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Re: [GIWorld-Hepatitis] FW: NATAP: EDITORIAL-24 wks PegIFN-2b for Geno 1/Lo VL

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  • avansi7465
    Well 24 weeks beats 48, BUT..............thanks for sending this. Happy New Year!!!!! Anne
    Message 1 of 2 , Dec 29, 2005
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      Well 24 weeks beats 48, BUT..............thanks for sending this. Happy New Year!!!!! Anne

      -----Original Message-----
      >From: alleypat <alleypat@...>
      >Sent: Dec 27, 2005 11:39 AM
      >To: GI World-Hepatitis <GIWorld-Hepatitis@yahoogroups.com>, Happy Heppers <happyheppers@yahoogroups.com>
      >Subject: [GIWorld-Hepatitis] FW: NATAP: EDITORIAL-24 wks PegIFN-2b for Geno 1/Lo VL
      >Editorial: 24 weeks PegIFN 2b for genotype 1/Low HCV-RNA
      >Efficacy of 24 weeks treatment with peginterferon alfa-2b plus ribavirin in
      >patients with chronic hepatitis C infected with genotype 1 and low
      >pretreatment viremia
      >Hepatology Jan 2006
      >Stefan Zeuzem
      >Background/Aims: Previous studies using standard interferon and ribavirin
      >combination therapy suggested that patients infected with HCV-1 and a low
      >pretreatment HCV-RNA level can be treated for 24 weeks without compromising
      >sustained virologic response rates. The aim of the present study was to
      >investigate this schedule in the era of pegylated interferon-N1 plus
      >Methods: Patients chronically infected with HCV-1 (n=235) and a screening
      >viremia b $600,000IU/mL (real-time PCR) were treated with peginterferon
      >alfa-2b 1.5N<g/kg subcutaneously once weekly plus ribavirin 800-1400mg/day
      >based on body weight for 24 weeks.
      >Results: End-of-treatment and sustained virologic response rates were 80 and
      >50%, respectively. The 48-week historical control (Manns et al., Lancet
      >2001;358:958-65) had similar end-of-treatment (74%) but higher sustained
      >virologic response rates (71%). This difference was due to a high virologic
      >relapse rate after 24 weeks of therapy (37%) compared with the historical
      >control (4%). A subset of patients who had undetectable serum HCV-RNA at
      >treatment week 4, however, achieved similar sustained virologic response
      >rate (89%) as in the control group (85%).
      >Conclusions: HCV-1 infected patients with a low baseline HCV-RNA
      >concentration who become HCV-RNA negative at week 4 may be treated for 24
      >weeks without compromising sustained virologic response rates.
      >Further study details are following the Editorial immediately below.
      >Treating patients with HCV genotype 1 and low viraemia: More than meets the
      >Hepatology Jan 2006
      >Antonio CraxC,, Calogero CammC
      >bb&b&At the present time, the strength of the evidence presented by Zeuzem
      >and co-workers is in our opinion not sufficient to generalize the
      >applicability of this approach to optimization. While further randomized
      >trials are in progress, subjects with genotype 1, a low viral load and an
      >early drop of HCV-RNA under therapy may be treated with this short schedule
      >if they have modest or no fibrosis and hence are unlikely to progress
      >significantly should HCV relapse. Those with more advanced fibrosis are
      >probably still better served by the conventional, more troublesome schedule
      >of 48 weeksb&..b
      >When a drug or a combination of drugs is first assessed to evaluate its
      >effectiveness in curing an illness, every effort is made in order to
      >maximize efficacy while still keeping side effects at an acceptable level.
