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    American Association for the Study of Liver Diseases 51st Annual Meeting and Postgraduate Course Therapy for Hepatitis C Nezam H. Afdhal, MD Introduction and
    Message 1 of 1 , Dec 29, 2000
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      American Association for the Study of Liver Diseases 51st Annual Meeting

      and Postgraduate Course

      Therapy for Hepatitis C

      Nezam H. Afdhal, MD

      Introduction and Background

      During the last decade, major advances have occurred in antiviral
      therapy for hepatitis
      C virus (HCV) infection. In the late 1980s, even before HCV was
      identified, trials of
      interferon alfa were commenced and resulted in limited efficacy.
      After this virus was
      identified, clinical trials could be designed to effectively
      measure loss of serum HCV
      RNA in addition to normalization of alanine aminotransferase (ALT)
      levels as suitable
      end points.

      The concept of a sustained virologic response (SR) was defined as
      someone who
      cleared virus at end of treatment (ETR), with this viral clearance
      persisting for 24
      weeks off treatment. More recently, Marcellin and colleagues[1]
      have shown that
      more than 95% of sustained responders remain virus free, with
      persistently normal
      ALT levels and even histologic regression of disease.

      The Question of Cure

      The concept of curing HCV is now accepted by most physicians. Using
      virologic end
      points (ie, SR) as the gold standard for response after therapy,
      standard interferon at
      3 MU 3 times per week for 24 weeks resulted in an SR in only 9% of
      patients, and
      extending therapy for 48 weeks increased the SR to, at best, 15%.
      The major
      problem with interferon monotherapy has been the high rates of
      viral recurrence or
      relapse after stopping therapy. In 1998, the addition of ribavirin,
      a nucleoside analog,
      to interferon resulted in an increase in SR in up to 41% of all
      patients treated.[2,3]
      Most recently, the introduction of pegylated interferons has
      improved the results of
      both monotherapy and combination therapy (with pegylated interferon
      plus ribavirin)
      to as much as 35% and 54%, respectively (Figure).



      Figure. IFN=interferon; IFN/RBV=interferon + ribavirin;
      PEG=pegylated interferon; PEG/RIB=pegylated interferon +
      ribavirin

      These results of therapy are truly astounding, with just over half
      of all patients infected
      with HCV now having a possibility of cure. However, many questions
      remain
      unanswered. Response rates are dependent on both host and viral
      factors. Major
      host factors are male sex, age (proportional to duration of
      infection), race (blacks
      respond less well than whites), and degree of liver fibrosis. Viral
      factors include
      genotype, with nongenotype 1 virus responding much better to
      therapy and viral load
      (Table 1).

      Table 1. Negative Response Factors to Interferon and Ribavirin
      Therapy

      Host Factors
      Viral Factors
      Age
      Genotype 1
      Male sex
      Viral load > 2 million copies
      Black race
      More quasispecies
      Duration of infection

      Degree of fibrosis



      Can We Improve the Response to Therapy?

      Multiple strategies have been developed to improve response rates,
      particularly in
      patients with genotype 1 infection and high viral load. This is the
      most common group
      of patients in the United States, and clinical trials have
      suggested that the SR in this
      population with combination interferon/ribavirin is only 25%,[2,3]
      vs the 65% SR seen
      in genotype 2 and 3 patients.

      One strategy that has been suggested for genotype 1 patients is the
      use of induction
      therapy to rapidly reduce viral kinetics and better control viral
      replication. Small pilot
      studies have suggested that interferon 5 MU (or preferably 10 MU)
      daily is better
      than 3 MU 3 times per week for controlling the rapid replication of
      HCV. This
      question of induction therapy was addressed in great detail at the
      recent proceedings
      of the American Association for the Study of Liver Diseases held in
      Dallas, Texas.

      Induction Therapy

      Rationale

      Kinetic studies of HCV have shown that interferon therapy can
      induce an initial
      decline in viral replication, which is dose dependent and maximal
      at interferon 10 MU
      daily.[4] This initial decline in viral replication appears
      important because one of the
      predictors of SR to standard interferon/ribavirin combination
      therapy is loss of virus at
      1 month. In the registration studies of interferon and ribavirin,
      loss of virus at 4 weeks
      was seen in 84% of sustained responders. In addition to the early,
      rapid decline in
      viral kinetics, interferon also induces a more gradual secondary
      decline that appears
      necessary if a patient is to have an SR.

