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18 months treatment to reduce relapse rates

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  • claudine intexas
    from NATAP www.natap.org by Jules Levin The data from the Benelux study has been presented at AASLD 2000 and EASL 2001. And it makes a good case to consider 18
    Message 1 of 1 , Jun 23, 2001
      from NATAP www.natap.org
      by Jules Levin

      The data from the Benelux study has
      been
      presented at AASLD 2000 and EASL 2001. And it makes a
      good case to
      consider
      18 months pegIFN+RBV treatment.

      18 Month Treatment Benelux Study

      ABSTRACT:

      REDUCTION OF RELAPSE IN CHRONIC HCV. A BENELUX STUDY
      IN 300 PATIENTS
      J.T Brouwer, S. W Schalm,
      University Hospital Rotterdam,

      Treatment of chronic HCV with Interferon is hampered
      by incomplete
      blocking
      of viral replication, limiting the initial response,
      and incomplete
      removal
      of infected hepatocytes, leading to frequent relapses.
      We aimed to
      improve
      the initial response by adding Ribavirin and to reduce
      the relapse rate
      by
      prolonging treatment to 18 months. Three hundred
      patients with chronic
      HCV
      and elevated transaminases were included from 25
      centers in Belgium,
      the
      Netherlands and Luxembourg: 69% genotype 1, 57% HCV
      RNA above 2x10E6
      copies/ml, 14% cirrhosis. Patients were randomized
      towards 18 months
      Interferon-a2b (3 MU tiw) plus Ribavirin, 18 months
      Interferon plus
      placebo,
      or 6 months combination. All 295 patients who started
      treatment were
      included
      in the intention-to-treat analysis; the per-protocol
      analysis included
      the
      238 who completed therapy. After 6 months treatment,
      HCVRNA was
      undetectable
      in 53% (p.p 59%) in combination therapy versus 29%
      (p.p. 31%) in
      monotherapy
      (p<0.001). The relapse rate was 40% for those who
      completed 6 months
      combination therapy, 22% after 18 months mono therapy,
      and only 7.7% in
      those
      who completed 18 months combination treatment
      (p=0.002). A sustained
      HCVRNA
      response was observed in 44% (p.p. 50%) in 18 months
      combination
      therapy
      versus 17% (p.p. 16%) in 18 months monotherapy and 34%
      (p.p. 35%) in 6
      months
      combination (p<0.001). In conclusion, this study
      confirms the enhanced
      initial response due to combination of Interferon with
      Ribavirin,
      whereas it
      shows an important reduction of relapse and thereby a
      high sustained
      response
      rate due to prolongation of treatment to 18 months.


      18 Months of Dual Therapy for Chronic Hepatitis C
      Decreases Relapse
      Rate and
      Suggests New Treatment Approach for Hard to Treat
      Patients with
      Cirrhosis,
      Genotype 1, and High Baseline Viral load
      q 300 patients without previous treatment in
      randomized, double blind,
      placebo-controlled study.
      q 2 arms treated with standard interferon alfa (not
      pegylated) plus
      ribavirin.
      q For those randomized to 18 months of dual therapy,
      the
      end-of-treatment
      response rate (ETR) was 51%, with a relapse rate of
      13% (vs 38%),
      leading to
      a sustained-virologic-response (SVR) rate of 44%,
      "ITT" analysis.
      q 70% genotype 1, 14% cirrhosis and 53% high baseline
      viral load.
      q Patients with genotype 1, cirrhosis, and high
      baseline viral load
      derived
      the greatest virologic benefits, in "as-treated"
      analysis.

      Perhaps one of the more interesting clinical
      presentations at EASL 2001
      that
      potentially could have a major impact on treatment
      outcome for patients
      with
      chronic hepatitis C was the Benelux Study. Benelux
      Study results were
      first
      reported at AASLD November 2000 (see NATAP Report
      http://www.natap.org/2000/nov/18_months_interferon112200.html)

      Dr. J.T. Brouwer of University Hospital in Rotterdam,
      The Netherlands
      presented the study results. Even though the study
      used the older
      standard
      combination (non-pegylated) interferon alfa plus
      ribavirin, the low
      relapse
      rate of only 13% in a predominant genotype-1
      population has significant
      potential implications, if similar [or better] results
      were to occur
      after 18
      months of pegylated interferon alfa plus ribavirin.

      Given that end-of-treatment virologic response (ETR)
      rates when
      treating
      chronic hepatitis C have always been higher than their
      associated
      sustained
      virologic response (SVR) rates, the researchers in
      this study were
      trying to
      determine whether longer treatment might increase
      either ETR, SVR or
      both.