      >It is hence not surprising that the pivotal phase III trials [1,2] which led
      >in the early 2000s to the registration of pegylated alfa interferons (PEG
      >IFNs) in combination with ribavirin for the treatment of naC/ve patients
      >with chronic hepatitis C have exploited the maximum permissible doses of PEG
      >IFN evaluated in earlier monotherapy trials [3,4] over a 48-week treatment
      >period. This duration of treatment had been shown to be the most effective
      >with the combination of standard IFNs and ribavirin [5,6], and was in fact
      >dictated by the need to demonstrate superiority of PEG over standard IFNs,
      >already registered for a 48 week combination schedule. Both studies were
      >concordant in showing a better efficacy of combination therapy with PEG
      >IFNs, but confirmed that genotype 1 was still harder to eradicate than
      >genotypes 2 and 3, and that subjects with severe fibrosis were less
      >responsive to therapy. An important and concordant finding among these
      >trials was that 12 weeks of treatment were enough to assess, by measuring
      >the drop in viral load, whether sustained virological response was likely to
      >be reached [7,8]. This early virological response (EVR) rule, allowing to
      >stop ineffective therapy at an early stage, and save unnecessary treatment
      >related morbidity could not be reliably used on standard IFN/ ribavirin
      >regimens before 24 weeks of therapy [5,6]. A further step towards
      >optimization was made by Hadziyannis et al. [9], who used a 4-arm design to
      >assess the relevance of duration (24 vs. 48 weeks) and of ribavirin dose
      >(800 vs. 1000-1200mg). This trial made it clear that genotype 1 patients
      >should receive the more intensive approach with a longer treatment duration
      >and higher doses of ribavirin, while genotypes 2 and 3 could do with shorter
      >schedules and lower amounts of ribavirin. Optimization of treatment was thus
      >initially addressed with the distinction between hard and easy to treat
      >genotypes. Still, there was a long way to go towards true individualization
      >of therapy, since the risk of overtreatment was still present for many
      >patients not accurately classified by a genotype-based approach. It has long
      >been known that viral load is also a major determinant of responsiveness to
      >IFN-based therapy, whatever the schedule used for monotherapy [10] or for
      >combination [11]. Problems with the reproducibility of quantitative
      >measurements of HCV-RNA [12,13] have hampered a more widespread use of this
      >predictor. Real-time PCR testing will probably be able to solve
      >inconsistencies and allow clinicians to progress further into
      >individualization of anti-HCV therapy.
      >The current 12 weeks EVR rule, when applied to genotype 1 patients, has a
      >negative predictive value approaching 100% [7,8] and is hence able to solve
      >the issue of overtreatment of nonresponders. It, however, leaves the field
      >open to the possibility of overtreating some genotype 1 patients with a
      >higher propensity for a sustained viral response, i.e. those with a
      >pre-treatment low viral load. These subjects, representing in our experience
      >15-20% of all genotype 1 infected cases, could hypothetically be cured by
      >shorter and/or less intensive treatment courses thus reducing costs and
      >improving acceptance and tolerability.
      >In this issue of the Journal, Zeuzem et al. [14] test the hypothesis that
      >patients infected with HCV 1 with low pretreatment HCV-RNA (b $600,000IU/ml
      >at baseline) can receive PEG IFN alfa2b 1.5N<g/kg weekly plus weight-based
      >Ribavirin (800-1400mg daily) for 24 weeks and obtain the same rate of SVR as
      >those treated for 48 weeks. The study is a single-arm, open-label historical
      >control trial conducted in 43 European Centres between 2001 and 2004, in
      >which 724 patients were screened and 237 enrolled. As a comparator, 38
      >comparable patients originally enrolled in the Manns' trial [1], who had
      >received PEG IFN alfa2b 1.5N<g/kg weekly plus Ribavirin b %10.6mg daily for
      >48 weeks, were re-analyzed. At first glance the results do not look
      >encouraging as a whole since, after reaching end-of-treatment response (ETR)
      >at a comparable rate (81% for 24 weeks and 74% for 48 weeks of treatment),
      >sustained virological response (SVR) was obtained only by 50% in the 24
      >weeks as compared to 71% in the 48 weeks historical control group. This
      >difference was due to the high rate of post-ETR virologic relapse (37%) on
      >the short regimen.
      >The relevant information comes from the analysis of early virologic response
      >(EVR) at 4, 12 and 24 weeks. A very high rate of SVR (89%) was in fact found
      >in the subgroup of patients who were already HCV-RNA negative at week 4 (47%
      >of all cases treated with the short course). Those with a slower response to
      >therapy had instead a low rate of SVR (25% for patients becoming HCV-RNA
      >negative at 12 weeks and 17% for those who cleared HCV-RNA only after 24
      >weeks). The pattern was seemingly different among patients treated for 48
      >weeks: SVR rates were 85, 93 and 67% for subjects clearing HCV-RNA at 4, 12
      >or 24 weeks, respectively. Thus low pretreatment viraemia associated to a
      >precocious response to PEG IFN plus ribavirin identifies a subgroup of
      >patients with genotype 1 in whom 24 weeks of treatment are sufficient to
      >obtain the maximal SVR rate allowed by combination therapy. Optimization by
      >avoiding overtreatment would thus become a reality in such cases. In fact,
      >the registration of PEG IFN alfa2b has already been revised by EMEA to
      >include this modality of use.
