Advances in Hepatology

Management of Posttransplant Hepatitis C Recurrence

Adrian M. Di Bisceglie

G&H What is the current rate of re-infection with hepatitis C virus in patients undergoing liver transplantation?

AD Cirrhosis related to chronic hepatitis C virus (HCV) infection is currently the leading indication for liver transplantation in adults in the United States and Western Europe. It is now well documented that virtually all of these patients are re-infected with HCV within days after transplantation. Hepatitis, as measured by raised liver enzymes or by liver biopsy, can appear in as short as a few weeks or be delayed by several months. The question then becomes one of how quickly the re-infection manifests as liver injury and how rapidly it progresses.

G&H Are there specific patient factors or disease factors that affect the rate of post-transplant disease progression?

AD If there are specific disease and patient factors that affect the progression of liver injury after transplant, they are not currently well characterized. In terms of pretransplant viral load, there is no evidence to support better outcomes in association with lower viral levels. However, patients with a sustained viral response to therapy before transplantation do not have recurrence of HCV infection and there is a possibility that patients who achieve viral negativity while on treatment or shortly after treatment, but cannot be defined as sustained responders, may be able to avoid recurrence, if the timing of transplant is conducive. Some ongoing research is focused on pretransplant treatment and attempting to achieve undetectable levels immediately preceding transplant, in order to achieve this status with some consistency.

We do know that the intensity and nature of immunosuppression required as part of the transplantation process likely has a role in the severity of HCV recurrence. In particular, the use of corticosteroids posttransplant has been associated with progression of re-infection and we try to avoid their use as much as possible. It is also thought that the short and intense courses of immunosuppressive therapy that are often used to treat organ rejection might exacerbate HCV re-infection.

G&H Is there a specific approach in attempting to avoid disease progression in posttransplant HCV patients?

AD In attempting to minimize disease progression after transplant, it is important to focus on the immunosuppressive regimen. Some physicians make a point of utilizing cyclosporine as the main immunosuppressive agent, based on evidence indicating that cyclosporine inhibits the replication of HCV to a mild degree. Thus, this agent is often favored over a tacrolimus-based regimen. In general, immunosuppression needs to be monitored and kept at the lowest effective level.

The other area of focus is on the early detection of recurrent HCV infection as it reaches a threshold appropriate for re-treatment with antiviral therapy. Some centers take liver biopsies annually to detect cirrhosis. Others monitor liver enzymes and then take a biopsy if they are sufficiently elevated, rather than waiting for a yearly interval. Another approach, which seems to be growing in favor, calls for treatment with antiviral therapy of any patients in whom there is no obvious contraindication.

G&H What are the challenges of re-treatment with standard therapy in the posttransplant setting?

AD Many posttransplant patients have minor renal dysfunction because of the calcineurin inhibitors (cyclosporine or tacrolimus) they are prescribed, which, in turn, severely limit their tolerance for full-dose ribavirin. Thus, posttransplant HCV therapy requires individualization on a patient-by-patient basis, as opposed to the standard or weight-based dosing utilized in pretransplant patients. Adjustment of both ribavirin and interferon may be necessary, and close monitoring throughout treatment is required.

G&H Is there any evidence supporting a role for low-dose maintenance therapy to slow or halt progression of posttransplant HCV?

AD We should first be clear that achievement of viral eradication and sustained viral response provides the best outcome in all patients, even those in the posttransplant setting. However, there is some suggestion that ongoing low-dose interferon-based regimens may be of some use in certain patients. Particularly in patients with severe recurrent HCV infection, a suppressive interferon regimen might slow disease progression when administered on an on-going basis. Evidence favoring this approach is anecdotal, but it could and should be considered in a prospective, randomized, controlled trial despite the difficulty of recruiting and carrying out large placebo-controlled trials in the posttransplant setting.

G&H What do you foresee as the future posttransplant role for the direct antiviral HCV agents that are currently under investigation?

AD Direct antiviral agents have a tremendous potential for use as part of the transplant process. One scenario would be to administer these agents immediately preceding transplant in order to achieve viral negativity, perform the transplant while the patient is still negative, and hopefully prevent the recurrence of HCV infection. Alternatively, it might be expected that the rate of sustained virologic response will be higher in the posttransplant population when direct antivirals are added to the regimen, just as it has proven higher in other HCV treatment populations.

There will be some cautions to consider in administering these drugs. Some direct antivirals affect the cytochrome P-450 system and can interfere with the metabolism of other drugs that the patient is taking, particularly their immunosuppressive, antirejection drugs. Although none of the direct antivirals have the potential for dose-dependent hemolysis as has been associated with ribavirin in posttransplant patients, each agent that is currently under investigation will have some issue of toxicity. With telaprevir, the issue is rash. With boceprevir, it is anemia. Other new drugs may be associated with enzyme induction and rash as well. All of these side effects have the potential to gain greater prominence in the posttransplant setting and need to be investigated as such.

G&H Are there any other cautions to be considered in treating patients in the posttransplant setting?

AD Administration of interferon is well known to precipitate organ rejection in the postkidney transplant setting. Although it does not seem to have the same effect in liver transplantation, my own experience coincides with a report in a recent issue of Liver Transplantation, where some patients, when treated to achieve a sustained virologic response, developed chronic ductopenic rejection.

Chronic rejection is a very serious condition, which leads to loss of the transplanted organ and leaves few viable options for the patient. Retransplantation for recurrent HCV is generally not undertaken, partly due to the limitations of the donor pool and partly because experience has shown that when a patient has lost one liver to recurrent HCV, they do very poorly when retransplanted. Thus, the possibility of chronic rejection needs to be considered and reinforces the need for close monitoring when administering interferon in posttransplant patients.