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Daily Interferon Regimen for Chronic HCV

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    Daily Interferon Regimen for Chronic Hepatitis C: A Prospective Randomised Study Raffaele Bruno, Division of Infectious and Tropical Diseases, University of
    Message 1 of 1 , Jul 31, 2000
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      Daily Interferon Regimen for Chronic

      Hepatitis C: A Prospective Randomised Study

      Raffaele Bruno, Division of Infectious and Tropical
      University of Pavia, IRCCS San Matteo, Pavia, Italy;
      Debiaggi, Institute of Microbiology, University of
      Pavia, Pavia,
      Italy; Paolo Sacchi, Elena Maffezzini, Francesca Zara,
      Brunetti, Carlo Filice, Savino F.A. Patruno, Gaetano
      Division of Infectious and Tropical Diseases,
      University of Pavia,
      IRCCS San Matteo, Pavia, Italy


      Objective: To compare the safety and efficacy of two
      regimens of
      lymphoblastoid interferon, 3MU daily for 12 months vs
      6MU three
      times weekly for 12 months, for the treatment of
      patients with
      chronic hepatitis C.
      Design: This was a prospective, randomised, nonblind
      Setting: The study was conducted in outpatients
      attending the
      University Hospital in Pavia, Italy, between 1997 and
      Patients: 100 treatment-naive outpatients with chronic
      hepatitis C
      genotype 1b participated in the study.
      Main Outcome Measures: We measured serum hepatitis C
      (HCV) RNA levels, serum alanine aminotransferase
      histological activity index score and fibrosis stage.
      Patients were
      classified as follows: primary responders (PR) when
      normalised and HCV-RNA became negative during
      nonresponders (NR) if ALT remained elevated and
      remained positive during treatment; sustained
      responders (SR)
      when HCV-RNA became persistently negative and ALT
      normalised during treatment and for at least 6 months
      treatment; relapsers (R) were PR whose ALT returned to
      values and HCV-RNA became positive again after the end
      Results: 50 patients received 3MU daily, of whom 42
      (84%) were
      PR and eight (16%) were NR. Of the 42 PR, 23 (54.7%)
      were SR
      and 19 (45.3%) were R. 50 patients received 6MU three
      weekly, of whom 21 (42%) were PR and 29 (58%) were NR.
      the 21 PR, five (23.8%) were SR and 16 (76.2%) were R.
      effects were comparable in the two groups and were
      never serious
      enough to require withdrawal of therapy.
      Conclusion: These findings support the choice of a 3MU
      regimen of lymphoblastoid interferon for the treatment
      of patients
      with chronic HCV infection and provide corroborative
      evidence in
      support of molecular virological data suggesting a
      relatively rapid
      viral turnover in this clinical setting. [Clin Drug
      18(1):11-16, 1999. � 1999 Adis International Limited]


      Interferon-alpha (IFNalpha) is currently the drug of
      choice, alone
      or in combination with ribavirin, for the treatment of
      patients with
      chronic hepatitis C.[1]

      Several controlled trials have been conducted to
      assess the
      minimum effective dose of IFNalpha in the treatment of
      hepatitis C. Such studies have demonstrated that a
      dose of 3MU
      administered three times a week for 6 months is
      effective in
      biochemical remission in less than 50% of patients,
      with a
      long-term sustained response rate of only 15 to
      20%.[2-5] This
      treatment schedule was the standard regimen until
      1993, when
      higher doses of interferon were administered for
      longer periods of
      time and with a more favourable outcome.[6] However,
      recent data
      on hepatitis C virus (HCV) viral dynamics and on the
      effect of
      interferon in blocking virion production and release
      have suggested
      a rationale for daily administration.[7]

      The aim of this study was to compare the safety and
      efficacy of
      daily interferon administration with the standard
      schedule of
      interferon given three times a week in patients with
      hepatitis C.