      >Issues arising during the phase of optimization of treatments are definitely
      >more complex than the pure demonstration of safety and efficacy in
      >registrative trials. Specifically, results generated by these trials in
      >highly selected and motivated patients must be fine-tuned to fit into the
      >complex array of real-life patients, who often have comorbidities or low
      >compliance, and also keep account of demographic, social and financial
      >constraints. It is of foremost importance, when interpreting the results of
      >these studies, to make a clearcut distinction between evidence generated
      >within RCTs by direct comparison of rigorously randomized groups and
      >indirect inferences derived from the confrontation of non-randomized or
      >'historical control' groups, from subgroup analyses and from the application
      >of a posteriori multivariate models or of mathematical situations. Only
      >direct comparisons allow a reliable confrontation between groups which are
      >fully comparable for all relevant features. At least two recent studies
      >[15,16] have addressed the issue of optimization, in both cases for the
      >easy-to-treat genotypes 2 and 3, using an appropriate design.
      >The Zeuzem study on genotype 1 patients with low viral load unfortunately
      >has a number of limitations which potentially detract from its
      >applicability. It has a low internal validity, due to the intrinsic weakness
      >of a design which allows the use of a historical control group, derived from
      >another study, performed more than 5 years ago. This control group is in
      >itself a very small subgroup distilled from a large cohort (11.9%, i.e. 38
      >out of 348 genotype 1 patients receiving PEG IFN alfa2b 1.5N<g/kg weekly
      >plus Ribavirin 800mg daily in the original Mann's study). Although selection
      >modalities are not stated, it may be inferred that patients were included in
      >the historical control group only if: (a) they had received enough ribavirin
      >in relation to body weight to allow for post-hoc adjustment of dosing at b
      >%10.6mg daily; (b) treatment had been given as assigned for the entire 48
      >week period; (c) samples were available for testing at 4, 12 and 24 weeks.
      >These requirements actually segregate a population of rather lean patients,
      >with a body weight inferior to 75.5kg, with a high compliance to therapy and
      >to follow-up, and with few or no treatment-related side effects forcing dose
      >reduction or withdrawal. It comes as no surprise that in these 'ideal'
      >subjects the SVR rate is 71%. By converse, it must be stressed that these
      >patients were treated at a time when PEG IFNs were still experimental drugs:
      >the degree of confidence of both the caregiver and the patient may well have
      >been different from the current standard. Finally, the small size of
      >subgroups in the EVR analysis (13 patients with EVR at 4 weeks, 15 at 12
      >weeks and 3 at 24 weeks) makes any comparison with the much larger 24 week
      >group hard to substantiate.
      >Weight-based ribavirin was given over an extended range of choice
      >(800-1400mg) in the intent to optimize the exposure to the drug. It is then
      >odd to note that subjects on the higher doses of 1000-1200 tended to have
      >more ribavirin-related adverse events than those on the lower dose. If a
      >true optimization of ribavirin dosing is to be achieved, further studies
      >taking into account individual variations in pharmacokinetics, possibly
      >measuring plasma or whole blood levels are needed [17].
      >PEG IFN alfa2b was given at the standard recommended dosage of 1.5N<g/kg
      >weekly. While this dosage is clearly the most effective when given with low
      >amounts of ribavirin (800mg), it is still debatable that such a dose is
      >really needed to obtain response in patients with genotype 1. As a matter of
      >fact, when PEG IFN alfa2b was used as monotherapy [3], 1.0N<g/kg performed
      >fractionally better than 1.5N<g/kg. Recent results from an Italian
      >multicenter trial in genotype 1 patients [18] show that an SVR of 41 can be
      >reached by giving PEG IFN alfa2b approx. 1.0N<g/kg weekly plus Ribavirin
      >1000-1200mg daily for 52 weeks. This response rate compares well with the
      >42% SVR reported by Manns [1] on 1.5N<g/kg. In the Italian study patients
      >who were HCV-RNA negative at 12 weeks had an ultimate SVR rate of 70%, thus
      >confirming that EVR also applies to lower PEG IFN doses. Clearly, there is
      >space for further optimization also in the reduction of the amount of IFN to
      >be used.
      >Another matter of concern is the limited external validity, due to the
      >modalities of inclusion within the study. A large number of cases (724) were
      >screened for eligibility, but only 237 patients were enrolled. The low
      >number of patients included at each site (on average 5.5 cases) represents a
      >source of selection bias, since no data concerning the consecutivity of
      >enrolment are given, and also a potential cause of heterogeneity in the
      >actual handling of treatment.
