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Hepatitis C Treatment after Liver Transplantation

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Hepatitis C Treatment after Liver Transplantation
—Liz Highleyman

Over years or decades, chronic hepatitis C virus (HCV) infection can progress to severe liver disease requiring liver transplantation, including decompensated cirrhosis and hepatocellular carcinoma (HCC).

Unfortunately, HCV almost always recurs soon after a transplant, potentially causing rapid disease progression and failure of the new liver.  Although progression is variable and unpredictable, studies suggest that as many as one-third of HCV-infected liver transplant recipients develop cirrhosis within five years, and that they progress to decompensated disease four times faster than non-transplanted hepatitis C patients.  Recurrent HCV is a leading cause of graft failure, retransplantation, and death in liver transplant recipients, and patients with hepatitis C generally fare worse than individuals transplanted for other reasons. 

As such, researchers have explored various management strategies for liver transplant recipients with HCV, including interferon-based therapy and modification of immuno-suppressive regimens to prevent organ rejection.  Antiviral therapy can be challenging for such patients, since many have difficulty tolerating interferon/ribavirin side effects, but this group has the most pressing need for effective treatment and therefore stands to gain the most benefit.

When to Start Therapy?
The optimal time to start interferon-based antiviral therapy in patients undergoing liver transplantation remains unclear.  Options include pre-transplant therapy aimed at achieving a sustained virological response (SVR) or “cure,” preemptive therapy started soon after the transplantation to prevent HCV recurrence and damage to the new liver, and post-transplant therapy after recurrent liver disease progression has been determined.

In theory, it would seem best to eradicate HCV prior to transplantation in order to protect the new liver.  But in practice, many patients with advanced liver disease cannot tolerate interferon-based therapy.  Hepatitis C patients with cirrhosis have significantly lower sustained response rates than those with less advanced disease, in part due to frequent dose reductions or discontinuation of therapy.  Due to the high risk of serious adverse events, antiviral therapy is generally contraindicated for individuals with decompensated cirrhosis, though it may be undertaken with careful monitoring, such as in a clinical trial.

Individuals who achieve SVR while awaiting a liver transplant appear to have a significantly lower risk of post-transplant HCV recurrence, and severity may be reduced if recurrence does occur.  In a 2005 study of patients with advanced cirrhosis treated with low accelerating doses of antiviral therapy, 13% of hard-to-treat genotype 1 patients and 50% with other genotypes achieved SVR.  Among 15 participants with undetectable viral load before transplantation, 12 remained HCV RNA negative six months thereafter.  Other studies, however, have found that a significant proportion of patients with undetectable HCV at the time of transplantation nevertheless experience recurrence. 

Treatment after Transplant
If pre-transplant therapy is not attempted or does not produce sustained response, post-transplant treatment is the next line of attack.  Unlike as with hepatitis B, prophylactic therapy using antiviral drugs and/or immune globulins (injected antibodies) around the time of transplantation does not prevent recurrence. 

Researchers have studied preemptive interferon-based therapy within 2-6 weeks after transplantation, with the rationale that treatment may be more successful if started while HCV RNA levels are still low and damage to the new liver has not yet occurred.  However, results have been disappointing, since transplant recipients at this stage have difficulty tolerating antiviral side effects, are at greatest risk for organ rejection, and are often receiving high doses of immunosuppressive drugs to prevent it. 

Many immediate post-transplant patients have blood cell deficiencies, kidney dysfunction, and susceptibility to infection that may be exacerbated by interferon and/or ribavirin.  As such, dose reduction and treatment discontinuation are common, leading to low sustained response rates.  A 2007 review of randomized trials of preemptive therapy using conventional or pegylated interferon (Pegasys or PegIntron) plus ribavirin, for example, found SVR rates ranging from about 10% to about 30%.

The risk of HCV recurrence after transplantation, as well as its severity, increases with the use of immunosuppressive steroids.  To address this issue, researchers have explored alternative immunosuppressive agents such as mycophenolate mofetil, monoclonal antibodies (e.g., daclizumab), calcineurin inhibitors (e.g., cyclosporine, tacrolimus), and thymoglobulin.  So far, however, an optimal regimen for transplant recipients with hepatitis C has not been established.

Watch and Wait
Since preemptive therapy does not appear to significantly reduce the risk of complications or improve survival – although the minority of patients who achieve SVR do seem to benefit – most experts recommend waiting until liver disease progression sets in.  An advantage of this approach is that some transplant recipients will never experience serious recurrent liver damage, and “watchful waiting” allows them to avoid unnecessary treatment.  In addition, patients generally become more clinically stable longer after transplantation, although HCV viral load is usually higher.  It is generally advised that transplant recipients should receive annual biopsies to check for disease progression. 

