Loading ...
Sorry, an error occurred while loading the content.

Updated Articles-Marty

Expand Messages
  • 2byteme@bellsouth.net
    American Association for the Study of Liver Diseases 51st Annual Meeting and Postgraduate Course Recent Developments in Chronic Hepatitis C K. Rajender Reddy,
    Message 1 of 1 , Dec 29, 2000
    • 0 Attachment
      American Association for the Study of Liver Diseases 51st Annual Meeting

      and Postgraduate Course

      Recent Developments in Chronic Hepatitis C

      K. Rajender Reddy, MD


      Hepatitis C is a global problem of immense importance. Currently,
      worldwide, there
      are an estimated 170 million people infected with the hepatitis C
      virus (HCV). The
      consequences of chronic hepatitis C include chronic disease,
      cirrhosis, and
      hepatocellular carcinoma. However, the course of this infection is
      variable and host,
      viral, or environmental factors may be associated with progression
      of the disease. For
      example, women appear to have a relatively slowly progressive
      course, and alcohol
      consumption seems to facilitate disease progression.

      Strides continue to be made in the treatment of chronic hepatitis
      C. The current
      standard of care is combination therapy with interferon alfa-2b and
      ribavirin, which
      achieves an approximately 40% sustained response rate. Response
      rates are
      dependent on several host and viral factors: women, particularly
      those younger than
      40 years, have a better response rate; HCV genotypes 2 and 3
      respond better than
      genotype 1; and low viral load and low body weight also correlate
      with a favorable
      response to therapy.

      At this year's annual meeting of the American Association for the
      Study of Liver
      Diseases, several treatment issues were addressed. Because the
      current treatment
      regimen is successful in less than 50% of patients and there are
      side effects associated
      with this therapy, attempts are being made to improve on this
      current standard of
      care. On the immediate horizon, the pegylated interferons are close
      to approval. The
      process of pegylation involves attachment of a polyethylene glycol
      (PEG) molecule to
      interferon alfa to produce a modified form of the drug with a
      prolonged half-life,
      thereby allowing sustained concentrations of interferon to be
      achieved over a longer
      period of time.

      The Pegylated Interferons

      Pegylation is not a new approach and other Food and Drug
      non-interferon compounds are available for clinical use. Pegylation
      of interferon
      allows for dosing at less frequent intervals, and related studies
      have used a regimen of
      once per week. Two forms of pegylated interferon have undergone
      clinical trials: a
      40-kD pegylated interferon alfa-2a and a 12-kD pegylated interferon
      alfa-2b. Earlier
      trials were conducted with the pegylated interferons as
      monotherapy, and currently,
      clinical trials have been completed or are near completion that use
      therapy with pegylated interferon plus ribavirin for the treatment
      of chronic hepatitis

      Pegylated Interferon Alfa-2b plus Ribavirin vs Standard
      Interferon Alfa-2b Plus Ribavirin

      Study Design

      A pivotal paper on therapy with pegylated interferon alfa-2b and
      ribavirin was
      presented by Dr. Michael Manns[1] at Presidential Plenary Session
      II. Dr. Manns
      discussed the results of a global trial involving 1530 previously
      untreated patients with
      chronic hepatitis C who were randomized to receive 1 of 3
      treatments for 48 weeks.
      Group A received the pegylated interferon at 1.5 mcg/kg of body
      weight per week
      for 4 weeks followed by a lower dose of 0.5 mcg/kg of body weight
      per week for 44
      weeks and ribavirin at 1000-1200 mg daily for 48 weeks. Group B
      received 1.5
      mcg/kg of body weight per week of the pegylated interferon and
      ribavirin 800 mg per
      day for 48 weeks. Group C received standard interferon alfa-2b 3 MU
      3 times per
      week subcutaneously and ribavirin 1000-1200 mg per day (based on
      body weight)
      for 48 weeks.


      The highest sustained virologic response (54%; negative HCV RNA 6
      months off of
      therapy) was seen in group B, which received 1.5 mcg/kg of body
      weight weekly of
      pegylated interferon plus ribavirin 800 mg per day for 48 weeks.
      This response rate
      was higher and statistically significant compared with those of the
      remaining 2
      treatment groups, which had similar sustained virologic response
      rates of 47%.
      Further analysis noted that genotype 1 patients had sustained
      response rates ranging
      from 33% to 42%, with the highest response rate being observed for
      patients in
      group B.