      >It is not stated whether patients were admitted into the selection process
      >before or after HCV-RNA quantification. If, as likely, quantification was
      >one of the criteria to be assessed during screening, then an unknown
      >proportion of the 454 who did not meet protocol criteria were left out
      >because of an HCV-RNA value >600,000IU/ml. How was this tested? The issue
      >may have major relevance in the context of a multicenter study, where 43
      >Centres have enrolled patients over a time span of 3 years. Since only a
      >generic statement about the use of an rt-PCR is given by the Authors, it is
      >possible that screening tests were actually done at each site with different
      >methods and with a high potential for inconsistencies. Moreover, due to the
      >spontaneous variations over time of HCV-RNA levels within a 0.5log range
      >[19], it would have been worth assessing baseline HCV-RNA as a mean of
      >values obtained at different points of observation in the months preceeding
      >the start of therapy.
      >Definitely, the indications of this study cannot be extrapolated to subjects
      >with advanced fibrosis or cirrhosis. Albeit individual data on the number of
      >patients with cirrhosis are not given in Zeuzem's paper, the low mean
      >Knodell score of 1.2 for fibrosis proves that advanced fibrosis was uncommon
      >in the 24 weeks group. Consequently, as found by the Authors, it would be
      >impossible to show upon univariate analysis any significant role of fibrosis
      >on response in this cohort. In all megatrials [1,2,9] fibrosis has instead
      >emerged as a significant predictor of resistance to the combination of PEG
      >IFNs and ribavirin, although to a lesser degree than observed with non PEG
      >IFNs. When fibrosis is assessed as a continuous variable [18], a clear cut
      >inverse relationship with response emerges at all stages. It is thus very
      >likely that, in the presence of more advanced liver disease, a short
      >treatment schedule would not obtain adequate rates of SVR. Since viraemia
      >tends to be lower when cirrhosis is more advanced, this issue may have
      >practical relevance.
      >Notwithstanding all the methodological criticisms, Zeuzem and co-workers
      >must be commended for pushing the issue of optimization beyond the
      >conventional wisdom of genotype, with a large single-arm trial for also
      >taking into consideration both quality and early assessment of viral drop.
      >There is an evident need for studies with truly prospective recruitment and
      >observation and a more articulate panel of options not only in terms of
      >length but also of dosing of PEG IFN and ribavirin. Also, if important
      >treatment decisions are to be made on viral loads, then standardization of
      >HCV-RNA tests and their prompt availability become paramount.
      >At the present time, the strength of the evidence presented by Zeuzem and
      >co-workers is in our opinion not sufficient to generalize the applicability
      >of this approach to optimization. While further randomized trials are in
      >progress, subjects with genotype 1, a low viral load and an early drop of
      >HCV-RNA under therapy may be treated with this short schedule if they have
      >modest or no fibrosis and hence are unlikely to progress significantly
      >should HCV relapse. Those with more advanced fibrosis are probably still
      >better served by the conventional, more troublesome schedule of 48 weeks.
      >Efficacy of 24 weeks treatment with peginterferon alfa-2b plus ribavirin in
      >patients with chronic hepatitis C infected with genotype 1 and low
      >pretreatment viremia
      >Hepatitis C virus (HCV) infection may progress to chronic hepatitis,
      >cirrhosis, and its sequelae [1-3]. Treatment of HCV-infected patients with
      >interferon-N1 can achieve viral clearance and improve histology and
      >prognosis [4,5]. In the era of standard interferon alfa plus ribavirin, the
      >duration of treatment in patients with chronic hepatitis C was tailored
      >according to HCV genotype and baseline viremia; patients infected with HCV
      >genotype 1 (HCV-1) and high baseline viremia were treated for 48 weeks,
      >while patients infected with HCV-1 and low baseline viremia as well as all
      >patients infected with HCV-2 or HCV-3 were treated for 24 weeks [6-8].
      >More recently, standard interferons have been chemically modified using
      >polyethylenglycol (PEG) to improve antiviral efficacy. Higher sustained
      >virologic response rates in patients with chronic hepatitis C have been
      >reported for the pegylated forms of interferons compared with standard
      >interferons both in monotherapy as well as in combination therapy with
      >ribavirin [9-12]. In these trials patients were treated for 48 weeks.
      >Additional prospective trials in patients chronically infected with
      >genotypes HCV-2 or HCV-3 showed that the treatment duration can be reduced
      >from 48 to 24 weeks without compromising antiviral efficacy [13,14]. Data
      >regarding optimal duration of treatment for patients infected with HCV-1,
      >however, are sparse.