Pegylated interferon plus ribavirin is more effective in post-transplant patients than conventional interferon or interferon monotherapy, but sustained response rates are lower than those of immunocompetent non-transplant patients.  While most studies find overall SVR rates of approximately 50% for genotype 1 and 70%-80% for genotypes 2 or 3, for transplant recipients these rates are closer to 20% and 50%, respectively.

As reported in the August 2008 Journal of Hepatology, M.  Berenguer and colleagues conducted a systematic review of published studies of pegylated interferon plus ribavirin in patients with recurrent HCV-related liver disease after transplantation (preemptive therapy was not included).  They identified 19 studies published between 2004 and 2007, including a total of 611 patients (86% with genotype 1), primarily from Europe and the United States. 

Participants started combination antiviral therapy an average of two years after transplantation, at which point most had mild to moderate liver disease.  The mean SVR rate was 30% (range 0%-50%), rising to 60%-75% for patients with genotypes other than 1.  Just over half (55%) achieved biochemical response, and biopsies generally showed improvement – or at least lack of progression – in histological activity.

About three-quarters of participants required interferon or ribavirin dose reduction, and about 25% discontinued therapy due to side effects.  As with non-transplant patients, low pre-treatment viral load, good adherence, and early response at week 12 predicted sustained response.  In their discussion, the investigators suggested that improvement in monitoring and managing side effects – for example, using growth factors to prevent and treat blood cell deficiencies – would be “useful in optimizing treatment outcomes.”

In a recent study published in the August 2008 European Journal of Gastroenterology & Hepatology, B.  Raziorrouh and colleagues retrospectively assessed antiviral therapy using conventional or pegylated interferon plus ribavirin for 48 weeks in 36 liver transplant recipients with HCV recurrence (27 with genotype 1; 9 with genotypes 2 or 3).  Here, the SVR rate for genotype 1 patients was similar to that observed in other studies (26%), but 100% of genotype 2 or 3 achieved sustained response. 

Another recent study, by A.  Kornberg and colleagues, looked at outcomes of long-term combination antiviral therapy in 30 liver transplant recipients with recurrent hepatitis C; results were reported in the August 15, 2008 issue of Transplantation.  After an average treatment duration of 46 months, biopsies demonstrated that while two-thirds of non-responders experienced fibrosis progression, this did not occur in any patients who achieved sustained HCV clearance.  “Our data indicate that an antiviral combination should aim at viral eradication in liver transplant patients with recurrent hepatitis C, because it improves survival,” the researchers concluded.  Kornberg’s team previously demonstrated that long-term interferon/ribavirin maintenance therapy in non-responder transplant recipients led to reduced liver inflammation and stable fibrosis despite persistent HCV viremia.

Hope for the Future
While SVR rates remain lower for transplant recipients than for non-transplant patients, it is clear that a significant proportion can and do benefit from existing combination therapy.  In the future, directly targeted antiviral agents now in the pipeline (such as HCV protease and polymerase inhibitors) offer the prospect of more effective treatment with fewer side effects.

Selected References

Arjal, R., et al. The treatment of hepatitis C virus recurrence after liver transplantation Alimentary Pharmacology & Therapeutics 26(2): 127-144. July 2007.

Berenguer, M. Systematic review of the treatment of established recurrent hepatitis C with pegylated interferon in combination with ribavirin. Journal of Hepatology 49(2): 274-287. August 2008.

Everson, G.T., et al. Treatment of advanced hepatitis C with a low accelerating dosage regimen of antiviral therapy. Hepatology 42(2): 255-262. August 2005.

Kornberg, A., et al. Antiviral maintenance treatment with interferon and ribavirin for recurrent hepatitis C after liver transplantation: Pilot study. Journal of Gastroenterology and Hepatology 22(12): 2135-2142. December 2007.

Kornberg, A., et al. Transplantation. Sustained clearance of serum hepatitis C virus-RNA independently predicts long-term survival in liver transplant patients with recurrent hepatitis C. Transplantation 86(3): 469-473. August 15, 2008.

Raziorrouh, B., et al. Antiviral therapy for recurrent hepatitis C after liver transplantation: sustained virologic response is related to genotype 2/3 and response at week 12. Eur. J. Gastroenterol. & Hepatol. 20(8): 778-783. August 2008.

Teixera, R., et al. Therapeutic management of recurrent hepatitis C after liver transplantation. Liver International 27(3): 302-312. April 2007.

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