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Hepatitis C virus (HCV)–related end stage cirrhosis is currently the leading indication for liver transplantation in Europe and in the United States.1, 2 HCV recurrence after transplantation is almost universal and 60 to 90% of patients will develop lesions of chronic hepatitis C on the graft.3, 4 Recent data confirm that HCV infection impairs patient and allograft survival.2 The course of HCV graft disease is accelerated in transplant recipients compared with immune-competent patients, with reported 5-year cirrhosis rates around 10 to 20%3, 4 and up to 28 to 40% in some series.5 This yields excess a risk of death or retransplantation for liver failure at 10–15 years posttransplant.2, 6 It appears now that the survival at 5–10 years is impaired in HCV-positive recipients in comparison to non-HCV recipients, due in part to the development of liver cirrhosis and of liver failure after liver transplantation.2 Given this risk, it appears important to offer antiviral therapy to liver transplant patients who develop a recurrence of chronic hepatitis C. Several approaches are under evaluation: the first option is to start the treatment just after transplantation as a preemptive therapy, the advantage is that the viral load is low at that time; however, tolerance of patients is poor in the immediate posttransplant period, and risk of rejection and of sepsis are high. The second option is to treat at time of acute hepatitis (in general during posttransplant months 1–6). The third option is to start the treatment at time of chronic hepatitis on the graft; in this latter situation the groups are heterogeneous, since some patients are treated during the first posttransplant year, some much later, with major differences both in the immunosuppressive drugs given to these patients, and in the severity of graft hepatitis. The type of antiviral treatment used is now mostly the combination therapy interferon plus ribavirin. Indeed, results with interferon alone have been disappointing in term of virologic response,7–9 several studies using nonpegylated interferon alone have reported a sustained virologic response rate below 10%. The combination interferon alpha-2b plus ribavirin combination therapy gave promising results in liver transplant patients with chronic hepatitis C on the graft, achieving sustained virologic response rate of 20 to 35%.9–17 It is not well known if the use of pegylated interferon in the combination therapy will further improve these results. However, the first reported results of posttransplant treatment with pegylated interferon plus ribavirin gave promising results, achieving sustained virologic response in 25 to 40% of the patients.18, 19 The antiviral treatment is particularly important in the management of these patients, since progression of fibrosis can probably be stopped after sustained virologic response. However, there are some controversies on the long-term outcome of the graft histology after sustained virologic response, and some authors have described a decreased activity grade and an absence of true improvement in the fibrosis score at least during the first years posttreatment.17, 20 Patients with HCV reinfection of the graft after liver transplantation differ from immune-competent patients in several ways: their viral load is very high, and most transplant patients in Europe are infected with genotype 1—both factors predictive of a lower virologic response rate. Despite the absence of certitude on the possibility of fibrosis regression, patients with sustained virologic response have normal liver enzymes level, a dramatic decrease of the activity score, and probably a much better long-term outcome in comparison to the patients with ongoing infection. For these reasons, the antiviral treatment is now fully part of the overall therapeutic strategy posttransplantation. The timing, the duration of treatment, the use of pegylated interferon instead of nonpegylated interferon, and the optimal dosage of ribavirin are still matter of debate. It has been clearly shown that in the absence of treatment there is no decrease of viral replication, no spontaneous clearance of the virus, and there is a progression of liver graft disease.17 The drawbacks of the treatment are a rather disappointing virologic efficacy and a poor tolerance. Indeed, the treatment with interferon plus ribavirin is poorly tolerated and tolerance appears lower than in immune-competent nontransplant patients. One of the main complications reported in comparison to nontreated patients is anemia; this is due to an increase toxicity of ribavirin in these patients with frequently impaired renal function, and with an impaired regenerative bone marrow. For this reason, it was necessary to introduce ribavirin at lower dosage than in nontransplant patients, to add erythropoietin administration in some patients, and to decrease the dosage of ribavirin, reducing the efficacy of the antiviral treatment. The other complications are similar to nontransplant patients: leukopenia, thrombocytopenia, depression, and irritability.

