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SAFE AND POTENT SUPPRESSION OF HEPATITIS B VIRUS (HBV) WITH L-DEOXYTHYMIDINE (LDT): RESULTS OF A DOSE-ESCALATION TRIAL

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    NATAP - www.natap.org ... AASLD Nov 9-13, Dallas Reported by Jules Levin Abstract 597. SAFE AND POTENT SUPPRESSION OF HEPATITIS B VIRUS (HBV) WITH
    Message 1 of 1 , Nov 30, 2001
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      NATAP - www.natap.org
      ----------------------

      AASLD
      Nov 9-13, Dallas
      Reported by Jules Levin

      Abstract 597. SAFE AND POTENT SUPPRESSION OF HEPATITIS
      B VIRUS (HBV) WITH L-DEOXYTHYMIDINE (LDT): RESULTS OF
      A DOSE-ESCALATION TRIAL


      Ching-Lung Lai, Univ of Hong Kong, Pok Fu Lam Hong
      Kong; Maureen W
      Myers,
      Deborah M Pow, Nathaniel A Brown, Novirio
      Pharmaceuticals, Inc,
      Cambridge,
      MA; Yin-Mei Lee, National Univ Hosp, Singapore
      Singapore; Man-Fung
      Yuen, Univ
      of Hong Kong, Pok Fu Lam Hong Kong; Seng Gee Lim,
      National Univ Hosp,
      Singapore Singapore


      Background: Therapy for chronic hepatitis B (CHB) is
      suboptimal due to
      frequent non-response to interferon and resistance
      with lamivudine. LdT
      has
      potent anti-HBV activity in vitro and in the woodchuck
      animal model and
      a
      potentially attractive safety profile (Bryant et al.,
      AAC Jan 2001).

      Methods: The antiviral activity of LdT in adults with
      CHB is being
      investigated in a dose-escalation trial, assessing 25,
      50, 100, 200 and
      400
      mg once a day for 4 weeks with 12 weeks follow-up.
      Serum HBV DNA levels
      are
      monitored weekly by a quantitative PCR method (COBAS
      Amplicor HBV
      Monitor
      assay, Roche Molecular Systems).

      Results: Four dosing cohorts (25, 50, 100, and 200
      mg/day), comprising
      24
      total patients, have completed treatment to date, with
      the 400 mg/day
      cohort
      presently ongoing. Over 4 weeks of treatment, mean
      (�SEM) total
      reductions in
      HBV DNA levels have been 2.4�0.3 log10, 2.7�0.2 log10,
      3.1�0.1 log10,
      and
      2.9�0.2 log10 for the 25, 50, 100 and 200 mg/day
      cohorts, respectively.
      Thus
      all LdT doses have been highly active, producing >99%
      reduction in
      serum
      viral load within 4 weeks in most patients. In the
      ongoing 400 mg/day
      cohort,
      HBV DNA reductions as high as 3.6 log10 have been
      observed by week 4.
      Analysis of serum HBV DNA reductions after Week 1
      indicates that
      second-phase
      HBV clearance is dose-proportional, and post-treatment
      return of HBV
      DNA is
      slower in the higher dose groups, consistent with a
      dose-related
      reduction of
      HBV-infected hepatocytes. Pharmacokinetic data
      indicate that daily LdT
      AUC is
      dose-proportional, so higher LdT doses will be tested
      to determine
      whether
      even greater HBV suppression can be achieved early
      during LdT
      treatment.

      Conclusions: LdT appears promising as a potent and
      safe new HBV
      therapeutic
      with marked anti-HBV activity within 4 weeks and a
      potential for
      profound HBV
      suppression with higher and/or longer dosing. No
      significant or
      dose-related
      toxicities have been identified to date.


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