Pegylated Interferon alfa-2b (PegIntron) Maintenance Monotherapy May Reduce Esophageal Varices in Hepatitis C Patients with Cirrhosis

By Liz Highleyman

Over years or decades, people with chronic hepatitis C virus (HCV) infection may develop advanced liver disease, including cirrhosis and hepatocellular carcinoma (HCC). In patients with compensated cirrhosis, the liver can still carry out its vital functions, but as disease progresses they may develop decompensated cirrhosis, characterized by symptoms including ascites (abdominal fluid accumulation), hepatic encephalopathy, and bleeding varices (stretched and weakened veins) in the esophagus and stomach.

Successful interferon-based therapy has been shown to slow, halt, or even reverse liver disease progression. It remains unclear, however, whether interferon maintenance monotherapy is beneficial for patients who do not achieve a sustained response to interferon/ribavirin combination therapy. In the HALT-C trial, for example, low-dose pegylated interferon alfa-2a (Pegasys) monotherapy did not reduce the rate of disease progression or death, though it did appear to improve various markers of liver damage.

At 44th Annual Meeting of the European Association for the Study of the Liver (EASL 2009) last month in Copenhagen, researchers presented results from the international EPIC3 study, sponsored by Schering-Plough, which included a prospective trial designed to assess the efficacy and tolerability of long-term, low-dose maintenance therapy with pegylated interferon alfa-2b (PegIntron).

A total of 631 patients who did not achieve sustained response to combination therapy with conventional or pegylated interferon alfa plus ribavirin were randomly assigned to receive either 0.5 mcg/kg/week of pegylated interferon alfa-2b (the usual dose in combination therapy is 1.5 mcg/kg/week) or observation with no further treatment. 454 participants rolled over from an earlier EPIC3 re-treatment phase, while 172 enrolled directly in the maintenance phase.

The primary efficacy endpoint was time to development of a first clinical event, defined as liver decompensation (variceal bleeding, grade 2 or higher hepatic encephalopathy, ascites requiring treatment, or Child-Pugh class C), development of hepatocellular carcinoma, liver transplantation, or death. Secondary endpoints included time to disease progression, Child-Pugh class B events other than those including in the primary endpoint, emergence of varices, and enlargement of pre-existing varices requiring additional treatment.

Results

In the primary analysis, 27 patients in the maintenance therapy arm experienced clinical events, compared with 36 in the untreated control arm, not a statistically significant difference (hazard ratio [HR] 1.45; P = 0.14).

In the secondary analysis, 63 clinical events occurred in the maintenance therapy arm compared with 87 in the control arm, which did reach statistical significance (HR 1.56; P = 0.01).

Development or enlargement of varices accounted for a majority of events making up the difference between the primary and secondary analyses (16 in the maintenance arm, 43 in the control arm).

Among 82 participants with esophageal varices at baseline, there were 4 events in the maintenance therapy arm versus 14 in the control arm, again a significant difference (P = 0.01).

The overall safety profile of pegylated interferon was similar to that observed in prior studies.

However, there were significantly more infectious serious adverse events in the maintenance therapy arm compared with the untreated arm (25 vs 3).

In the primary analysis, the investigators concluded, "PegIntron maintenance was not superior to observational control in preventing the occurrence of clinical events."

However, they continued, "there was a statistically significant reduction in clinical events of hepatic decompensation on protocol-defined secondary analysis as well as in subjects with pre-existing esophageal varices. These data suggest that PegIntron therapy may delay the progression of portal hypertension and associated bleeding events."

Hospital Clinic I Provincial, Barcelona, Spain; Hopital La Petie Salpetriere, Paris, France; Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milano, Italy; University of Miami, Miami, FL; Universitaet Bern, Bern, Switzerland; Heritage Medical Research Clinic, University of Calgary, Canada; University Health Network, Toronto Western Hospital, Toronto, Ontario, Canada; Charite - Campus Virchow Klinikum, Berlin, Germany; CIF BIOTEC/Hospital Medica Sur, Mexico City, Mexico; Hospital Universitario Gaffree & Guinle, Rio de Janeiro, Brazil; Universitaetsklinikum Schleswig-Holstein, Kiel, Germany; St. Josef-Hospital Oberhausen, Oberhausen, Germany; Hospital Municipal de Gastroenterologia Dr. Bonorino Udaondo, Buenos Aires, Argentina; Schering-Plough Research Institute, Kenilworth, NJ.

5/05/09

Reference
J Bruix, T Poynard T, M Colombo, and others. PegIntron Maintenance Therapy in Cirrhotic (Metavir F4) HCV Patients Who Failed to Respond to Interferon/Ribavirin (IR) Therapy: Final Results of the EPIC3 Cirrhosis Maintenance Trial. 44th Annual Meeting of the European Association for the Study of the Liver (EASL 2009). Copenhagen, Denmark. April 22-26, 2009.

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