      Finally, as one would expect, genotype 2 and 3 patients did the
      best, with response
      rates ranging from 79% to 82%. The response rates observed in this
      trial were better
      than in previous trials for genotype 2 and 3 patients, which were
      in the order of 65%.
      Therefore, this trial observed better responses across all
      categories, particularly for
      genotype 1 patients. There were no differences in side effects
      among the various
      treatment groups.

      Overall tolerability was good, with anemia occurring in the 10% to
      12% range;
      however, discontinuation occurred in less than 1%. Neutropenia also
      was observed in
      2% to 18% of patients (grade 3 and grade 4), with discontinuation
      being, at most,
      1% due to neutropenia. The safety profile was comparable among all


      In summary, it appears that combination pegylated interferon
      alfa-2b plus ribavirin has
      an advantage over the current treatment of choice of standard
      interferon plus ribavirin.
      The 7% increase in response rate with pegylated interferon plus
      ribavirin (group B;
      54%),when compared with standard interferon and ribavirin (group C;
      47%), was
      statistically significant. Thus, the relative advantage is
      approximately 7%, and this
      would suggest that pegylated interferon/ribavirin combination
      therapy is likely to
      replace the current regimen (which was used in group C patients).

      High-Dose Daily Induction Interferon Plus Ribavirin vs Standard
      Interferon Plus Ribavirin

      Rationale and Study Design

      One of the questions addressed in an oral presentation by Dr.
      Robert Carithers[2] was
      whether intensive high-dose daily therapy with interferon alfa-2b
      plus ribavirin
      improved both early reduction in HCV RNA levels as well as
      sustained response
      rates. A randomized multinational, multicenter open-label
      controlled trial was
      conducted in treatment-naive chronic hepatitis C patients who had
      elevated alanine
      aminotransferase (ALT) levels and compensated liver disease.

      Six hundred twenty-five patients were randomized to receive either
      interferon alfa-2b 3 MU 3 times per week and ribavirin 1-1.2 g per
      day for 48 weeks
      or an induction regimen of interferon alfa-2b 10 MU daily for 2
      weeks followed by 5
      MU daily for 6 weeks, followed by 3 MU daily for 16 weeks, and then
      3 MU 3
      times per week for 24 additional weeks with concurrent ribavirin
      1-1.2 g per day.


      The end-of-treatment responses were comparable overall and ranged
      from 61% in
      the standard treatment group to 68% in the induction group. The
      breakdown of
      end-of-treatment responses did not vary by genotypes. Overall dose
      discontinuations for all causes, and discontinuation due to adverse
      events were higher
      in the induction group compared with the standard treatment group.


      In conclusion, Dr. Carithers indicated that the induction regimen
      led to a more
      pronounced initial viral decline compared with the standard
      regimen, but that this did
      not translate into superior sustained response rates. The adverse
      event profile of the
      intensive regimen was worse than for standard therapy. This large
      study should
      emphasize that induction therapy currently offers no advantage over

      Do the Dynamics of the Viral Response Differ for Pegylated
      Interferon Alfa-2a?

      Physicians who are involved in the care of hepatitis C patients may
      wish to tailor
      treatment to a given case and in this effort, continually seek
      information on the factors
      predictive of response.

      There have been well-defined predictors of response and additional
      work was
      presented from a large database on clinical trials with the 40-kD
      pegylated interferon
      alfa-2a given at a dose of 180 mcg per week for 48 weeks. Several
      of the previously
      described factors shown to be associated with favorable response or
      lack of
      response along with several other newer factors were evaluated by
      Samuel Lee and

      Factors predictive of favorable response to therapy, as defined in
      this study and
      several previous reports, generally include HCV nongenotype 1 (ie,
      2 and 3), low
      viral load, age younger than 40 years, relatively mild histology,
      and lower body
      weight. Lee and colleagues observed that an ALT level of greater
      than 3 times the
      upper limit of normal at baseline and a histologic activity index
      score of greater than
      10 were also predictors of favorable response. However, contrary to
      observations, gender was not found to be associated with a
      favorable response to
      therapy. These data further solidify our previous observations and
      should therefore be
      helpful in allowing us to better predict response in a given
      patient based on one or
      more such characteristics.

