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Hepatitis B Therapy at AASLD

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  • claudine intexas
    NATAP - www.natap.org ... Hepatitis B Therapy at AASLD Nov 9-13 Written for NATAP by Douglas T. Dieterich, MD Cabrini Hospital and NYU Medical Center, NYC See
    Message 1 of 1 , Nov 15, 2001
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      NATAP - www.natap.org
      ----------------------

      Hepatitis B Therapy at AASLD
      Nov 9-13

      Written for NATAP by Douglas T. Dieterich, MD
      Cabrini Hospital and NYU Medical Center, NYC
      See ongoing reporting from AASLD at NATAP website

      The therapy of hepatitis B is becoming almost as
      complicated as the
      disease
      itself. It is suffering from the success of all the
      new therapies
      coming as
      well as some information on the older therapies. I
      will attempt to keep
      this
      as uncomplicated as possible and have been debating
      how to organize
      this,
      alphabetical order or order of likely approval and I
      think it would be
      better
      to put this in historical perspective to build on the
      base and educate
      those
      still confused by the field.

      The first treatment approved by the FDA for HBV was
      alfa interferon 2b
      at a
      disabling dose of 10 MIU thrice weekly or 5 MIU daily
      for 4 months.
      This
      resulted in about a 25% HbeAg to HbeAb seroconversion
      rate and a
      histological
      benefit on liver biopsy. In late 1998 3TC or
      lamivudine was approved at
      a
      dose of 100 mg per day, considerably less than the HIV
      dose of 300 mg
      per
      day. One years��� treatment resulted in a
      seroconversion rate of about
      25%,
      like interferon and a histological benefit on biopsy
      similar to
      interferon���s.
      The difference in this therapy was that HBV resistance
      developed in
      nearly as
      many patients who seroconverted per year. The good
      news was that the
      resistant virus was seen as more benign than the wild
      type virus and
      even
      though the virus was still replicating, the
      seroconversion rate was
      significantly higher if the patients continued taking
      3TC. News from
      this
      meeting however suggested that the early biopsy
      benefit is lost after 4
      years
      on 3TC and the biopsies start to worsen again. This is
      beginning to
      sound
      like the HIV story where sequential nucleoside
      analogue therapy
      resulted in
      sequential nucleoside resistance and I believe that is
      clearly the
      case.

      Why not combine the two therapies? Well there were
      several combination
      trials
      presented here in Dallas. They, unlike the first study
      performed a few
      years
      ago, showed that combination 3TC and interferon is
      better than either
      alone
      and that interferon prevents the development of 3TC
      resistance
      mutations.
      There was even a combination trial of famciclovir and
      interferon, which
      showed some benefit. Famciclovir is approved for the
      treatment of
      herpes
      virus infections but not for hepatitis B. It does
      however have some
      activity
      against hepatitis B albeit slightly less than 3TC.
      Famciclovir and 3TC
      share
      some resistance mutations as well, but not all and
      there is one paper
      from
      2000 at least that demonstrates synergy between the
      two. In my
      practice, for
      patients not on clinical trials, I always use the
      combination of
      famciclovir
      and 3TC.

      The advances in interferon technology to pegylate it
      and lengthen the
      half
      life so that it can be administered weekly, have
      spread to hepatitis B
      treatment as well. One study showed that pegylated
      interferon alfa 2 a
      is
      clearly superior to plain alfa 2a interferon thrice
      weekly in the
      treatment
      of hepatitis B. Clearly the next step is to combine
      pegylated
      interferon and
      3TC in a trial. That trial is now in progress, but has
      no results to
      date.

