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New Therapeutic Strategies for Hepatitis C

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  • claudine intexas
    Reports for NATAP AASLD Conference: New Therapeutic Strategies for Hepatitis C June 15-16, 2001 Chicago Report 1 Report 2 Report 3 Report 1 Reported by Jules
    Message 1 of 1 , Aug 5, 2001
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      Reports for
      NATAP AASLD Conference:
      New Therapeutic Strategies for Hepatitis C
      June 15-16, 2001
      Report 1 Report 2 Report 3

      Report 1
      Reported by Jules Levin

      Eugene Schiff, MD (University of Miami Center for
      Liver Diseases), known as the Dean of Hepatitis,
      opened the two day conference with a talk called "The
      Challenge of Hepatitis". He said safe and effective
      vaccines for Hepatitis A and B are readily available.
      Treatment for chronic hepatitis B is increasingly
      successful and for those with end stage liver disease,
      recurrent hepatitis B can be prevented. However,
      witness the recent case of HBV/HIV for Larry Kramer
      where he is facing a liver transplant, as reported
      recently in Newsweek.

      Schiff said the overriding challenge in this decade is
      hepatitis C. This disease, with a worldwide prevalence
      of over 170 million, notoriously (85%) evolves into
      chronic hepatitis, which will progress to cirrhosis in
      about 20% of cases. Data from a number of studies
      shows HIV accelerates HCV progression substantially
      for many people. He warned that the aging cohort of
      more than 2 million people in the US can be
      anticipated to generate increasing numbers of patients
      with end stage liver disease, many of whom will
      develop fatal consequences including hepatocellular
      carcinoma. He also expressed a positive attitude by
      saying that the explosion of information from studies
      in molecular biology and gene therapy undoubtedly will
      result in the conquering of this disease. New
      antiviral, anti-fibrotic and immunostimulatory agents
      are in the pipeline, he said. And they appear to be.
      In the first of the two days conference we heard a
      number of talks about research programs into new drugs
      for hepatitis C.

      Many drug companies and researchers are here at this
      conference, as the room is filled to capacity with
      about 300 people. Schiff said first and foremost is to
      prevent new cases of HCV, most effectively achieved
      with the development of a safe and effective vaccine.
      Second will be the advent of even more effective
      therapy than currently available for those with
      chronic HCV. Finally the patients with far advanced
      liver disease must have effective antiviral therapy
      that will prevent recurrent infection in the liver
      transplant graft.

      Schiff reported that in the USA:

      72% have genotype 1
      68% have a high viral load
      50% have both
      He showed data displaying how Japan has the most
      advanced death rate increase from HCV: 21% in 1980 to
      51% in 1995. Three to 4 million have HCV in the US,
      85% go on to chronic infection, and 10% develop
      decompensated cirrhosis ( 4% HCC, 6% decompensation,
      3.6% death). He estimated that 61% would have
      cirrhosis by 2008, 68% HCC, and liver related death
      would increase 233%.

      Hepatitis C Genetic Diversity and High Level of Viral
      Replication Pose a Challenge

      Charles Rice, PhD (Rockefeller University) and
      Particia Farci (University of Cagliari, Italy) talked
      about hepatitis C viral diversity. Within an
      individual, the virus exists as a quasispecies
      (mutated forms) and among isolates worldwide 6 major
      genotypes and numerous subtypes are recognized. Virus
      replication is a dynamic process with virion half life
      of 2-3 hours and an estimated production rate of about
      1012 virions per day. HCV RNA occurs via synthesis of
      a complementary negative-strand RNA intermediate and
      is error prone resulting in the generation of a large
      number of variants. Such high replication rates and
      the resulting genetic diversity pose important
      challenges for vaccination and treatment. Evidence is
      accumulating to suggest that the diverse genetic
      nature of HCV may have important biologic & clinical
      implications for viral persistence, for drug
      resistance and for vaccine failure, so said Farci. She
      continued that genetic variability is a critical
      mechanism for the virus to persist in the host (human)
      by escaping the immune system. Some patients can clear
      HCV but it remains unknown why. But recent evidence
      suggests that an increase in viral diversity during
      acute infection is associated with progression to
      chronicity, while self-limited clearance is associated
      with a virus which does not increase in diversity but
      remains stable. These data indicate that the early
      events of the virus-host interaction may determine the
      outcome of HCV infection. She said that patients who
      respond to interferon therapy with sustained HCV
      clearance exhibit a significant decrease in viral
      diversity and in the number of viral strains, with a
      similar pattern to that seen in patients who
      spontaneously clear the virus. By contrast, patients
      who do not respond to therapy show persistence of the
      original dominant viral strains, suggesting that
      resistant strains are already present prior to

