after orthotopic liver transplantation,” Hepatology, vol. 20, no. 4, pp. 829–838, 1994. View at: Google Scholar
  43. R. J. Ploeg, A. M. D'Alessandro, S. J. Knechtle et al., “Risk factors for primary dysfunction after liver transplantation—a multivariate analysis,” Transplantation, vol. 55, no. 4, pp. 807–813, 1993. View at: Google Scholar
  44. A. Nocito, A. M. El-Badry, and P. A. Clavien, “When is steatosis too much for transplantation?” Journal of Hepatology, vol. 45, no. 4, pp. 494–499, 2006. View at: Publisher Site | Google Scholar
  45. V. Subramanian, A. B. Seetharam, and N. Vachharajani, “Donor graft steatosis influences immunity to hepatitis C virus and allograft outcome after liver transplantation,” Transplantation, vol. 92, no. 11, pp. 1259–1268, 2011. View at: Google Scholar
  46. M. L. Shiffman, R. T. Stravitz, M. J. Contos et al., “Histologic recurrence of chronic hepatitis C virus in patients after living donor and deceased donor liver transplantation,” Liver Transplantation, vol. 10, no. 10, pp. 1248–1255, 2004. View at: Publisher Site | Google Scholar
  47. M. Schmeding, U. P. Neumann, G. Puhl, M. Bahra, R. Neuhaus, and P. Neuhaus, “Hepatitis C recurrence and fibrosis progression are not increased after living donor liver transplantation: a single-center study of 289 patients,” Liver Transplantation, vol. 13, no. 5, pp. 687–692, 2007. View at: Publisher Site | Google Scholar
  48. A. Humar, K. Horn, A. Kalis, B. Glessing, W. D. Payne, and J. Lake, “Living donor and split-liver transplants in hepatitis C recipients: does liver regeneration increase the risk for recurrence?” American Journal of Transplantation, vol. 5, no. 2, pp. 399–405, 2005. View at: Publisher Site | Google Scholar
  49. L. Guo, M. Orrego, H. Rodriguez-Luna et al., “Living donor liver transplantation for hepatitis C-related cirrhosis: no difference in histological recurrence when compared to deceased donor liver transplantation recipients,” Liver Transplantation, vol. 12, no. 4, pp. 560–565, 2006. View at: Publisher Site | Google Scholar
  50. N. A. Terrault, M. L. Shiffman, A. S. F. Lok et al., “Outcomes in hepatitis C virus-infected recipients of living donor vs. deceased donor liver transplantation,” Liver Transplantation, vol. 13, no. 1, pp. 122–129, 2007. View at: Publisher Site | Google Scholar
  51. C. Feray, L. Caccamo, and G. J. Alexander, “European collaborative study on factors influencing outcome after liver transplantation for hepatitis C. European Concerted Action on Viral Hepatitis (EUROHEP) Group,” Gastroenterology, vol. 117, no. 3, pp. 619–625, 1999. View at: Google Scholar
  52. H. E. Vargas, T. Laskus, L. F. Wang et al., “The influence of hepatitis C virus genotypes on the outcome of liver transplantation,” Liver Transplantation and Surgery, vol. 4, no. 1, pp. 22–27, 1998. View at: Google Scholar
  53. M. Berenguer, J. Crippin, R. Gish et al., “A model to predict severe HCV-related disease following liver transplantation,” Hepatology, vol. 38, no. 1, pp. 34–41, 2003. View at: Publisher Site | Google Scholar
  54. M. Charlton, E. Seaberg, R. Wiesner et al., “Predictors of patient and graft survival following liver transplantation for hepatitis C,” Hepatology, vol. 28, no. 3, pp. 823–830, 1998. View at: Google Scholar
  55. R. Sreekumar, A. Gonzalez-Koch, Y. Maor-Kendler et al., “Early identification of recipients with progressive histologic recurrence of hepatitis C after liver transplantation,” Hepatology, vol. 32, no. 5, pp. 1125–1130, 2000. View at: Google Scholar
  56. G. W. McCaughan and A. Zekry, “Mechanisms of HCV reinfection and allograft damage after liver transplantation,” Journal of Hepatology, vol. 40, no. 3, pp. 368–374, 2004. View at: Publisher Site | Google Scholar
  57. A. L. Doughty, D. M. Painter, and G. W. McCaughan, “Post-transplant quasispecies pattern remains stable over time in patients with recurrent cholestatic hepatitis due to hepatitis C virus,” Journal of Hepatology, vol. 32, no. 1, pp. 126–134, 2000. View at: Google Scholar
  58. A. C. Lyra, X. Fan, D. M. Lang et al., “Evolution of hepatitis C viral quasispecies after liver transplantation,” Gastroenterology, vol. 123, no. 5, pp. 1485–1493, 2002. View at: Google Scholar
  59. M. Selzner, A. Kashfi, N. Selzner et al., “Recipient age affects long-term outcome and hepatitis C recurrence in old donor livers following transplantation,” Liver Transplantation, vol. 15, no. 10, pp. 1288–1295, 2009. View at: Publisher Site | Google Scholar
  60. R. J. Firpi, M. F. Abdelmalek, C. Soldevila-Pico et al., “One-year protocol liver biopsy can stratify fibrosis progression in liver transplant recipients with recurrent hepatitis C infection,” Liver Transplantation, vol. 10, no. 10, pp. 1240–1247, 2004. View at: Publisher Site | Google Scholar
  61. P. S. Pang, A. Kamal, and J. S. Glenn, “The effect of donor race on the survival of black Americans undergoing liver transplantation for chronic hepatitis C,” Liver Transplantation, vol. 15, no. 9, pp. 1126–1132, 2009. View at: Publisher Site | Google Scholar
  62. V. Saxena, J. C. Lai, J. G. O'Leary et al., “Recipient-donor race mismatch for African American liver transplant patients with chronic hepatitis C,” Liver Transpl, vol. 18, no. 5, pp. 524–531, 2012. View at: Google Scholar
  63. M. Moeller, A. Zalawadia, A. Alrayes, G. Divine, K. Brown, and D. Moonka, “The impact of donor race on recurrent hepatitis C after liver transplantation,” Transplantation Proceedings, vol. 42, no. 10, pp. 4175–4177, 2010. View at: Publisher Site | Google Scholar
  64. T. Walter, J. Dumortier, O. Guillaud, V. Hervieu, J. Y. Scoazec, and O. Boillot, “Factors influencing the progression of fibrosis in patients with recurrent hepatitis C after liver transplantation under antiviral therapy: a retrospective analysis of 939 liver biopsies in a single center,” Liver Transplantation, vol. 13, no. 2, pp. 294–301, 2007. View at: Publisher Site | Google Scholar
  65. J. C. Lai, E. C. Verna, R. S. Brown et al., “Hepatitis c virus-infected women have a higher risk of advanced fibrosis and graft loss after liver transplantation than men,” Hepatology, vol. 54, no. 2, pp. 418–424, 2011. View at: Publisher Site | Google Scholar
  66. M. R. Charlton, A. Thompson, B. J. Veldt et al., “Interleukin-28B polymorphisms are associated with histological recurrence and treatment response following liver transplantation in patients with hepatitis C virus infection,” Hepatology, vol. 53, no. 1, pp. 317–324, 2011. View at: Publisher Site | Google Scholar
  67. C. M. Lange, D. Moradpour, A. Doehring et al., “Impact of donor and recipient IL28B rs12979860 genotypes on hepatitis C virus liver graft reinfection,” Journal of Hepatology, vol. 55, no. 2, pp. 322–327, 2011. View at: Publisher Site | Google Scholar
  68. T. Fukuhara, A. Taketomi, T. Motomura et al., “Variants in IL28B in liver recipients and donors correlate with response to peg-interferon and ribavirin therapy for recurrent hepatitis C,” Gastroenterology, vol. 139, no. 5, pp. 1577–1585, 2010. View at: Publisher Site | Google Scholar
  69. M. Coto-Llerena, G. Crespo, P. González et al., “Determination of IL28B polymorphisms in liver biopsies obtained after liver transplantation,” Journal of Hepatology, vol. 56, no. 2, pp. 355–358, 2012. View at: Publisher Site | Google Scholar
  70. E. C. Verna, E. De Martin, P. Burra et al., “The impact of hepatitis C and biliary complications on patient and graft survival following liver transplantation,” American Journal of Transplantation, vol. 9, no. 6, pp. 1398–1405, 2009. View at: Publisher Site | Google Scholar
  71. A. Bozorgzadeh, M. Orloff, P. Abt et al., “Survival outcomes in liver transplantation for hepatocellular carcinoma, comparing impact of hepatitis C versus other etiology of cirrhosis,” Liver Transplantation, vol. 13, no. 6, pp. 807–813, 2007. View at: Publisher Site | Google Scholar
