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Effect of peginterferon alfa-2a on liver histology in chronic hepatitis C: A meta-analysis of individual patient data

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    Effect of peginterferon alfa-2a on liver histology in chronic hepatitis C: A meta-analysis of individual patient data Hepatology Volume 39, Issue 2, February
    Message 1 of 1 , Feb 6, 2004
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      Effect of peginterferon alfa-2a on liver histology in chronic
      hepatitis C: A meta-analysis of individual patient data

      Hepatology
      Volume 39, Issue 2, February 2004

      Calogero Camm� 1 2 *, Danilo Di Bona 1 2, Filippo Schepis 3, E. Jenny
      Heathcote 4, Stefan Zeuzem 5, Paul J. Pockros 6, Patrick Marcellin 7,
      Luis Balart 8, Alfredo Alberti 9, Antonio Crax� 21IBIM, Consiglio
      Nazionale delle Ricerche, Palermo, Italy2Cattedra e Unit� Operativa
      di Gastroenterologia, University of Palermo, Palermo,
      Italy3Department of Internal Medicine, University of Modena and
      Reggio Emilia, Modena, Italy4Department of Medicine, University
      Health Network, Toronto Western Hospital, Toronto, ON,
      Canada5Klinikum der Johann Wolfgang Goethe University, Frankfurt,
      Germany6Scripps Clinic, La Jolla, California7INSERM U481, Service
      d'Hepatologie Hospital Beaujon, Clichy, France8Louisiana State
      University Health Science Center, New Orleans, Louisiana9Dipartimento
      di Medicina Clinica e Sperimentale, University of Padua, Padua, Italy


      The authors said: "....In the current study.....the available
      evidence was sufficient to conclude that 1) peginterferon alfa-2a was
      more efficacious than conventional IFN alfa-2a in improving liver
      histology; 2) peginterferon alfa-2a induced a marked reduction in
      both stage and grade in patients with SVRs and, to a lesser degree,
      in patients with recurrent disease, but provided no benefit for
      nonresponders after 24-48 weeks of treatment; patients with BMI < 30
      kg/m2 and high pretreatment ALT levels had the greatest probability
      of experiencing histologic improvement; and 3) peginterferon alfa-2a
      at 180 g/week for 48 weeks was the best dosing option in terms of
      grading improvement..... Poynard et al recently suggested that
      peginterferon alfa-2b combined with ribavirin slows the natural
      progression of fibrosis in virologic nonresponders, as well as in
      responders and patients with recurrent disease (see discussion by
      authors at end of this article)".

      ABSTRACT/SUMMARY

      Multicenter randomized trials have shown that once-weekly pegylated
      interferon (peginterferon) alfa-2a is more efficacious than
      conventional interferon alfa-2a (IFN) in patients with chronic
      hepatitis C.

      We performed a meta-analysis of 1,013 previously untreated patients
      (from 3 randomized trials) with pretreatment and post-treatment liver
      biopsies to assess the differences between peginterferon alfa-2a and
      IFN in terms of their effects on liver histology.

      Reported values were standardized mean differences (SMD) between
      patients receiving peginterferon alfa-2a and those receiving IFN
      (post-treatment value minus baseline value for each group). We used a
      random-effects model to quantify the average effect of peginterferon
      alfa-2a on liver histology.

      Peginterferon alfa-2a significantly reduced fibrosis compared with
      IFN (SMD, -0.14; 95% CI: -0.27, -0.01; P = .04). A reduction in
      fibrosis was observed among sustained virologic responders (SMD,
      -0.59; 95% CI: -0.89, -0.30; P < .0001) and patients with recurrent
      disease [relapsers] (SMD, -0.34; 95% CI: -0.54, -0.14; P = .0007),
      whereas no significant reduction was observed among nonresponders
      (SMD, -0.13; 95% CI: -0.32, 0.05; P = .15).

      Logistic regression analysis indicated that patients with sustained
      virologic responses (SVRs) had an odds ratio (OR) of 1.61 (95% CI:
      1.14, 2.29) for reduction in fibrosis compared with patients without
      SVRs, whereas obese patients (body mass index [BMI] > 30 kg/m2) had
      an OR of 0.56 (95% CI: 0.35, 0.90) compared with normal-weight (BMI <
      25 kg/m2) and overweight patients (BMI, 25-30 kg/m2).

