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EASL 2010: PROTECT Study Finds One-third of Liver Transplant Patients Achieve Sustained Response to Pegylated Interferon plus Ribavirin

Combination therapy with pegylated interferon alfa-2b (PegIntron) plus ribavirin led to sustained virological response (SVR) in about 30% of hepatitis C patients after liver transplantation, according to final results from the PROTECT study reported at the 45th Annual Meeting of the European Association for the Study of the Liver (EASL 2010) last month in Vienna. A similar proportion, however, were unable to complete therapy due to adverse events.

Liver transplantation is currently the only treatment for highly advanced liver damage due to chronic hepatitis C virus (HCV) infection. But the virus almost always re-infects the new liver, often leading to poor outcomes.

F.D. Gordon and fellow investigators with the Phase 3b PROTECT study, sponsored by Schering-Plough, evaluated the safety and efficacy of 1.5 mcg/kg/week pegylated interferon alfa-2b plus 400-1200 mg/day ribavirin for up to 48 weeks in patients with recurrent HCV infection following orthotopic liver transplantation.

The single-arm, open-label study enrolled 125 participants at 24 U.S. sites. Most (85%) were men, 81% were white, and most had hard-to-treat HCV genotype 1 (84%) and high baseline HCV viral load > 600,000 IU/mL (89%).

Results

  • 73 participants completed treatment and 52 discontinued therapy early.
  • In an intent-to-treat analysis, the overall SVR rate was 28.8%.
  • Genotype 1: 23.8%;
  • Genotypes 2 or 3: 55.0%.
  • Among patients who completed therapy, however, the sustained response rate was 54.5%.
  • Genotype 1: 50.5%;
  • Genotypes 2 or 3: 68.8%.
  • 83.3% of patients who achieved rapid virological response (RVR) at week 4 went on to achieve SVR.
  • 66.7% of participants with complete early virological response (EVR) at week 12 achieved SVR, compared to 36.1% with only partial EVR.
  • The overall relapse rate was 18.2% (19.4% for genotype 1, 15.4% for genotypes 2 or 3).
  • Patients who achieved SVR received a significantly higher mean ribavirin dose than non-responders (10.4 vs 8.8 mg/kg/day, respectively).
  • 55% of participants required dose reductions and 30% discontinued treatment due to adverse events.
  • 26% of patients experienced serious adverse events.
  • Reported adverse events included anemia (74%), fatigue (71%), headaches (62%), neutropenia (30%), insomnia (29%), depression (23%), and anxiety (15%).
  • Just over half had severe anemia and a similar proportion had severe neutropenia (low level of infection-fighting white blood cells).
  • 4 patients (3%) experienced rejection of the new liver.

Overall, 29% of post-orthotopic liver transplant patients receiving pegylated interferon alfa-2b plus ribavirin achieved SVR, or 54.5% among treatment completers, the study investigators concluded.

"End of treatment response was predictive of SVR, with a relapse rate of 18%," they continued. "RVR and complete EVR were also predictive of SVR and rejection rate was low."

They suggested that hematologic adverse events, or low blood cell counts -- a common reason for early discontinuation -- "may be a modifiable barrier to treatment in this population." Use of erythropoietin to manage anemia or growth factors to manage neutropenia, for example, might allow more people to stay on treatment.

Researcher affiliations: Transplantation, Lahey Clinic Medical Center, Burlington, MA; Columbia University College of Physicians & Surgeons, New York-Presbyterian Hospital, New York, NY; Medicine, Indiana University, Indianapolis, IN; The Liver Institute at Methodist Dallas Medical Center, Dallas, TX; Washington University, St. Louis, MO; Division of Transplantation Medicine, Mayo Clinic, Scottsdale, AZ; Henry Ford Hospital, Detroit, MI; Mount Sinai Medical Center, New York, NY; Schering-Plough Research Institute, Kenilworth, NJ.

5/4/10

Reference

FD Gordon, RS Brown, P Kwo, and others. Peginterferon alfa-2b and ribavirin for hepatitis C recurrence post orthotopic liver transplantation (OLT): final results from the PROTECT Study. 45th Annual Meeting of the European Association for the Study of the Liver (EASL 2010). Vienna, Austria. April 14-18, 2010.