PHOENIX: A randomized controlled trial of peginterferon alfa-2a plus ribavirin as a prophylactic treatment after liver transplantation for hepatitis C virus

Abstract

The efficacy, tolerability, and safety of the prophylactic treatment of hepatitis C virus (HCV) after liver transplantation (LT) with peginterferon alfa-2a and ribavirin are not known. LT recipients with HCV were randomized to peginterferon alfa-2a/ribavirin treatment or observation 10 to 26 weeks post-LT. Prophylaxis patients received peginterferon alfa-2a (135 μg/week for 4 weeks and then 180 μg/week for 44 weeks) plus ribavirin (the initial dose of 400 mg/day was escalated to 1200 mg/day). Observation patients received the same regimen only upon significant HCV recurrence (histological activity index ≥ 3 and/or fibrosis score ≥ 2). The primary endpoint was the proportion of patients with histological evidence of significant HCV recurrence 120 weeks after randomization. In all, 115 patients were randomized (prophylaxis arm, n = 55; observation arm, n = 60). Sustained virological response was achieved by 12 of 54 prophylaxis patients (22.2%) and by 3 of 14 observation patients who switched to treatment (21.4%). On an intent-to-treat basis, significant HCV recurrence at 120 weeks was similar in the prophylaxis (61.8%) and observation arms (65.0%, P = 0.725). The patient and graft survival rates and the rates of biopsy-proven acute cellular rejection were similar in the 2 study arms. Approximately 70% of the treated patients in both arms had at least one dose reduction for safety reasons. The most common adverse event leading to treatment withdrawal was anemia. Because of the safety profile of peginterferon alfa-2a/ribavirin and the lack of a clear benefit in terms of HCV recurrence and patient or graft survival, this study does not support the routine use of prophylactic antiviral therapy.

Trial registration: ClinicalTrials.gov NCT00087633.

Copyright © 2011 American Association for the Study of Liver Diseases.

Figures

Figure 1

Overview of the study and its subjects. Patients were randomized 10 to 26 weeks post-LT to receive peginterferon alfa-2a/ribavirin therapy either prophylactically or upon observation of HCV recurrence. The study duration was 120 weeks: prophylaxis patients received 48 weeks of treatment and 72 weeks of follow-up, observation patients who received no treatment received 48 weeks of observation and 72 weeks of follow-up, and observation patients who switched to treatment received 0 to 48 weeks of observation followed by 48 weeks of treatment and 24 to 72 weeks of follow-up.

Figure 2

Kaplan-Meier estimates of the time to first HCV recurrence after randomization (the ITT population). P = 0.178 (log-rank test comparing survival curves between the prophylaxis and observation arms).

Figure 3

Virological responses in prophylaxis patients and in observation patients who switched to treatment (the ITT population). RVR was defined as undetectable HCV RNA after 4 weeks of treatment, cEVR was defined as undetectable HCV RNA after 12 weeks of treatment, and SVR was defined as undetectable HCV RNA 24 weeks after the end of treatment. *Before receiving any study medication, 1 prophylaxis patient withdrew consent.