  72. A. Moya, M. Berenguer, V. Aguilera et al., “Hepatocellular carcinoma: can it be considered a controversial indication for liver transplantation in centers with high rates of hepatitis C?” Liver Transplantation, vol. 8, no. 11, pp. 1020–1027, 2002. View at: Publisher Site | Google Scholar
  73. R. J. Firpi, V. Clark, C. Soldevila-Pico et al., “The natural history of hepatitis C cirrhosis after liver transplantation,” Liver Transplantation, vol. 15, no. 9, pp. 1063–1071, 2009. View at: Publisher Site | Google Scholar
  74. K. H. W. Böker, G. Dalley, M. J. Bahr et al., “Long-term outcome of hepatitis C virus infection after liver transplantation,” Hepatology, vol. 25, no. 1, pp. 203–210, 1997. View at: Google Scholar
  75. E. Melum, S. Friman, K. Bjøro et al., “Hepatitis C impairs survival following liver transplantation irrespective of concomitant hepatocellular carcinoma,” Journal of Hepatology, vol. 47, no. 6, pp. 777–783, 2007. View at: Publisher Site | Google Scholar
  76. D. N. Samonakis, C. K. Triantos, U. Thalheimer et al., “Immunosuppresion and donor age with respect to severity of HCV recurrence after liver transplantation,” Liver Transplantation, vol. 11, no. 4, pp. 386–395, 2005. View at: Publisher Site | Google Scholar
  77. Y. Sugawara, S. Tamura, and N. Kokudo, “Liver transplantation in HCV/HIV positive patients,” World Journal of Gastrointestinal Surgery, vol. 3, no. 2, pp. 21–28, 2011. View at: Google Scholar
  78. J. C. Duclos-Vallee, B. Falissard, and D. Samuel, “Liver transplant outcomes in HIV-infected patients: a systematic review and meta-analysis with a synthetic cohort,” AIDS, vol. 25, no. 13, pp. 1675–1676, 2011. View at: Google Scholar
  79. J. C. Duclos-Vallee, C. Feray, and M. Sebagh, “Survival and recurrence of hepatitis C after liver transplantation in patients coinfected with human immunodeficiency virus and hepatitis C virus,” Hepatology, vol. 47, no. 2, pp. 407–417, 2008. View at: Google Scholar
  80. A. Moreno, C. Cervera, J. Fortun et al., “Epidemiology and outcome of infections in human immunodeficiency virus/hepatitis c virus-coinfected liver transplant recipients: a FIPSE/GESIDA Prospective Cohort Study,” Liver Transplantation, vol. 18, no. 1, pp. 70–81, 2012. View at: Google Scholar
  81. M. E. De Vera, I. Dvorchik, K. Tom et al., “Survival of liver transplant patients coinfected with HIV and HCV is adversely impacted by recurrent hepatitis C,” American Journal of Transplantation, vol. 6, no. 12, pp. 2983–2993, 2006. View at: Publisher Site | Google Scholar
  82. J. Fung, B. Eghtesad, K. Patel-Tom, M. DeVera, H. Chapman, and M. Ragni, “Liver transplantation in patients with HIV infection,” Liver Transplantation, vol. 10, no. 10, supplement, pp. S39–S53, 2004. View at: Publisher Site | Google Scholar
  83. K. Wojcik, M. Vogel, E. Voigt et al., “Antiviral therapy for hepatitis C virus recurrence after liver transplantation in HIV-infected patients: outcome in the Bonn cohort,” AIDS, vol. 21, no. 10, pp. 1363–1365, 2007. View at: Publisher Site | Google Scholar
  84. N. M. Kemmer and K. E. Sherman, “Liver transplantation trends in the HIV population,” Digestive Diseases and Sciences, vol. 56, no. 11, pp. 3393–3398, 2011. View at: Google Scholar
  85. E. J. Gane, N. V. Naoumov, K. P. Qian et al., “A longitudinal analysis of hepatitis C virus replication following liver transplantation,” Gastroenterology, vol. 110, no. 1, pp. 167–177, 1996. View at: Publisher Site | Google Scholar
  86. I. A. Hanouneh, A. E. Feldstein, A. J. McCullough et al., “The significance of metabolic syndrome in the setting of recurrent hepatitis C after liver transplantation,” Liver Transplantation, vol. 14, no. 9, pp. 1287–1293, 2008. View at: Publisher Site | Google Scholar
  87. G. V. Papatheodoridis, S. G. R. G. Barton, D. Andrew et al., “Longitudinal variation in hepatitis C virus (HCV) viraemia and early course of HCV infection after liver transplantation for HCV cirrhosis: the role of different immunosuppressive regimens,” Gut, vol. 45, no. 3, pp. 427–434, 1999. View at: Google Scholar
  88. N. A. Shackel, J. Jamias, W. Rahman et al., “Early high peak hepatitis C viral load levels independently predict hepatitis C-related liver failure post-liver transplantation,” Liver Transplantation, vol. 15, no. 7, pp. 709–718, 2009. View at: Publisher Site | Google Scholar
  89. H. R. Rosen, S. Chou, C. L. Corless et al., “Cytomegalovirus viremia: risk factor for allograft cirrhosis after liver transplantation for hepatitis C,” Transplantation, vol. 64, no. 5, pp. 721–726, 1997. View at: Publisher Site | Google Scholar
  90. K. W. Burak, W. K. Kremers, K. P. Batts et al., “Impact of cytomegalovirus infection, year of transplantation, and donor age on outcomes after liver transplantation for hepatitis C,” Liver Transplantation, vol. 8, no. 4, pp. 362–369, 2002. View at: Publisher Site | Google Scholar
  91. A. Humara, D. Kumar, J. Raboud et al., “Interactions between cytomegalovirus, human herpesvirus-6, and the recurrence of hepatitis C after liver transplantation,” American Journal of Transplantation, vol. 2, no. 5, pp. 461–466, 2002. View at: Publisher Site | Google Scholar
  92. R. Teixeira, S. Pastacaldi, S. Davies et al., “The influence of cytomegalovirus viraemia on the outcome of recurrent hepatitis C after liver transplantation,” Transplantation, vol. 70, no. 10, pp. 1454–1458, 2000. View at: Google Scholar
  93. S. Baid, A. B. Cosimi, M. Lin Farrell et al., “Posttransplant diabetes mellitus in liver transplant recipients: risk factors, temporal, relationship with hepatitis C virus allograft hepatitis, and impact on mortality,” Transplantation, vol. 72, no. 6, pp. 1066–1072, 2001. View at: Google Scholar
  94. M. R. Foxton, A. Quaglia, R. Muiesan et al., “The impact of diabetes mellitus on fibrosis progression in patients transplanted for hepatitis C,” American Journal of Transplantation, vol. 6, no. 8, pp. 1922–1929, 2006. View at: Publisher Site | Google Scholar
  95. A. A. AlDosary, A. S. Ramji, T. G. Elliott et al., “Post-liver transplantation diabetes mellitus: an association with hepatitis C,” Liver Transplantation, vol. 8, no. 4, pp. 356–361, 2002. View at: Publisher Site | Google Scholar
  96. E. J. Gane, “Diabetes mellitus following liver transplantation in patients with hepatitis C virus: risks and consequences,” American Journal of Transplantation, vol. 12, no. 3, pp. 531–538, 2012. View at: Publisher Site | Google Scholar
  97. S. G. Tueche, “Diabetes mellitus after liver transplant new etiologic clues and cornerstones for understanding,” Transplantation Proceedings, vol. 35, no. 4, pp. 1466–1468, 2003. View at: Publisher Site | Google Scholar
  98. K. C. Abbott, K. L. Lentine, J. R. Bucci et al., “Impact of diabetes and hepatitis after kidney transplantation on patients who are affected by hepatitis C virus,” Journal of the American Society of Nephrology, vol. 15, no. 12, pp. 3166–3174, 2004. View at: Publisher Site | Google Scholar
  99. B. J. Veldt, J. J. Poterucha, K. D. S. Watt et al., “Insulin resistance, serum adipokines and risk of fibrosis progression in patients transplanted for hepatitis C,” American Journal of Transplantation, vol. 9, no. 6, pp. 1406–1413, 2009. View at: Publisher Site | Google Scholar
  100. J. R. Lake, “The role of immunosuppression in recurrence of hepatitis C,” Liver Transplantation, vol. 9, no. 11, pp. S63–S66, 2003. View at: Publisher Site | Google Scholar
  101. P. A. Sheiner, M. E. Schwartz, E. Mor et al., “Severe or multiple rejection episodes are associated with early recurrence of hepatitis C after orthotopic liver transplantation,” Hepatology, vol. 21, no. 1, pp. 30–34, 1995. View at: Google Scholar