      Pegylated Interferon vs Standard Interferon in Blacks With
      Hepatitis C


      Thus far, interferon monotherapy of chronic hepatitis C in blacks
      has been associated
      with suboptimal response. There have been limited data suggesting
      that these patients
      respond better to combination interferon plus ribavirin. However,
      these data are
      flawed in that the number of black patients actually treated has
      been rather small
      relative to the magnitude of the problem of hepatitis C infection
      in these individuals,
      which is on the order of 2- to 3-fold higher compared with whites.
      Further analyses
      were done on pegylated interferon trials, and again, several of
      these trials had small
      numbers of patients. In multiple trials with the 40-kD pegylated
      interferon alfa-2a that
      involved 1205 patients, only 55 were black.[4]

      Analyses of Data

      When analyzed, both end-of-treatment and sustained virologic
      responses were
      significantly higher in black patients who were treated with the
      pegylated interferon
      alfa-2a given subcutaneously at 180 mcg per week for 48 weeks,
      compared with the
      standard (unpegylated) interferon alfa-2a given thrice weekly.
      However, overall
      responses were lower in black patients compared with whites (15% vs
      respectively). Histologic response (2-point decrease in Hepatitis
      Activity Index score)
      was observed in 33% of blacks compared with 61% of whites.

      Data from 2173 chronic hepatitis C patients in trials with the
      pegylated interferon
      alfa-2b had 85 blacks. Fourteen percent of these black patients
      treated with this
      pegylated interferon (alfa-2b) at 1.5 mg/kg of body weight weekly
      for 48 weeks,
      achieved a sustained response compared with 23% of whites.[5] When
      data were
      analyzed for genotype 1, 8% of blacks vs 13% of whites achieved a
      However, data from both of these pegylated interferon trials[4,5]
      showed that 0% had
      a sustained response to standard interferon monotherapy.


      In summary, in blacks, pegylated interferons given weekly achieved
      better response
      rates compared with their conventional unpegylated interferon
      counterparts given 3
      times per week but overall were still lower than responses achieved
      in whites. Larger
      clinical trials are warranted to evaluate these patients, and
      moreover, mechanisms
      underlying suboptimal response that may include host immunogenetics
      and viral
      factors also need to be elucidated.

      Adverse Effects


      The current treatment regimen of interferon alfa-2b 3 MU 3 times
      per week plus
      ribavirin daily is associated with a variety of side effects that
      have led to decreases in
      drug doses and even discontinuation. Combination interferon and
      ribavirin therapy is
      associated with adverse experiences that may include "flu-like
      symptoms," psychiatric
      episodes of depression, psychosis, aggressive behavior,
      hallucinations, suicidal
      attempts, and although, rarely, homicidal ideation.

      More specifically related to ribavirin use, anemia can be profound
      and may lead to
      exacerbation of coronary artery disease symptoms. Lastly, extreme
      caution is
      exercised with women of childbearing age because of its potential
      Ribavirin dose has been based on patient weight, with individuals
      75 kg or lighter
      receiving 1000 mg per day and individuals heavier than 75 kg
      receiving 1200 mg per
      day. Dose modification may be necessary because of anemia or other
      side effects.

      Dosing Effects

      Dr. John McHutchison[6] presented response rates based on the doses
      received by
      individuals. He evaluated an 80/80/80 group, which represented
      patients who
      received more than 80% of the interferon regimen, more than 80% of
      ribavirin, and
      more than 80% of the expected duration of therapy. A second group
      was categorized
      based on having received less than 80% of the interferon regimen
      and/or less than
      80% of the ribavirin dose and/or less than 80% of the expected
      duration of therapy.
      Dr. McHutchison concluded that 60% to 70% of patients could be
      maintained on
      more than 80% of the dose for both drugs for more than 80% of the
      duration of
      therapy. Ninety percent of patients who take either drug also
      tolerate the other drug,
      and patients who require dose reductions usually have reductions in
      both drugs.
      Individuals who can be maintained on more than 80% of the
      interferon and ribavirin
      regimen for the proposed duration of therapy may have an enhanced
      response rate, and therefore, maintenance of both drugs appears to
      be equally
      important for achieving a sustained response. Dose reductions
      either in early or late
      stages of therapy may have similar effects on response rates and
      his recommendation
      was that every effort should be made to continue the maximum
      tolerable doses of
      therapy to achieve the best response rate.

