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[NATAP] Pegasys for 16 or 24 weeks in genotype 2/3

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  • claudine intexas
    Subject: [NATAP] Pegasys for 16 or 24 weeks in genotype 2/3 NATAP http://natap.org/ _______________________________________________ Peginterferon-α-2a (40KD)
    Message 1 of 1 , Aug 6, 2005
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      Subject: [NATAP] Pegasys for 16 or 24 weeks in genotype 2/3

      NATAP http://natap.org/
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      Peginterferon-α-2a (40KD) and Ribavirin for 16 or 24 Weeks in Patients With Genotype 2 or 3 Chronic Hepatitis C
      patients chronically infected with HCV-2 (independent from pretreatment viremia) and those infected with HCV-3 and a pretreatment HCV RNA level equal or below 800,000 IU/mL, who can achieve a rapid virologic response defined as HCV RNA below 600 IU/mL at week 4, can be treated for only 16 weeks with peginterferon-α-2a and ribavirin without compromising the chances for a sustained virologic response. The data of the present study are less conclusive for HCV-3-infected patients with a pretreatment viremia above 800,000 IU/mL, who achieve a rapid virologic response as well as for those patients who cannot achieve a rapid virologic response

      Gastroenterology
      Volume 129, Issue 2, Pages 522-527 (August 2005)

      Data of the present study were presented in part at the 55th Annual Meeting of the American Association for the Study of Liver Diseases, October 29-November 2, 2004, Boston, Massachusetts.

      Michael von Wagner⁎, Miriam Huber‡, Thomas Berg§, Holger Hinrichsen‖, Jens Rasenack¶, Tobias Heintges#, Alexandra Bergk§, Christine Bernsmeier‖, Dieter Häussinger#, Eva Herrmann⁎, Stefan Zeuzem*

      ABSTRACT
      Background & Aims: Standard therapy of patients with chronic hepatitis C virus (HCV) infected with HCV genotype-2 or -3 is the combination of pegylated interferon-α and ribavirin for 24 weeks. Whether shorter treatment durations are possible for these patients without compromising sustained virologic response rates is unknown.

      Methods: Patients chronically infected with HCV-2 (n = 39), HCV-2/3 (n = 1), or HCV-3 (n = 113) were treated with peginterferon-α-2a (180 μg/wk) plus ribavirin 800-1200 mg/day. HCV RNA was quantitatively assessed after 4 weeks. Patients with a rapid virologic response (HCV RNA below 600 IU/mL) were randomized for a total treatment duration of 16 (group A) or 24 weeks (group B). All patients with HCV RNA ≥600 IU/mL at week 4 (group C) were treated for 24 weeks. End-of-treatment and sustained virologic response were assessed by qualitative RT-PCR (sensitivity 50 IU/mL).

      Results:

      Only 11 of 153 patients (7%) were allocated to group C. End-of-treatment and sustained virologic response rates were 94% and 82%, (group A), 85% and 80% (group B), and 73% and 36% (group C), respectively.

      In patients infected with genotype HCV-3 and high viral load (>800,000 IU/mL), a significant lower sustained virologic response rate was found than in patients infected with HCV-3 and a viral load lower or equal to 800,000 IU/mL (59% vs 85%, respectively; P = .003).

      Conclusions: In HCV-2 and -3 (low viral load)-infected patients who have a rapid virologic response, treatment for 16 weeks with peginterferon-α-2a and ribavirin is sufficient. In patients infected by HCV-3 (high viral load), longer treatment may be necessary.

      MORE RESULTS
      Virologic Response According to HCV Genotype and Pretreatment Viremia

      Sustained virologic response rates in genotype HCV-2-infected patients were higher than in genotype HCV-3-infected patients (92% vs 73%, respectively) and were not affected by pretreatment viremia. Genotype HCV-3-infected patients with a baseline viremia above 800,000 IU/mL, however, achieved a lower sustained virologic response rate compared with patients with a baseline viremia equal or below 800,000 IU/mL (59% vs 85%, respectively, P = .003).