      In conclusion, in patients with chronic hepatitis C with or without
      cirrhosis, peginterferon alfa-2a (relative to IFN) significantly
      reduced fibrosis. The beneficial effects of peginterferon on liver
      histology are closely related to virologic response.

      INTRODUCTION

      Patients with chronic hepatitis C typically undergo liver biopsy to
      determine the severity of disease and thereby assess the urgency of
      treatment. The histologic findings on biopsy also enable the
      clinician to evaluate the probability of a response to interferon
      alfa-2a (IFN). Liver histology provides direct evidence of hepatic
      necroinflammatory activity, fibrosis, and progression to cirrhosis,
      and is a surrogate endpoint of the long-term efficacy of IFN
      treatment.

      As a tool for evaluating response to treatment, histologic findings
      have several significant limitations and sources of bias. For
      example, different scoring systems can be used to compare paired
      liver biopsies; in addition, biopsies may be performed at different
      times, and they may be evaluated by different pathologists in
      multicenter trials of antiviral therapy. Therefore, it is difficult
      to accurately and reliably assess the relatively small changes
      induced by treatment over short time periods.

      The most frequently used systems in randomized controlled trials
      (RCTs) are the Histologic Activity Index (HAI) and the METAVIR
      system. The use of the combined HAI (Knodell score), in which four
      discontinuous scales (three for necroinflammation and one for
      fibrosis) are combined, represents a source of inconsistency in many
      clinical trials. However, the HAI's discontinuous fibrosis scale has
      an important advantage over the continuous METAVIR scale. In
      particular, the HAI score increases both intraobserver and
      interobserver reliability by clearly separating mild (+1) fibrosis
      from extensive (+3) fibrosis, which possesses the most relevant
      prognostic impact.

      In 1997, a meta-analysis of 17 RCTs (n = 1223) demonstrated that
      conventional IFN significantly improved liver histology compared with
      no treatment. Histologic improvement was clearly related to antiviral
      responses. Recently, pegylated interferon (peginterferon) was
      developed by attaching a polyethylene glycol moiety to IFN alfa.
      Subsequently, several large multicenter RCTs have clearly
      demonstrated that peginterferon alfa-2a produces significantly
      greater virologic responses compared with conventional IFN.
      Nonetheless, the results of published studies on the effects of this
      new drug on liver histology remain inconsistent, and the overall
      effect of treatment is difficult to evaluate.

      To overcome some of the limitations associated with the use of
      histologic findings, to increase the relevance of statistical
      analysis, and to improve estimates of effect magnitudes, we performed
      a meta-analysis of individual patient data (MIPD). The aims of the
      current MIPD were 1) to assess the differences between peginterferon
      alfa-2a and conventional IFN with respect to changes in liver
      histology; 2) to identify predictors of histologic improvement; and
      3) to evaluate the optimal treatment schedule for bringing about
      histologic improvement.

      Patients

      The current MIPD was designed to pool data on a large number of
      individuals from tertiary referral specialty units in an attempt to
      define the efficacy of peginterferon alfa-2a with respect to liver
      histology. We analyzed data on individual patients from three RCTs of
      peginterferon alfa-2a. These studies are the only three RCTs that
      compare peginterferon alfa-2a with conventional IFN and include
      previously untreated patients with pretreatment and post-treatment
      liver biopsies. Written consent was obtained from the principal
      investigator at each trial center. The study database consisted of
      patients who had the following baseline characteristics: age greater
      than 18 years, alanine aminotransferase (ALT) levels greater than the
      upper limit of normal on 2 occasions during the preceding 6 months,
      positive status for anti-hepatitis C virus (HCV) antibody, negative
      status for serum hepatitis B surface antigen, negative status for
      human immunodeficiency virus antibody, and self-reported complete
      abstinence from alcohol. Laboratory tests, including assessment of
      serum HCV RNA levels (Cobas Amplicor HCV Monitor [Version 2.0]; Roche
      Diagnostics, Branchburg, NJ), were performed at a central laboratory.
      Sustained virologic response (SVR) was defined as the absence of
      detectable HCV RNA at the end of treatment and at 24 weeks after
      cessation of therapy. Recurrent disease was defined by HCV RNA levels
      that were undetectable at the end of treatment but were detectable
      again within 6 months of cessation of treatment. Lack of response was
      defined by detectable HCV RNA levels at 6 months after the start of
      therapy.