      The next drug likely to be approved in the US for HBV
      is adefovir. It
      is a
      nuceotide analogue similar to tenofovir which just
      arrived on pharmacy
      shelves in early November for the treatment of HIV.
      Adefovir was
      studied in
      HIV patients and had little activity and quite a bit
      of kidney toxicity
      at
      120 mg and 60 mg per day. The HBV dose is fortunately
      only 10 mg and so
      far
      has demonstrated very little toxicity and a great deal
      of efficacy.
      Long-term
      data were presented up to 136 weeks for adefovir,
      which showed a
      seroconversion rate of 21% and only 3/39 patients
      discontinued drug for
      toxicity. Also encouraging was the loss of e Ag in 39%
      and the HBV DNA
      < 400
      copies of 61% at week 48 and 70% at week 100
      demonstrating a 3.75 log
      drop in
      HBV DNA. One of the biggest advantages of adefovir
      was that over 2
      years no
      resistance developed! There were some mutations found
      in the HBV
      genome, but
      they did not confer resistance to adefovir. That is
      very promising and
      encouraging. HIV HBV infection is becoming a bigger
      problem each year
      because after 4 years of 3TC treatment over 90% of HIV
      HBV infected
      patients
      demonstrate 3TC resistant HBV. An abstract from Paris
      clearly showed in
      35
      HIV HBV co-infected patients with 3TC resistant HBV
      that adefovir
      reduced
      HBV DNA by 4.74 logs. This was accompanied by 3/33
      patients
      seroconverting
      from e Ag to e Ab. This demonstrates the efficacy of
      adefovir in 3TC
      resistant virus even in HIV patients. There was no
      change in HIV RNA or
      CD4
      count in these patients. Combinations of adefovir and
      3TC were studied
      for
      drug-drug interactions and there appear to be none,
      paving the way for
      a
      combination adefovir 3TC trial, which is ongoing now.
      There is every
      reason
      to believe that this drug will be licensed in the US
      by this time next
      year
      for the treatment of hepatitis B and 3TC resistant
      hepatitis B

      Next in the arena is FTC, a close cousin of 3TC.
      There was originally
      no
      real reason to suspect that this would be any better
      than 3TC. However
      in a
      large multiple dose trial presented here the highest
      dose 200 mg
      resulted in
      61% of patients with <4700 copies of HBV DNA, but
      even more
      impressive was
      the e Ag loss of 50% and the eAb seroconversion rate
      of 23%. Only 2
      patients
      developed the classic 550 and 526 mutations, which are
      the same as the
      3TC
      resistant ones. There were no serious side effects
      noted in this trial.
      From
      the same company, Triangle, another drug clevudine or
      L-FMAU was
      studied
      first in an animal toxicology study and shown to be
      safe in animals.
      Then it
      was studied in a 28 day trial in man . The results
      were somewhat
      surprisingly good. All three doses showed as much as a
      3 log drop in
      HBV DNA
      in the 28 days, but what was surprising was that HBV
      DNA stayed down by
      as
      much as 2 logs even 5 months after stopping
      clevudine!. The highest
      dose
      resulted in some ALT elevations, but that just may
      mean that it is
      working
      well. The obvious next step is to combine these two
      agents and the
      results of
      that trial will be really interesting.

      editorial note: Entecavir is a new hepatitis B drug. A
      study was
      presented on
      entecavir vs 3TC resistance-

      New Hepatitis B Drugs at AASLD (LDT, adefovir,
      entecavir)
      <A HREF="http://www.natap.org/2001/aasld2/day13.htm">
      http://www.natap.org/2001/aasld2/day13.htm</A>

      One study of entecavir in transplant patients clearly
      showed activity
      of
      about a 1.5 log drop in HBV DNA in heavily pre treated
      patients
      suggesting
      that entecavir may indeed be active in 3TC resistant
      patients.

      LDT is another nucleoside made by Novirio which has
      good activity
      against HBV
      and HIV and the phase I dose escalation results were
      presented here
      which
      showed linear pharmacokinetics, a good thing to have.
      A large
      combination
      trial with 3TC is due to get started in the US any day
      now and it
      should be
      exciting. The trial design is very intriguing and
      adventurous and
      should look
      immediately for synergies between the two drugs.

      D4C is the Achillion addition to the hepatitis B
      nucleoside pool. A
      phase I
      trial in healthy volunteers was presented which
      revealed good
      absorption and
      good half-life. In vitro this drug shows activity
      against both wild
      type and
      3TC resistant hepatitis B. This is also a promising
      new agent for which
      trials are presently underway.

      There is much progress in the world of hepatitis B now
      and much of it
      is
      proceeding in the direction of combination therapy
      based on the
      building
      blocks of 3 TC and perhaps pegylated interferon.
      Nucleoside only
      combinations, of course have fewer side effects and
      appear to be the
      wave of
      the future.

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