      >The aim of the present study was to investigate efficacy and safety of
      >peginterferon alfa-2b plus ribavirin administered for 24 weeks in patients
      >chronically infected with HCV-1 and a low baseline serum HCV RNA
      >For this study, which was performed between October 2001 and October 2004 in
      >43 European centers, 724 patients were screened and 237 patients were
      >enrolled. Two patients did not have adequate information for analysis, and,
      >therefore, will be presented in demographics and adverse events, but not in
      >the efficacy analyses. Of the remaining 235 patients, two did not receive
      >treatment and are included in the efficacy analysis as nonresponders. The
      >baseline characteristics of the patients are summarized in Table 1.
      >Baseline serum HCV-RNAd
      > b $600,000IU/mL 200 (84%)
      > >600,000IU//mL 37 (16%)
      >Mean Knodell score
      > I (periportalB1bridging necrosis) 2.7
      > II (parenchymal injury) 1.9
      > III (portal inflammation) 2.7
      > I+II+III (total inflammation) 7.2
      > IV (fibrosis) 1.2
      > 0 96 (41%)
      > >0-5% 84 (35%)
      > >5-32% 40 (17%)
      > >32-66% 1 (<1%)
      > >66% 0 (0%)
      > Missing 16 (7%)
      >(d)Pretreatment HCV RNA levels were determined at the screening and entry
      >visits. Protocol eligibility was determined from the screening viral load.
      >However, for purposes of analysis, the pretreatment virologic sample closest
      >(in time) to the enrollment date was used to determine the baseline viral
      >load. All 37 patients who had a baseline viral load of >600,000IU/mL had a
      >viral load of b $600,000IU/mL at the screening determination.
      >Biochemical and virological response
      >An overall intent-to-treat virologic response at the end of therapy was
      >achieved by 189 of 235 patients (80%) and a sustained virologic response by
      >117 of 235 patients (50%). Using the data of the study by Manns et al. [11],
      >a sustained virologic response rate of 69% was predicted if the present
      >study cohort was treated for 48 weeks. This estimated sustained virologic
      >response rate fell outside the 95% confidence interval (43-56%) of the
      >observed virologic response rate after 24 weeks treatment in the study
      >cohort and therefore did not meet the criterion for establishing
      >effectiveness specified for the present study.
      >At the end of follow-up 134 of 235 patients (57%) had ALT levels within the
      >normal reference range and 110 of 235 patients (47%) had both normal ALT and
      >undetectable HCV-RNA. The correlation between sustained biochemical and
      >virologic response was 94%. ALT levels in sustained virologic but not
      >biochemical responders (n=5) ranged from 1.03 to 1.25 times the upper limit
      >of normal. However, all five patients had lower ALT values at the end of
      >follow-up compared with pretreatment levels. On the pretreatment liver
      >biopsy two of the five patients had grade 2 steatosis (>5-b $32% fat), 2
      >patients had grade 1 steatosis (>0-b $5% fat), and one patient did not have
      >a biopsy sample submitted.
      >Predictors of response
      >Single-variable analysis identified baseline HCV-RNA level, duration of
      >treatment, and age as potential predictors of response. After stepwise
      >multivariable logistic regression analysis, baseline HCV-RNA level
      >(P<0.0001) and treatment duration for at least 16 weeks (P=0.0135) remained
      >significant independent predictors of sustained virologic response (Table
      >2). Body weight was not a predictor of sustained virologic response by
      >either single-variable or stepwise analysis.
      >Undetectable serum HCV-RNA after 4 weeks of therapy was an important
      >predictor of sustained virologic response. The sustained virologic response
      >rate was 89% for those who were first HCV-RNA negative at week 4, compared
      >to 25 and 17% in those who had their first undetectable HCV-RNA at week 12
      >or 24, respectively. Patients who had undetectable HCV-RNA at weeks 4 and 24
      >of treatment had a sustained response rate of 92%.
      >The classification tree model demonstrated that a baseline HCV-RNA level of
      >250,000IU/mL best discriminated between patients with or without sustained
      >virologic response. Patients with a baseline HCV-RNA b $250,000IU/mL had a
      >significantly higher sustained virologic response rate of 67% (93/138)
      >compared with 25% (24/97) in patients with a baseline HCV-RNA level
      >>250,000IU/mL (P<0.0001). This was due to both a higher end of treatment
      >virologic response rate (89 vs 68%) and a lower confirmed virologic relapse
      >rate (23 vs 63%) in patients with baseline HCV-RNA levels below
      >250,000IU/mL. Initial viral load and early response were linked. In patients
      >with HCV-RNA concentration of b $250,000IU/mL, 68% (94/138) had their first
      >undetectable serum HCV-RNA after 4 weeks of treatment compared with 16%
      >(16/97) with baseline HCV-RNA concentration of >250,000IU/mL.