  102. M. Charlton and E. Seaberg, “Impact of immunosuppression and acute rejection on recurrence of hepatitis C: results of the national institute of diabetes and digestive and kidney diseases liver transplantation database,” Liver Transplantation and Surgery, vol. 5, no. 4, supplement 1, pp. S107–S114, 1999. View at: Google Scholar
  103. U. P. Neumann, T. Berg, M. Bahra et al., “Long-term outcome of liver transplants for chronic hepatitis C: a 10-year follow-up,” Transplantation, vol. 77, no. 2, pp. 226–231, 2004. View at: Publisher Site | Google Scholar
  104. S. Mukherjee and M. F. Sorrell, “Controversies in liver transplantation for hepatitis C,” Gastroenterology, vol. 134, no. 6, pp. 1777–1788, 2008. View at: Publisher Site | Google Scholar
  105. M. Berenguer, V. Aguilera, M. Prieto et al., “Significant improvement in the outcome of HCV-infected transplant recipients by avoiding rapid steroid tapering and potent induction immunosuppression,” Journal of Hepatology, vol. 44, no. 4, pp. 717–722, 2006. View at: Publisher Site | Google Scholar
  106. S. Brillanti, M. Vivarelli, N. De Ruvo et al., “Slowly tapering off steroids protects the graft against hepatitis C recurrence after liver transplantation,” Liver Transplantation, vol. 8, no. 10, pp. 884–888, 2002. View at: Publisher Site | Google Scholar
  107. M. Vivarelli, P. Burra, G. L. Barba et al., “Influence of steroids on HCV recurrence after liver transplantation: a prospective study,” Journal of Hepatology, vol. 47, no. 6, pp. 793–798, 2007. View at: Publisher Site | Google Scholar
  108. G. Sgourakis, A. Radtke, I. Fouzas et al., “Corticosteroid-free immunosuppression in liver transplantation: a meta-analysis and meta-regression of outcomes,” Transplant International, vol. 22, no. 9, pp. 892–905, 2009. View at: Publisher Site | Google Scholar
  109. J. D. Eason, S. Nair, A. J. Cohen, J. L. Blazek, and G. E. Loss, “Steroid-free liver transplantation using rabbit antithymocyte globulin and early tacrolimus monotherapy,” Transplantation, vol. 75, no. 8, pp. 1396–1399, 2003. View at: Publisher Site | Google Scholar
  110. C. Margarit, I. Bilbao, L. Castells et al., “A prospective randomized trial comparing tacrolimus and steroids with tacrolimus monotherapy in liver transplantation: the impact on recurrence of hepatitis C,” Transplant International, vol. 18, no. 12, pp. 1336–1345, 2005. View at: Publisher Site | Google Scholar
  111. T. Kato, J. J. Gaynor, H. Yoshida et al., “Randomized trial of steroid-free induction versus corticosteroid maintenance among orthotopic liver transplant recipients with hepatitis C virus: impact on hepatic fibrosis progression at one year,” Transplantation, vol. 84, no. 7, pp. 829–835, 2007. View at: Publisher Site | Google Scholar
  112. L. Lladó, J. Fabregat, J. Castellote et al., “Impact of immunosuppression without steroids on rejection and hepatitis C virus evolution after liver transplantation: results of a prospective randomized study,” Liver Transplantation, vol. 14, no. 12, pp. 1752–1760, 2008. View at: Publisher Site | Google Scholar
  113. F. Filipponi, F. Callea, M. Salizzoni et al., “Double-blind comparison of hepatitis C histological recurrence rate in HCV+ Liver Transplant Recipients Given Basiliximab+Steroids or Basiliximab+Placebo, in addition to Cyclosporine and Azathioprine,” Transplantation, vol. 78, no. 10, pp. 1488–1495, 2004. View at: Publisher Site | Google Scholar
  114. D. L. Segev, S. M. Sozio, E. J. Shin et al., “Steroid avoidance in liver transplantation: meta-analysis and meta-regression of randomized trials,” Liver Transplantation, vol. 14, no. 4, pp. 512–525, 2008. View at: Publisher Site | Google Scholar
  115. P. Manousou, D. Samonakis, E. Cholongitas et al., “Outcome of recurrent hepatitis C virus after liver transplantation in a randomized trial of tacrolimus monotherapy versus triple therapy,” Liver Transplantation, vol. 15, no. 12, pp. 1783–1791, 2009. View at: Publisher Site | Google Scholar
  116. G. B. Klintmalm, G. L. Davis, and L. Teperman, “A randomized, multicenter study comparing steroid-free immunosuppression and standard immunosuppression for liver transplant recipients with chronic hepatitis C,” Liver Transplantation, vol. 17, no. 12, pp. 1394–1403, 2011. View at: Google Scholar
  117. M. Nakagawa, N. Sakamoto, and N. Enomoto, “Specific inhibition of hepatitis C virus replication by cyclosporin A,” Biochemical and Biophysical Research Communications, vol. 313, no. 1, pp. 42–47, 2004. View at: Google Scholar
  118. S. D. Henry, H. J. Metselaar, R. C. B. Lonsdale et al., “Mycophenolic acid inhibits hepatitis C virus replication and acts in synergy with cyclosporin A and interferon-α,” Gastroenterology, vol. 131, no. 5, pp. 1452–1462, 2006. View at: Publisher Site | Google Scholar
  119. K. Watashi, M. Hijikata, M. Hosaka, M. Yamaji, and K. Shimotohno, “Cyclosporin A suppresses replication of hepatitis C virus genome in cultured hepatocytes,” Hepatology, vol. 38, no. 5, pp. 1282–1288, 2003. View at: Publisher Site | Google Scholar
  120. R. D. Kim, S. Mizuno, J. B. Sorensen, J. J. Schwartz, and S. Fujita, “Impact of calcineurin inhibitors on hepatitis C recurrence after liver transplantation,” Digestive Diseases and Sciences, vol. 57, no. 2, pp. 568–572, 2012. View at: Publisher Site | Google Scholar
  121. R. J. Firpi, H. Zhu, G. Morelli et al., “Cyclosporine suppresses hepatitis C virus in vitro and increases the chance of a sustained virological response after liver transplantation,” Liver Transplantation, vol. 12, no. 1, pp. 51–57, 2006. View at: Publisher Site | Google Scholar
  122. R. J. Firpi, C. Soldevila-Pico, G. G. Morelli et al., “The use of cyclosporine for recurrent hepatitis C after liver transplant: a randomized pilot study,” Digestive Diseases and Sciences, vol. 55, no. 1, pp. 196–203, 2010. View at: Publisher Site | Google Scholar
  123. L. J. W. Van Der Laan, M. Hudson, S. McPherson et al., “Results of a two-center study comparing hepatic fibrosis progression in HCV-positive liver transplant patients receiving cyclosporine or tacrolimus,” Transplantation Proceedings, vol. 42, no. 10, pp. 4573–4577, 2010. View at: Publisher Site | Google Scholar
  124. L. C. Fusté, “Cyclosporine a-based immunosuppression reduces relapse rate after antiviral therapy in transplanted patients with hepatitis C virus infection: a large multicenter cohort study,” Transplantation, vol. 92, no. 3, pp. 334–340, 2011. View at: Publisher Site | Google Scholar
  125. P. Martin, R. W. Busuttil, R. M. Goldstein et al., “Impact of tacrolimus versus cyclosporine in hepatitis C virus-infected liver transplant recipients on recurrent hepatitis: a prospective, randomized trial,” Liver Transplantation, vol. 10, no. 10, pp. 1258–1262, 2004. View at: Publisher Site | Google Scholar
  126. J. G. O'Grady, P. Hardy, A. K. Burroughs et al., “Randomized controlled trial of tacrolimus versus microemulsified cyclosporin (TMC) in liver transplantation: poststudy surveillance to 3 years,” American Journal of Transplantation, vol. 7, no. 1, pp. 137–141, 2007. View at: Publisher Site | Google Scholar
  127. G. Levy, G. L. Grazi, and F. Sanjuan, “12-month follow-up analysis of a multicenter, randomized, prospective trial in de novo liver transplant recipients (LIS2T) comparing cyclosporine microemulsion (C2 monitoring) and tacrolimus,” Liver Transplantation, vol. 12, no. 10, pp. 1464–1472, 2006. View at: Google Scholar
  128. M. Berenguer, V. Aguilera, F. San Juan et al., “Effect of calcineurin inhibitors in the outcome of liver transplantation in hepatitis C virus-positive recipients,” Transplantation, vol. 90, no. 11, pp. 1204–1209, 2010. View at: Publisher Site | Google Scholar