      Patients and Methods

      Selection of Patients

      One hundred adult patients seropositive for HCV-RNA
      genotype 1b and with a persistently elevated serum
      aminotransferase (ALT) level, at least 1.5 times the
      upper limit for
      at least 6 months, were considered eligible for the
      study after
      having undergone a liver biopsy with results
      consistent with a
      diagnosis of chronic hepatitis. We selected only
      patients with
      genotype 1b, which is generally associated with a poor

      Patients with the following characteristics were
      excluded from the
      study: HCV genotypes different from 1b, previous
      immunosuppressive or interferon therapy, an aetiology
      from chronic liver disease (i.e. hepatitis B,
      autoimmune hepatitis,
      haemochromatosis, Wilson's disease, or
      deficiency), alcohol or drug abuse, pregnancy,
      lactating status,
      serum positivity for hepatitis B surface antigen,
      antibodies, liver cirrhosis at any stage, autoimmune
      thyroid disease
      and any serious medical illness that could preclude
      the patient from
      completing the study.

      The study was approved by the ethics review board and
      informed consent was obtained from all patients.

      Study Design and Organisation

      This prospective randomised trial was conducted at the
      Division of
      Infectious and Tropical Diseases of the University of
      Pavia, San
      Matteo Hospital, from 1997 to 1998.

      The patients were randomly allocated to two different
      schedules by a simple random method of sampling. The
      list of
      randomisation was obtained using the software package
      SPSS. 50
      patients received lymphoblastoid interferon-alpha 6MU
      three times
      weekly for 12 months and 50 patients received
      interferon-alpha 3MU daily for 12 months.

      All patients were assessed as outpatients before the
      beginning of
      treatment and at weeks 2, 4, 6 and 8, and then every 4
      weeks during
      treatment. Biochemical and haematological tests were
      using standard laboratory methods. Serum HCV-RNA
      levels were
      determined before treatment and then at weeks 1, 4,
      12, 24 and 48,
      and then every 3 months for 1 year after the
      completion of the
      treatment. The serum HCV-RNA concentration was
      determined in a
      single laboratory using a competitive
      polymerase chain reaction with a sensitivity of 100
      The commercially available kit INNO-LiPA HCV II
      Zwijndrecht, Belgium) was used for HCV genotyping.
      and post-treatment biopsy samples of all sustained
      were compared and analysed by a single pathologist.


      The primary efficacy end-point was a sustained
      response defined as a lack of detectable HCV-RNA in
      the serum at
      24 weeks after treatment was completed. Secondary
      were normalisation of ALT levels and an improvement in
      histology results.

      Hepatic inflammation and fibrosis were graded using
      the modified
      Knodell histological activity index.[9] The
      inflammation score was
      determined by combining the first three index scores:
      periportal and lobular inflammation. The inflammation
      score has a
      range from 0 to 18; the higher score indicates more
      histological abnormalities. The degrees of fibrosis
      were: 0, no
      fibrosis; 1, portal fibrosis; 3, bridging fibrosis;
      and 4, cirrhosis.
      Improvement was defined as a decrease of the
      inflammation score
      when compared with the pretreatment biopsy sample. The
      biochemical response and a combination of sustained
      and virological response were also assessed.

      Patients were classified as follows: primary
      responders if ALT
      normalised and HCV-RNA became negative during
      nonresponders if ALT remained elevated and HCV-RNA
      positive during treatment; sustained responders if
      became negative and ALT normalised during treatment,
      remained so for at least 24 weeks after treatment and
      when ALT and HCV-RNA returned to abnormal values after

      Statistical Analysis

      The quantitative data of the daily and
      three-times-weekly regimens
      were compared using the t-test. Because the variance
      was not
      homogeneous, the HCV-RNA levels for the daily and
      three-times-weekly regimens were compared using the
      Mann-Whitney U test. Response to therapy was compared
      chi2 with Yates's correction. Differences in the liver
      biopsy score
      within each group were compared using the t-test.


      The baseline characteristics of the patients in the
      two groups were
      similar and are summarised in table I.

      The proportion of patients with a primary response was
      significantly higher in the daily administration group
      (84%) than in
      the three-times-weekly administration group (42%, p <
      Furthermore, the percentage of nonresponders was lower
      in the
      daily-dose group (table II).