      A total of 300 treatment-na��ve (no previous therapy)
      patients with
      chronic
      hepatitis C (positive HCV RNA, increased liver enzyme
      ALT, abnormal
      liver
      biopsy) were randomized to one of 3 treatment arms in
      a double-blind
      fashion
      (treatment unknown to patient or treating physician).
      They were: (1)
      interferon alfa 2b (Intron A), 3 MIU (million
      international units)
      injected
      3-times weekly plus oral ribavirin 1,000-1,200 mg
      daily for 18 months*;
      (2)
      the same drug regimen in (1), except for only 6
      months; or (3)
      interferon
      alfa 2b monotherapy, same dose as above, plus oral
      placebo (inactive
      drug)
      for 18 months*. *Note that after 6 months, the
      duration of the
      treatment arms
      only was revealed (unblinded), and all patients who
      were non-responders
      at
      that time (detectable viral load and ALT greater than
      1-times the upper
      limit
      of normal) stopped therapy (due to evidence that they
      would not respond
      [virologically] thereafter).

      The 3 study arms were well randomized in terms of age
      (mean 43-47
      years),
      gender (sex, 63% men in combination arms, although
      monotherapy arm had
      46%
      men), ("compensated," stable) cirrhosis rate (liver
      scarring, F4,
      13-15%),
      genotype 1 (most difficult to treat, 66-75%), and
      baseline HCV RNA
      greater
      than 3 million copies/mL (50-55%) with 57% overall
      having greater than
      2
      million copies/mL. Patients were from 25 centers in
      Belgium,
      Luxembourg and
      the Netherlands.

      The results were as follows. Stopping at 6 months due
      to non-response
      included 10% from arm 1 (combination 18 months) and
      28% of arm 3
      (interferon
      18 months); all in arm 2 stopped at that time as per
      protocol.
      Withdrawal
      from study due to any reason during the first 6 months
      included 10%
      each of
      arms 1 and 2 and 5% of arm 3. Withdrawal due to any
      reason between
      months 6
      and 18 included 13% of arm 1 and 20% of arm 3.
      Reasons for withdrawal
      were
      not presented. Using a strict "intent-to-treat" (ITT)
      analysis (all
      patients
      included), the end-of-treatment (ETR) viral
      undetectability (limit 100
      copies/mL) response rates were 51% (arm 1, combination
      18 months), 55%
      (arm
      2, combination 6 months) and 27% (arm 3, monotherapy
      18 months). There
      was
      no significant difference between arms 1 and 2, with
      very little
      additional
      response in arm 1 after 6 months.

      Treatment Outcomes in Benelux Study of 300 Patients

      Arm 1: interferon alfa 2b* plus ribavirin ** \
      Arm 2: interferon alfa 2b* plus ribavirin **
      Arm 3: interferon alfa 2b* plus oral placebo

      Arm 1
      Arm 2 Arm
      3
      Length of therapy 18mos 6 mos
      18 mos
      ETR (ITT) 51% 55%
      27%
      Relapse Rate (ITT) 13% 38%
      39%
      SVR (ITT) 43% 34%
      16%
      Withdraw 0-6 mos 10% 10%
      5%
      Withdraw 6-18 mos 13% NA
      20%






      Duration of therapy 18 months 6 months 18 months
      End of Treatment Response *** Rate, ITT # 51% 55%
      27%
      Relapse Rate (see text), ITT # 13% 38% 39%
      Sustained Virologic Response Rate, ITT # 43% 34%
      16%
      Withdrawal, 0-6 months 10% 10% 5%
      Withdrawal, 6-18 months 13% Not applicable 20%
      * Interferon dose was 3 million international units
      injected 3-times
      weekly
      (see row 2 for duration)
      ** Ribavirin dose was 1,000-1,200 mg orally each day
      (see row 2 for
      duration).
      *** Percentage undetectable HCV RNA, limit 100 copies
      per milliliter
      # ITT = Intent-to-treat analysis, including all
      enrolled patients

      However, after 6 months of follow-up in each arm, the
      relapse rate
      (virus
      becoming detectable after being undetectable at the
      end of treatment)
      was
      significantly lower in arm 1 (combination 18 months)
      than in arm 2
      (combination 6 months). Those relapse rates were: 13%
      (arm 1), 38%
      (arm 2)
      and 39% (arm 3), using an ITT analysis. Therefore,
      this led to a SVR
      (sustained virologic response) rate of 43% (arm 1),
      34% (arm 2) and 16%
      (arm
      3).