      >Baseline viral load
      >Thirty-seven patients (16%) had a screening viral load of b $600,000IU/mL,
      >followed by a viral load of >600,000IU/mL before initiating treatment. This
      >finding is consistent with the known c0.5log assay variation of real-time
      >PCR testing wherein a proportion of patients with initial viral loads close
      >to the 600,000IU/mL screening cut-off should retest higher than
      >600,000IU/mL. This finding reinforces the concept that one should not
      >attribute clinical significance to small changes (<1log) in serum viral
      >titers of individual patients with hepatitis C virus infection.
      >Two hundred twenty-one (94%) patients completed at least 80% of the planned
      >treatment duration. Patients were considered adherent to the treatment
      >regimen if they received at least 80% of the assigned dose of both drugs for
      >at least 80% of the treatment duration [16]. Patients who were able to
      >adhere to the assigned treatment regimen were compared with patients who
      >received less than 80% of one or both drugs or completed less than 80% of
      >the treatment duration. The sustained virologic response rate in adherent
      >patients was 52% (102 of 195 patients) compared with 54% (14 of 26 patients)
      >in nonadherent patients. Dose reduction did not seem to affect sustained
      >virologic response rates among HCV-1 infected patients with low baseline
      >HCV-RNA levels, but this observation is based on a small sample size, since
      >only 12% (26/221) were considered nonadherent. Therapy for at least 16
      >weeks, however, was a strong predictor of sustained virologic response.
      >Adverse events
      >Serious adverse events (SAE) were reported in 25 patients during the
      >treatment period, representing an SAE rate of 11%. In 19 of the 25 patients
      >the event was considered by the investigator as probably or possibly related
      >to study medication (depression, asthenia, abdominal pain, fever, anemia,
      >neutropenia, hypocalcemia, pruritus, rash, psoriasis, allergy, thyroiditis,
      >hearing impairment). Seven of 237 patients (3%) discontinued therapy because
      >of adverse events. Two patients discontinued due to depression and one
      >patient each for asthenia, anemia, asthenia plus anemia, breast cancer and
      >psoriasis, respectively.
      >Sixty-one of 237 patients (26%) required dose reduction or interruption due
      >to adverse events (excluding patients who later discontinued due to an
      >adverse event). Anemia (12%) thrombocytopenia (4%), and neutropenia (3%)
      >were the most common adverse events leading to dose modification. Dose
      >modifications were lower in those patients receiving 800mg/day of ribavirin
      >(9% or 8/87 patients), but similar in patients receiving 1000mg/day and
      >1200mg/day (14% or 16/114 patients and 15% or 5/34 patients, respectively).
      >Treatment-emergent SAEs occurred at similar rates in the present 24-week
      >treatment study and the historical control of patients treated for 48 weeks
      >(11 vs 12%) [11]. However, adverse events leading to discontinuation of
      >therapy (3 vs 14%) or dose modifications due to adverse events (26 vs 49%)
      >were considerably lower in the present study compared with the 48-week
      >historical control study [11]. In addition, adverse events leading to
      >discontinuation or dose modifications in this study were lower than those
      >reported in the initial 24 weeks of therapy in the historical control (11
      >and 41%, respectively) [11].
      >This study demonstrates that 24 weeks of therapy with peginterferon alfa-2b
      >1.5N<g/kg/week plus weight-based ribavirin dosing is insufficient for the
      >treatment of patients infected with HCV-1 and a baseline HCV-RNA level equal
      >or below 600,000IU/mL. Using the data of the study by Manns et al. [11], a
      >sustained virologic response rate of 69% was predicted if the patients in
      >the present study would have been treated for 48 weeks. This estimated
      >sustained virologic response rate fell outside the 95% confidence interval
      >(43-56%) of the observed virologic response rate after 24 weeks treatment in
      >the study cohort and therefore did not satisfy the criterion for
      >establishing effectiveness for the present study.
      >The classification tree model demonstrated that a pretreatment HCV-RNA level
      >of 250,000IU/mL best discriminated between patients with or without a
      >sustained virologic response after combination therapy with peginterferon
      >alfa-2b and ribavirin for 24 weeks. Future prospective studies should
      >investigate whether only one threshold differentiating between low and high
      >pretreatment viremia is sufficient or whether several ranges of pretreatment
      >HCV-RNA levels could be used to individualize treatment duration. The
      >current definition of low and high viral load originates from the median
      >pretreatment HCV-RNA levels in several pivotal trials, i.e.