      The rationale of induction therapy is to increase the number of
      patients who have an
      early loss of virus and then to reduce interferon to the standard 3
      times per week
      dosing to produce the secondary decline in HCV levels and thus
      achieve an SR.
      Multiple different induction regimens have been proposed.
      Interferon induction alone
      as monotherapy is NOT effective. The majority of induction regimens
      use daily
      interferon from 5-10 MU for anywhere from as little as 2 weeks to
      as long as 24
      weeks, and then step down to either 3 or 5 MU daily. The interferon
      is combined
      with ribavirin at standard doses of 1000-1200 mg according to body
      weight.

      Induction Therapy With High-Dose Daily Interferon Plus Ribavirin

      There have been many small studies of maintenance therapy presented
      and nearly all
      have shown that there is indeed early loss of virus and even a
      higher ETR, but until
      now, sustained response data have not been available.

      Study No. 1. At a breakout session, Robert Carrithers from the
      University of
      Washington, Seattle,[5] presented the results of an international
      multicenter study on
      high-dose induction interferon plus ribavirin vs standard
      interferon/ribavirin therapy.
      The study enrolled 625 patients into the 2 arms, and pretreatment
      demographics were
      similar for age, sex, viral load, histologic diagnosis, and
      genotype. The induction arm
      was as follows:

      Interferon -- 10 MU daily for 2 weeks; 5 MU daily for 6 weeks; 3 MU
      daily for 16
      weeks; and then, 3 MU 3 times per week for 24 weeks

      All patients received ribavirin at 1000-1200 mg daily, according to
      body weight.

      The results for viral clearance in the treatment phase showed a
      more rapid clearance
      of HCV RNA at week 8 among patients in the induction group (Table
      2).

      Table 2. Virologic Response to Induction Therapy vs Standard
      Interferon/Ribavirin Therapy


      Induction
      Standard Combination
      Therapy
      8-week viral clearance
      44%
      32%
      Genotype 1
      46%
      21%



      ETR (week 48)
      68%
      61%
      Genotype 1
      57%
      49%



      SR (week 24 post
      treatment)
      37%
      33%


      As can be seen from data in the table above, although at the early
      8-week time point
      there is an advantage to induction therapy in genotype 1 patients,
      this does not carry
      over into the SR rate.

      Study No. 2. A second study performed by Kristian Bjoro and
      colleagues from
      Oslo[6] used an induction regimen in 256 HCV treatment-naive
      patients.

      Patients were randomized to either standard interferon/ribavirin
      combination therapy
      (interferon alfa-2b 3 MU 3 times per week plus ribavirin 1000-1200
      mg/day) or to
      induction therapy with 6 MU daily for 4 weeks and then 3 MU 3 times
      per week for
      22 weeks. The total treatment period was 26 weeks, with a 26-week
      follow-up for
      SR. Groups were well matched, but unlike the previous study,
      genotypes 2b and 3a
      were present in 122 patients (47%), which is much higher than what
      is seen in US
      studies. Surprisingly, with only 26 weeks of therapy, at 52 weeks,
      genotype 1
      patients had an SR similar to that found in the study by Carrithers
      and colleagues for
      this group (where all patients received 48 weeks of therapy): 34%
      SR in the induction
      arm and 37% SR in the standard treatment arm. The even more
      remarkable finding
      was the improvement in SR in nongenotype 1 patients with induction:
      84% compared
      with 63% in the standard treatment arm.

      Compliance and side effect profile were similar for the induction
      and standard therapy
      groups in both trials.

      Conclusions. How can we reconcile the findings from these 2
      investigations with
      those of prior studies and the new information from combination
      pegylated interferon
      plus ribavirin trials?