      No differences in sustained virologic response rates were observed between treatment groups A and B for patients infected with genotype HCV-2. The sustained virologic response rate of HCV-3-infected patients with a pretreatment viremia equal or below 800,000 IU/mL was not compromised by a 16-week treatment duration (group A) compared with 24 weeks (group B) (Figure 2). The sustained virologic response rate in HCV-3-infected patients with a baseline viremia above 800,000 IU/mL was higher with 24 weeks of combination therapy in group B than with 16 weeks treatment in group A (67% vs 55%, respectively, P > .2) but did not reach statistical significance.

      Characteristics of the Patients
      This study was performed between January 2002 and March 2004 in 6 German tertiary referral centers. According to the inclusion and exclusion criteria, 153 patients were enrolled: 39 (26%) and 113 patients (74%) were infected with genotypes HCV-2 and -3, respectively, whereas in 1 patient (<1%), genotypes HCV-2 and -3 could not be differentiated.

      Virologic and Biochemical Response
      After 4 weeks treatment with peginterferon-α-2a plus ribavirin, HCV RNA was below 600 IU/mL in 142 of 152 patients (93%). This rapid virologic response was achieved by 37 of 38 patients (97%) infected with genotype HCV-2 and by 103 of 112 patients (92%) infected with genotype HCV-3 (P > 0.2). These patients and 1 patient who was negative at week 2 with a missing HCV RNA result at week 4 were randomized to groups A (n = 71) and B (n = 71). Patients with HCV RNA ≥600 IU/mL at week 4, including 1 patient with missing HCV RNA results at weeks 2 and 4, were allocated to group C (n = 11).

      An overall intent-to-treat virologic response at the end of therapy was achieved in 135 of 153 patients (88%) and a sustained virologic response in 119 of 153 patients (78%). Virologic response rates were similar in patients randomized to either 16 weeks (group A) or 24 weeks of combination therapy (group B). In groups A and B, 67 of 71 patients (94%) and 60 of 71 patients (85%) achieved an end of treatment response and 58 of 71 patients (82%) and 57 of 71 patients (80%) sustained a virologic response, respectively. This corresponds to a difference in sustained virologic response between groups A and B of at most 11.5% (97.5% 1-sided confidence interval). The sustained virologic response rate in patients without a rapid virologic response who were treated for 24 weeks (group C), however, was lower than in group B (36% vs 81%, respectively, P = .005), whereas the end-of-treatment response rate was only slightly lower in group C (72% vs 84%, respectively, P = ns).

      Sustained biochemical response rates in groups A, B, and C were 89%, 87%, and 67%, respectively. Sustained biochemical response was observed in 110 of 115 sustained virologic responders (96%), whereas 5 sustained virologic responders did not show a biochemical response with ALT levels ranging up to 2.95 times the upper limit of normal. Each of the 5 subjects was infected with HCV-2.

      Other Predictors of Response
      From multivariate logistic regression analysis of all patients, genotype HCV-2, low viral load, and low γ-glutamyltransferase (GGT) value were independent factors of sustained virologic response. When the analysis was based on patients infected with genotype HCV-3 only, baseline viral load (P = .01) and GGT value (P = .02) remained as independent negative predictors for sustained virologic response. Fibrosis score and GGT were slightly higher in patients without rapid virologic response (group C) compared with patients with rapid virologic response (groups A and B); however, differences did not reach statistical significance.
      Adverse Events and Dose Modifications

      Seven serious adverse events were reported by the 153 patients enrolled into this study (bacterial infection, carcinoma, diverticulitis, paranoid reaction, pneumonia, pregnancy of partner, tuberculosis). Only 1 patient (group B) discontinued therapy because of an adverse event (intravenous drug abuse). In addition, 8 patients (1 in group A, 5 in group B, and 2 in group C) prematurely withdrew from therapy for nonsafety reasons. Adverse events were typical of those previously reported with combination therapy with (pegylated) interferon and ribavirin. In general, the frequency of adverse events was lower in the 16-week treatment group (group A) compared with the 24-week treatment groups (groups B and C).

      Twenty-two of 153 patients (14%) and 17 of 153 patients (11%) required dose reduction or treatment interruption because of adverse events of peginterferon-α and ribavirin, respectively. Neutropenia (3%) and anemia (6%) were the most common adverse events leading to dose modification.