      David Ho talked about what has been learned in HIV
      saying that much less is known today about HCV. In HIV
      we know how HIV reproduces itself, but we don�t know
      the process yet in HCV. Understanding this process has
      been limited by the fact that we do not have a cell
      culture system (test tube) where HCV can be placed to
      watch it replicate. Therefore, you can�t place a drug
      in the test tube to see if and how the drug changes or
      inhibits replication. HCV disappears in the test tube.
      But it appears as though a new system is being
      developed and used in some labs that addresses some of
      the needs posed by the lack of such a system. Ho
      described daily production of HCV (1.3 x 1012 ), HIV
      (1010 ), and HBV 2.1 x 1012 ). In HIV, viral invasion
      into an infected call contributes to cell death and
      the immune system may play a role in killing off
      infected cd4 cells. In HCV it remains unknown why
      cells die off.

      New Drugs In Development

      The HCV gene was described and the various enzymes
      that comprise the gene were described as targets for
      which to develop drugs, as in HIV. The reverse
      transcriptase and protease enzymes are targets for HIV
      drug therapy. In HCV, the IRES, helicase, protease,
      and polymerase enzymes were discussed. Researchers
      described ongoing efforts to better understand how
      these enzymes assist in the process of virus
      replication, and at which points in these processes
      drugs can be developed for use. A few polymerase
      inhibitors are in development: two in clinical trials.
      But there is no data yet and speculation scuttle-but
      in the halls here was that these drugs may have
      limited antiviral activity. But hopefully more potent
      polymerase inhibitors will be developed. Several
      companies are researching the development of protease
      inhibitors for HCV. Boerhinger Ingleheim reports here
      of their HCV protease inhibitor going into phase 1 in
      uninfected in about 1 month. There is considerable
      controversy here about the viability of developing a
      protease inhibitor for HCV. Many researchers have been
      saying how difficult it is to develop a PI in HCV. But
      several researchers here reported that they feel
      encouraged that their HCV development program will be
      successful. Bear in mind that the Boerhinger PI is the
      first to go into humans and that none of the other PI
      programs are that far developed.

      Also discussed were ongoing research into antisense
      and ribozymes. Larry Blatt from Ribozyme
      Pharmaceuticals discussed the drug they have in early
      human studies. He reported it to be well tolerated in
      animals, good safety profile so far in humans, potent
      in cell culture, well tolerated in humans in phase 1
      by subcutaneous administration. He also said phase 2
      in combination with interferon will be started and
      that the drug abundantly gets into liver cells.

      John McHutchison (Scripps Clinic) reported on a dose
      escalation trial of ISIS 14803 in patients with
      chronic HCV. They are calling this an antisense
      inhibitor of HCV but one researcher told me he feels
      it works differently. In this initial study ISIS 14803
      was administered three times weekly for 4 weeks either
      by 2 hour intravenous infusion or bolus subcutaneous
      injection following, by at least 7 days, a single
      dose. The first 11 patients in the study received ISIS
      14803 by IV infusion. 10 had previously received
      interferon. Sequential groups of 3 patients were
      treated at 0.5, 1, and 2 mg/kg with another 2 patients
      receiving 2 mg/kg single doses and 1 mg/kg three times
      per week doses. Two out of 4 patients treated with 2
      mg/kg for 30 days or more had decreases in plasma HCV
      RNA viral load greater than 1 log. Two others had
      reductions of 0.5 log or more. Of these, 3 experienced
      elevations in ALT >10 x upper limit of normal. Liver
      biopsies performed on 2 experiencing an ALT flare did
      not reveal evidence of drug induced hepatotoxicity. A
      4th patient experienced an ALT elevation of <10 x ULN
      without a reduction in plasma HCV levels. Six patients
      were observed to have mild to moderate fatigue. No
      other clinical signs or lab evidence of toxicity were
      observed. Further evaluation of patients with the same
      administration routes is ongoing, and additional
      immunological studies of the ALT flares are planned.

      Several researchers I spoke with estimated it will
      take 4-5 years for promising HCV antiviral drugs
      discussed above such as helicase, protease, and
      polymerase inhibitors to enter clinical trials in HCV

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