Antiviral treatment of recurrent hepatitis C after liver transplantation: The need for a multifaceted approach
Authors: Didier Samuel
Journal: Hepatology (2005)

Hepatitis C virus (HCV)–related 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%-90% of patients will develop lesions of chronic hepatitis C on the graft.3 The course of HCV graft disease is accelerated in transplant recipients compared with immune-competent patients, with reported incidence rates of cirrhosis at 5 years of approximately 10%-30%.3-5 This results in an excess risk of death or retransplantation for liver failure at 10 to 15 years posttransplantation.2, 6 HCV, hepatitis C virus; FCH, fibrosing cholestatic hepatitis; SVR, sustained virological response. The reasons for this accelerated course are incompletely understood. Several factors are involved: viral-related (genotype, amount of virus, quasispecies selection), immunological in nature (immunosuppression, quality and intensity of immune response), as well as related to the transplant itself (quality of the graft, age of the donor). Two main types of chronic graft lesions have been described. The first, named "fibrosing cholestatic hepatitis" (FCH), is rare and severe. FCH usually occurs during the first posttransplantation year, represents 10% of the cases of posttransplantation hepatitis, and is characterized by the association of jaundice and liver failure.7 FCH appears to arise from the inability of the immune system of the recipient to clear HCV from the liver, leading to a very high HCV load in the graft associated with a stable HCV quasispecies.8 It has therefore been suggested that in this particular context, HCV becomes cytopathic.7 Otherwise, the course is more classical, but much more rapid than in immunocompetent patients. Acute hepatitis occurs between 1 and 4 months posttransplantation followed by a chronic course. It has been shown that administration of steroids increases the viral load, and indeed the viral load is significantly higher after liver transplantation in comparison to the pretransplantation values.9 The peak of viral load in the liver graft is observed at the time of acute lobular hepatitis, then the amount of virus decreases in parallel to the progression to chronic hepatitis, suggesting that the immune response to HCV graft lesions is responsible for the severity of chronic hepatitis.10 It has also been suggested that HCV genotype 1 b11 and some particularly aggressive viral strains12 are associated with a more severe course. Several authors have suggested the involvement of other factors in the development of severe recurrence. It has been noted that the course of HCV recurrence is more severe and rapid in patients who have undergone transplantation in recent years.5 The causes for this recent aggravation are multifactorial. A relationship between the age of the donor and the development of graft fibrosis has been shown by different groups.13-15 Recent changes in immunosuppression may also play a role in progression of fibrosis: it is now accepted that boluses of high doses of steroids, use of ATG, or OKT 3 are deleterious. Recently, it has also been suggested that the rapid withdrawal of steroids16 could be responsible for an immune rebound, deleterious for the graft.7 The respective role of anti-IL2 receptors, tacrolimus, cyclosporine and mycophenolate mofetil is still debated; however, rejection episodes and treatment of rejection were associated with rapid progression of fibrosis.17 Thus, it appears important to offer antiviral therapy to liver transplant recipients at the risk of severe recurrence of chronic hepatitis C. Treatment can be done before liver transplantation in selected patients with Child A or B cirrhosis. It has been shown that patients with cirrhosis awaiting liver transplantation with sustained virological response (SVR) will not develop HCV recurrence.18, 19 However, the rate of virological response in such patients varies from 11% in genotype 1 patients to 30% in genotypes 2 and 3. In addition, antiviral treatment cannot be safely completed in all patients with cirrhosis who are candidates for liver transplantation. The other option is to preemptively start the treatment after liver transplantation (i.e., in the first 3 posttransplantation weeks) or after occurrence of acute or chronic hepatitis on the graft. The aim of preemptive treatment is to treat before the occurrence of acute hepatitis C in order to prevent the development of fibrosis on the graft. The potential advantage is that the viral load is low, particularly within the first days.20 However, preemptive treatment with interferon plus ribavirin is poorly tolerated, because of anemia, leukopenia, thrombocytopenia at baseline, and is associated with a risk of rejection and sepsis. Treatment can be started later, at time of acute hepatitis (months 1 to 6 posttransplantation) or at time of chronic hepatitis in the graft. The type of antiviral treatment currently used is mostly the combination therapy of interferon plus ribavirin. Indeed, SVR with interferon alone is below 10%.21, 22 Several pilot studies22-25 and one randomized study26 of the