Management of Recurrent Hepatitis C Following Liver Transplantation: Antiviral Therapy

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Treatment Before Transplantation

Although PegIFN in combination with RBV remains the gold standard for the treatment of chronic HCV infec­tion in the pretransplant setting, long-term viral sup­pression can be achieved in only approximately one half of patients. Antiviral therapy in patients with HCV cirrhosis awaiting liver transplantation should be consid­ered in select individuals; however, poor tolerability may limit virologic response. Although successful response to PegIFN therapy has been described in compensated cirrhotics, sustained virologic response (SVR) can be significantly reduced in those with decompensated disease. Up to 50% of decompensated cirrhotics may experience significant hematologic side effects associated with PegIFN and RBV, leading to dose reductions and treatment discontinuation. Consequently, low SVR rates have been reported in 7-13% of genotype 1 patients and up to 50% of nongenotype 1 patients. In light of the potential benefit of viral eradication and avoidance of allograft re-infection, antiviral therapy prior to liver transplantation is recommended in patients who are can­didates, primarily those with Child-Turcotte-Pugh scores of no more than 7 and model for end-stage liver disease (MELD) scores of no more than 18.

Post-Transplant Strategies

The principal strategies that have emerged involving antiviral therapy for recurrent HCV include a preemptive approach (with initiation of treatment immediately fol­lowing transplantation) and a recurrence-based approach (in which treatment candidates are selected based upon histologic evidence of HCV-associated liver disease). An advantage of the preemptive strategy is the ability to initi­ate therapy when serum HCV RNA levels are character­istically low; however, selecting candidates able to tolerate therapy at an early time point following transplantation is a major challenge. Prospective studies evaluating a preemptive approach with IFN-based therapy are lim­ited. Only 2 small trials have evaluated the efficacy of PegIFN in this setting (Table 2), one of which noted that only 41% of screened transplant recipients were eli­gible to begin therapy. These studies reported a relatively low SVR (5-18%) following 48 weeks of PeglFN-based therapy, as well as discontinuation in approximately one third of patients and dose reductions in up to 85%.
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Table 2. Prospective Clinical Trials of Preemptive Peginterferon Alfa for Recurrent Hepatitis C Following Liver Transplantation


Study


Treatment arms*


Patients


(n)


Genotype


1 (%)


SVR


(%)


Discontinuation


(%)


Dose reduction


(%)


Shergill AK, et al.


IFN-2b or PegIFN-2b IFN-2b or PegIFN-2b/RBV


22 22


5 18


37


85


Chalasani N, et al.


PegIFN-2a No treatment


26 28


73 75


8 0


31


42

Recurrence-based strategies of antiviral therapy in HCV transplant recipients have been more extensively studied, though prospective comparative clinical trials with treatment arms including PeglFN are limited. Based upon these studies, the SVR associated with PeglFN therapy in predominantly genotype 1-infected popula­tions has been reported to range from 12% to as high as 50% (Table 3). A recent extensive review of prospec­tive and retrospective clinical studies describing antiviral therapy with combination PeglFN and RBV in this popu­lation reported a mean SVR of 30%. It is important to note that not only have these studies reported a wide range of success rates, but they also vary greatly in factors such as the choice of immunosuppressive regimens, inclusion cri­teria, and timing of antiviral therapy. As noted in the pre­emptive approach, treatment of established HCV recur­rence may be significantly limited by patient tolerability, with treatment being discontinued in up to one third of patients and dose reductions required in the majority of patients. In patients with advanced fibrosis or cho- lestatic hepatitis, discontinuation of therapy may occur in over 50%. Extended duration antiviral therapy has also been described in patients with established recurrent HCV; however, no clear long-term benefit of this treat­ment approach has been established. Viagra Professional

It is evident that more controlled prospective data are required in order to determine the safest and most effective treatment approach in this population, with the goals of achieving HCV eradication and prevention of progressive liver disease. The results of 2 multicenter pro­spective studies assessing the safety, efficacy, and benefit of preemptive or recurrence-based antiviral therapy, respec­tively, have recently been presented in abstract form.

Table 3. Comparative Prospective Clinical Trials of Peginterferon Alfa in the Treatment of Established Recurrent Hepatitis C Virus Following Liver Transplantation


Patients


Genotype 1


SVR


PegIFN


PegIFN


RBV


Study


Treatment arms*


(n)


(%)


(%)


DC (%)


DR (%)


DR (%)


Chalasani N, et al.


PegIFN-2a


34


79


12


30


61


No treatment


33


75


0


Castells L, et al.


PegIFN-2b/RBV


24


100


35


0


25


58


No treatment


24


0


Angelico M, et al.


PegIFN-2a/RBV


21


81


33


33


38


75


PegIFN-2a


21


86


38


28


33


Carrion JA, et al.


PegIFN-2b/RBV (F0-F2)


27


85


48


22


11


67


PegIFN-2b/RBV (F3-F4, CH)


27


100


19


56


37


67


No treatment (F0-F2)


27


85


0


Bizollon T, et al.


PegIFN-2b/RBV


27


74


30


7


No treatment


21


86


0


Nair S, et al.


PegIFN-2b/RBV


45


80§


50


62′


66


PegIFN-2b/RBV/amantadine


26


Firpi RJ, et al.


PegIFN-2a/RBV/TAC


20


85


35


10


60


90

The PHOENIX (Pegasys and Copegus Administered After Liver Transplantation for Hepatitis C) trial random­ized patients after liver transplantation to receive 48 weeks of preemptive combination therapy or to undergo obser­vation with the potential for treatment initiation once histologic evidence of recurrent HCV was established. A relatively low SVR was found in 22% of patients who received preemptive therapy, as well as discontinuation of therapy in over 40%, and increased reports of hematologic side effects. The PROTECT (Pegylated Interferon Alfa- 2b and Ribavirin After Orthotopic Liver Transplantation: Efficacy and Safety in Hepatitis C Recurrence Therapy) study evaluated the treatment of established recurrent HCV following liver transplantation. Although the overall reported SVR was 29%, sustained response rates were over 50% in genotype 2 or 3 patients and in those who were able to complete a course of therapy. Similar to previous reports, hematologic side effects were prevalent; over 50% of patients required dose reductions; and up to 30% of patients discontinued therapy.
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