Reduced Dose and Duration of PegIntron plus Ribavirin Is Not as Effective as Standard Therapy for Genotype 2 and 3 Hepatitis C Patients

By Liz Highleyman

Interferon-based therapy for chronic hepatitis C virus (HCV) infection produces a high sustained response rate -- generally in the 70% to 80% range -- in people with easier-to-treat HCV genotypes 2 or 3. But therapy is costly and associated with difficult side effects, leading researchers to study reduced doses and shorter treatment durations.

At the 44th Annual Meeting of the European Association for the Study of the Liver (EASL 2009) last month in Copenhagen, M. Manns and an international team of colleagues reported findings from the REDD 2/3 Trial, showing that a reduced treatment duration or a decreased dose of pegylated interferon produced inferior results compared with standard therapy in treatment-naive genotype 2 or 3 patients in Europe and Asia.

The recommended standard treatment for patients with HCV genotype 2 or 3 is pegylated interferon plus ribavirin for 24 weeks. Shorter-duration treatment of such patients has been "largely unsuccessful compared with standard-duration treatment," the investigators noted as background. However, the implications of reduced pegylated interferon dosing in this group are unknown.

The aim of the present study was to evaluate the effect of shorter treatment duration and reduced doses of pegylated interferon alfa-2b (PegIntron) on sustained virological response (SVR; continued undetectable HCV RNA 24 weeks after completion of therapy) and relapse rates.

This open-label study began in 2003 as a "real world" investigator-initiated trial conducted in Germany by Hep-Net. In January 2005, Schering-Plough assumed sponsorship, and the population was expanded in the REDD 2/3 trial to include patients at additional sites in Poland, Israel, India, Indonesia, Malaysia, Singapore, and Thailand.

In total, 347 patients were from the original Hep-Net cohort and 335 were from the expanded REDD 2/3 cohort. Overall, about 65% were men and the mean age was about 40 years. Most (80%) had HCV genotype 3, while the rest had genotype 2; about half had high (> 600,000 IU/mL) baseline HCV viral load. People coinfected with HIV or hepatitis B were excluded.

Eligible patients were randomly assigned to receive either the standard dose of 1.5 mcg/kg/week PegIntron for the usual 24 weeks, a lower dose of 1.0 mcg/kg/week PegIntron for 24 weeks, or the standard dose of 1.5 mcg/kg/week for only 16 weeks. In addition, all participants received 800-1200 mg/day weight-adjusted ribavirin.

The primary endpoint was non-inferiority between the standard therapy arm and the reduced dose and reduced duration arms.

Results

Overall, in an intent-to-treat (ITT) analysis, participants who received the reduced dose and shorter duration of treatment had lower SVR rates than those who received standard therapy:

All patients:

66.5% with 1.5 mcg/kg/week for 24 weeks;

64.3% with 1.0 mcg/kg/week for 24 weeks;

56.6% with 1.5 mcg/kg/week for 16 weeks.

Hep-Net Cohort:

58.6% with 1.5 mcg/kg/week for 24 weeks;

60.0% with 1.0 mcg/kg/week for 24 weeks;

47.4% with 1.5 mcg/kg/week for 16 weeks.

REDD 2/3 Cohort:

74.6% with 1.5 mcg/kg/week for 24 weeks;

68.8% with 1.0 mcg/kg/week for 24 weeks;

66.1% with 1.5 mcg/kg/week for 16 weeks.

Asian patients responded somewhat better than whites, but the difference in SVR rates did not reach statistical significance.

End-of-treatment response rates and SVR rates in a per-protocol (as-treated) analysis were in line with ITT results.

Neither primary endpoint -- non-inferiority of lower dose or of shorter duration -- was achieved.

Relapse rates were lower with 24 weeks of therapy compared with 16 weeks (17.8% and 16.3% vs 29.3%, respectively).

Adverse events were similar regardless of treatment duration or PegIntron dose.

Based on these findings, the researchers stated that they were "statistically unable to demonstrate" that the lower-dose pegylated interferon regimen is non-inferior to the standard-dose regimen.

"This study of [genotype 2 or 3] patients, most of whom were difficult-to-treat European and Asian patients, confirms that pegylated interferon alfa-2b 1.5 mcg/kg/week for 24 weeks remains the most effective treatment for all [genotype 2 or 3] patients," they concluded.

Medical School of Hannover, Hannover, Germany; J.W. Goethe University Hospital, Frankfurt, Germany; Dayanand Medical College & Hospital, Ludhiana, Punjab, India; Sourasky Medical Center, Tel Aviv, Israel; University of Wuerzburg Medical Center, Würzburg, Germany; Selayang Hospital, Selangor, Malaysia; Hebrew University-Hadassah Medical Center, Jerusalem, Israel; University of Munich, Munich, Germany; Schering-Plough Corporation, Kenilworth, NJ.

5/29/09

Reference

M Manns, S Zeuzem, A Sood, and others. Reduced Dose and Duration of Peginterferon Alfa-2b and Weight-Based Ribavirin in European and Asian Genotype 2 and 3 Chronic Hepatitis C Patients (REDD 2/3 Trial). 44th Annual Meeting of the European Association for the Study of the Liver (EASL 2009). Copenhagen, Denmark. April 22-26, 2009.


Other Source
Schering-Plough. Schering-Plough Highlights Hepatitis C Clinical Data Presentations at the European Association for the Study of the Liver (EASL) Annual Meeting. Press release. April 27, 2009.

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