      Quality-of-Life Issues


      Because hepatitis C may be relatively mild in some individuals who
      are often therefore
      asymptomatic, and because current treatments are associated with
      side effects,
      quality of life (QOL) has always been of interest as related to the
      disease itself and to
      the regimens.

      There are several health-related quality-of-life (HQOL) instruments
      that have been
      used to address issues in this context. A well-validated form is
      SF-36, which looks at
      several domains, including physical function, role limitations
      (physical), vitality, general
      health perceptions, pain, social function, role limitations
      (emotional), and mental
      health. Summary scores include both the physical and mental
      components. Other
      instruments that have been used include Fatigue Severity Scale
      (FSS), Beck's
      Depression Inventory (BDI), and the Work Productivity and Activity
      (WPAI) scale.

      Clinical Trials

      Two trials evaluated SF-36 and WPAI in patients on pegylated
      interferon alfa-2a.

      Dr. Robert Perillo[7] presented his observations and reported that
      hepatitis C patients
      who were on pegylated interferon alfa-2a 180 mcg per week appeared
      to have a
      better HQOL compared with patients treated with interferon alfa-2b
      plus ribavirin. In
      addition, there seemed to be superior work productivity and a
      superior safety profile
      for patients on pegylated interferon alfa-2a alone, compared with
      interferon alfa-2b
      plus ribavirin.

      Similar observations were made by Jens Rasenack,[8] who presented
      QOL data from
      a large European trial comparing pegylated interferon alfa-2a 180
      mcg per week for
      48 weeks with interferon alfa-2a given 3 MU 3 times per week in an
      regimen of 6 MU 3 times per week for 3 months followed by 3 MU 3
      times per
      week for 9 months. During the first 12 weeks of therapy, pegylated
      interferon alfa-2a
      therapy was associated with enhanced QOL, with less fatigue
      compared with
      interferon alfa-2a.

      Lastly, Dr. Feagan[9] presented QOL data from trials involving 2
      regimens of
      pegylated interferon alfa-2b, given at 0.5 mcg/kg of body weight
      weekly for 48
      weeks or at 1.5 mcg/kg of body weight weekly, respectively,
      compared with
      interferon alfa-2b given at 3 MU 3 times per week for 48 weeks. He
      concluded that
      pegylated interferon alfa-2b 0.5 mcg/kg once weekly dosing
      significantly improved
      HQOL and concurrently had better responses, compared with
      interferon alfa-2b.


      Therefore, it appears that the pegylated interferons are well
      tolerated and may even
      be better tolerated than either interferon monotherapy or
      combination therapy.

      Tolerability and Effectiveness of Antiviral Therapy in Patients
      Awaiting Liver Transplantation


      The number of patients with end-stage liver disease due to
      hepatitis C infection that
      are on liver transplantation lists at various institutions
      continues to grow.
      Posttransplant recurrence of hepatitis C infection is universal,
      and recurrent chronic
      hepatitis and graft failure are problematic issues.

      Clinical Studies

      Jeffrey S. Crippin[10] presented data from a pilot study evaluating
      the tolerability and
      efficacy of antiviral therapy in patients awaiting liver
      transplantation. Only 15 patients
      from 4 centers were recruited, and he made the point that very few
      awaiting liver transplantation were eligible for treatment based on
      acceptable criteria
      for selection.

      Dr. Crippin concluded that pretransplant antiviral therapy with the
      agents and doses
      used in this study was poorly tolerated in the relatively few
      patients of UNOS (United
      Network for Organ Sharing) status 2b who were eligible for
      inclusion in the trial.
      Adverse events, particularly infectious complications, were of
      concern. He suggested
      that a strategy of treating patients before transplantation should
      perhaps involve those
      with more stable and compensated liver disease who might therefore
      meet the criteria
      for listing as status 3.