      Role of the Funding Source

      The current study was designed by the principal investigators.
      Hoffmann-La Roche (Basel, Switzerland) staff members collected data
      from designated clinical sites and assembled the database, and
      Hoffmann-La Roche supported the study with an investigational grant.
      The principal investigators analyzed and interpreted the data, wrote
      the current article, and submitted the article for publication.

      Assessment of Histology

      Slides of liver biopsy specimens obtained before the study and at 24
      weeks after discontinuation of treatment were coded and read by a
      single pathologist (Sugantha Govindarajan), who was unaware of
      patient identities, treatment regimens, and biopsy dates. A minimum
      length of 15 mm of liver biopsy specimen was required. Liver biopsy
      specimens were evaluated for changes in HAI score (maximum score,
      22)[7] relative to the values recorded at the beginning of treatment
      (i.e., at baseline). The following four categories were assessed and
      scored using the Knodell system: 1) piecemeal and bridging necrosis;
      2) intralobular necrosis; 3) portal inflammation; and 4) fibrosis.

      In the trials conducted by Heathcote et al. and Pockros et al., two
      different peginterferon alfa-2a treatment arms (180 ug vs. 90 ug in
      the former and 180 ug vs. 135 ug in the latter) were compared, with
      the same conventional IFN arm as a control in both. To avoid
      stochastic dependencies involving effect magnitudes, we combined the
      results from the peginterferon alfa-2a arms in both trials.
      Therefore, the statistical analysis involved only independent
      estimators of effect magnitude.

      We defined a histologic response as a decrease of at least 1 point in
      the fibrosis score (staging) relative to the baseline biopsy score or
      a decrease of at least 2 points in the activity score (grading). This
      definition was based on recommendations appearing in the most recent
      consensus statements of the European Association for the Study of
      Liver Disease and the National Institutes of Health Consensus
      Development Conference on Hepatitis C.

      To examine the extent to which differences in the observed treatment
      effects could be explained by differences in patient characteristics
      or in the therapeutic regimens administered, several independent
      variables were included in a multivariate model.

      Thus, two binary logistic regression models were developed to
      investigate potential correlations between histologic response
      probability and the explanatory variables. The dependent variable in
      the first model was the change in activity score (grading) from
      before treatment to after treatment, coded as 0, worsened or
      stabilized (any increase, no change, or a decrease of less than 2
      points in activity score relative to baseline biopsy); or 1, improved
      (a decrease of at least 2 points in activity score relative to
      baseline biopsy). The dependent variable in the second model was the
      change in fibrosis score (staging) from before treatment to after
      treatment, coded as 0, worsened or stabilized (any increase or no
      change in fibrosis score relative to baseline biopsy); or 1, improved
      (a decrease of at least 1 point in fibrosis score relative to
      baseline biopsy). In the second model, patients with Stage 4 fibrosis
      (i.e., cirrhosis) at baseline were excluded, because it was not
      possible for their fibrosis score to increase. Likewise, patients
      with Stage 0 fibrosis (no fibrosis) at baseline were excluded,
      because their score could not decrease. A subgroup analysis of
      patients with cirrhosis was performed to avoid the loss of
      information that would have been caused by eliminating this subgroup
      from the multivariate analysis. As candidate predictors of
      improvement in terms of fibrosis score and activity score, we
      selected age, sex, race, body mass index (BMI; obese [> 30 kg/m2] vs.
      normal [< 25 kg/m2] vs. overweight [25-30 kg/m2]), source of
      infection, baseline ALT quotient (calculated as the average of the
      serum ALT levels before treatment divided by the upper limit of
      normal; > 3 vs. <=3), HCV RNA levels before treatment, treatment
      regimen, and virologic response (SVR vs. no SVR). Variables found to
      be significant on univariate analysis (P < .05) were included in the
      multivariate logistic regression model. Statistical significance was
      tested using the Wald chi-squared test. Regression analysis was
      performed using PROC LOGISTIC software (SAS Institute, Cary, NC).