  129. M. Berenguer, A. Royuela, and J. Zamora, “Immunosuppression with calcineurin inhibitors with respect to the outcome of HCV recurrence after liver transplantation: results of a meta-analysis,” Liver Transplantation, vol. 13, no. 1, pp. 21–29, 2007. View at: Publisher Site | Google Scholar
  130. W. D. Irish, S. Arcona, D. Bowers, and J. F. Trotter, “Cyclosporine versus tacrolimus treated liver transplant recipients with chronic hepatitis C: outcomes analysis of the UNOS/OPTN database,” American Journal of Transplantation, vol. 11, no. 8, pp. 1676–1685, 2011. View at: Publisher Site | Google Scholar
  131. H. R. Rosen, C. R. Shackleton, L. Higa et al., “Use of OKT3 is associated with early and severe recurrence of hepatitis C after liver transplantation,” American Journal of Gastroenterology, vol. 92, no. 9, pp. 1453–1457, 1997. View at: Google Scholar
  132. A. Marcos, B. Eghtesad, J. J. Fung et al., “Use of alemtuzumab and tacrolimus monotherapy for cadaveric liver transplantation: with particular reference to hepatitis C virus,” Transplantation, vol. 78, no. 7, pp. 966–971, 2004. View at: Publisher Site | Google Scholar
  133. S. Nair, G. E. Loss, A. J. Cohen, and J. D. Eason, “Induction with rabbit antithymocyte globulin versus induction with corticosteroids in liver transplantation: impact on recurrent hepatitis C virus infection,” Transplantation, vol. 81, no. 4, pp. 620–622, 2006. View at: Publisher Site | Google Scholar
  134. N. De Ruvo, A. Cucchetti, A. Lauro et al., “Preliminary results of a “prope” tolerogenic regimen with thymoglobulin pretreatment and hepatitis C virus recurrence in liver transplantation,” Transplantation, vol. 80, no. 1, pp. 8–12, 2005. View at: Publisher Site | Google Scholar
  135. Y. Calmus, J. R. Scheele, I. Gonzalez-Pinto et al., “Immunoprophylaxis with basiliximab, a chimeric anti-interleukin-2 receptor monoclonal antibody, in combination with azathioprine-containing triple therapy in liver transplant recipients,” Liver Transplantation, vol. 8, no. 2, pp. 123–131, 2002. View at: Publisher Site | Google Scholar
  136. G. B. G. Klintmalm, W. K. Washburn, S. M. Rudich et al., “Corticosteroid-free immunosuppression with daclizumab in HCV+ liver transplant recipients: 1-year interim results of the HCV-3 study,” Liver Transplantation, vol. 13, no. 11, pp. 1521–1531, 2007. View at: Publisher Site | Google Scholar
  137. P. Neuhaus, P. A. Clavien, D. Kittur et al., “Improved treatment response with basiliximab immunoprophylaxis after liver transplantation: results from a double-blind randomized placebo-controlled trial,” Liver Transplantation, vol. 8, no. 2, pp. 132–142, 2002. View at: Publisher Site | Google Scholar
  138. D. R. Nelson, C. Soldevila-Pico, A. Reed et al., “Anti-interleukin-2 receptor therapy in combination with mycophenolate mofetil is associated with more severe hepatitis C recurrence after liver transplantation,” Liver Transplantation, vol. 7, no. 12, pp. 1064–1070, 2001. View at: Publisher Site | Google Scholar
  139. A. Jain, R. Kashyap, A. J. Demetris, B. Eghstesad, R. Pokharna, and J. J. Fung, “A prospective randomized trial of mycophenolate mofetil in liver transplant recipients with hepatitis C,” Liver Transplantation, vol. 8, no. 1, pp. 40–46, 2002. View at: Publisher Site | Google Scholar
  140. R. H. Wiesner, J. S. Shorr, B. J. Steffen, A. H. Chu, R. D. Gordon, and J. R. Lake, “Mycophenolate mofetil combination therapy improves long-term outcomes after liver transplantation in patients with and without hepatitis C,” Liver Transplantation, vol. 11, no. 7, pp. 750–759, 2005. View at: Publisher Site | Google Scholar
  141. F. Sánchez-Bueno, M. L. Ortiz, J. Bermejo et al., “Prognostic factors for hepatitis C recurrence in patients undergoing orthotopic liver transplantation,” Transplant Immunology, vol. 17, no. 1, pp. 47–50, 2006. View at: Publisher Site | Google Scholar
  142. T. M. Manzia, R. Angelico, L. Toti et al., “Long-term, maintenance MMF monotherapy improves the fibrosis progression in liver transplant recipients with recurrent hepatitis C,” Transplant International, vol. 24, no. 5, pp. 461–468, 2011. View at: Publisher Site | Google Scholar
  143. A. Kornberg, B. Küpper, A. Tannapfel, M. Hommann, and J. Scheele, “Impact of mycophenolate mofetil versus azathioprine on early recurrence of hepatitis C after liver transplantation,” International Immunopharmacology, vol. 5, no. 1, pp. 107–115, 2005. View at: Publisher Site | Google Scholar
  144. A. Kornberg, B. Küpper, J. Wilberg et al., “Conversion to mycophenolate mofetil for modulating recurrent hepatitis C in liver transplant recipients,” Transplant Infectious Disease, vol. 9, no. 4, pp. 295–301, 2007. View at: Publisher Site | Google Scholar
  145. M. Bahra, U. I. F. P. Neumann, D. Jacob et al., “MMF and calcineurin taper in recurrent hepatitis C after liver transplantation: impact on histological course,” American Journal of Transplantation, vol. 5, no. 2, pp. 406–411, 2005. View at: Publisher Site | Google Scholar
  146. A. Zekry, M. Gleeson, S. Guney, and G. W. McCaughan, “A prospective cross-over study comparing the effect of mycophenolate versus azathioprine on allograft function and viral load in liver transplant recipients with recurrent chronic HCV infection,” Liver Transplantation, vol. 10, no. 1, pp. 52–57, 2004. View at: Publisher Site | Google Scholar
  147. G. Germani, M. Pleguezuelo, F. Villamil et al., “Azathioprine in liver transplantation: a reevaluation of its use and a comparison with mycophenolate mofetil,” American Journal of Transplantation, vol. 9, no. 8, pp. 1725–1731, 2009. View at: Publisher Site | Google Scholar
  148. T. Kawahara, S. Asthana, and N. M. Kneteman, “m-TOR inhibitors: what role in liver transplantation?” Journal of Hepatology, vol. 55, no. 6, pp. 1441–1451, 2011. View at: Google Scholar
  149. S. Asthana, C. Toso, G. Meeberg et al., “The impact of sirolimus on hepatitis C recurrence after liver transplantation,” Canadian Journal of Gastroenterology, vol. 25, no. 1, pp. 28–34, 2011. View at: Google Scholar
  150. S. J. F. Harper, W. Gelson, I. G. Harper, G. J. M. Alexander, and P. Gibbs, “Switching to sirolimus-based immune suppression after liver transplantation is safe and effective: a single-center experience,” Transplantation, vol. 91, no. 1, pp. 128–132, 2011. View at: Publisher Site | Google Scholar
  151. H. R. Rosen, D. R. Gretch, M. Oehlke et al., “Timing and severity of initial hepatitis C recurrence as predictors of long-term liver allograft injury,” Transplantation, vol. 65, no. 9, pp. 1178–1182, 1998. View at: Publisher Site | Google Scholar
  152. M. Prieto, M. Berenguer, J. M. Rayón et al., “High incidence of allograft cirrhosis in hepatitis C virus genotype 1b infection following transplantation: relationship with rejection episodes,” Hepatology, vol. 29, no. 1, pp. 250–256, 1999. View at: Publisher Site | Google Scholar
  153. A. Sánchez-Fueyo, J. C. Restrepo, L. Quintó et al., “Impact of the recurrence of hepatitis c virus infection after liver transplantation on the long-term viability of the graft,” Transplantation, vol. 73, no. 1, pp. 56–63, 2002. View at: Google Scholar
  154. M. Guido, S. Fagiuoli, G. Tessari et al., “Histology predicts cirrhotic evolution of post transplant hepatitis C,” Gut, vol. 50, no. 5, pp. 697–700, 2002. View at: Publisher Site | Google Scholar
  155. G. Testa, J. S. Crippin, G. J. Netto et al., “Liver transplantation for hepatitis C: recurrence and disease progression in 300 patients,” Liver Transplantation, vol. 6, no. 5, pp. 553–561, 2000. View at: Google Scholar
