2008 Updates Series : Hepatitis C And Transplant
Hepatitis C virus (HCV) is the single most common indication for liver transplantation in the United States [17]. Recurrent HCV-related cirrhosis is accelerated in the immunosuppressed individual and develops in 8–44% of patients within 5–7 years [17,18].
The best strategy to prevent severe posttransplant recurrence of HCV is to eliminate the virus before transplantation. Antiviral therapy of HCV with interferon and ribavirin is difficult to tolerate and associated with poor response rates in patients with decompensated cirrhosis [19]. The International Liver Transplant Society consensus conference suggested that patients with decompensated cirrhosis and a Model for End Stage Liver Disease (MELD) score of less than 18 could be considered for antiviral therapy [20].
Antiviral therapy for HCV after liver transplantation has recently been associated with encouraging results, particularly if treatment is started early. In a Spanish trial [21••], patients with mild HCV recurrence (fibrosis stage F0–F2) were randomized to treatment with pegylated interferon and ribavirin for 48 weeks or no treatment. All patients with severe recurrence (F3–F4 or fibrosing cholestatic hepatitis) received interferon and ribavirin. Sustained virologic response (SVR) was 48% in the mild recurrence group that received antiviral therapy and only 18.5% in the severe recurrence group that received antiviral therapy. Liver fibrosis also progressed by at least one stage in 70% of untreated patients with mild recurrence and only in 26% of treated patients with mild recurrence and 54% of treated patients with severe recurrence. Fibrosis improvement was independently associated with treatment, especially in those with viral clearance or alanine aminotransferase (ALT) normalization. Patients with HCV recurrence after transplantation show better results if treated early.
In a study of retreatment after previously failed interferon therapy [22], 30% of 27 liver transplant recipients retreated with pegylated interferon and ribavirin achieved SVR. SVR was associated with early virologic response (decline in viral load by 2 logs at 12 weeks of treatment) and cyclosporine use. Histological benefit was seen in 76% of treated patients and 5% of untreated patients. Interestingly, improvement of fibrosis was not associated with SVR.
In another study of pegylated interferon and ribavirin after liver transplantation, 28% achieved SVR. The presence of genotype 2, absence of cirrhosis and higher dose of antivirals were associated with SVR. Patients with SVR had significantly higher survival compared with nonresponders [23•].
A recent systematic review of interferon-based combination antiviral therapy for HCV after liver transplantation [24] showed pooled SVR rates of 24% [95% confidence interval (CI) 20–27%] for regular interferon plus ribavirin and 27% (95% CI 23–31%) for pegylated interferon plus ribavirin. Discontinuation rates were 24–26%, although dose reductions were performed in up to 60%. No therapeutic advantages were seen for pegylated interferon compared with regular interferon as is seen in nontransplant HCV infection. Trials of novel better tolerated antiviral agents (protease inhibitors) with and without interferon are needed in transplant patients to improve the dismal outcomes associated with recurrent HCV.
The role of retransplantation in HCV-infected recipients continues to be a focus of debate. The perception in the transplant community is that outcomes after retransplantation for recurrent HCV are poor. A US study group [25•] looked at this issue retrospectively and compared survival after retransplantation in HCV versus other indications; only patients retransplanted after 90 days were included. The 1 and 3-year survival rates after retransplantation were similar in HCV and non-HCV groups and unlike previous studies MELD was not predictive of survival after retransplantation in HCV recipients. Duration of hospitalization and ICU days were similar as well. Of the HCV patients not listed for retransplantation, the most common reasons were fibrosing cholestatic hepatitis C (19%), recurrent HCV within 6 months (22%) and renal dysfunction (9%). Retransplantation within 1 year of primary transplantation is associated with significantly reduced survival compared with later retransplants. In a retrospective study of 131 HCV-positive liver transplant recipients, the mean survival time from the time of retransplantation was 9.6 ± 3.3 months when retransplantation was in the first year and 24.5 ± 7.5 months when retransplantation took place after a longer interval [26].
In recent years the rate of severe recurrence of HCV after transplantation appears to have increased [27]. Factors identified for more severe recurrence include multiple steroid pulses for treatment of rejection, rapid steroid tapering, high pretransplant HCV viral load, older donor age and increased histological activity early after transplant in the first year [28–34]. With increasing trends to accept older donors, this problem may be compounded in HCV-positive recipients [35].
More potent recent immunosuppressants such as tacrolimus and mycophenolate may be detrimental for hepatitis C [35,36]. Recent intriguing reports have shown that cyclosporine may have an additive antiviral effect on HCV when combined with interferon, an effect that is not seen with tacrolimus [37]. This study, as well as others, has also shown an antiviral effect of cyclosporine in HCV replicon models [38,39•]. Azathioprine has also been shown to have an anti-HCV effect in the replicon model [40]. Most studies, however, have reported no differences in HCV outcomes following transplantation between cyclosporine and tacrolimus [41–43]. Confirming the potential for specific immunosuppressant combinations to have a salutary effect on HCV progression in liver transplant recipients awaits better clinical trials of appropriate power and duration
Said, Adnan; Lucey, Michael R
Section of Gastroenterology and Hepatology, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, Wisconsin, USA
The best strategy to prevent severe posttransplant recurrence of HCV is to eliminate the virus before transplantation. Antiviral therapy of HCV with interferon and ribavirin is difficult to tolerate and associated with poor response rates in patients with decompensated cirrhosis [19]. The International Liver Transplant Society consensus conference suggested that patients with decompensated cirrhosis and a Model for End Stage Liver Disease (MELD) score of less than 18 could be considered for antiviral therapy [20].