      Examination of the association between the change in a variable and
      its initial value is complicated by the presence of errors in
      measurement and by intrinsic within-subject variability. Because of
      such variation, the actual levels, on average, will decrease even in
      the absence of any treatment. This artifactual decrease, an example
      of regression to the mean, will be greatest for patients with the
      highest initial recorded values and therefore will induce a spurious
      association between observed change and initial value. To assess
      whether the amount of improvement in grade after treatment depended
      on the baseline value, the average of the initial and final values
      was included in the multivariate model.

      RESULTS

      Baseline Patient Characteristics.

      Of the 1,441 patients enrolled in the 3 RCTs, 1,013 (70.3%) had
      paired liver biopsies that were obtained before treatment and at 24
      weeks after the end of treatment. The main baseline characteristics
      of these 1,013 patients did not differ significantly from the
      characteristics of the entire patient series. The proportion of
      patients who underwent a second liver biopsy was similar across the
      studies, ranging from 62.5% to 79.5%, regardless of virologic
      response. Patient characteristics were comparable in all trials
      (Table 1). Sixty-eight percent of patients were male, and 86.3% were
      Caucasian. The proportion of intravenous drug users was high (42%),
      and the majority of patients were overweight (mean BMI � standard
      deviation, 26.7 � 4.8 kg/m2). Inclusion criteria were uniform in all
      but one RCT, which included only patients with cirrhosis or bridging
      fibrosis.[11] Overall, 198 patients (19.5%) had cirrhosis at
      baseline. In all studies, the duration of treatment was 48 weeks. The
      peginterferon alfa-2a dose ranged from 90 to 180 ug/week.

      No significant differences were observed at baseline between the two
      treatment groups. The peginterferon alfa-2a and conventional IFN
      groups were comparable with respect to total HAI score and with
      respect to each of the four HAI components at baseline. The
      likelihood of SVR was significantly greater among patients treated
      with peginterferon alfa-2a (33.4%) compared with patients treated
      with conventional IFN (17.6%; P = .001). Similar results were
      observed in terms of sustained biochemical response. Nearly all
      patients who experienced SVR also had normal ALT values at the end of
      follow-up (269 of 280 [96%]). Of the 280 patients who achieved SVR
      (215 treated with peginterferon and 65 treated with IFN), 94 (33.5%)
      had abnormal ALT values at the end of treatment. Of these 94
      patients, 78 (36.2% of the peginterferon SVR group) were treated with
      peginterferon and 16 (24.6% of the IFN SVR group) were treated with
      IFN (P = .08). A sustained biochemical response eventually was
      observed in 83 of these 94 patients (88.3%), while ALT values
      remained abnormal in 11 of 94 patients (11.7%; 7 treated with IFN and
      4 treated with peginterferon) 24 weeks after the end of treatment.

      The overall rate of improvement in grading (activity) was 81.1% (151
      of 186 patients) among patients with SVR and normal ALT levels at the
      end of treatment and 81.9% (77 of 94 patients) among those with SVR
      and abnormal ALT levels at the end of treatment (P = .80). Staging
      (fibrosis) improved at a comparable rate among patients with SVR and
      normal ALT levels at the end of treatment (64 of 186 patients
      [34.4%]) and patients with SVR and abnormal ALT levels at the end of
      treatment (28 of 94 patients [29.7%]; P = .43).

      Effect Magnitude for Continuous Data

      We analyzed the SMDs in grading and staging between the peginterferon
      alfa-2a and conventional IFN groups. Peginterferon alfa-2a was more
      efficacious than was conventional IFN in improving both grading and
      staging in all comparisons. The SMDs in grading for the individual
      trials ranged from -0.30 to -0.04, and the SMDs for staging ranged
      from -0.23 to -0.03. The overall SMDs were -0.12 (95% CI: -0.25,
      0.01; P = .06) for grading and -0.14 (95% CI: -0.27, -0.01; P = .04)
      for staging.