  156. M. Berenguer, J. M. Rayón, M. Prieto et al., “Are posttransplantation protocol liver biopsies useful in the long term?” Liver Transplantation, vol. 7, no. 9, pp. 790–796, 2001. View at: Publisher Site | Google Scholar
  157. M. Sebagh, K. Rifai, C. Féray et al., “All liver recipients benefit from the protocol 10-year liver biopsies,” Hepatology, vol. 37, no. 6, pp. 1293–1301, 2003. View at: Publisher Site | Google Scholar
  158. A. Blasco, X. Forns, J. A. Carrión et al., “Hepatic venous pressure gradient identifies patients at risk of severe hepatitis C recurrence after liver transplantation,” Hepatology, vol. 43, no. 3, pp. 492–499, 2006. View at: Publisher Site | Google Scholar
  159. D. N. Samonakis, E. Cholongitas, U. Thalheimer et al., “Hepatic venous pressure gradient to assess fibrosis and its progression after liver transplantation for HCV cirrhosis,” Liver Transplantation, vol. 13, no. 9, pp. 1305–1311, 2007. View at: Publisher Site | Google Scholar
  160. G. Kalambokis, P. Manousou, D. Samonakis et al., “Clinical outcome of HCV-related graft cirrhosis and prognostic value of hepatic venous pressure gradient,” Transplant International, vol. 22, no. 2, pp. 172–181, 2009. View at: Publisher Site | Google Scholar
  161. E. Cholongitas, E. Tsochatzis, J. Goulis, and A. K. Burroughs, “Noninvasive tests for evaluation of fibrosis in HCV recurrence after liver transplantation: a systematic review,” Transplant International, vol. 23, no. 9, pp. 861–870, 2010. View at: Publisher Site | Google Scholar
  162. C. Kamphues, K. Lotz, C. Röcken et al., “Chances and limitations of non-invasive tests in the assessment of liver fibrosis in liver transplant patients,” Clinical Transplantation, vol. 24, no. 5, pp. 652–659, 2010. View at: Publisher Site | Google Scholar
  163. J. A. Carrión, M. Navasa, J. Bosch, M. Bruguera, R. Gilabert, and X. Forns, “Transient elastography for diagnosis of advanced fibrosis and portal hypertension in patients with hepatitis C recurrence after liver transplantation,” Liver Transplantation, vol. 12, no. 12, pp. 1791–1798, 2006. View at: Publisher Site | Google Scholar
  164. C. Rigamonti, M. F. Donato, M. Fraquelli et al., “Transient elastography predicts fibrosis progression in patients with recurrent hepatitis C after liver transplantation,” Gut, vol. 57, no. 6, pp. 821–827, 2008. View at: Publisher Site | Google Scholar
  165. F. Corradi, F. Piscaglia, S. Flori et al., “Assessment of liver fibrosis in transplant recipients with recurrent HCV infection: usefulness of transient elastography,” Digestive and Liver Disease, vol. 41, no. 3, pp. 217–225, 2009. View at: Publisher Site | Google Scholar
  166. N. Harada, Y. Soejima, A. Taketomi et al., “Assessment of graft fibrosis by transient elastography in patients with recurrent hepatitis C after living donor liver transplantation,” Transplantation, vol. 85, no. 1, pp. 69–74, 2008. View at: Publisher Site | Google Scholar
  167. J. A. Carríon, F. Torres, G. Crespo et al., “Liver stiffness identifies two different patterns of fibrosis progression in patients with hepatitis C virus recurrence after liver transplantation,” Hepatology, vol. 51, no. 1, pp. 23–34, 2010. View at: Publisher Site | Google Scholar
  168. V. S. Lee, F. H. Miller, R. A. Omary et al., “Magnetic resonance elastography and biomarkers to assess fibrosis from recurrent hepatitis c in liver transplant recipients,” Transplantation, vol. 92, no. 5, pp. 581–586, 2011. View at: Publisher Site | Google Scholar
  169. T. J. S. Cross, D. Jothimani, M. A. Heneghan, and P. M. Harrison, “Non-invasive assessment of fibrosis in liver grafts due to hepatitis C virus recurrence,” Clinical Transplantation, vol. 25, no. 3, pp. 345–351, 2011. View at: Publisher Site | Google Scholar
  170. T. J. S. Cross, V. Calvaruso, M. R. Foxton et al., “A simple, noninvasive test for the diagnosis of liver fibrosis in patients with hepatitis C recurrence after liver transplantation,” Journal of Viral Hepatitis, vol. 17, no. 9, pp. 640–649, 2010. View at: Publisher Site | Google Scholar
  171. J. A. Carrión, G. Fernández-Varo, M. Bruguera et al., “Serum fibrosis markers identify patients with mild and progressive hepatitis C recurrence after liver transplantation,” Gastroenterology, vol. 138, no. 1, pp. 147–158, 2010. View at: Publisher Site | Google Scholar
  172. S. Benlloch, L. Heredia, C. Barquero et al., “Prospective validation of a noninvasive index for predicting liver fibrosis in hepatitis C virus-infected liver transplant recipients,” Liver Transplantation, vol. 15, no. 12, pp. 1798–1807, 2009. View at: Publisher Site | Google Scholar
  173. S. Benlloch, M. Berenguer, M. Prieto, J. M. Rayón, V. Aguilera, and J. Berenguer, “Prediction of fibrosis in HCV-infected liver transplant recipients with a simple noninvasive index,” Liver Transplantation, vol. 11, no. 4, pp. 456–462, 2005. View at: Publisher Site | Google Scholar
  174. S. Pungpapong, D. P. Nunes, M. Kirshna et al., “Serum fibrosis markers can predict rapid fibrosis progression after liver transplantation for hepatitis C,” Liver Transplantation, vol. 14, no. 9, pp. 1294–1302, 2008. View at: Publisher Site | Google Scholar
  175. P. Toniutto, C. Fabris, D. Bitetto et al., “Role of AST to platelet ratio index in the detection of liver fibrosis in patients with recurrent hepatitis C after liver transplantation,” Journal of Gastroenterology and Hepatology, vol. 22, no. 11, pp. 1904–1908, 2007. View at: Publisher Site | Google Scholar
  176. B. Roche and D. Samuel, “Hepatitis C virus treatment pre- and post-liver transplantation,” Liver International, vol. 32, supplement 1, pp. 120–128, 2012. View at: Google Scholar
  177. J. A. Carrión, E. Martínez-Bauer, G. Crespo et al., “Antiviral therapy increases the risk of bacterial infections in HCV-infected cirrhotic patients awaiting liver transplantation: a retrospective study,” Journal of Hepatology, vol. 50, no. 4, pp. 719–728, 2009. View at: Publisher Site | Google Scholar
  178. X. Forns, M. García-Retortillo, T. Serrano et al., “Antiviral therapy of patients with decompensated cirrhosis to prevent recurrence of hepatitis C after liver transplantation,” Journal of Hepatology, vol. 39, no. 3, pp. 389–396, 2003. View at: Publisher Site | Google Scholar
  179. J. S. Crippin, T. McCashland, N. Terrault, P. Sheiner, and M. R. Charlton, “A pilot study of the tolerability and efficacy of antiviral therapy in hepatitis C virus-infected patients awaiting liver transplantation,” Liver Transplantation, vol. 8, no. 4, pp. 350–355, 2002. View at: Publisher Site | Google Scholar
  180. G. T. Everson, J. Trotter, L. Forman et al., “Treatment of advanced hepatitis C with a low accelerating dosage regimen of antiviral therapy,” Hepatology, vol. 42, no. 2, pp. 255–262, 2005. View at: Publisher Site | Google Scholar
  181. R. M. Thomas, J. J. Brems, G. Guzman-Hartman, S. Yong, P. Cavaliere, and D. H. Van Thiel, “Infection with chronic hepatitis C virus and liver transplantation: a role for interferon therapy before transplantation,” Liver Transplantation, vol. 9, no. 9, pp. 905–915, 2003. View at: Publisher Site | Google Scholar
  182. N. A. Terrault, “Prophylactic and preemptive therapies for hepatitis C virus-infected patients undergoing liver transplantation,” Liver Transplantation, vol. 9, no. 11, pp. S95–S100, 2003. View at: Publisher Site | Google Scholar
  183. B. Roche and D. Samuel, “Is early antiviral therapy for recurrent hepatitis C after liver transplantation superior to later treatment? the answer is no,” Liver Transplantation, vol. 17, no. 5, pp. 488–491, 2011. View at: Publisher Site | Google Scholar
  184. G. L. Davis, D. R. Nelson, N. Terrault 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 Transplantation, vol. 11, no. 8, pp. 941–949, 2005. View at: Publisher Site | Google Scholar
