By Professor Sandeep Mukherjee, MBBCh, MPH, FRCPC
Associate Professor in Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, Corresponding Author: smukherj AT unmc.edu
Hepatitis C virus (HCV)-associated liver disease continues to be the most common indication for liver transplantation (LT) in the United States accounting for nearly 50% of all liver transplants. Recurrence is universal in patients viremic at the time of transplantation with histological hepatitis developing in the majority of patients. Although the natural history of recurrent HCV is difficult to predict, it is widely accepted that cirrhosis from recurrent HCV occurs in up to 30% of patients within five years of transplantation. Once cirrhosis is established, the annual risk of hepatic decompensation defined as the development of ascites, hepatic encephalopathy or variceal bleeding, is 42% . These statistics highlight the importance of recurrent HCV after LT, which in turn has stimulated the controversy surrounding retransplantation of recurrent HCV, particularly in the first post-operative year when retransplantation for severe recurrence is not recommended due to poor outcomes . It would seem insightful that eradicating HCV either before LT or treating recurrent HCV shortly after LT would have a major impact on decreasing the incidence of recurrent HCV and its expected complications. Unfortunately, most patients referred for LT evaluation have decompensated disease and are often unable to tolerate pegylated interferon and ribavirin therapy . The treatment of recurrent HCV is complicated further by poor sustained viral response (SVR) rates and reports of progressive fibrosis with hepatic decompensation despite SVR. The most successful approach to the treatment of recurrent HCV remains eradicating HCV before hepatic decompensation in which reported SVR rates with pegylated interferon and ribavirin vary from 50% to 70%. The natural history of recurrent HCV, risk factors associated with severe recurrence and the treatment of recurrent HCV will be discussed in this article.
POST TRANSPLANT COURSE OF HCV INFECTION
HCV infection of the allograft occurs at the time of transplantation, with HCV ribonucleic acid (RNA) detectable in the first postoperative week. HCV RNA is cleared rapidly from serum during the anhepatic phase and levels typically increase rapidly from week two posttransplantation, peaking by the fourth postoperative month . Acute hepatitis typically develops between months one and four posttransplantation, whereas changes consistent with chronic hepatitis usually are seen after months two to three . However, severe recurrent HCV developing as early as the ninth post-operative day has been described . By the fifth postoperative year between 10- 30% of patients have progressed to cirrhosis-once cirrhosis is established, the one year actuarial risk of hepatic decompensation is approximately 40%. A small proportion of patients (5%) may develop an accelerated course of liver injury called fibrosing cholestatic hepatitis C (FCH) which is associated with severe jaundice in the absence of biliary or vascular disease and elevated levels of HCV RNA. This syndrome is characterized histologically by severe hepatocyte ballooning particularly in the perivenular zone, intrahepatic cholestasis, pericellular and/or portal fibrosis and a paucity of inflammation. A diagnosis of FCH portends a poor prognosis due to the development of rapid allograft failure and often a lack of response to antiviral therapy . Possible explanations for FCH development include defects in innate immunity such as reduced counts and impaired cytolytic activity of non killer cells, down regulation of CD16 and upregulation of Fas ligand, a marker of hepatotoxicity . The initial enthusiasm for liver transplantation for HCV has waned as initial reports that five year survival rates were comparable to other liver transplant recipients may not be reproducible for medium- and long-term survival [9, 10].
Immunosuppression impacts the natural history of recurrent HCV at all stages of the transplant process from induction therapy to maintenance treatment and during the treatment of rejection. Despite several advances in our understanding on the impact of various medications on HCV recurrence, the ideal immunosuppressive regimen for these patients has not been established. We will discuss the impact of various immunosuppressive drugs on the post transplant outcome of HCV induced liver disease.