      In nonresponders, we observed negligible changes in necroinflammation
      and no significant change in fibrosis ; the overall SMDs were -0.04
      (95% CI: -0.22, 0.14; P = .70) for activity and -0.13 (95% CI: -0.32,
      0.05; P = .15) for fibrosis. In patients with recurrent disease,
      histologic improvement was statistically significant in terms of both
      necroinflammation and fibrosis; the overall SMDs were -0.37 (95% CI:
      -0.62, -0.12; P = .004) for activity and -0.34 (95% CI: -0.54, -0.14;
      P = .0007) for fibrosis. Among patients with SVRs, there were
      substantial reductions in necroinflammation and fibrosis; the overall
      SMDs were -1.77 (95% CI: -2.02, -1.53; P < .00001) for activity and
      -0.59 (95% CI: -0.89, -0.30; P < .0001) for fibrosis.

      Variables Associated With Histologic Improvement

      The activity grade improved in 48.4% of patients, it remained stable
      in 34.5% of patients, and it became worse in 16.9% of patients.
      Improved grading was observed in 231 of 427 patients (54.1%) with
      early biochemical responses (defined by normal ALT levels by Week 12)
      and in 249 of 566 patients (43.9%) without early biochemical
      responses (P = .006).

      Model I, which considered baseline ALT levels, pretreatment serum HCV
      RNA levels, mean of the initial and final activity scores, virologic
      response, and treatment regimen, indicated that both SVR (odds ratio
      [OR], 6.20; 95% CI: 4.28, 8.98) and baseline ALT quotient > 3 (OR,
      1.35; 95% CI: 1.11, 1.63) were independent and significant predictors
      of improvement in grading (Table 4). Similar results were obtained
      when SVR was replaced by sustained biochemical response (OR, 4.90;
      95% CI: 3.57, 6.73).

      We performed subgroup analyses to assess the difference in the
      likelihood of activity score improvement between the standard (180 g)
      and low-dose (90-135 g) peginterferon alfa-2a treatment groups.
      Improvements in grading were significantly more common in the
      standard-dose group (232 of 412 patients [56.3%]) than in the
      low-dose group (101 of 232 patients [43.5%]; P = .0002).

      Fibrosis stage improved in 25.7% of patients, it remained stable in
      63.6% of patients, and it became worse in 10.5% of patients (Table
      3). Among the 775 patients with Stage 1 or 3 fibrosis at baseline,
      fibrosis stage improved in 25% (n = 194), remained stable in 65% (n =
      503), and became worse in 10% (n = 78).

      Logistic regression analysis showed that patients with SVRs had an OR
      of 1.61 (95% CI: 1.14, 2.29) for improvement in fibrosis relative to
      patients without SVRs and that obese patients had an OR of 0.56 (95%
      CI: 0.35, 0.90) relative to normal-weight and overweight patients.
      Similar results were obtained when SVR was replaced by sustained
      biochemical response (OR, 1.42; 95% CI: 1.10, 1.77). Among the 498
      patients without virologic responses, the mean baseline BMI was 26.7
      � 3.9 kg/m2 for the 107 patients with reduced fibrosis, 27.6 � 5.8
      kg/m2 for the 313 patients with unchanged fibrosis, and 28.2 � 4.9
      kg/m2 for the 78 patients with increased fibrosis (P = .03). Subgroup
      analysis indicated that there was no significant difference in terms
      of reduced fibrosis between the standard (117 of 412 patients
      [28.4%]) and low-dose (54 of 232 patients [23.3%]) peginterferon
      alfa-2a groups (P = .27).

