Treatment of Hepatitis C Virus in Liver Transplant Recipients

Hepatology - Hepatitis C Management in Special Populations

Authors: Mark S. Sulkowski, MD (More Info)

Last Reviewed: 3/1/12

The decision to initiate hepatitis C virus (HCV) therapy must weigh the benefits of achieving a sustained virologic response (SVR) vs the risks of triggering graft rejection and the side effects associated with immunosuppressive therapy. Although a preemptive antiviral approach intuitively seems to offer the best chance for liver transplant recipients, several reasons prevent the American Association for the Study of Liver Diseases (Management Guidelines)^{[Ghany 2009]} and the European Association for the Study of the Liver (Management Guidelines) from recommending this approach:^{[EASL 2011]}

• Postoperative increases in human leukocyte antigen and major histocompatibility complex elevate the risk of acute rejection in the presence of immunomodulators such as interferon-based therapy
• Patients have a reduced clinical status while recovering from surgery
• Between 30% and 50% of patients will not develop chronic liver disease
• 40% to 60% of patients are not candidates for this therapy because of cytopenias, renal disease, or other underlying conditions
• Early therapy has been associated with high rates of adverse effects, an increased risk of graft rejection, and higher proportions of patients requiring dose reductions

Thus, the recommended standard of care is the treatment of histologically confirmed recurrent disease, either by persistent, unexplained elevated alanine aminotransferase levels or by histologically confirmed fibrosis once rejection, biliary obstruction, and vascular damage have been ruled out.^{[Ghany 2009; Ponziani 2011]}

Peginterferon alfa alone or in combination with ribavirin are recommended for the treatment of recurrent HCV infection in posttransplanted patients.^{[EASL 2011; Ghany 2009]} However, severe adverse effects, including anemia, thrombocytopenia, and leukopenia, contribute to the low adherence to the recommended dose of ribavirin, which may lead to the low response rates of transplant recipients (Figure), even when hematopoietic growth factors are administered.^{[Ponziani 2011]}

Figure. Response rates with peginterferon plus ribavirin for the treatment of recurrent HCV postliver transplantation.

The HCV protease inhibitors boceprevir and telaprevir have not been studied and therefore are not approved in patients with liver transplants. However, a study of telaprevir plus peginterferon alfa-2a and ribavirin is planned for stable liver transplant patients (Clinical Trial: NCT01467505). Because this and other studies are completed with HCV protease inhibitors in the transplantation setting, drug-drug interactions will become an important consideration. Indeed, since both boceprevir and telaprevir inhibit CYP3A4, coadministration with any medication that is known to be metabolized by CYP3A4 should be done under close clinical supervision and monitoring.^{[Ghany 2011]} Unfortunately, 2 drugs commonly used to prevent allograft rejection, cyclosporine and tacrolimus, are metabolized via the CYP3A4 pathway. In a phase I, nonrandomized pharmacokinetic study involving 10 healthy volunteers, coadministration of cyclosporine and telaprevir increased the elimination half-life of cyclosporine from 12 ± 1.67 hours to 42.1 ± 11.3 hours; tacrolimus and telaprevir coadministration increased the half-life of tacrolimus from 40.7 ± 5.85 hours to 196 ± 159 hours.^{[Garg 2011]} A comparable study of the impact of boceprevir on the pharmacokinetics of cyclosporine and tacrolimus was also conducted.^{[Hulskotte 2011]} In contrast to telaprevir, boceprevir is primarily metabolized by aldo-keto reductase with a lesser contribution from CYP3A4. In a study of 10 healthy volunteers, coadministration of boceprevir with cyclosporine induced a 2.01-fold increase in C_max and a 2.70-fold increase in the area under the concentration time curve (AUC) from time 0 to infinity after single dosing (AUC_inf) of cyclosporine. By contrast, coadministration of boceprevir and tacrolimus caused a 9.9-fold increase in C_max and a 17.1-fold increase in AUC_inf of tacrolimus. These data indicate that coadministration of boceprevir with either cyclosporine or tacrolimus would require significant dose adjustments of the calcineurin inhibitors and attentive monitoring of their trough concentrations, of renal function, and of potential adverse effects; in particular, coadministration with tacrolimus would likely require significant dose reduction and/or prolonged dosing. When considering the results of these studies, it is important to emphasize that the populations assessed involved healthy participants. In the context of liver transplant recipients with HCV recurrence, the pharmacokinetic effects of boceprevir or telaprevir on elimination of these immunosuppressive agents may be greater.^{[Charlton 2011]} Thus, these protease inhibitors should not be used in combination with the calcineurin inhibitors cyclosporine and tacrolimus until the appropriate dose reductions are understood.^{[Garg 2011]} Finally, many other agents that require cytochrome P450 enzymes for their metabolism are often administered in the transplantation setting, including mycophenolate mofetil, macrolides, calcium channel blockers, and others.^{[Charlton 2011]} As a result, pharmacokinetic interactions with cyclosporine or tacrolimus provide only a partial view of potential protease inhibitor effects that may be relevant to liver transplant recipients.

A summary of recommendations for the management of recurrent HCV in liver transplant recipients is shown in Table 10.

Table 10. Summary of Recommendations for the Management of Recurrent HCV in Liver Transplant Recipients

• Prophylactic HCV therapy in liver graft recipients is not recommended.
• Histologically confirmed recurrent disease, either by persistent, unexplained elevated alanine aminotransferase levels or by histologically confirmed fibrosis once rejection, biliary obstruction, and vascular damage have been ruled out, should be treated.
• Peginterferon alfa alone or in combination with ribavirin are recommended for the treatment of recurrent HCV infection in posttransplanted patients.
• The HCV protease inhibitors boceprevir and telaprevir have not been studied and therefore are not approved in liver transplant patients.

Source

Also See: An Open Label Study of the Effect of Telaprevir in Combination With Ribavirin and Peginterferon on HCV Infection in Stable Liver Transplant Patients