High dose corticosteroids were historically used during induction therapy and for the treatment of rejection. However, several studies have reported that repeated administration of high dose corticosteroids in patients with recurrent HCV, regardless of the indication, is associated with poorer outcomes and should be avoided unless absolutely necessary . Until recently, steroids were often discontinued in most LT programs by three months due to their long-term side effects and inherent belief steroids increased HCV liver injury. However, a single-center, retrospective study by Brillanti et al  reported slow steroid tapering was associated with less severe recurrent disease at six and twelve months. This was supported by Berenguer et al  who compared outcomes between two cohorts of recurrent HCV patients. The first group was transplanted between 2001 and 2004 and the second between 1999 and 2000 before dual immunosuppression (cyclosporine or tacrolimus plus steroids) or slow steroid taper over six months was instituted. Severe disease was considerably lower in the group transplanted between 2001 and 2004 (29% versus 48%; P = 0.02) although definite conclusions could not be made due to the retrospective nature of the study and selective bias. An important prospective study by Vivarelli et al  assessed the effect of long-term maintenance steroids (slow taper over two years) versus steroid withdrawal at 90 days. Although histological recurrence was similar in both groups, only 7.6% of patients developed advanced fibrosis in the slow taper group in contrast to 42.1% in the rapid taper group at 1 year post transplantation (P=0.03). Two year advanced fibrosis-free survival was also greater in the slow taper group versus the rapid taper group (93.7% versus 60.7%, P = 0.02). However, there were several unanswered question such as duration of therapy with low dose steroid and whether these medications could be discontinued. Two studies also evaluated the impact of steroid-free protocols on HCV recurrence and fibrosis. Kato et al  reported no differences in mean fibrosis stage between the three different immunosuppression groups but noted that patients who developed acute cellular rejection had a 63% chance of developing advanced fibrosis, defined as stage 2 -4 fibrosis. Klintmalm et al  also reported similar rates of HCV recurrence (60% at one year) in all groups using similar immunosuppression and confirmed that acute cellular rejection and older donor age were associated with early and more severe recurrence.
(b) Calcineurin inhibitors
Calcineurin inhibitors remain the most commonly used medications for maintenance therapy and their impact on the natural history of recurrent HCV has been extensively studied. This is in part related to in vitro studies which have shown an inhibitory effect of cyclosporine on HCV replication which is enhanced in the presence of interferon [17, 18]. Recent clinical studies in non-transplant patients have reported that the use of a cyclophilin-inhibitor without calcineurin binding properties has both additive and synergistic effects when combined with pegylated interferon and specifically targeted antiviral therapy for hepatitis C [19, 20]. Although no studies of the independent impact of tacrolimus on HCV viremia have been reported, posttransplant HCV levels are similar among patients receiving tacrolimus and patients receiving cyclosporine A. In a prospective randomized controlled study by Levy G et al , no difference was seen in the histological recurrence rate of hepatitis C at twelve months posttransplantation between patients receiving cyclosporine versus tacrolimus. A recent meta-analysis of five randomized, controlled trials on 366 patients comparing cyclosporine with tacrolimus reported similar rates of acute rejection, FCH, fibrosis and patient and graft survival at one year regardless of which calcineurin inhibitor was chosen . These findings are interesting as the inhibitory effect of cyclosporine on HCV replication has not translated into improved outcomes in post-transplant patients. It could be argued initial maintenance immunosuppression for recipients with HCV infection should be with tacrolimus but switched to cyclosporine at the initiation of interferon-based therapy. This would take advantage of cyclophilin inhibiting properties of cyclosporine during antiviral therapy and the greater immunosuppressive potency of tacrolimus during maintenance therapy but needs to be affirmation in controlled trials.
(c) Azathioprine and mycophenolate mofetil
There has been a strong interest in MMF, a potent inosine monophosphate inhibitor, as it has antiviral properties against flaviviruses and in theory may decrease HCV recurrence Although numerous studies have evaluated the impact of azathioprine (AZA) and mycophenolate mofetil (MMF) on HCV recurrence, most of these studies were retrospective or single center studies and are unlikely to be repeated in a controlled manner as AZA use currently is virtually obsolete. However, data on the impact of azathioprine and MMF on HCV recurrence has been conflicting For example, smaller and nonrandomized studies have reported worsening HCV RNA viremia upon either azathioprine substitution for MMF or when azathioprine is compared with MMF . However, a randomized, prospective study of 106 patients comparing tacrolimus plus steroids versus. tacrolimus plus steroids plus MMF showed no effect of MMF on patient or graft survival or HCV recurrence . A further randomized, double blind study of AZA versus MMF with cyclosporine and steroids had several interesting findings . The investigators reported that the incidence of rejection and graft loss was reduced in the MMF arm versus AZA at six months post-transplant as was the incidence of recurrent HCV (MMF 18%, AZA 29%, P< 0.05). However, at twelve months follow up, there was no statistically significant difference in the incidence of rejection between the two arms (MMF 31%, AZA 39%, P=0.1). These findings do not support a beneficial effect of either drug on the natural history of recurrent HCV, suggesting overall intensity of immunosuppression may have a more significant impact on HCV recurrence than the independent action of either AZA or MMF.