combination interferon alpha-2b plus ribavirin gave better results, achieving SVR rate in 20%-35% of the cases.22-26 It is not well known whether the use of pegylated interferon in the combination therapy will further improve these results. The combination pegylated interferon plus ribavirin gave promising results achieving a SVR in 25% to 40% of the patients.27, 28 In the February issue of HEPATOLOGY, Chalasani and colleagues treated patients undergoing liver transplantation either preemptively or after acute hepatitis with peginterferon alpha-2a alone in two separate controlled, randomized studies.29 This report is singular in that it presents both approaches: preemptive treatment and treatment of recurrent hepatitis C. Fifty-four patients were included in the preemptive trial, 26 in the peginterferon group, and 28 in the untreated group. Sixty-seven patients were included in the treatment trial, 34 were randomized to peginterferon group, and 33 did not receive therapy. In the prophylaxis arm, virological results were disappointing, with a SVR of 8% versus 0% in the nontreated arm (not significant). In the therapy group, virological results were also disappointing: the SVR was 12% in the peginterferon group versus 0% in the nontreated group (not significant). Among the 4 patients with SVR, 3 were infected by genotypes 2 and 3, both genotypes being known as more sensitive to interferon therapy. Another end point was the development of fibrosis. In the preemptive trial, fibrosis scores at baseline and at week 72 were 0.2 and 0.6, respectively, in the peginterferon group and were 0.1 and 1.1, respectively, in the untreated group. There was a statistically nonsignificant trend for a lower increase in fibrosis score in the peginterferon group. In the therapeutic trial, fibrosis scores at baseline and at week 72 were 0.8 and 1.1, respectively, in the peginterferon group and were 0.7 and 1.3, respectively, in the untreated group. The increase in fibrosis score was lower but not statistically significant in the peginterferon group (0.3 vs. 0.6). Other end points are worth highlighting. In the preemptive trial, 42% of the patients experienced dose reductions mainly due to leukopenia and thrombocytopenia. One patient in the peginterferon group developed severe life-threatening rejection. In the therapy trial, 20 patients required dose reductions of peginterferon, and 4 in the peginterferon group developed nonsevere rejection versus none in the untreated group. Thus, what can be concluded from these two trials? First, in both trials the antiviral effect was disappointing, lower to that reported using combination of nonpegylated interferon plus ribavirin.26 The aim of using peginterferon alone preemptively is to avoid ribavirin-related anaemia. It is probable that the combination of peginterferon plus ribavirin will be superior to achieve SVR than the combination nonpegylated interferon plus ribavirin, as suggested in a pilot study.27 Second, there was a nonsignificant trend for a reduction of progression of fibrosis in the peginterferon group in comparison to the untreated group both in the preemptive and therapeutic trials. However, it has been shown in several trials that fibrosis did not improve significantly, even in long-term transplant recipients with SVR in contrast to what is observed in nontransplant recipients.26, 30 Third, tolerance was poor; in both trials, a reduction of dose was necessary in more than 40% of the patients of the peginterferon group, and antiviral treatment was stopped in 30% of the patients.29 Rejection rate was not significantly higher in the peginterferon group, whereas there was a trend for more rejection episodes in the peginterferon arm of the treatment trial. The risk of rejection in transplant patients remains a matter of debate; some cases of acute or chronic rejection are related to the use of interferon, and this risk cannot be dismissed.31 In conclusion, the improvement of the course of HCV posttransplantation will be part of a multifaceted approach. It is unclear whether preemptive therapy is better than treatment once acute or chronic hepatitis C exists in the graft. Preemptive treatment is supposed to prevent development of fibrosis rather than to control existing fibrosis. However, preemptive treatment is logical only if started in the first posttransplant days, when viral load is low, rather than at 3 weeks posttransplant. A better understanding of the role of immunosuppressive therapy, the avoidance of high-dose steroids, and the use of grafts from young donors will reduce the severity of HCV recurrence. Peginterferon plus ribavirin should be preferred to peginterferon alone. The dosage of ribavirin should be adapted to the renal clearance of patients undergoing transplantation.26 Improvement in the tolerance of the treatment in order to increase the rate of SVR is mandatory, and erythropoietin administration can improve this tolerance (personal data). The place of ribavirin analogues (viramidin, levovirin) should be evaluated in the near future. This multifaceted approach is necessary while waiting for the advent of a new generation of antiviral drugs.32