      In a separate "as-treated" analysis including patients
      who completed
      80% of
      therapy for 80% of the intended duration or who
      stopped therapy
      according to
      protocol, among patients in arm 1 (combination 18
      months), those with
      cirrhosis had a higher SVR (57%) than those without
      cirrhosis (42%).
      The
      usual, opposite trend occurred in arm 2 (combination 6
      months), with a
      SVR of
      29% for those with and 37% for those without cirrhosis
      ("as-treated"
      analysis). And the usual trend also occurred in arm 3
      (monotherapy),
      with a
      SVR among 10% for those with and 18% for those without
      cirrhosis.
      (Note that
      "as-treated" ETR was 56% in arm 1, 60% in arm 2 and
      25% in arm 3. "As
      treated" relapse rates were 7% (arm 1), 38% (arm 2)
      and 32% (arm 3).
      "As-treated" SVR was 52% (arm 1), 36% (arm 2) and 17%
      (arm 3).

      (editorial note from Jules Levin: The preliminary ETR
      for
      Pegasys+ribivarin
      reported at EASL were 58% for monotherapy and 68% for
      combination
      therapy. In
      this or any study, if you were to look at the response
      rates for
      patients who
      are adherent and complete the course of treatment the
      response rates
      would be
      expected to be considerably better. This was reflected
      in the Benelux
      study
      as the SVR for arm 1 was 43%, while in the
      "as-treated" analysis the
      SVR was
      57% for cirrhotics and 42% for non-cirrhotics. This
      emphasizes the
      importance
      of adherence. Adherence support for coinfected
      patients receiving
      IFB+RBV
      will be helpful. We will have to see if HIV-infected
      can tolerate
      ribivarin
      for 18 months due to reduced hemoglobin and similar
      adverse effects on
      other
      blood tests).

      Interestingly, the SVR was higher only for genotype 1
      patients taking
      combination treatment for 18 months (arm 1, 36%) than
      for those taking
      it for
      6 months (arm 2, 23%), since those with genotype 2 or
      3 had a nearly
      identical SVR whether they took combination therapy
      for either 18
      months (arm
      1, 71% SVR) or 6 months (arm 2, 72%). However, the
      genotype analysis
      was
      only presented "as-treated." In a similar pattern,
      the SVR was higher
      for
      those with a higher baseline viral load (greater than
      3 million
      copies/mL)
      taking combination treatment for 18 months (arm 1,
      42%) than for those
      taking
      it for 6 months (arm 2, 18%), since those with a low
      baseline viral
      load
      (less than 3 million copies/mL) had a nearly identical
      SVR whether they
      took
      combination therapy for either 18 months (arm 1, 47%)
      or 6 months (arm
      2,
      49%). Again, however, the baseline viral load, SVR
      analysis was
      presented
      only "as-treated."

      Taken together, the "as-treated" results (cirrhosis,
      genotype and
      baseline
      viral load) suggest that a longer duration of therapy,
      here 18 months,
      may be
      particularly beneficial for those patients who
      previously have been
      more
      difficult to treat, i.e., with "unfavorable" baseline
      characteristics.
      This
      suggests that "longer" might be better in terms of
      being able to
      eradicate
      more HCV from more hepatocytes (liver cells) or by
      having more time for
      the
      immune system to remove more HCV-infected hepatocytes.
      Yet, those with
      genotypes 2 or 3 or those with a low baseline viral
      load did not derive
      any
      additional SVR benefits by treatment with combination
      therapy for more
      than 6
      months.

      Dr. Brouwer concluded that prolonged (18 months)
      combination therapy
      had "no
      effect on response beyond 6 months [but had a] clear
      effect on relapse
      rate
      (less than 10%) if [the] therapy is maintained." Note
      that liver
      biopsy
      results at the time of SVR were not reported.
      However, it is likely
      that
      similar or possibly more (or better) improvements on
      liver biopsy would
      be
      observed for those in arm 1 than in arm 2. However,
      specific types and
      rates
      of adverse events and reasons for withdrawal were not
      presented.

      A similar study would need to be undertaken using a
      "control" arm with
      today���s standard of pegylated interferon alfa plus
      ribavirin for 12
      months
      (versus 18 months) to determine whether similar
      additional benefits
      might be
      derived, particularly for those with unfavorable
      baseline
      characteristics.
      However, since the SVR could only be measured 24
      months (2 years) after
      entering into such a study (for the 18-month arm), it
      is quite possible
      that
      a new standard-of-care would replace the current one
      when such a study
      were
      finished. In the mean time, with the limitation that
      this is only one
      study
      with these results and considering data not reported
      (as discussed
      above),
      those with genotype 1, a high baseline viral load
      and/or cirrhosis
      might want
      to have their physicians consider longer treatment for
      18 months,
      preferably
      in a study or at least in an observational study.
      (Editorial note: as
      mentioned above, an 18-month study in HCV/HIV
      coinfected would be
      useful to
      evaluate tolerability and adverse effects on
      bloodwork).


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