      A related and perhaps relatively more optimistic presentation was
      made by Dr.
      Gregory Everson from the University of Colorado,[11] in which an
      regimen of interferon alfa-2b plus ribavirin was used in patients
      with advanced chronic
      hepatitis and decompensated liver disease. The regimen involved
      initiating therapy at a
      lower dose of interferon alfa-2b of 1.5 MU 3 times per week plus
      ribavirin 600 mg
      per day, with a stepwise incremental change in the doses to achieve
      the standard
      regimen of 3 MU of interferon alfa-2b 3 times per week plus
      ribavirin 1000-1200 mg
      per day. Granulocyte colony-stimulating factor and human
      recombinant erythropoietin
      were used to treat absolute neutrophil counts of less than 800 and
      hemoglobin of less
      than 10 mg/dL, respectively.

      He presented data on 47 patients and was able to achieve sustained
      responses in 17%. An encouraging observation was that 4 patients
      who had sustained
      virologic response went on to be transplanted and during follow-up
      have not
      demonstrated any evidence of graft infection. Again, Dr. Everson
      suggested caution in
      interpreting these data and given the fact that these patients are
      very ill, he
      recommended that additional, larger trials be conducted to
      establish guidelines for
      therapy in this setting.


      1.Manns MP, McHutchison JG, Gordon S, et al. Peginterferon
      alfa-2b plus
      ribavirin compared to interferon alfa-2b plus ribavirin for
      the treatment of
      chronic hepatitis C: 24 week treatment analysis of a
      multicenter, multinational
      phase III randomized controlled trial. Hepatology.
      2000;32:297A. Abstract
      2.Carithers RL Jr, Zeuzem S, Manns MP, et al. Multicenter,
      controlled trial comparing high dose daily induction
      interferon plus ribavirin
      versus standard interferon alfa-2b plus ribavirin. Hepatology.
      Abstract 631.
      3.Lee SS, Heathcote EJ, Reddy KR, et al. Prognostic factors and
      predictability of sustained viral response (SVR) in patients
      treated with
      pegylated (40 kD) interferon alfa-2a (PEGASYS): a new profile.
      2000;32:370A. Abstract 843.
      4.Shiffman ML, Fromm H, Mills P. et al. Enhanced efficacy of
      pegylated (40
      kD) interferon alfa-2a (PEGASYS) compared with interferon
      (ROFERON-A) for chronic hepatitis C in blacks. Hepatology.
      2000;32:348A. Abstract 753.
      5.Lindsay KL, McHutchison JG, Ling MH, et al. Response to
      PEG-IFN alfa-2b
      (PEG-INTRON) in blacks and Hispanics with HCV is higher than
      standard IFN alfa-2b (IFN). Hepatology. 2000;32:347A. Abstract
      6.McHutchison JG, Poynard T, Harvey J, et al. The effect of dose
      reduction on
      sustained response in patients with chronic hepatitis C
      receiving interferon
      alfa-2b in combination with ribavirin. Hepatology.
      2000;32:223A. Abstract
      7.Perillo RP, Clin O, Thuluvath PJ, et al. Improved work
      productivity, safety,
      and quality of life with pegylated (40 kD) interferon alfa-2a
      therapy in the treatment of chronic hepatitis C. Hepatology.
      Abstract 809.
      8.Rasenack J, Zeuzem S, Feinman SV, et al. Therapy with
      pegylated (40 kD)
      interferon alfa-2a (PEGASYS) significantly enhances quality of
      life compared
      with standard interferon alfa-2a (Roferon-A) in patients with
      chronic hepatitis
      C. Hepatology. 2000;32:307A. Abstract 591.
      9.Feagan BG, Trepo C, Lindsay KL, et al. The impact of pegylated
      alfa-2b on health-related quality of life in chronic hepatitis
      C patients.
      Hepatology. 2000;32:307A. Abstract 590.
      10.Crippin JS, Sheiner P, Terrault NA, et al. A pilot study of
      the tolerability and
      efficacy of antiviral therapy in patients awaiting liver
      transplantation for hepatitis
      C. Hepatology. 2000;32:308A. Abstract 594.
      11.Everson GT, Trouillot T, Trotter J, et al. Treatment of
      cirrhotics with a low-accelerating dose regimen (LADR) of
      interferon alfa-2b
      plus ribavirin: safety and efficacy. Hepatology. 2000;32:308A.
      Abstract 595.

      Return To Conference Summaries for American Association for the Study
      of Liver Diseases 51st
      Annual Meeting and Postgraduate Course
    Your message has been successfully submitted and would be delivered to recipients shortly.