Rapamycin has gained widespread use in few transplant programs as a maintenance agent because of its renal-sparing effects. An interesting case series on two patients with recurrent HCV reported spontaneous HCV RNA clearance when immunosuppression was switched to rapamycin in the absence of antiviral therapy . However, in the absence of well-designed, randomized trials, there is little evidence to support its widespread role in recurrent HCV patients and treatment should be determined on a case by case basis.
(e) T-cell depleting therapies
OKT3 administration has consistently been identified as a significant risk factor for rapid onset and the severity of histological recurrence of HCV . The notion of a negative impact of T-cell depletion on posttransplant outcomes in recipients with HCV infection is supported by the potent effect of alemtuzumab (campath) in exacerbating recurrence of HCV . Data concerning the impact of rabbit antithymocyte globulin (ATG), an increasingly popular induction agent are less clear. An early randomized study reported a reduced incidence of recurrent HCV in ATG-treated patients (50%) versus steroid bolus recipients (71%), although this was not a statistically significant difference . Outcomes in patients with HCV infection who received induction ATG have been reported to be similar to controls who did not receive ATG, with an analysis of outcomes from three centers further suggesting that induction with ATG is associated with less severe fibrosis progression . Interpreting these studies is limited by the lack of protocol biopsies and the use of historical controls. While it is possible that the complex effects of ATG results in an environment that favors less severe recurrence of HCV (in contrast to the specific CD3 depletion associated with OKT3), there is a paucity of data which definitively shows that ATG has a positive impact on HCV recurrence when compared to steroid induction.
IMPACT OF DONOR AND RECIPIENT FACTORS
(a) Viral and recipient factors
Although HCV genotype and quasispecies emergence have been reported to affect the severity of recurrent HCV, these factors lack sufficient sensitivity and specificity to be used in determining eligibility of patients for liver transplantation or identifying candidates for preemptive antiviral therapy. The same holds true for recipient variables such as age, gender, HLA type and ethnicity [31, 32].
(b) Donor factors
Donor factors are potentially modifiable and are thus of particular interest as they may influence the natural history of recurrent HCV. An association of advancing donor age, with donor age greater than 65 years associated with more rapid progression of fibrosis and allograft failure as well as with more rapid and severe histological progression of HCV recurrence has been very reproducible . Prolonged cold and warm ischemia times have also been identified as risk factors for more severe post-LT HCV infection, as has early posttransplant preservation injury and excess donor fat content, although the latter is not specific for HCV . A prospective study of 76 patients followed for 36 months reported no difference between the frequency of development of recurrent HCV and fibrosis between patients who received living-donor organs compared to deceased-donor organs .
One of the more controversial issues regarding extended-criteria donors revolves around the potential positive impact of HCV-infected donors on short-term outcomes. Initial reluctance with using HCV positive donors was misguided until data confirmed that patient and graft survival comparable to patients who received non-HCV donors . A recent interesting case-control study by Wilson et al  using data from United Network for Organ Sharing (UNOS) and local donor data showed that one year patient survival rates of 97% favored recipients of HCV-infected livers compared with one year patient survival rates of 87.5% for recipients of organs meeting UNOS criteria. Demographics, cold and warm ischemic times were similar between both groups. A 26% increase in fibrosis developed in HCV-infected organs at one year post-LT compared with a 69% increase in fibrosis in the UNOS-approved group. The findings of this study have important implications because such organs are underused but over represented in the donor pool.
(c) Cytomegalovirus (CMV)
Posttransplant CMV infection has been strongly associated with increased severity of recurrence, even after adjusting for covariables such as degree of immunosuppression.This link appears to be strengthened if patients are genotype 1a. However, a long term retrospective study of liver transplant recipients with CMV disease did not report any significant differences in graft survival, HCV recurrence, or incidence of rejection compared with a control arm who never developed CMV disease or received CMV prophylaxis . Recurrent HCV occurred in 55.6% of the patients with CMV treated with preemptive therapy and 49.8% of those without CMV infection (P > 0.20). While this recent data suggests that targeted prophylaxis against CMV may not reduce the impact of CMV infection on posttransplant outcomes in HCV-infected liver transplant recipients, a randomized controlled trial directly addressing this question has never been performed.