      At the end of the follow-up, the rates of virological
      response were
      higher in the patients receiving daily administration
      (54.7%) than
      in those treated with the three-times-weekly regimen
      (23.8%, p =
      0.0392) [table II].

      The patients with viral clearance at week 4 included a
      proportion of sustained responders, as reported
      previously.[10] In
      the daily-dose group, 20 of the 23 sustained
      responders (86%) had
      a rapid clearance of HCV after the first week of

      Normalisation of serum ALT levels was associated with
      undetectable levels of serum HCV-RNA in primary
      responders and
      in sustained responders, whereas in nonresponders and
      in patients
      who had a relapse, ALT values followed the trend of

      Histological improvement was observed in 11 of 23
      (47%) in the daily-dose group who had a sustained
      response, and
      in one of the five sustained responders (20%) in the
      three-times-weekly group. The observed trend in
      improvement is presented in table III.

      The daily treatment regimen was the only variable
      predicting a
      response. Sustained virological response was not
      related to age or
      gender. No difference was observed with regard to
      HCV-RNA at
      baseline or histological score.

      No significant adverse events or toxicity were
      observed in the two
      groups. A reduction of the platelet count to less than
      60 000/mm3
      was observed in 29% of the patients in the daily-dose
      group (table
      IV). All the patients completed the study period
      without a
      discontinuation of therapy and/or dosage reduction.


      The standard regimen in the treatment of chronic
      hepatitis C is the
      administration of IFNalpha three times weekly for at
      least 48
      weeks. This therapy can lead to a sustained response
      rate of
      approximately 15 to 20%.[2] Recently it has been
      demonstrated that
      combination therapy with interferon plus ribavirin is
      effective than interferon alone in treatment-naive
      patients, with a
      two-fold improved response rate.[1,11]

      We found that a daily interferon regimen leads to
      higher primary
      and sustained response rates, with a lower rate of
      relapse. Daily
      administration appears to be superior to
      administration with respect to virological,
      biochemical and
      histological end-points. Recent data indicate that
      these sustained
      virological responses are usually long-lasting and
      correlate with
      progressive histological improvement.[12,13] In our
      study, rapid
      clearance of HCV-RNA was associated with an elevated
      response rate.

      Several recent reports support the rationale for daily
      administration of interferon. The rate of HCV
      production is very
      high (about 1012 viral particles per day),
      significantly greater than
      that estimated for the human immunodeficiency virus
      (HIV). The
      large viral production rate explains why HCV appears
      quasi-species. This implies that mutations improving
      viral fitness
      in treatment could appear rapidly. Therefore, failure
      of interferon
      treatment is associated with large quasi-species
      diversity and a
      high viral load. Initial aggressive treatment of HCV,
      as with HIV,
      may be a means of increasing the success of
      Furthermore, it has been demonstrated that
      therapy induces the production of quasi-species.[14]
      Uncovering the
      rapid dynamics of HCV has implications for the
      development of
      viral resistance to new therapeutic agents, for
      example protease
      inhibitors for HCV.[7] Increasing the interferon dose,
      as in the daily
      administration regimen, enhances antiviral activity
      and blocks the
      emergence of quasi-species.[14]

      The choice of lymphoblastoid IFNalpha-n1 has been
      justified by its
      superior efficacy in inducing a sustained
      response.[15] We did not
      observe treatment-related adverse effects leading to
      discontinuation of therapy or dosage reduction.
      therapy causes more adverse events, probably related
      to the


      We have demonstrated that daily interferon
      administration is more
      effective than three-times-weekly administration for
      the treatment
      of hepatitis C and increases the percentage of
      sustained responders.
      Further studies need to be performed with a larger
      patient pool to
      confirm the encouraging results obtained in this
      study. Furthermore,
      it would be interesting to compare the efficacy and
      safety of a daily
      regimen with combination therapy. Although currently
      drugs do not represent the ideal therapy for chronic
      hepatitis C, it
      is important to optimise the interferon regimen in
      order to obtain
      the best therapeutic results.


      The authors thank Fabio G. Crippa, MD, for
      collaboration in the
      collection of clinical data. This study received no


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