      The study by Carrithers and colleagues appears to be the more
      reproducible in that
      benefit is more common with induction in genotype 1 patients for
      ETR; but thus far,
      only 1 study by Peter Ferenci and colleagues[7] from Austria has
      shown a genotype 1
      ETR resulting in an improvement in SR. The Norwegian study has
      surprisingly high
      response rates for 26 weeks of treatment, and the high level of
      genotype 2 and 3
      patients makes comparison with data from the study by Carrithers
      and colleagues
      very difficult. Interesting to note is that the 84% response rate
      seen for nongenotype 1
      patients is similar to that reported in trials of pegylated
      interferon plus ribavirin.

      Clinical Commentary

      Thus, what can we say about induction therapy? The promise of
      induction on viral
      phase 1 kinetics does appear to hold true in terms of higher viral
      clearance and ETR,
      especially in genotype 1 patients. The inability to convert this
      effect into an SR is
      disappointing, but there are several daily dose studies of
      interferon with ribavirin that
      may address this issue. Certainly, daily dosing is the nearest
      schema to pegylated
      interferon plus ribavirin and similar responses should be seen.

      New data on pegylated interferon alfa-2b plus ribavirin were
      presented by Michael
      Manns[8] from Hannover, Germany. Although reviewed elsewhere in
      this program, it
      is important to briefly discuss the findings here as well, within
      the context of induction
      therapy.

      In a large multicenter study, pegylated interferon alfa-2b (1.5
      mcg/kg) plus ribavirin
      was compared with standard combination interferon alfa-2b plus
      ribavirin therapy in a
      well-matched large group of patients. The results showed an overall
      54% SR to the
      pegylated interferon alfa-2b plus ribavirin combination therapy vs
      47% in the standard
      arm. Overall, 42% of genotype 1 patients had an SR, which
      represents an
      improvement over the previously reported 28% SR achieved with the
      standard
      interferon plus ribavirin regimen and which is better than that
      seen with the induction
      therapy approach, as discussed above.

      The convenience and better tolerance of pegylated interferons and
      this improved
      efficacy should put the role of induction therapy to rest.

      Predictors of Response to Pegylated Interferon

      Background

      As new therapies are introduced, such as the pegylated interferons,
      we need to
      reexamine the positive and negative predictors of response that are
      listed in Table 1
      above.

      Pegylated interferons, because of their higher serum
      concentrations, may improve
      response rates compared with the standard 3 times per week
      interferons by either
      preventing viral breakthrough or by increasing early antiviral
      effect, with more patients
      having rapid viral response (RVR) at week 4. This RVR is somewhat
      similar to the
      rapid viral clearance described with induction therapy above and is
      defined as a 2-log
      scale reduction in HCV RNA at week 4, with either a further 2-log
      reduction by
      week 8 or serum HCV RNA negative results at week 8.

      Study Design and Results

      Neumann and colleagues from Israel and Europe[9] looked at 254
      patients on
      pegylated interferon alfa-2a and 259 patients on standard
      (unpegylated) interferon
      alfa-2a 6 MU 3 times per week for 12 weeks followed by 3 MU 3 times
      per week
      for a further 36 weeks.

      RVR was achieved in 54% of patients on the pegylated interferon
      compared with
      38% of patients on the conventional interferon. RVR was independent
      of genotype,
      weight, age, sex, or baseline viral load. There was a marked
      reduction in viral
      breakthrough also seen for those on the pegylated interferon vs
      those on the
      unpegylated interferon. Failure to reduce HCV RNA to less than
      400,000 copies/mL
      at 4 weeks was predictive of no response to the pegylated
      interferon. In multivariate
      regression, only baseline viral load and RVR were predictors of
      response to
      pegylated interferon.

      Conclusions

      Clinically, this type of study is very important as new therapies
      become available.
      Unlike in the case of the standard interferon/ribavirin combination
      regimen, the
      baseline HCV RNA and SR are important predictors of response here
      and should
      lead to rationalization of therapeutic strategies for pegylated
      interferon alfa
      monotherapy. In patients on standard interferon/ribavirin therapy,
      genotype and
      response at 6 months are the best predictors of SR.