Antiviral therapy for HCV after liver transplantation has recently been associated with encouraging results, particularly if treatment is started early. In a Spanish trial [21••], patients with mild HCV recurrence (fibrosis stage F0–F2) were randomized to treatment with pegylated interferon and ribavirin for 48 weeks or no treatment. All patients with severe recurrence (F3–F4 or fibrosing cholestatic hepatitis) received interferon and ribavirin. Sustained virologic response (SVR) was 48% in the mild recurrence group that received antiviral therapy and only 18.5% in the severe recurrence group that received antiviral therapy. Liver fibrosis also progressed by at least one stage in 70% of untreated patients with mild recurrence and only in 26% of treated patients with mild recurrence and 54% of treated patients with severe recurrence. Fibrosis improvement was independently associated with treatment, especially in those with viral clearance or alanine aminotransferase (ALT) normalization. Patients with HCV recurrence after transplantation show better results if treated early.
In a study of retreatment after previously failed interferon therapy [22], 30% of 27 liver transplant recipients retreated with pegylated interferon and ribavirin achieved SVR. SVR was associated with early virologic response (decline in viral load by 2 logs at 12 weeks of treatment) and cyclosporine use. Histological benefit was seen in 76% of treated patients and 5% of untreated patients. Interestingly, improvement of fibrosis was not associated with SVR.
In another study of pegylated interferon and ribavirin after liver transplantation, 28% achieved SVR. The presence of genotype 2, absence of cirrhosis and higher dose of antivirals were associated with SVR. Patients with SVR had significantly higher survival compared with nonresponders [23•].
A recent systematic review of interferon-based combination antiviral therapy for HCV after liver transplantation [24] showed pooled SVR rates of 24% [95% confidence interval (CI) 20–27%] for regular interferon plus ribavirin and 27% (95% CI 23–31%) for pegylated interferon plus ribavirin. Discontinuation rates were 24–26%, although dose reductions were performed in up to 60%. No therapeutic advantages were seen for pegylated interferon compared with regular interferon as is seen in nontransplant HCV infection. Trials of novel better tolerated antiviral agents (protease inhibitors) with and without interferon are needed in transplant patients to improve the dismal outcomes associated with recurrent HCV.
The role of retransplantation in HCV-infected recipients continues to be a focus of debate. The perception in the transplant community is that outcomes after retransplantation for recurrent HCV are poor. A US study group [25•] looked at this issue retrospectively and compared survival after retransplantation in HCV versus other indications; only patients retransplanted after 90 days were included. The 1 and 3-year survival rates after retransplantation were similar in HCV and non-HCV groups and unlike previous studies MELD was not predictive of survival after retransplantation in HCV recipients. Duration of hospitalization and ICU days were similar as well. Of the HCV patients not listed for retransplantation, the most common reasons were fibrosing cholestatic hepatitis C (19%), recurrent HCV within 6 months (22%) and renal dysfunction (9%). Retransplantation within 1 year of primary transplantation is associated with significantly reduced survival compared with later retransplants. In a retrospective study of 131 HCV-positive liver transplant recipients, the mean survival time from the time of retransplantation was 9.6 ± 3.3 months when retransplantation was in the first year and 24.5 ± 7.5 months when retransplantation took place after a longer interval [26].
In recent years the rate of severe recurrence of HCV after transplantation appears to have increased [27]. Factors identified for more severe recurrence include multiple steroid pulses for treatment of rejection, rapid steroid tapering, high pretransplant HCV viral load, older donor age and increased histological activity early after transplant in the first year [28–34]. With increasing trends to accept older donors, this problem may be compounded in HCV-positive recipients [35].
More potent recent immunosuppressants such as tacrolimus and mycophenolate may be detrimental for hepatitis C [35,36]. Recent intriguing reports have shown that cyclosporine may have an additive antiviral effect on HCV when combined with interferon, an effect that is not seen with tacrolimus [37]. This study, as well as others, has also shown an antiviral effect of cyclosporine in HCV replicon models [38,39•]. Azathioprine has also been shown to have an anti-HCV effect in the replicon model [40]. Most studies, however, have reported no differences in HCV outcomes following transplantation between cyclosporine and tacrolimus [41–43]. Confirming the potential for specific immunosuppressant combinations to have a salutary effect on HCV progression in liver transplant recipients awaits better clinical trials of appropriate power and duration
Said, Adnan; Lucey, Michael R
Section of Gastroenterology and Hepatology, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, Wisconsin, USA
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