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4th International Workshop on Therapies for Viral Hepatitis

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    NATAP - www.natap.org 4th International Workshop on Therapies for Viral Hepatitis October 29-31, 2002, Boston, MA Reported by Jules Levin This is a 2-day
    Message 1 of 1 , Oct 31, 2002
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      NATAP - www.natap.org

      4th International Workshop on Therapies for Viral Hepatitis
      October 29-31, 2002, Boston, MA
      Reported by Jules Levin

      This is a 2-day meeting immediately prior to the annual American
      Association
      For The Study of Liver Disease conference, the leading liver
      conference.

      NEW DRUGS

      There were several discussions of new drugs for HCV. There appear to
      be
      a
      bunch of antiviral drugs in various stages of very early development
      including polymersase and helicase inhibitors. There was a brief
      presentation
      on the first HCV protease inhibitor to reach clinical trials, BILN
      2061. This
      drug is being developed by Boerhinger Ingleheim and is the subject of
      4
      studies being presented at the upcoming AASLD. These presentations
      are
      the
      first publicly revealed data on this drug. Researchers will report
      initial
      study results from HCV-infected patients. There were also a few talks

      here on
      early results from studies exploring the potential use of certain
      non-nucleosides and nucleosides in HCV. The development of any drug
      is
      subject to the vagaries of development: will it prove to be safe and
      effective. Many drugs do not make it past the early stages of
      development.

      Interferon Plus Pegylated Interferon

      There was an interesting pilot study presented here by a Brazil
      research
      group (abstract 36) that raises a question I feel is worthy. They
      used
      Consensus Interferon (CIFN) in this study but I think that any
      interferon
      could be used. The notion is that starting therapy with interferon
      for
      a day
      or more and then using pegylated interferon may yield better results
      for hard
      to treat patients such as genotype 1, previous non-responders, and
      HIV-infected patients. This approach is experimental and needs
      further
      study
      and refinement. For example, do you use one or two days of a daily
      dose
      of
      interferon and how much do you use? Do you then use pegylated
      interferon on
      the following day or do you start both together? Although this
      concept
      makes
      sense I���d like to see studies showing it improves the sustaimed
      response. An
      initial loading dose of interferon may improve the initial reduction
      in
      viral
      load but studies need to explore if the sustained response rates are
      improved.

      The purpose of this study was to analyze early HCV viral load
      decrease
      after
      CIFN on the first day followed by 180 ug of peg-IFN/weekly + 1000 mg
      of
      ribavirin per day. HCV RNA was determined by qualitative and/or
      quantitative
      PCR (Amplicor Roche Monitor) pre-treatment, 24 hour and at weeks 2,
      4,
      and
      12. 5 patients, a small study, were treated with 24-30 ug of CIFN on
      the
      first day followed by peginterferon. The researchers reported that
      the
      median
      HCV viral loads at pretreatment were 6.3 log and 4.2 log after 24
      hours
      (after the initial CIFN dose). At week two the median HCV RNA viral
      load was
      2.1 log and it was 2.5 log at week 4. At weeks 2 and 4, 2/5 and 2/5
      patients
      had negative viral load, respectively. The researchers concluded that

      the use
      of a "fast acting" interferon (CIFN) at the first day of treatment
      resulted
      in a profound viral load decrease in 24 hours. All patients showed an

      absolute count less than 5 log, including a decrease of more than 1.7

      log
      (mean drop 2.1 log) in all but one patient. In the opening session in
      a
      talk
      on viral load kinetics after starting HCV therapy, Avidan Neumann (a
      noted
      HCV viral kinetics researcher), also suggested that for some hard to
      treat
      patients such as non-responders or genotype 1 using a brief loading
      dose
      approach with daily interferon may help improve responses.

      Treating Cirrhosis

      This morning Jenny Heathcote (University of Toronto) talked about
      treating
      patients with cirrhosis and chronic HCV. She said that non-responders

      to HCV
      therapy can slow or reduce fibrosis rate of progress and reduce risk
      of
      hepatocellular carcinoma (liver cancer). Of course sustained
      responders
      have
      a better chance of slowing or reversing disease. She referred to a
      study
      where 56% of sustained responders reversed fibrosis and 30% of
      non-responders
      reversed fibrosis. She spoke in support of the findings from Poynard
      and
      McHutchison reported at AASLD last year and archived on my website
      that
      49%
      of patients with cirrhosis showed reversal of fibrosis with paired
      biopsies
      20 months apart. In that study, Poynard suggested that with longer
      term
      followup the percent of patients with improved fibrosis might
      increase.

      Alternatives to Ribavirin

      Johnson Lau and colleagues from Ribapharm reported early results from

      their
      research into 2 alternatives to ribavirin that appear more effective
      than
      ribavirin but still need further study in HCV-infected individuals.
      Here is
      the information presented by Lau. Ribavirin, in combination with a
      long-acting interferon, is currently the recommended therapy for
      patients
      with chronic hepatitis C. The mechanism of action of ribavirin is
      unknown but
      proposed mechanisms include (1) switching the host immune response
      through
      tilting the Th1/Th2 balance, (2) inhibition of host IMPDH, (3) direct

      inhibition of hepatitis C virus, and (4) inducing replication error
      catastrophies. Another important feature of ribavirin is that it
      accumulates
      in erythrocytes, and haemolytic anemia is one of the dose limiting
      features.
      As well, the anemia causes difficult to tolerate toxicities and side
      effects
      often leading to drug discontinuation by patients.

      Two ribavirin analogues (similar in molecular makeup to ribavirin but

      slightly different) are currently being developed by Ribapharm
      researchers.
      In in vitro and in vivo studies, levovirin also switches the Th1/Th2
      balance,
      similar to ribavirin. However, levovirin does not undergo
      phosphorylation and
      hence there are no monophosphate and triphosphate metabolites;
      therefore, the
      haemolytic anemia side effect as well as the weak direct antiviral
      effect is
      also absent. The safety profile of levovirin has been confirmed in a
      number
      of animal studies. Phase I studies have also confirmed the safety of
      levovirin in humans. Lau said that if switching Th1/Th2 is the main
      mechanism
      of action of ribavirin, levovirin will be an excellent compound with
      similar
      or better efficacy (with more effective dosing) and a much improved
      safety
      profile compared with ribavirin. Further studies are ongoing.
      Ribapharm
      has a
      development agreement for levovirin with Roche.

      The second compound, viramidine, is a liver-targeting version of
      ribavirin.
      This is based on the premise that not enough ribavirin is delivered
      to
      the
      liver and too much ribavirin is delivered to the erythrocytes.
      Preclinical
      studies presented at this meeting showed that viramidine is
      concentrated at a
      much better ratio between the liver versus the erythrocyte
      compartments.
      Clinical results from Phase I study in healthy volunteers based on
      similar
      doses of viramidine versus ribavirin have confirmed the improved
      safety
      profile of viramidine when compared with similar dosing of ribavirin,

      and
      these data will be presented in a few days at the AASLD meeting.
      Further
      clinical studies are required to establish that this drug has similar

      effectiveness in reducing HCV viral load in combination with
      interferon, as
      well as in establishing safety in HCv-infected individuals.


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