      Thus, as physicians have multiple therapeutic options for HCV,
      treatment strategies
      will have to be developed for each regimen to determine the best
      candidates for
      continuing treatment. Certainly, the RVR is an important predictor
      of response to
      pegylated interferon monotherapy (as demonstrated in this study
      with pegylated
      interferon alfa-2a) and should be evaluated in combination
      pegylated interferon plus
      ribavirin studies.

      Role of Amantadine

      In some very early studies, amantadine was shown to be effective
      against HCV.
      Mangia and colleagues from Italy[10] reported the results of a
      large multicenter,
      controlled trial of interferon plus amantadine vs interferon
      monotherapy in previously
      untreated patients with HCV.

      Patients without cirrhosis were randomized to interferon 6 MU 3
      times per week
      alone, or in combination with amantadine 200 mg daily, and all
      patients were treated
      for 48 weeks. There was an improvement in both ETR (41% vs 22%) and
      SR (30%
      vs 16%) in the amantadine-treated group vs the monotherapy group,
      respectively.

      This is really the first time that combining interferon with
      amantadine has been shown
      to have a reasonable improvement in SR. However, the SR does not
      compete with
      that achieved with either the pegylated interferon alfa-2a
      monotherapy (36%)
      regimen, the standard interferon/ribavirin combination (41%), or
      the pegylated
      interferon plus ribavirin (54%) regimen.

      The role for amantadine is likely to be very limited and will need
      to be further studied
      in combination with both pegylated interferon and as triple therapy
      with pegylated
      interferon plus ribavirin.

      References

      1.Marcellin P, Boyer N, Gervais A, et al. Long-term histologic
      improvement and
      loss of detectable intrahepatic HCV RNA in patients with
      chronic hepatitis C
      and sustained response to interferon-alpha therapy. Ann Intern
      Med.
      1997;127:875-881.
      2.McHutchinson JG, Gordon SC, Schiff ER, et al. Interferon
      alfa-2b alone or in
      combination with ribavirin as initial treatment for chronic
      hepatitis C. N Engl J
      Med. 1998;339:1485-1492.
      3.Poynard T, Marcellin P, Lee SS, et al. Randomised trial of
      interferon alfa 2b
      plus ribavirin for 48 weeks or for 24 weeks versus interferon
      alfa-2b plus
      placebo for 48 weeks for treatment of chronic infection with
      hepatitis C virus.
      Lancet. 1998;352:1426-1432.
      4.Neumann AV, Lam NP, Dahari H, et al. Hepatitis C viral
      dynamics in vivo and
      the antiviral efficacy of interferon-alpha therapy. Science.
      1998;282:103-107.
      5.Carrithers RL, Zeuzem S, Manns MP, et al. Multicenter
      randomized controlled
      trial comparing high dose daily induction interferon plus
      ribavirin versus
      standard interferon alpha 2b plus ribavirin. Hepatology.
      2000;32:317A.
      Abstract 631.
      6.Bjoro K, Bell H, Hellum K, et al. Randomized trial of
      interferon alpha
      induction plus ribavirin versus standard interferon alpha plus
      ribavirin for
      chronic HCV in previously untreated patients. Hepatology.
      2000;32:317A.
      Abstract 632.
      7.Ferenci P, Brunner H, Vogel W, et al. Combination of
      interferon induction
      therapy and ribavirin in chronic hepatitis C. Program and
      Abstracts of
      Digestive Disease Week, May 21-24, 2000, San Diego,
      California. Abstract
      977.
      8.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
      552.
      9.Neumann A, Zeuzem S, Brunda MJ. Rapid viral response to
      treatment with
      pegylated 40Kda interferon alfa-2a (PEGASYS) is strongly
      predictive of a
      sustained virologic response in patients with chronic
      hepatitis. Hepatology.
      2000;32:318A. Abstract 633.
      10.Mangia A, Santoro R, Villani MR, et al. Long term response to
      amantadine +
      interferon is significantly higher than that to interferon
      alone in chronic hepatitis
      C: final report of a randomized clinical trial. Hepatology.
      2000;32:318A.
      Abstract 636.

      Return To Conference Summaries for American Association for the Study
      of Liver Diseases 51st
      Annual Meeting and Postgraduate Course
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