      >2,000,000copies/mL [6,7]. Unfortunately, the conversion according to the WHO
      >standard is currently inconsistent. According to a real-time quantitative
      >PCR assay developed by Schering Plough Research Institute and other assays
      >the threshold between low and high pretreatment viremia is 600,000 or
      >800,000IU/mL, respectively [11-14]. Furthermore, the natural fluctation of
      >HCV-RNA as well as the intra-assay variability of quantitative assays must
      >be kept in mind.
      >Data of the present study show that a subgroup of HCV genotype 1 infected
      >patients who had pretreatment HCV RNA levels below 600,000IU/mL and became
      >serum HCV-RNA negative after 4 weeks of treatment achieved an excellent
      >sustained virologic response rate of almost 90% (compared with 85% in the
      >historical control group treated for 48 weeks [11]). These data are in line
      >with a recent prospective study in which treatment of patients with chronic
      >hepatitis C was individualized according to the early virologic response
      >[17]. In that study, serum HCV-RNA was frequently quantified during the
      >initial 6 weeks of peginterferon alfa-2a plus ribavirin combination therapy,
      >and patients were classified as rapid, slow, flat, or null responders. The
      >sustained virologic response rate in HCV-1 infected patients with an initial
      >rapid virologic response who were treated only for 24 weeks was substantial
      >(65%) but was lower than in those patients treated for 48 weeks (83%). This
      >difference was significant in patients with a baseline HCV-RNA
      >>800,000IU/mL, but not in patients with lower baseline viral load [17].
      >Beyond the initial virologic response at treatment week 4 only two
      >pretreatment parameters (baseline HCV-RNA level and treatment duration for
      >at least 16 weeks) remained significant independent predictors of sustained
      >virologic response in the present study after stepwise multivariable
      >logistic regression analysis. These predictors as well as the fact that body
      >weight was not a predictor of sustained virologic response are in accordance
      >with a similar study in patients infected with HCV genotypes 2 or 3 [14].
      >However, in the study with HCV-2 or HCV-3 infected patients hepatic
      >steatosis of less than 5% was an additional independent predictor of
      >sustained virologic response [14]. This can be explained because infection
      >particularly with HCV-3 leads to hepatic steatosis [18,19].
      >Overall, the safety profile of the present 24-week treatment regimen was
      >improved compared with patients in the study of Manns et al. [11] who
      >received more than 10.6mg/kg/day ribavirin for 48 weeks. Adverse events
      >leading to treatment discontinuation or dose reduction occurred at
      >considerably lower rates in the present study compared with the historical
      >control study. Improved adverse event rates in this study were also seen
      >compared with the initial 24 weeks of treatment in the historical control.
      >Over the recent years, investigators may have become more familiar with the
      >medications and the management of their adverse events, leading to this
      >improved safety profile.
      >In general, patients chronically infected with HCV-1 should receive
      >combination therapy with a pegylated interferon plus weight-based ribavirin
      >for 48 weeks. An exception comprises HCV-1 infected patients with a low
      >pretreatment HCV-RNA concentration (below 600,000IU/mL) who become
      >undetectable for serum HCV-RNA already after 4 weeks of combination therapy.
      >In this subset of patients treatment for 24 weeks does not impair the
      >sustained virologic response rate. Although a baseline HCV-RNA concentration
      >of less than 250,000IU/mL may predict the need for shorter course therapy,
      >the strongest predictor is virologic response after 4 weeks of therapy.
      >Given the intra-assay variability of PCR testing (c0.5log), response after
      >4 weeks of therapy is the most useful predictor of sustained virologic
      >response in clinical practice.
      >Patients and methods
      >Male and female patients aged 18-70 years with compensated chronic HCV-1
      >infection not previously treated with interferon, ribavirin and/or
      >amantadine were eligible for enrollment. Eligible patients tested positive
      >for HCV-RNA by reverse transcription-polymerase chain reaction with a
      >concentration b $600,000IU/mL, had a liver biopsy taken within 12 months
      >prior to the screening visit showing chronic hepatitis, and had at least one
      >elevated serum alanine aminotransferase (ALT) level at screening or entry
      >into the trial. Entry leucocyte and platelet counts had to be at least 3000
      >and 80,000/N<L, respectively. Hemoglobin values at entry visit had to be at
      >least 12g/dL for females and at least 13g/dL for males.