      Predictive Value of Early Virologic Response

      Nine hundred ninety-three patients were eligible for the analysis of
      early virologic response to treatment, whereas quantitative data on
      HCV RNA were not available for 20 patients. By Week 12, 64.2% of
      patients (638 of 993) had experienced an early virologic response,
      defined as a 2-log decrease in HCV RNA levels relative to baseline
      (245 of 638 patients [38.4%]) or the absence of detectable serum HCV
      RNA (393 of 638 patients [61.6%]). Fifty-seven percent of patients
      with early virologic responses (364 of 638) subsequently experienced
      an improvement in grading, and 28% (179 of 638 patients) experienced
      an improvement in staging after treatment. Of the 355 patients who
      did not have early virologic responses, 239 (67%) did not experience
      an improvement in grading after treatment, and 278 (78.3%) did not
      experience an improvement in staging.

      Among nonresponders, we did not observe a correlation between the
      2-log HCV RNA reduction at 12 weeks and histologic response. The mean
      log change in HCV RNA levels from baseline to Week 12 of treatment
      was -1.63 � 1.77 for the 106 patients who experienced an improvement
      in fibrosis and -1.49 � 1.60 for the 383 patients who did not
      experience an improvement in fibrosis (P = .42).

      Subgroup Analysis of Patients With Cirrhosis

      The database contained 198 patients with cirrhosis. At second biopsy,
      a reduction in fibrosis stage was observed in 67 of these patients
      (33.8%; to Stage 3 in 48 patients [24.2%] and to Stage 1 in 19
      patients [9.6%]). Complete resolution of cirrhosis (from Stage 4 to
      Stage 0) was not observed.

      A 2-point decrease in grade was observed in 86 of the 198 patients
      with cirrhosis (43.4%). Among patients with cirrhosis who received
      peginterferon alfa-2a, the overall rate of improvement in terms of
      grading was 56.9% (41 of 72 patients) in the 180 g/week group and
      37.3% (22 of 59 patients) in the 90-135 g/week group (P = .025). In
      contrast, no significant difference in improved staging between the
      180 g/week group (28 of 72 patients [38.9%]) and the 90-135 g/week
      group (16 of 59 patients [27.1%]) was observed (P = .15). Virologic
      response was the only significant predictor for improvement in terms
      of both grading (OR, 23.7; 95% CI: 6.7, 80.9) and staging (OR, 2.16;
      95% CI: 1.04, 4.47) among patients with cirrhosis.

      DISCUSSION by authors

      In the current study, we found that peginterferon alfa-2a
      significantly reduces fibrosis compared with conventional IFN. Our
      MIPD has demonstrated conclusively that impressive improvements in
      terms of fibrosis can be achieved in patients with SVRs and, to a
      lesser degree, in patients with recurrent disease. No significant
      changes were observed in nonresponders.

      Our data indicate that patients with BMI 30 kg/m2 have the greatest
      likelihood of experiencing a reduction in fibrosis. The observation
      that obesity (BMI > 30 kg/m2) is a risk factor for progression of
      fibrosis is consistent with the results of 3 recently published
      studies. Although the mechanisms responsible for the effect of BMI on
      liver histology are unknown, a practical recommendation to reduce
      body weight before starting therapy may be beneficial. This statement
      is strengthened by our observation of reduced fibrosis in the small
      proportion of nonresponders with the lowest BMI values.

      According to recent reports, steatosis is a cofactor of fibrosis
      progression as well as response to therapy in patients with chronic
      hepatitis C. Unfortunately, we did not collect data on hepatic
      steatosis. Nonetheless, it recently was demonstrated that in patients
      with chronic hepatitis C, BMI is closely correlated with the degree
      of hepatic steatosis. Therefore, we are confident in our assumption
      that BMI is a surrogate marker for steatosis in the current analysis.
      Finally, Bressler et al. recently reported that high BMI, but not
      steatosis, was an independent risk factor for nonresponse to
      antiviral treatment.

      Our data suggest that patients with high baseline ALT levels
      experience the largest improvements in grading. This finding may be
      linked to the higher degree of clearance of virally infected cells
      during the second phase of response to treatment.[29] Furthermore,
      the magnitude of the effect of treatment (i.e., the reduction of
      inflammation under treatment) is more easily measurable when the
      initial grade of activity is high.

