Pegylated Interferon Aids in Post-Transplant HCV

VALENCIA, Spain, July 10 -- With a combination of pegylated interferon and Rebetol (ribavirin), liver transplant recipients with recurrent hepatitis C (HCV) infection respond as well as non-transplants patients, according to researchers here.

One third of patients treated with either standard Intron A (interferon alfa-2b) plus Rebetol, or Rebetol plus a pegylated interferon -- either Pegasys (pegylated interferon alfa-2a) or Pegintron (pegylated interferon alfa-2b) -- had a sustained virologic response, reported Marina Berenguer, M.D., and colleagues of the Hospital Universitari La Fe in Valencia. However 40% of these patients had to halt either the interferon, Rebetol, or both, within 48 weeks because of adverse reactions.

"Our results indicate that response of hepatitis C liver transplant patients to pegylated interferon-ribavirin can closely mirror the response obtained in the non-transplant population," the investigators wrote in the July issue of Liver Transplantation.. "The tolerance though is unsatisfactory, and rejection remains a matter of concern in these patients."

In an accompanying editorial, James R. Burton, Jr., M.D., and Hugo R. Rosen, M.D., of the University of Colorado in Denver said that the study provides important information for the management of patients with recurrent HCV infection following liver transplantation.

"We still need randomized controlled trials of pegylated interferon and ribavirin compared to standard interferon and ribavirin to determine if improved tolerability equates to higher rates of sustained virologic response," the editorialists wrote.

They suggested a potential treatment algorithm until further studies are available. "Assuming the presence of fibrosis in the transplant recipient does not significantly reduce the likelihood of virologic response, we can probably afford to take a 'wait and treat progressive disease' approach, reducing risk of rejection, allowing lower doses of immunosuppression and increasing the likelihood of patient tolerability to therapy," they continued.

Dr. Berenguer and colleagues conducted a retrospective analysis looking at 67 liver transplants patients with recurrent HCV, 92.5% of whom were infected with HCV genotype 1. In all, 51% of the patients had stage 3 fibrosis, and 13% had stage 4 fibrosis.

Forty-six percent of the patients had received standard Intron A with Rebetol, and the remaining 54% were treated with either Pegasys or Pegintron plus Rebetol.

The investigators looked at only those patients for whom at least six months of follow-up data were available following discontinuation of antiviral therapy.

Under the protocol, patients would receive 48 weeks of antiviral therapy with erythropoietin and/or granulocyte colony stimulating factor given as needed.

The primary study endpoint was sustained virologic response, which the investigators defined as HCV RNA negativity on polymerase chain reaction assay at six months after the end of treatment.

They also looked at biochemical response, defined as normalization of serum alanine aminotransferase and aspartate aminotransferase, and end of treatment virologic response rates.

In all, 46% of patients had an end of treatment response, and 33% had sustained virologic responses. There were significant differences between patients treated with the standard or pegylated interferons, however, with only 13% of patients who received Intron A having a sustained virologic response, compared with 55% of those who received a pegylated interferon (P= 0.001). However, patients who received a pegylated interferon were treated earlier than those receiving standard interferon.

Premature discontinuation of one or both components of the treatment regimen occurred in 40% of patients because of adverse events, which included anemia, rejection episodes, and drug intolerance. An additional 57% of patients had adverse events, mainly anemia, neutropenia, or thrombocytopenia, that required dose reductions of either interferon (in 36% of all patients) or ribavirin (45%).

The ability to achieve a sustained virologic response did not appear to depend either on previous (pre-transplant) antiviral therapy or on the type of immunosuppressant used.

Predictors for sustained virologic response include type of antiviral therapy used, erythropoietin use, compliance, and an early virologic response, defined as a decline in viral load higher than 2 logs from baseline. In multivariate analysis, however, only early virologic response remained as an independent predictor of a sustained response. No difference in sustained virologic response was seen with respect to the presence or absence of significant fibrosis.

There were a total of six episodes of rejection-two chronic, and four acute. Three of the four patients who developed chronic rejection had a sustained virologic response, but neither of the patients with acute rejection had a sustained response.

The lessons of the study, the authors said, are that:

• Pegylated interferons in combination with Rebetol induce a significantly higher rate of HCV clearance in liver transplant recipients.
• A lack of early virologic response at three months can predict treatment failure.
• The type of calcineurin inhibitor used does not determine the outcome of antiviral therapy.
• Prior failure to respond to antivirals does not predict the outcome of antiviral therapy post-transplant.

They also found that "although HCV clearance is achieved in a significant proportion of HCV-1b infected liver transplant recipients treated with pegylated or standard interferon- ribavirin, treatment may be hampered by the development of severe rejection, potentially leading to graft loss."

Additionally, "rejection following the use of interferon pegylated interferon therapy is difficult to predict with current easily obtainable variables, but appears to be more common with the pegylated form of interferon," they wrote.

"The most recent paper from the Valencia group adds to our rapidly evolving understanding of how best to manage patients with HCV, underscoring that some rules apply and others do not," Dr. Burton and Dr. Rosen wrote in their editorial. "We look forward to results from multicenter studies to more fully define the rules for treating these very challenging patients."