  185. T. D. Schiano, M. Charlton, Z. Younossi et al., “Monoclonal antibody HCV-AbXTL68 in patients undergoing liver transplantation for HCV: results of a phase 2 randomized study,” Liver Transplantation, vol. 12, no. 9, pp. 1381–1389, 2006. View at: Publisher Site | Google Scholar
  186. A. K. Shergill, M. Khalili, S. Straley et al., “Applicability, tolerability and efficacy of preemptive antiviral therapy in hepatitis C-infected patients undergoing liver transplantation,” American Journal of Transplantation, vol. 5, no. 1, pp. 118–124, 2005. View at: Publisher Site | Google Scholar
  187. V. Mazzaferro, “Prevention of recurrent hepatitis C after liver transplantation with early interferon and ribavirin treatment,” Transplantation Proceedings, vol. 33, no. 1-2, pp. 1355–1357, 2001. View at: Publisher Site | Google Scholar
  188. S. Tamura, Y. Sugawara, N. Yamashiki, J. Kaneko, N. Kokudo, and M. Makuuchi, “Pre-emptive antiviral therapy in living donor liver transplantation for hepatitis C: observation based on a single-center experience,” Transplant International, vol. 23, no. 6, pp. 580–588, 2010. View at: Publisher Site | Google Scholar
  189. A. Kuo, V. Tan, B. Lan et al., “Long-term histological effects of preemptive antiviral therapy in liver transplant recipients with hepatitis C virus infection,” Liver Transplantation, vol. 14, no. 10, pp. 1491–1497, 2008. View at: Publisher Site | Google Scholar
  190. N. Chalasani, C. Manzarbeitia, P. Ferenci et al., “Peginterferon Alfa-2a for hepatitis C after liver transplantation: two randomized, controlled trials,” Hepatology, vol. 41, no. 2, pp. 289–298, 2005. View at: Publisher Site | Google Scholar
  191. N. Singh, T. Gayowski, C. F. Wannstedt et al., “Interferon-α for prophylaxis of recurrent viral hepatitis C in liver transplant recipients: a prospective, randomized, controlled trial,” Transplantation, vol. 65, no. 1, pp. 82–86, 1998. View at: Publisher Site | Google Scholar
  192. N. Bzowej, D. R. Nelson, N. A. Terrault et al., “PHOENIX: a randomized controlled trial of peginterferon alfa-2a plus ribavirin as a prophylactic treatment after liver transplantation for hepatitis C virus,” Liver Transplantation, vol. 17, no. 5, pp. 528–538, 2011. View at: Publisher Site | Google Scholar
  193. M. Berenguer, “Treatment of hepatitis C after liver transplantation,” Clinics in Liver Disease, vol. 9, no. 4, pp. 579–600, 2005. View at: Publisher Site | Google Scholar
  194. C. S. Wang, H. H. Ko, E. M. Yoshida, C. A. Marra, and K. Richardson, “Interferon-based combination anti-viral therapy for hepatitis C virus after liver transplantation: a review and quantitative analysis,” American Journal of Transplantation, vol. 6, no. 7, pp. 1586–1599, 2006. View at: Publisher Site | Google Scholar
  195. M. Berenguer, “Systematic review of the treatment of established recurrent hepatitis C with pegylated interferon in combination with ribavirin,” Journal of Hepatology, vol. 49, no. 2, pp. 274–287, 2008. View at: Publisher Site | Google Scholar
  196. E. Xirouchakis, C. Triantos, P. Manousou et al., “Pegylated-interferon and ribavirin in liver transplant candidates and recipients with HCV cirrhosis: systematic review and meta-analysis of prospective controlled studies,” Journal of Viral Hepatitis, vol. 15, no. 10, pp. 699–709, 2008. View at: Publisher Site | Google Scholar
  197. P. Guillouche and C. Féray, “Systematic review: anti-viral therapy of recurrent hepatitis C after liver transplantation,” Alimentary Pharmacology and Therapeutics, vol. 33, no. 2, pp. 163–174, 2011. View at: Publisher Site | Google Scholar
  198. K. S. Gurusamy, E. Tsochatzis, B. R. Davidson, and A. K. Burroughs, “Antiviral prophylactic intervention for chronic hepatitis C virus in patients undergoing liver transplantation,” Cochrane Database of Systematic Reviews, vol. 12, Article ID CD006573, 2010. View at: Google Scholar
  199. H. Rodriguez-Luna, A. Khatib, P. Sharma et al., “Treatment of recurrent hepatitis C infection after liver transplantation with combination of pegylated interferon α2b and ribavirin: an open-label series,” Transplantation, vol. 77, no. 2, pp. 190–194, 2004. View at: Publisher Site | Google Scholar
  200. G. W. Neff, M. Montalbano, C. B. O'Brien et al., “Treatment of established recurrent hepatitis C in liver-transplant recipients with pegylated interferon-alfa-2b and ribavirin therapy,” Transplantation, vol. 78, no. 9, pp. 1303–1307, 2004. View at: Publisher Site | Google Scholar
  201. A. S. Ross, A. K. Bhan, M. Pascual, M. Thiim, A. B. Cosimi, and R. T. Chung, “Pegylated interferon α-2b plus ribavirin in the treatment of post-liver transplant recurrent hepatitis C,” Clinical Transplantation, vol. 18, no. 2, pp. 166–173, 2004. View at: Publisher Site | Google Scholar
  202. J. Dumortier, J. Y. Scoazec, P. Chevallier, and O. Boillot, “Treatment of recurrent hepatitis C after liver transplantation: a pilot study of peginterferon alfa-2b and ribavirin combination,” Journal of Hepatology, vol. 40, no. 4, pp. 669–674, 2004. View at: Publisher Site | Google Scholar
  203. M. Babatin, L. Schindel, and K. W. Burak, “Pegylated-interferon alpha 2b and ribavirin for recurrent hepatities C after liver liver transplantation: from a Canadian experience to recommendations for therapy,” Canadian Journal of Gastroenterology, vol. 19, no. 6, pp. 359–365, 2005. View at: Google Scholar
  204. P. Toniutto, C. Fabris, E. Fumo et al., “Pegylated versus standard interferon-α in antiviral regimens for post-transplant recurrent hepatitis C: comparison of tolerability and efficacy,” Journal of Gastroenterology and Hepatology, vol. 20, no. 4, pp. 577–582, 2005. View at: Publisher Site | Google Scholar
  205. L. Castells, V. Vargas, H. Allende et al., “Combined treatment with pegylated interferon (α-2b) and ribavirin in the acute phase of hepatitis C virus recurrence after liver transplantation,” Journal of Hepatology, vol. 43, no. 1, pp. 53–59, 2005. View at: Publisher Site | Google Scholar
  206. M. Biselli, P. Andreone, A. Gramenzi et al., “Pegylated interferon plus ribavirin for recurrent Hepatitis C infection after liver transplantation in naïve and non-responder patients on a stable immunosuppressive regimen,” Digestive and Liver Disease, vol. 38, no. 1, pp. 27–32, 2006. View at: Publisher Site | Google Scholar
  207. M. Berenguer, A. Palau, A. Fernandez et al., “Efficacy, predictors of response, and potential risks associated with antiviral therapy in liver transplant recipients with recurrent hepatitis C,” Liver Transplantation, vol. 12, no. 7, pp. 1067–1076, 2006. View at: Publisher Site | Google Scholar
  208. E. Oton, R. Barcena, J. M. Moreno-Planas et al., “Hepatitis C recurrence after liver transplantation: viral and histologic response to full-dose peg-interferon and ribavirin,” American Journal of Transplantation, vol. 6, no. 10, pp. 2348–2355, 2006. View at: Publisher Site | Google Scholar
  209. S. Mukherjee and E. Lyden, “Impact of pegylated interferon α-2B and ribavirin on hepatic fibrosis in liver transplant patients with recurrent hepatitis C: an open-label series,” Liver International, vol. 26, no. 5, pp. 529–535, 2006. View at: Publisher Site | Google Scholar
  210. S. Mukherjee and E. Lyden, “Impact of pegylated interferon alfa-2a and ribavirin on hepatic fibrosis in liver transplant patients with recurrent hepatitis C: an open-label series,” Hepato-Gastroenterology, vol. 53, no. 70, pp. 561–565, 2006. View at: Google Scholar
  211. I. Fernández, J. C. Meneu, F. Colina et al., “Clinical and histological efficacy of pegylated interferon and ribavirin therapy of recurrent hepatitis C after liver transplantation,” Liver Transplantation, vol. 12, no. 12, pp. 1805–1812, 2006. View at: Publisher Site | Google Scholar