(d) Human Immunodeficiency Virus (HIV)
HIV co-infection has recently emerged as an important predictor of poor survival among liver transplant recipients with HCV infection. One year patient mortality attributable to HCV in co-infected recipients ranges between 27-54%. Factors associated with increased risk of post-LT mortality among HCV–HIV co-infected recipients include African-American recipient ethnicity, pre-LT Model of End-Stage Liver Disease (MELD) score of > 20, intolerance of Highly Active Anti-Retroviral Therapy (HAART) and higher pre-LT HCV level of viremia.. Reduced response rates to treatment of HCV with interferon and ribavirin further attenuate post-LT outcomes in HIV–HCV co-infected liver transplant recipients . In a single center study from France, investigators compared the survival and severity of recurrent HCV infection after liver transplantation in HIV-HCV-coinfected and HCV-monoinfected patients. Seventy-nine patients receiving a first liver graft for HCV were included of whom 35 had HAART-controlled HIV infection . All patients were monitored for HCV viral load and liver histology during the posttransplantation course. Two and five year survival rates were 73% and 51% and 91% and 81% in coinfected patients and monoinfected patients, respectively (log-rank P = 0.004). Under multivariate Cox analysis, survival was related only to the MELD score Progression to fibrosis was also significantly higher in the coinfected group (P < 0.0001).The investigators concluded that outcomes of LT in HIV-HCV-coinfected patients were satisfactory in terms of survival benefit.
The National Institutes of Health in the United States is currently funding a multicenter trial to prospectively evaluate outcomes of LT for HIV-HCV coinfected patients (www.HIVTransplant.com). The study aims to enrol 125 patients at twenty major transplant centers. Until the findings from this study are available, it appears reasonable to recommend LT for these patients provided clinicians adhere to standard guidelines and liaise closely with an HIV specialist.
(a) Pretransplant anti-viral therapy
A landmark study reported that patients with high preliver transplant HCV RNA titers experienced greater mortality and graft loss rates than recipients with lower titers . This has led investigators to treat patients with advanced or decompensated cirrhosis, a group at high-risk for developing complications from anti-viral therapy, in an attempt to render patients HCV RNA negative prior to transplantation [42-44]. In the pilot study of 11 patients by Crippin et al , no patient achieved undetectable HCV RNA. In addition, several patients developed severe infections with two patients dying as a consequence of their anti-viral therapy. The largest study to date consisted of 124 patients with decompensated cirrhosis treated with a low accelerating dose of either interferon alpha-2b or pegylated interferon alpha-2b with ribavirin . Overall SVR was 24% but closer inspection of the data reveal that 45% of patients had compensated cirrhosis, 49% of non genotype one patients had CTP class 3 and only 13% of genotype one patients achieved SVR. Life-threatening complications were also more common in these patients, a complication reproducible in all 4 studies. Due to the high frequency of serious adverse events (33%), among patients with more severe liver disease (Child’s class B or C), the International Liver Transplant Society consensus panel concluded that treatment should be limited to cirrhotic patients with Child-Turcotte-Pugh (CTP) score ≤ 7 or MELD score < 18 and is contraindicated when the CTP score is >11 or MELD score is > 25 . The risks and benefits of antiviral therapy need to be carefully evaluated in these vulnerable patients and should only be undertaken in an environment where these patients can be closely supervised.
(b) Post transplantation early prophylactic treatment
There are two randomized, controlled trials-a prophylaxis trial and a treatment trial-reporting the safety and efficacy of peginterferon alpha-2a in the early postoperative period . In the prophylaxis trial, treatment was initiated within three weeks after LT versus 6-60 months in the treatment trial. Only two patients treated in the prophylaxis trial (8%) and three in the treatment trial (12%) achieved an SVR. A nonrandomized preemptive therapy study reported similar (5%) SVR rates. These studies confirm the findings of previous single center studies that prophylactic therapy is frequently ineffective and not recommended for recurrent HCV .
(c) Post transplantation treatment of recurrence
There is a lack of well designed randomized studies evaluating the outcome of interferon-based treatment in LT patients. Most studies report an SVR between 33% and 42% when treating patients with histologic recurrence and 0-33% when used in a pre-emptive protocol for genotype one patients . This was supported by a recent randomized controlled trial from Spain in which patients were randomized to no treatment (group A, n = 27) or peginterferon alpha-2b/ribavirin for 48 weeks (group B, n = 27). All patients with with severe recurrent HCV were also treated (group C, n = 27). Only 13 (48%) patients of group B and 5 (18.5%) of group C achieved sustained virological response, translating to an efficacy of pegylated interferon and ribavirin of approximately one-third less than in the nontransplant setting . These investigators also reported that response to antiviral therapy was influenced by stage of fibrosis. For example, SVR was 48% in patients with fibrosis stages 0-2 compared to 18% in patients with fibrosis stages 3-4. In addition, fibrosis correlated closely with wedged hepatic venous pressures (kappa value of 0.65) and this raises the question whether this investigation should be performed in all patients with recurrent HCV.