      Poynard et al recently suggested that peginterferon alfa-2b combined
      with ribavirin slows the natural progression of fibrosis in virologic
      nonresponders, as well as in responders and patients with recurrent
      disease. The discrepancy between this finding and our conclusion
      probably stems from the fact that Poynard et al. based their analysis
      on the comparison of fibrosis progression rate per year before and
      after treatment. There are flaws inherent in the use of fibrosis
      progression rate as a basis for modeling the indication for
      treatment, due to inaccurate estimation of the duration of infection
      and the nonlinearity of fibrosis progression over time. In fact, two
      studies of the validity of fibrosis progression rate demonstrated
      that this rate is not a reliable and accurate tool for predicting
      histologic improvement. The discord between the findings of Poynard
      et al. and our findings also may result from the fact that many
      patients in the study by Poynard et al. received combination therapy,
      whereas patients in the current study received peginterferon
      monotherapy.

      Poynard et al found six indicators that were useful in identifying
      patients with a high probability of reduction in fibrosis; among
      these indicators were low baseline staging and grading scores. The
      results reported by Poynard et al. appear to rely on the definition
      of the endpoint, described as the absence of significant fibrosis
      (i.e., the absence of METAVIR Stage F2/F3/F4 fibrosis) on second
      biopsy. This definition is flawed, because the majority of patients
      (75%) included in the PEG-Fibrosis Project Group database already
      were free of significant fibrosis (i.e., they had METAVIR Stage F0/F1
      fibrosis) at baseline. Thus, the cross-sectional evaluation of
      staging on second biopsy only, regardless of the fibrosis score on
      first biopsy, practically hinders the evaluation of changes between
      paired biopsies.

      Unlike Poynard et al., we did not observe complete resolution of
      cirrhosis (from Stage 4 to Stage 0) after treatment in any of nearly
      200 patients with cirrhosis. A decrease in fibrosis score after
      treatment was observed in only 33% of patients with cirrhosis. The
      large size of the cohort with cirrhosis or bridging fibrosis (447 of
      1013 patients [44%]) in the current study enhances the statistical
      relevance of our conclusions.

      The main limitation of the current study, as well as other studies,
      is the very short time between paired biopsies. In RCTs, the
      post-treatment biopsy generally is performed only 24 weeks after the
      end of treatment. The current analysis indicated that approximately
      two-thirds of all patients did not experience a change in fibrosis
      stage between paired biopsies. Because histologic improvement is a
      slow process, particularly for fibrosis, it may be advisable to
      repeat liver biopsy 2 or 3 years after the end of treatment to assess
      the treatment benefit with respect to fibrosis. Due to the large
      number of patients analyzed in the current MIPD, we believe that a
      moderate but clinically relevant treatment benefit with respect to
      liver fibrosis was not overlooked. Because of the different clinical
      settings and groups of patients analyzed, and because the small
      number of studies included in the current meta-analysis reduces the
      statistical power to test for heterogeneity, we have presented the
      findings of random-effects models.

      Many studies have attempted to identify the peginterferon dose that
      maximizes benefit with respect to liver histology. Poynard et al.
      compared 10 different regimens of peginterferon alfa-2b and
      conventional IFN with and without ribavirin with a regimen of 3
      megaunits of conventional IFN 3 times weekly for 24 weeks. We
      compared only 3 different regimens of peginterferon alfa-2a
      monotherapy with a control regimen of conventional IFN at a dose of
      at least 3 megaunits 3 times weekly for 48 weeks. The current MIPD
      provides evidence that of the three peginterferon doses assessed, a
      standard dose (180 ug/week) is the best option with respect to
      grading improvement in patients with or without cirrhosis.

      The available evidence was sufficient to conclude that 1)
      peginterferon alfa-2a was more efficacious than conventional IFN
      alfa-2a in improving liver histology; 2) peginterferon alfa-2a
      induced a marked reduction in both stage and grade in patients with
      SVRs and, to a lesser degree, in patients with recurrent disease, but
      provided no benefit for nonresponders after 24-48 weeks of treatment;
      patients with BMI < 30 kg/m2 and high pretreatment ALT levels had the
      greatest probability of experiencing histologic improvement; and 3)
      peginterferon alfa-2a at 180 g/week for 48 weeks was the best dosing
      option in terms of grading improvement.


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