  212. U. Neumann, G. Puhl, M. Bahra et al., “Treatment of patients with recurrent hepatitis C after liver transplantation with peginterferon alfa-2B plus ribavirin,” Transplantation, vol. 82, no. 1, pp. 43–47, 2006. View at: Publisher Site | Google Scholar
  213. F. P. Picciotto, G. Tritto, A. G. Lanza et al., “Sustained virological response to antiviral therapy reduces mortality in HCV reinfection after liver transplantation,” Journal of Hepatology, vol. 46, no. 3, pp. 459–465, 2007. View at: Publisher Site | Google Scholar
  214. M. Angelico, A. Petrolati, R. Lionetti et al., “A randomized study on Peg-interferon alfa-2a with or without ribavirin in liver transplant recipients with recurrent hepatitis C,” Journal of Hepatology, vol. 46, no. 6, pp. 1009–1017, 2007. View at: Publisher Site | Google Scholar
  215. J. A. Carrión, M. Navasa, M. García-Retortillo et al., “Efficacy of antiviral therapy on hepatitis C recurrence after liver transplantation: a randomized controlled study,” Gastroenterology, vol. 132, no. 5, pp. 1746–1756, 2007. View at: Publisher Site | Google Scholar
  216. P. Sharma, J. A. Marrero, R. J. Fontana et al., “Sustained virologic response to therapy of recurrent hepatitis C after liver transplantation is related to early virologic response and dose adherence,” Liver Transplantation, vol. 13, no. 8, pp. 1100–1108, 2007. View at: Publisher Site | Google Scholar
  217. T. Zimmermann, W. O. Böcher, S. Biesterfeld et al., “Efficacy of an escalating dose regimen of pegylated interferon α-2a plus ribavirin in the early phase of HCV reinfection after liver transplantation,” Transplant International, vol. 20, no. 7, pp. 583–590, 2007. View at: Publisher Site | Google Scholar
  218. S. Dinges, I. Morard, M. Heim et al., “Pegylated interferon-alpha2a/ribavirin treatment of recurrent hepatitis C after liver transplantation,” Transplant Infectious Disease, vol. 11, no. 1, pp. 33–39, 2009. View at: Publisher Site | Google Scholar
  219. F. Lodato, S. Berardi, A. Gramenzi et al., “Clinical trial: peg-interferon alfa-2b and ribavirin for the treatment of genotype-1 hepatitis C recurrence after liver transplantation,” Alimentary Pharmacology and Therapeutics, vol. 28, no. 4, pp. 450–457, 2008. View at: Publisher Site | Google Scholar
  220. I. A. Hanouneh, C. Miller, F. N. Aucejo, R. Lopez, M. K. Quinn, and N. N. Zein, “Recurrent hepatitis C after liver transplantation: ON-treatment prediction of response to peginterferon/ribavirin therapy,” Liver Transplantation, vol. 14, no. 1, pp. 53–58, 2008. View at: Publisher Site | Google Scholar
  221. S. C. Schmidt, M. Bahra, S. Bayraktar et al., “Antiviral treatment of patients with recurrent hepatitis c after liver transplantation with pegylated interferon,” Digestive Diseases and Sciences, vol. 55, no. 7, pp. 2063–2069, 2010. View at: Publisher Site | Google Scholar
  222. A. Jain, R. Sharma, C. Ryan et al., “Response to antiviral therapy in liver transplant recipients with recurrent hepatitis C viral infection: a single center experience,” Clinical Transplantation, vol. 24, no. 1, pp. 104–111, 2010. View at: Publisher Site | Google Scholar
  223. W. Al-Hamoudi, H. Mohamed, F. Abaalkhail et al., “Treatment of genotype 4 hepatitis C recurring after liver transplantation using a combination of pegylated interferon alfa-2a and ribavirin,” Digestive Diseases and Sciences, vol. 56, no. 6, pp. 1848–1852, 2011. View at: Publisher Site | Google Scholar
  224. P. J. Gaglio, S. Malireddy, B. S. Levitt et al., “Increased risk of cholestatic hepatitis C in recipients of grafts from living versus cadaveric liver donors,” Liver Transplantation, vol. 9, no. 10, pp. 1028–1035, 2003. View at: Publisher Site | Google Scholar
  225. M. Garcia-Retortillo, X. Forns, J. M. Llovet et al., “Hepatitis C recurrence is more severe after living donor compared to cadaveric liver transplantation,” Hepatology, vol. 40, no. 3, pp. 699–707, 2004. View at: Publisher Site | Google Scholar
  226. D. G. Maluf, R. T. Stravitz, A. H. Cotterell et al., “Adult living donor versus deceased donor liver transplantation: a 6-year single center experience,” American Journal of Transplantation, vol. 5, no. 1, pp. 149–156, 2005. View at: Publisher Site | Google Scholar
  227. P. J. Thuluvath and H. Y. Yoo, “Graft and patient survival after adult live donor liver transplantation compared to a matched cohort who received a deceased donor transplantation,” Liver Transplantation, vol. 10, no. 10, pp. 1263–1268, 2004. View at: Publisher Site | Google Scholar
  228. M. W. Russo, J. Galanko, K. Beavers, M. W. Fried, and R. Shrestha, “Patient and graft surivival in hepatitis C recipients after adult living donor liver transplantation in the United States,” Liver Transplantation, vol. 10, no. 3, pp. 340–346, 2004. View at: Publisher Site | Google Scholar
  229. A. Bozorgzadeh, A. Jain, C. Ryan et al., “Impact of hepatitis C viral infection in primary cadaveric liver allograft versus primary living-donor allograft in 100 consecutive liver transplant recipients receiving tacrolimus,” Transplantation, vol. 77, no. 7, pp. 1066–1070, 2004. View at: Publisher Site | Google Scholar
  230. H. Van Vlierberghe, R. Troisi, I. Colle, S. Ricciardi, M. Praet, and B. De Hemptinne, “Hepatitis C infection-related liver disease: patterns of recurrence and outcome in cadaveric and living-donor liver transplantation in adults,” Transplantation, vol. 77, no. 2, pp. 210–214, 2004. View at: Publisher Site | Google Scholar
  231. T. D. Schiano, J. A. Gutierrez, J. L. Walewski et al., “Accelerated hepatitis C virus kinetics but similar survival rates in recipients of liver grafts from living versus deceased donors,” Hepatology, vol. 42, no. 6, pp. 1420–1428, 2005. View at: Publisher Site | Google Scholar
  232. N. Selzner, N. Girgrah, L. Lilly et al., “The difference in the fibrosis progression of recurrent hepatitis C after live donor liver transplantation versus deceased donor liver transplantation is attributable to the difference in donor age,” Liver Transplantation, vol. 14, no. 12, pp. 1778–1786, 2008. View at: Publisher Site | Google Scholar
  233. A. Jain, A. Singhal, R. Kashyap, S. Safadjou, C. K. Ryan, and M. S. Orloff, “Comparative analysis of hepatitis C recurrence and fibrosis progression between deceased-donor and living-donor liver transplantation: 8-year longitudinal follow-up,” Transplantation, vol. 92, no. 4, pp. 453–460, 2011. View at: Publisher Site | Google Scholar
  234. M. Cescon, G. L. Grazi, A. Cucchetti et al., “Predictors of sustained virological response after antiviral treatment for hepatitis C recurrence following liver transplantation,” Liver Transplantation, vol. 15, no. 7, pp. 782–789, 2009. View at: Publisher Site | Google Scholar
  235. B. Raziorrouh, M. C. Jung, C. A. Schirren et al., “Antiviral therapy for recurrent hepatitis C after liver transplantation: sustained virologic response is related to genotype 2/3 and response at week 12,” European Journal of Gastroenterology and Hepatology, vol. 20, no. 8, pp. 778–783, 2008. View at: Publisher Site | Google Scholar
  236. M. Berenguer, C. Ortíz-Cantó, J. J. Abellán et al., “Hepatitis C virus viral kinetics during α-2a or α-2b pegylated interferon plus ribavirin therapy in liver transplant recipients with different immunosuppression regimes,” Journal of Clinical Virology, vol. 53, no. 3, pp. 231–238, 2012. View at: Publisher Site | Google Scholar
  237. T. Walter, J. Y. Scoazec, O. Guillaud et al., “Long-term antiviral therapy for recurrent hepatitis C after liver transplantation in nonresponders: biochemical, virological, and histological impact,” Liver Transplantation, vol. 15, no. 1, pp. 54–63, 2009. View at: Publisher Site | Google Scholar