The reported incidence of acute cellular rejection on interferon-based antiviral therapy ranges from 0-25% with a mean incidence of 12% . This wide range is in part due to the difficulties encountered in differentiating recurrent HCV from mild or moderate rejection, particularly when they may co-exist . Alloimmune hepatitis can also occur in association with post-LT antiviral therapy in approximately 5% of cases, typically after HCV RNA clearance and associated with an important risk of graft failure . Immunosuppression levels can decrease significantly in patients responding favorably to anti-HCV therapy, predisposing to acute cellular rejection. In a retrospective single center study of 44 patients treated with antiviral therapy, 5 patients developed acute rejection while receiving interferon of whom 4 had undetectable serum HCV RNA . Two patients did not respond to standard treatment for rejection-one patient died and the other was successfully retransplanted. Two of the three patients who were successfully treated developed cirrhosis leading the authors to conclude that interferon may cause rejection and despite achieving SVR, progressive fibrosis and cirrhosis can still develop in selected patients. There also is evidence of progressive liver fibrosis after SVR eradication in patients treated with interferon-based therapies. In some instances this has led to decompensated cirrhosis requiring retransplantation in patients remaining serum HCV RNA negative at a mean follow-up period of eighteen months after LT . Other centers have reported the development of chronic rejection in patients who have achieved SVR after anti-HCV therapy which has required retransplantation 
A cost-effectiveness study by Saab et al  of treatment with standard interferon and ribavirin reported an incremental cost-effectiveness ratio of $29,100 per life-year saved for men > 55 years. The investigators used a model sensitive to medication costs, rate of cirrhosis development and SVR. Furthermore, the two way sensitivity analysis showed that antiviral therapy remained cost-effective even if drug costs increased provided these increased costs occurred in concert with an improved SVR.
(d) IL28 genotyping and Protease inhibitors
Pre-transplant patients who are –CC- homozygous for the gene coding for interferon lambda 3 (IL28B rs12979860) are more likely to achieve SVR and this appears to hold true for post-transplant patients in a few recent studies. However, the role of protease inhibitors for treating recurrent HCV is contraindicated due to the inhibition of cytochrome CYP 3A5/5 activity, an important cytochrome in calcineurin inhibitor metabolism, leading to toxic levels of these immunosuppressants.
Several studies have reported poor outcomes compared with other liver retransplant recipients, particularly for those transplanted for severe early recurrent HCV occurring within 6-12 months of LT . However, the policy for retransplantation continues to vary between transplant programs in part owing to subjective differences in perceived results between transplant physicians, surgeons, and the patient-family unit despite widely published data supporting comparable results with non-HCV retransplants if guidelines are followed . A recent multicenter study by McCashland et al  concluded that patients retransplanted for recurrent HCV had similar 1- and 3-year survival rates when compared with patients undergoing retransplantation for other indications although many patients with recurrent HCV were not considered for retransplantation and died from recurrent disease.
HCV-associated liver failure continues to be the most common indication for LT, with virological recurrence virtually universal after LT. Although outcomes for recipients with HCV infection are generally comparable to those for other indications for liver transplantation, the impact of HCV recurrence on posttransplant patient and graft survival is substantial. Approximately 30% of HCV-infected recipients will die or lose their allograft or develop cirrhosis secondary to HCV recurrence by the fifth postoperative year. Strategies for minimizing the frequency of severe HCV recurrence are evolving and include avoidance of older donors, early diagnosis and treatment of CMV and minimization of immunosuppression such as T-cell depleting therapies and pulsed corticosteroid treatment of acute cellular rejection. Competing goals of reducing immunosuppression and avoiding treatment of acute cellular rejection complicate the choice of immunosuppressive agents. Treatment with pegylated interferon and ribavirin is advised once histological evidence of recurrence of HCV is confirmed but patients still require education on the side effects and poor efficacy of antiviral therapy [61,62].
List of Abbreviations
- FCH | fibrosing cholestatic hepatitis C
- RNA | ribonucleic acid
- HCV | hepatitis C virus
- LT | liver transplantation
- EVR | early virological response
- SVR | sustained viral response
- MMF | Mycophenolate mofetil
- ATG | antithymocyte globulin
- AZA | azathioprine
- MELD | Model of End-Stage Liver Disease
- CTP | Child-Turcotte-Pugh
- CMV | Cytomegalovirus
- HIV | Human Immunodeficiency Virus
- HAART | Highly Active Anti-Retroviral Therapy
- UNOS | United Network for Organ Sharing
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