Comparison of Pegasys Versus Peg-Intron for Treatment of Chronic Hepatitis C Genotype 4
Condition: Hepatitis C
MeSH terms: Hepatitis A; Hepatitis C; Hepatitis C, Chronic; Hepatitis; Hepatitis, Chronic
Study type: Interventional
Phase: Phase 4

Summary: 
      Genotype 4 hepatitis C virus is the cause of approximately 20% of the 170 million cases of
      chronic hepatitis C in the world. Although rare in western nations, genotype 4 is the most
      common variant of the hepatitis C virus in Egypt and is also found throughout Africa and the
      Middle East. Early reports on the treatment of patients with genotype 4 chronic hepatitis C
      with interferon-alfa (IFN)-alfa monotherapy indicate poor rates of sustained viral response
      (SVR). With the introduction of ribavirin combination therapy and with pegylation of the IFN
      alfa molecule, however, response rates have improved dramatically, and current clinical trial
      data indicate that SVR rates between 43 and 79% are attainable in genotype 4 patients who are
      receiving pegylated IFN alfa plus ribavirin for 48 weeks. Clinical advances to optimize
      treatment for each patient have also been made, and tailored treatment options are now being
      developed that are comparable to the treatment approaches for genotype 1, 2, and 3 patients.
      A treatment duration of between 36 and 48 weeks appears to be optimal for most patients with
      chronic hepatitis C genotype 4.The aim of this study is to assess the efficacy and safety of
      pegylated interferon alpha 2a in patients with chronic hepatitis C genotype 4 in comparison
      to a historical cohort of patients treated with pegylated interferon alpha 2b
    

Detailed description: 
      The treatment of chronic hepatitis C with interferon (IFN)-based medicines has advanced
      steadily since publication of the first clinical trials in the late 1980s.Initial
      interventions using IFN-alfa monotherapy achieved limited success, but the introduction of
      IFN-alfa plus ribavirin combination therapy and the pegylation of the IFN alfa molecule,
      which improved pharmacokinetics and simplified dosing regimens, resulted in a steady
      improvement in overall treatment outcomes. Sustained virologic responses (SVR, defined as
      undetectable HCV RNA 24 weeks after completing treatment) have increased from 6% with IFN
      alfa monotherapy to more than 50% with pegylated interferon alfa (PEG-IFN alfa) plus
      ribavirin regimensObservations specific to genotype 4 chronic hepatitis C have followed a
      similar path, with initial investigations of IFN-alfa monotherapy producing limited success
      .These studies found that IFN-alfa monotherapy, which is usually administered at a dose of
      3-5 MIU three times a week for six months, resulted in an SVR in only 5-25% of treated
      patients.[24-26] The subsequent inclusion of ribavirin in treatment regimens had a dramatic
      improvement on SVR attainment, with rates of 8 and 42% reported for patients receiving
      IFN-alfa alone and in combination with ribavirin (1000-1200 mg/day), respectively.

      Pegylation of the IFN alfa molecule was the next major advance in the treatment of genotype 4
      chronic hepatitis C.Although two early studies failed to demonstrate a significant difference
      in SVR rates between PEG-IFN alfa-2b plus ribavirin and native IFN alfa-2b plus ribavirin
      (e.g., 42.9% vs. 32.3%, p = 0.43)[27], subsequent investigations reported SVR rates of 50 to
      79% in patients receiving PEG-IFN alfa-2b plus ribavirin (800-1,200 mg/day) for 48 weeks.[
      Overall, meta-analysis of clinical trial data shows that SVR rates are significantly higher
      among genotype 4 patients receiving PEG-IFN alfa plus ribavirin than in those receiving
      IFN-alfa plus ribavirin (55% vs. 30%, p = 0.0088).[33] This analysis also confirms the
      importance of adequate ribavirin dosing with higher SVR rates in patients receiving PEG-IFN
      alfa in combination with high-dose (1000¬-1200 mg/day) and low-dose (800 mg/day) ribavirin
      (72.0 and 45.8%, respectively; p value not presented). The importance of ribavirin dosing in
      genotype 4 patients with chronic hepatitis C is also demonstrated in an analysis of the
      genotype 4 patients included in the registration studies for PEG-IFN alfa-2a.[22, 34] In this
      analysis, SVR rates were 79% among patients receiving PEG-IFN alfa-2a (180 mcg/week) plus
      ribavirin (1000-1200 mg/day) for 48 weeks compared with 63% in those receiving the same
      regimen plus a lower dose of ribavirin (800 mg/day).The optimization of treatment duration is
      critical in ensuring that SVR rates are maximized without exposing the patient to an
      unnecessarily long treatment regimen that may have unfavorable implications in terms of cost
      and tolerability. The question of optimal treatment duration for genotype 4 chronic hepatitis
      C was addressed in a prospective randomized study in which patients received PEG-IFN alfa-2b
      (1.5 mcg/kg/week) plus ribavirin (1000-1200 mg/day) for 24, 36, or 48 weeks.Overall, SVR
      rates were significantly higher in patients receiving treatment for 36 or 48 weeks than in
      those treated for 24 weeks (66 and 69% vs. 29%; p = 0.001 for each comparison) (Fig. 2).
      Relapse appeared to be a major factor in determining treatment outcomes: virologic relapse
      during follow-up was highest among patients treated for 24 weeks (20 of 45, 44%) but
      relatively rare among the longer treatment arms.

      There was no significant difference between the 36-week and 48-week treatment regimens for
      the overall cohort. However, among patients with baseline viral load >2 million copies/mL who
      attained SVR, 65% were treated for 48 weeks and 35% were treated for 36 weeks: all patients
      with high baseline viral load treated for 24 weeks failed to attain SVR. This suggests that
      the 48-week treatment regimen may be better suited to patients with high baseline viremia.
      The efficacy and safety of pegylated interferon 2a has not be adequately evaluated in chronic
      hepatitis C genotype 4 patients in well conducted clinical trials involving well
      characterized cohorts and long follow up.
    

Intervention name(s): Pegylated interferon alpha 2a; Ribavirin; Pegylated interferon alpha 2 b plus ribavirin
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Injections: 180 ug once per week; Tablets, 1000-1200 daily; Pegylated interferon alpha 2 b injections
Other intervention name(s): Pegaesys; Viracure; PEG-Interon
Intervention MeSH terms: Interferons; Ribavirin; Interferon-alpha; Interferon alpha-2; Peginterferon alfa-2a; Peginterferon alfa-2b
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Chronic hepatitis C; pegylated interferon alfa-2a; ribavirin, rapid virologic response; early virologic response; sustained virologic response