  238. B. J. Veldt, J. J. Poterucha, K. D. S. Watt et al., “Impact of pegylated interferon and ribavirin treatment on graft survival in liver transplant patients with recurrent hepatitis C infection,” American Journal of Transplantation, vol. 8, no. 11, pp. 2426–2433, 2008. View at: Publisher Site | Google Scholar
  239. M. Berenguer, A. Palau, V. Aguilera, J. M. Rayón, F. S. Juan, and M. Prieto, “Clinical benefits of antiviral therapy in patients with recurrent hepatitis C following liver transplantation,” American Journal of Transplantation, vol. 8, no. 3, pp. 679–687, 2008. View at: Publisher Site | Google Scholar
  240. D. Samuel, T. Bizollon, C. Feray et al., “Interferon-α 2b plus ribavirin in patients with chronic hepatitis C after liver transplantation: a randomized study,” Gastroenterology, vol. 124, no. 3, pp. 642–650, 2003. View at: Publisher Site | Google Scholar
  241. R. T. Stravitz, M. L. Shiffman, A. J. Sanyal et al., “Effects of interferon treatment on liver histology and allograft rejection in patients with recurrent hepatitis C following liver transplantation,” Liver Transplantation, vol. 10, no. 7, pp. 850–858, 2004. View at: Publisher Site | Google Scholar
  242. M. Kugelmas, M. J. Osgood, J. F. Trotter et al., “Hepatitis C virus therapy, hepatocyte drug metabolism, and risk for acute cellular rejection,” Liver Transplantation, vol. 9, no. 11, pp. 1159–1165, 2003. View at: Publisher Site | Google Scholar
  243. C. M. Stanca, M. I. Fiel, N. Kontorinis, K. Agarwal, S. Emre, and T. D. Schiano, “Chronic ductopenic rejection in patients with recurrent hepatitis C virus treated with pegylated interferon alfa-2a and ribavirin,” Transplantation, vol. 84, no. 2, pp. 180–186, 2007. View at: Publisher Site | Google Scholar
  244. N. Selzner, M. Guindi, E. L. Renner, and M. Berenguer, “Immune-mediated complications of the graft in interferon-treated hepatitis C positive liver transplant recipients,” Journal of Hepatology, vol. 55, no. 1, pp. 207–217, 2011. View at: Publisher Site | Google Scholar
  245. E. Cholongitas, D. Samonakis, D. Patch et al., “Induction of autoimmune hepatitis by pegylated interferon in a liver transplant patient with recurrent hepatitis C virus,” Transplantation, vol. 81, no. 3, pp. 488–490, 2006. View at: Publisher Site | Google Scholar
  246. N. Kontorinis, K. Agarwal, N. Elhajj, M. I. Fiel, and T. D. Schiano, “Pegylated interferon-induced immune-mediated hepatitis post-liver transplantation,” Liver Transplantation, vol. 12, no. 5, pp. 827–830, 2006. View at: Publisher Site | Google Scholar
  247. S. Berardi, F. Lodato, A. Gramenzi et al., “High incidence of allograft dysfunction in liver transplanted patients treated with pegylated-interferon alpha-2b and ribavirin for hepatitis C recurrence: possible de novo autoimmune hepatitis?” Gut, vol. 56, no. 2, pp. 237–242, 2007. View at: Publisher Site | Google Scholar
  248. T. Asselah and P. Marcellin, “New direct-acting antivirals' combination for the treatment of chronic hepatitis C,” Liver International, vol. 31, no. 1, pp. 68–77, 2011. View at: Publisher Site | Google Scholar
  249. V. Garg, R. van Heeswijk, J. Eun Lee, K. Alves, P. Nadkarni, and X. Luo, “Effect of telaprevir on the pharmacokinetics of cyclosporine and tacrolimus,” Hepatology, vol. 54, no. 1, pp. 20–27, 2011. View at: Publisher Site | Google Scholar
  250. M. Charlton, “Telaprevir, boceprevir, cytochrome P450 and immunosuppressive agents—a potentially lethal cocktail,” Hepatology, vol. 54, no. 1, pp. 3–5, 2011. View at: Publisher Site | Google Scholar
  251. N. Fausto and J. S. Campbell, “The role of hepatocytes and oval cells in liver regeneration and repopulation,” Mechanisms of Development, vol. 120, no. 1, pp. 117–130, 2003. View at: Publisher Site | Google Scholar
  252. M. A. Zimmerman and J. F. Trotter, “Living donor liver transplantation in patients with hepatitis C,” Liver Transplantation, vol. 9, no. 11, pp. S52–S57, 2003. View at: Publisher Site | Google Scholar
  253. K. M. Olthoff, “Hepatic regeneration in living donor liver transplantation,” Liver Transplantation, vol. 9, no. 10, pp. S35–S41, 2003. View at: Google Scholar
  254. G. T. Everson and J. Trotter, “Role of adult living donor liver transplantation in patients with hepatitis C,” Liver Transplantation, vol. 9, no. 10, supplement, pp. S64–S68, 2003. View at: Google Scholar
  255. R. Manez, R. Mateo, J. Tabasco, S. Kusne, T. E. Starzl, and R. J. Duquesnoy, “The influence of HLA donor-recipient compatibility on the recurrence of HBV and HCV hepatitis after liver transplantation,” Transplantation, vol. 59, no. 4, pp. 640–642, 1995. View at: Google Scholar
  256. J. A. Carrión, M. Navasa, and X. Forns, “Retransplantation in patients with hepatitis C recurrence after liver transplantation,” Journal of Hepatology, vol. 53, no. 5, pp. 962–970, 2010. View at: Publisher Site | Google Scholar
  257. H. Y. Yoo, A. Maheshwari, and P. J. Thuluvath, “Retransplantation of liver: primary graft nonfunction and hepatitis C virus are associated with worse outcome,” Liver Transplantation, vol. 9, no. 9, pp. 897–904, 2003. View at: Publisher Site | Google Scholar
  258. G. W. Neff, C. B. O'Brien, J. Nery et al., “Factors that identify survival after liver retransplantation for allograft failure caused by recurrent hepatitis C infection,” Liver Transplantation, vol. 10, no. 12, pp. 1497–1503, 2004. View at: Publisher Site | Google Scholar
  259. S. J. Pelletier, D. E. Schaubel, J. D. Punch, R. A. Wolfe, F. K. Port, and R. M. Merion, “Hepatitis C is a risk factor for death after liver retransplantation,” Liver Transplantation, vol. 11, no. 4, pp. 434–440, 2005. View at: Publisher Site | Google Scholar
  260. S. Roayaie, T. D. Schiano, S. N. Thung et al., “Results of retransplantation for recurrent hepatitis C,” Hepatology, vol. 38, no. 6, pp. 1428–1436, 2003. View at: Publisher Site | Google Scholar
  261. H. R. Rosen, J. P. Madden, and P. Martin, “A model to predict survival following liver retransplantation,” Hepatology, vol. 29, no. 2, pp. 365–370, 1999. View at: Publisher Site | Google Scholar
  262. F. Y. Yao, S. Saab, N. M. Bass et al., “Prediction of survival after liver retransplantation for late graft failure based on preoperative prognostic scores,” Hepatology, vol. 39, no. 1, pp. 230–238, 2004. View at: Publisher Site | Google Scholar
  263. T. McCashland, K. Watt, E. Lyden et al., “Retransplantation for hepatitis C: results of a U.S. multicenter retransplant study,” Liver Transplantation, vol. 13, no. 9, pp. 1246–1253, 2007. View at: Publisher Site | Google Scholar
  264. H. R. Rosen, M. Prieto, T. Casanovas-Taltavull et al., “Validation and refinement of survival models for liver retransplantation,” Hepatology, vol. 38, no. 2, pp. 460–469, 2003. View at: Publisher Site | Google Scholar
  265. K. D. S. Watt, E. R. Lyden, and T. M. McCashland, “Poor survival after liver retransplantation: is hepatitis C to blame?” Liver Transplantation, vol. 9, no. 10, pp. 1019–1024, 2003. View at: Publisher Site | Google Scholar
  266. J. Martí, R. Charco, J. Ferrer et al., “Optimization of liver grafts in liver retransplantation: a European single-center experience,” Surgery, vol. 144, no. 5, pp. 762–769, 2008. View at: Publisher Site | Google Scholar
  267. P. G. Northup, T. L. Pruett, D. M. Kashmer, C. K. Argo, C. L. Berg, and T. M. Schmitt, “Donor factors predicting recipient survival after liver retransplantation: the retransplant donor risk index,” American Journal of Transplantation, vol. 7, no. 8, pp. 1984–1988, 2007. View at: Publisher Site | Google Scholar

Copyright © 2012 Nobuhisa Akamatsu and Yasuhiko Sugawara. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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