      >Patients with the following criteria were excluded: any other cause of liver
      >disease or other relevant disorders including human immunodeficiency or
      >hepatitis B virus coinfection, clinically significant hematologic, hepatic,
      >metabolic, renal, rheumatologic, anaphylactic reactions, neurological or
      >psychiatric disease, clinically significant cardiac or cardiovascular
      >abnormalities, organ grafts, systemic infection, clinically significant
      >bleeding disorders, evidence of malignant neoplastic disease, average daily
      >intake of alcohol exceeding 80g of ethanol, or drug abuse within the past
      >two years. Further exclusion criteria were pregnancy and lactation.
      >Study design
      >This phase 4, single-arm, open-label, historical-control study assessed the
      >safety and efficacy of 24 weeks of treatment with peginterferon alfa-2b plus
      >ribavirin in previously untreated patients with chronic hepatitis C who were
      >infected with HCV-1 with a screening HCV-RNA concentration b $600,000IU/mL.
      >Eligible patients were treated with peginterferon alfa-2b (PegIntronB.,
      >Schering Plough Corp., Kenilworth, NJ) 1.5N<g/kg once per week
      >subcutaneously plus ribavirin (RebetolB., Schering Plough Corp., Kenilworth,
      >NJ) 800-1400mg/day orally (<65kg, 800mg; 65-85kg, 1000mg; >85-105kg, 1200mg;
      >>105kg, 1400mg). Weight-based dosing of ribavirin (>10.6mg/kg/day) was
      >selected to provide the standard of care dosing regimen as well as the
      >optimal dosing regimen with regard to safety and efficacy as established in
      >the historical control [11].
      >The dose of each study medication was based on the patient's weight at
      >entry. Patients were treated for 24 weeks, then followed for an additional
      >24 weeks. The study was approved by the ethics committees at the
      >participating centers and conducted according to the Declaration of Helsinki
      >and the ICH/CPMP guidelines 'Good Clinical Practice'. All patients gave
      >written informed consent before enrollment.
      >Patients were evaluated as outpatients for safety, tolerance, and efficacy
      >at weeks 4, 8, 12, 18, and 24 during treatment and at weeks 4, 12, and 24
      >following the end of treatment. HCV-RNA was quantified by real-time
      >polymerase chain reaction technology (lower limit of detection 29IU/mL). HCV
      >genotyping was performed by direct sequencing of the 5'-noncoding region.
      >Liver biopsy specimens were assessed by an experienced pathologist who was
      >unaware of clinical and biochemical data as well as of treatment regimen and
      >response. Steatosis was graded according to the percentage of hepatocytes
      >containing visible macrovesicular steatosis. Histological results were
      >classified according to internationally standardized criteria [15].
      >Study end points
      >The primary efficacy endpoint for this study was the proportion of patients
      >with a sustained virologic response, defined as undetectable plasma HCV-RNA
      >levels at 24 weeks following the end of treatment. The secondary endpoint
      >was the proportion of patients with a sustained virologic response and
      >normalization of alanine aminotransferase (ALT) at the end of the follow-up
      >period. The safety and efficacy of 24 weeks of treatment in this trial were
      >compared with the historical control that treated patients with combination
      >therapy including >10.6mg/kg/day of ribavirin for 48 weeks [11]. Safety data
      >were also compared with the initial 24 weeks of therapy in the historical
      >Statistical analysis
      >The primary efficacy analysis was based on 235 enrolled patients. A
      >prediction model for sustained virologic response was developed using data
      >from Manns et al. [11]. This model included the following prognostic
      >factors: genotype, baseline HCV-RNA level, presence or absence of bridging
      >fibrosis (F3) or cirrhosis (F4), age and gender. The model was then used to
      >predict sustained virologic response rates for the HCV-1 infected patients
      >with low baseline viremia in the present study, had they received 48 weeks
      >of treatment. If the estimated sustained virologic response rate for 48
      >weeks of treatment based on the model fell within the 95% confidence
      >interval of the actually observed sustained virologic response rate of the
      >present study, then it was concluded that 24 weeks of treatment is
      >equivalent to 48 weeks of treatment.
      >Single-variable logistic regression was used to compute p-values and odds
      >ratios for the effect of prognostic factors (those observed at baseline and
      >also treatment duration) upon sustained response. Stepwise regression
      >analysis was performed to determine the significance of the results from the
      >single-variable logistic regression analysis. The classification tree
      >approach (SAS Enterprise Miner, Tree model using the Chi-square splitting
      >criterion) determined the relationship between baseline viral load and
      >sustained virologic response.
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