http://www.hivandhepatitis.com/hep_c/news/041902a.html

The double combination of Pegasys (peginterferon alfa-2a) plus ribavirin produces some of the best clinical results ever seen for patients with chronic hepatitis C, especially for those with genotype 1, according to data from an international, multicenter, randomized Phase III trial presented today (April 18, 2002) at the 37th Annual Meeting of the European Association for the Study of the Liver (37th EASL) in Madrid, Spain.

Highlights of Study Outcome

The Pegasys/ribavirin double combination produced an overall 61 percent sustained virologic response (SVR), the highest SVR ever reported in a prospective trial for a pegylated interferon using an intent-to-treat analysis. "Overall" means all genotypes included. These patients received Pegasys 180 micrograms (mcg) once weekly and ribavirin 1000-1200 milligrams (mg) daily for 48 weeks.

Patients in the study with genotype 1 (the most difficult strain of HCV to treat) achieved a 51 percent SVR. This represents the highest SVR ever achieved among this population of patients. The trial results demonstrate that those with genotype 1 need standard dose ribavirin (1000-1200 mg daily) plus Pegasys (180 mcg weekly) in order to achieve the best clinical outcome.

Patients in the trial with genotype non-1 taking Pegasys and low dose ribavirin (800 mg daily) for 24 weeks achieved a 78 percent SVR. Previously, this patient population achieved a 78 percent SVR only when on therapy for 48 weeks. "These data are important because we know that for certain patients, we can use a lower dose of therapy and cut the treatment duration by half without sacrificing efficacy," said Donald Jensen, MD, a US investigator in the trial and director of Hepatology at Rush-Presbyterian-St. Luke's Medical Center in Chicago.

Study Objectives

The primary goals of the Pegasys/ribavirin Phase III trial were threefold:

to compare the effectiveness and safety of the double combination of Pegasys plus ribavirin when used for 24 weeks versus 48 weeks;

to compare the safety and effectiveness of two different doses of ribavirin (800 mg vs 1000-1200 mg) when taken with Pegasys; and

to provide additional data to submit to FDA for an expedited review of Pegasys's approval application (for approval as a prescription drug for the treatment of chronic HCV infection)

Design of the Phase III Trial

A total of 1,284 patients at 99 sites in 21 countries were randomized and given treatment as follows:

Group A: Pegasys 180 mcg once weekly plus ribavirin 800 mg daily for 24 weeks

Group B: Pegasys 180 mcg once weekly plus ribavirin 1000-1200 mg daily for 24 weeks

Group C: Pegasys 180 mcg once weekly plus ribavirin 800 mg daily for 48 weeks

Group D: Pegasys 180 mcg once weekly plus ribavirin 1000-1200 mg daily for 48 weeks

All patients were followed up for 24 weeks after discontinuing treatment.

Patients were further stratified by HCV genotype (1 vs. non-1) and viral load (low vs high, defined as less than or equal to or greater than 2 million copies/mL, respectively, and by geographical region;

Treatment duration was blinded until week 24;

Dose of ribavirin blinded throughout the study.

Summary Results of the Phase III Trial

An overall SVR of 61% in patients treated for 48 weeks with Pegasys 180 mcg once weekly and ribavirin 1000-1200 mg daily;

Overall safety profile similar to prior studies (depression, flu-like symptoms,
fatigue;

Genotype 1 Patients
      • A 51%A SVR achieved with 48 weeks treatment, 1000-1200 mg ribavirin;
      • Shorter duration of therapy and/or lower ribavirin dose reduces efficacy;

Genotype Non-1 Patients
     • SVR of 78% with 24 weeks of therapy and 800 mg ribavirin;
     • Increasing duration of therapy and/or dose of ribavirin gave no increase in efficacy;
Shorter treatment associated with fewer SAEs and withdrawals for safety

Lower dose ribavirin associated with fewer
     • SAEs (24 weeks)
     • ribavirin dose modifications
     • Large decreases in hemoglobin

Key Charts on the Data Presented

04/17/02

Source
Teleconference with Chris Pappas, MD, of Roche Laboratories. April 18, 2002.

Reference
S J Hadziyannis and others. PEGINTERFERON ALFA-2A (40KD) (PEGASYS) IN COMBINATION WITH RIBAVIRIN (RBV): EFFICACY AND SAFETY RESULTS FROM A PHASE III, RANDOMIZED, DOUBLE-BLIND, MULTICENTRE STUDY EXAMINING EFFECT OF DURATION OF TREATMENT AND RBV DOSE. Abstract 536. 37th Annual Meeting of the European Association for the Study of the Liver. April 18-21, 2002. Madrid, Spain.

By Brian Boyle, MD

http://www.hivandhepatitis.com/hep_c/news/041902b.html

A large number of persons are infected with hepatitis C virus (HCV) in the United States, with estimates as high as 4 million. Many of these individuals have known risk factors for HCV or have been diagnosed with HCV, but a significant number of HCV-infected individuals do not have a known risk factor and have not been tested for or diagnosed with HCV.

While liver disease is clearly the predominate risk of chronic HCV infection, other systemic conditions are also associated with HCV, including abnormalities in peripheral blood counts, especially platelet counts. Still, the effect of HCV infection on peripheral blood counts has never been extensively evaluated and documented.

In a study published in Hepatology, investigators evaluated the prevalence of peripheral blood count abnormalities among HCV-infected adults. The investigators used the data collected in the third National Health and Nutrition Examination Survey (NHANES III). The population evaluated in this study included 16,196 individuals in NHANES III who were at least 18 years of age and who had peripheral blood counts and data on HCV infection recorded. The enrolled patients were assessed for low peripheral blood counts, with "low" being defined as the lowest fifth percentile of each component of the peripheral blood count.

The investigators found that HCV antibody-positive individuals were 3 times more likely to have a low neutrophil count than individuals who were HCV-antibody negative (9% versus 3%, respectively, P < .0001). In addition, they found that HCV antibody-positive individuals were 2.6 times more likely to have low platelet counts than individuals who were HCV-antibody negative (13% versus 5%, respectively, P < .0001). There was no association, however, found between HCV antibody status and anemia or other peripheral blood cell components.

The authors conclude, "HCV-infected persons in the general population of the United States are more likely to have low neutrophil and platelet counts, and HCV testing should be considered for persons with unexplained neutrophil counts below 1.0 × 10⁹/L or platelet counts less than 100 × 10⁹/L. Alternate causes of anemia should be considered for HCV-infected persons with low red blood cell counts."