The risk of rejection in transplant patients treated with interferon is specific to transplant recipients, but remains a matter of debate. It is well known that interferon can provoke acute or chronic rejection of the renal allograft in renal transplant patients; there are numerous reports of irreversible renal failure due to rejection in renal transplant recipients treated with interferon.21, 22 Until recently, interferon was still considered as a contraindication in renal transplant patients. The risk and severity of rejection due to interferon in liver transplant recipients are still controversial. Despite some reports on the possible occurrence of acute or chronic rejection in liver transplant recipients,7, 23, 24 this complication is not always recognized, and the role of interferon is controversial. This may be due to several factors: the risk of rejection due to interferon is probably lower in liver transplant recipients than in renal transplant recipients, the liver being considered as more resistant to rejection than the kidney. Not all patients have been biopsied in the presence of abnormal liver enzymes during interferon, and the risk of rejection is probably underestimated. The risk of rejection with interferon might be dependent of the posttransplant interval and of the level of immunosuppressive drugs. It is unclear whether the risk of rejection due to interferon is modified by the use of pegylated interferon or by the adjunction of ribavirin. Pegylated interferon may theoretically increase the risk of rejection, due to its greater efficacy, its different pharmacokinetics, and its renal clearance, which is frequently decreased in liver transplant patients. On the contrary, it has been suggested that the adjunction of ribavirin might decrease the risk of rejection, since ribavirin has immune modulatory action. This has been suggested by the lower number of reported cases of rejection in liver transplant patients treated with interferon plus ribavirin therapy than with interferon alone and by a recent report of 4 cases of renal transplant patients treated successfully for acute hepatitis C without occurrence of rejection.25 The report by Saab et al.26 in this issue of Liver Transplantation highlights the risk of rejection in liver transplant patients treated with combination pegylated or nonpegylated interferon plus ribavirin. Five out of 41 patients experienced acute or chronic rejection episodes during combination treatment, leading in several cases to discontinuation of the antiviral treatment. Several points appeared from this study: 1) the cases of rejection are well documented; 2) the risk of rejection appeared as relatively low (4/41, 10%) but remains high if the late period after transplantation is taken into account; 3) the consequences of these episodes of rejection can be severe, since some patients died or were retransplanted for chronic rejection. Most of these patients experienced rejection at long-term posttransplantation, at a time where the risk of rejection is usually low reinforcing the deleterious role of interferon in these cases; 4) rejection occurs relatively rapidly after the start of the treatment, during the first 3 months in 4 out of 5 cases. The immunosuppressive regimen was relatively low in most patients at the start of the treatment. In the report of Feray et al.7 with interferon alone, the rate of rejection was higher (35%), mostly represented by severe chronic rejection, and was significantly higher than pair-matched untreated HCV liver transplant patients. In the report of Saab et al.,26 patients experienced both features of acute and chronic rejection. The mechanisms of action of interferon on rejection are not well known, however, it seems to activate human leukocyte antigen class II expression on biliary ducts, triggering lymphocyte infiltrate or disappearance of interlobular biliary ducts. The fact that ribavirin may decrease the risk of rejection of interferon has been suggested but has not been really proven.10 In a randomized study with interferon plus ribavirin, we observed 1/28 episodes of rejection in the treated group vs. 0/24 in the nontreated group.17

Why these differences in the prevalence and the severity of rejection episodes during interferon treatment among different studies? First, the delay when initiating the treatment after transplantation is important, the risk of rejection being higher in the first months posttransplant. Second, the immunosuppression dosage used at the time antiviral treatment begins may interfere positively or negatively with the risk of rejection. Third, the prevalence of rejection can be underestimated particularly in nonresponding patients, the increase in liver enzymes being considered falsely as due to hepatitis C in the absence of liver biopsy. Fourth, the use of pegylated vs. nonpegylated interferon and the combination with ribavirin might modify the prevalence of rejection. Indeed, pegylated interferon might increase the risk of rejection due to its long-lasting effect and its renal clearance in patients with impaired renal function. Recently, a prevalence of 25% of mild rejection episodes was reported in a series of 20 patients treated with pegylated-interferon plus ribavirin.18

In conclusion, from these reports, we can conclude that while there is a risk of rejection during interferon-based treatment for hepatitis C recurrence after liver transplantation, the prevalence and the severity of rejection remains matters for debate. The risk of rejection might be higher in patients receiving pegylated interferon, however this has not yet be proven. The decreased risk of rejection due to the combined use of ribavirin has been suggested, but not proven. Finally, these reports point out the need to perform a liver biopsy before starting the antiviral treatment, to eliminate any ongoing histological rejection, to maintain a sufficient level of immunosuppression (which should be balanced with the need to decrease viral replication), to closely monitor liver tests during antiviral treatment, and to perform a liver biopsy in case of increased liver enzymes. The risk of rejection during interferon-based treatment should not be ruled out and should be evaluated in further studies.

References

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  2. References
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