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Day 1 Report 53rd Annual meeting of AASLD

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  • claudine intexas
    NATAP - www.natap.org Day 1 Report 53rd Annual meeting of AASLD - American Association for the Study of Liver Diseases Nov 2-5, 2002, Boston, MA Viral Kinetics
    Message 1 of 1 , Nov 2, 2002
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      NATAP - www.natap.org

      Day 1 Report
      53rd Annual meeting of AASLD - American Association for the Study of
      Liver
      Diseases
      Nov 2-5, 2002, Boston, MA

      Viral Kinetics
      Reported by Jules Levin

      "HEPATITIS C VIRUS DYNAMICS DURING THERAPY WITH PEGINTERFERON ALFA-2A

      (40KD)
      (PEGASYS) COMPARED TO PEGINTERFERON ALFA-2B (12KD) (PEGINTRON) IN
      NAIVE
      PATIENTS WITH CHRONIC HEPATITIS C" (poster abstract 159)

      Italian study investigators (poster abstract 159) randomized 22
      previously
      untreated patients to receive Pegasys 180 mcg or or 1.0 mcg/kg, both
      once
      weekly plus 1000/1200 mg ribavirin. Patients had chronic HCV and had
      persistently elevated ALT. Baseline viral load was about the same.
      6/12
      on
      PegIntron and 7/10 on Pegasys had genotype 1. 20% (2/10) of patients
      had
      cirrhosis/transition to cirrhosis in the Pegasys group vs 16% (2/12)
      in
      the
      PegIntron group. Investigators reported that the average reduction in

      VL
      after 4 weeks was about the same for both drugs: Pegasys VL at
      baseline
      5.75
      log, week 4 was 3.32 log; PegIntron baseline VL 5.64, week 4 was 3.64

      log. At
      week 12 the viral load was significantly lower in Pegasys group (2.81

      log vs
      3.87 log). When authors assessed viral load over time out to 12 weeks

      in only
      patients with genotype 1 there was an observed difference between the

      two
      treatment groups but the differenvce was not significant. By looking
      at
      the
      graph the difference in genotype 1 patients started to diverge after
      1
      week
      increased by 4 weeks and appeared wider by week 12.

      The authors said these results could be due to different exposure of
      the two
      drugs, which may result a different sustained exposure to the two
      agents
      during the dosing interval.

      "HCV DYNAMICS IN HIV/HCV COINFECTED PATIENTS TREATED WITH PEGYLATED
      INTERFERON AND RIBAVIRIN" (poster abstract 154).

      Andrew Talal and colleagues reported on viral kinetics in HCV/HIV
      coinfected
      patients. Talal reported that this is the first study in HCV
      monoinfected or
      HCV/HIV coinfected with a detailed characterization of HCV dynamics
      of
      the
      first 3 doses of peg-IFN. 20 coinfected patients received PegIntron
      1.5
      ug/kg and ribavirin weight based dose at 13 mg/kg. All
      patientsreceived
      liver
      biopsy to assess grade and stage. All patients were hospitalized for
      24
      hours
      during the first two doses of Peg-IFN administration with outpatient
      visits
      on day 2, 3, 5, 6, 9, 14, 15 and 16. Talal is collecting data on
      various
      types of immune system related cells to assess the immune response.
      HCV
      RNA
      was measured regularly during day 1, at 48 and 72 hours; and days 5
      and
      6
      after the first dose; at 0.6, 12, 24, and 48 hours after the second
      dose.;
      and on dys 0, 1, 2 after the third dose. Baseline HCV viral load was
      6.5 log,
      14/20 patients were on HAART. Most patients had undetectable HIV.
      Average CD4
      count among responders was 400 and nonresponders 550, but both groups

      had the
      same stage & grade of disease at baseline. There were 4
      African-Americans
      among responders vs 6 among the nonresponders. Average 9 patients had

      undetectable HIV viral load, and average cd4 count was 469. All
      patients were
      genotype 1, except 1 who had indeterminate genotype.

      As of Sept 2002 8/20 individuals had a virologic response. 2 of 10
      were
      late
      responders: 3-8 months on treatment; in these patients HCV RNA begins

      to
      decline after week 8 and becomes undetectable after week 24. The
      study
      data
      finds a poor response rate in coinfected patients and suggests HIV
      impairs
      the response to therapy. Talal reports it takes longer for cells to
      die
      off
      for these patient: average infected cell half-life ranged from 18
      hours
      to 5
      days. Average free virus half-life is 4.6 hours. This suggests
      perhaps
      conifected patients should be treated for longer. 10/20 patients had
      no
      phase
      1 decline during therapy, phase I is the first few days.

      Immunologic Responses. Talal reports observing significant decreases
      in
      responses to C22.5 (NS3) and NS5 in responders compared to
      nonresponders.
      Decrease in response to HIV gag also observed at week 1.

      From anecdotal clinic reports it appears as though response to
      therapy
      is
      delayed for some coinfected patients, but this needs further study.
      Viral
      load response may appear after the first 28 days or be be slow in
      starting
      and gaining momentum. Data during the initial 3 days for 9 patients
      showed a
      mean virus half-life of 3 hours, as previously reported, and that the

      mean
      drug efficacy over this period is 93%. After this period, the model
      of
      HCV
      kinetics (Neumann et al, Science, 1998) no longer applies due to a
      reduction
      in drug effectivess.

      Talal conclusions. We have developed a new model that includes the
      decline in
      effectiveness, due to the exponential decay in peg-IFN
      concentrations,
      and
      which explains the data over the first week. With subsequent
      administrations
      of the drug, the high efficacy is reestablished and the viral load
      once
      again
      drops sharply. Immunomodulatory effect of IFN is different in
      responders
      compared with nonresponders.

      Viral Kinetics in HCV Monoinfection During Therapy

      Avidan Neumann (a noted viral kineticist) presented data from his
      viral
      kinetics study in which patients received PegIntron plus ribavirin at

      the
      Viral Hepatitis Therapy Workshop just prior to AASLD. So I can report

      that
      information but his more detailed poster at AASLD is not presented
      yet
      so
      these details will be reported later. At the Workshop Neumann
      reported
      viral
      load on average declined substantially during the first few days of
      PegIntron
      plus ribavirin. However, after a few days all the patients
      experienced
      an
      increase in viral load. Of course at the end of the first week on
      therapy
      there was a net decline in viral load. Viral load declines again in
      each
      following week in a similar fashion: down the first few days with
      increase in
      the next few days of the week.

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