      AUTHOR DISCUSSION
      Discussion
      return to Article Outline

      Previous studies have convincingly shown that combination therapy with pegylated interferon-α plus ribavirin for 24 weeks achieves similar sustained virologic response rates in patients infected with genotype HCV-2 or -3 as combination therapy for 48 weeks.9,10 Subsequent approaches are currently investigating whether either the dose for peginterferons and/or the duration of therapy can be reduced without compromising sustained virologic response rates. In the present study, patients infected with genotype HCV-2 or -3 who achieved a rapid virologic response were randomized to either the standard treatment duration of 24 weeks or a shorter duration of 16 weeks. Patients received a standard dose of peginterferon-α-2a (180 μg once per week) and weight-based ribavirin doses (800-1200 mg/day).

      The mechanism of action of ribavirin in the treatment of patients with chronic hepatitis C remains unknown. Ribavirin in addition to (pegylated) interferon enhances the virologic response and more importantly reduces relapse rates in patients who achieve an end-of-treatment virologic response. Therefore, it was decided to use a high dose of ribavirin (800-1200 mg/day according to body weight) in the present study to avoid virologic relapse, particularly in patients randomized to 16 weeks of combination therapy. During the course of the present study, Hadziyannis et al reported that 24 weeks of combination therapy with a flat ribavirin dose of 800 mg/day is sufficient in patients infected with genotype HCV-2 or -3.9 Whether 800 mg of ribavirin per day is sufficient for treatment durations shorter than 24 weeks will be answered by an international multicenter trial (ACCELERATE).

      The present study demonstrates that 16 weeks of therapy with peginterferon-α-2a plus weight-based ribavirin is sufficient for patients chronically infected with genotype HCV-2 or -3 who achieve a rapid virologic response at week 4. Patients treated for 16 weeks also tended to report adverse events less frequently than patients treated for 24 weeks. The rapid virologic response was independent from baseline HCV RNA levels. Seven percent of mainly HCV-3-infected patients could not achieve a rapid virologic response at week 4 and were treated according to current guidelines for 24 weeks. The sustained virologic response rate, however, was significantly impaired in these patients.

      Several studies have shown that an early virologic response predicts sustained virologic response.12-14 A less than 2 log10 decline of HCV RNA within the initial 12 weeks of therapy has been generally accepted as an early stopping algorithm with a negative predictive value of 98%-100%.12,15 However, this algorithm is only useful in genotype HCV-1-infected patients, and less than 2% of patients infected with genotype HCV-2 or -3 are unable to meet this criterion.

      In the present study, the sustained virologic response rate was higher in patients infected with HCV-2 than in those infected with HCV-3, supporting the concept that virologic response rates should be presented according to single genotypes rather than to a combination of genotypes. The rapid and the sustained virologic response rates in HCV-2-infected patients were above 90%, suggesting that neither quantification of HCV RNA before starting nor during therapy is required to define the duration of treatment in these patients.

      In HCV-3-infected patients, however, a different algorithm may be required. Within the group of chronically HCV-3-infected patients treated for 16 weeks, a higher virologic relapse rate was observed in patients with a baseline HCV RNA concentration of more than 800,000 IU/mL, and, in this subgroup, the sustained virologic response rate was lower for the 16-week compared with the 24-week treatment group. Quantification of HCV RNA at baseline and at early time points during therapy (eg, at 4 weeks as in the present study) may allow to individualize treatment duration in these patients. However, further detailed analyses of baseline parameters, initial viral decline, and sustained virologic outcome are required to define the optimal duration of therapy in these patients. It is also conceivable that a small subgroup of HCV-3-infected patients can be identified according to baseline parameters and/or slower early decline of HCV RNA, who may benefit from longer than 24 weeks of therapy.

      The concept of shorter combination therapy with pegylated interferon and ribavirin in patients chronically infected with genotype HCV-2 or -3 is supported by 2 other trials. In an uncontrolled study, Dalgard et al determined the efficacy of 14 weeks combination treatment with peginterferon-α-2b (1.5 μg/kg once per week) plus ribavirin (800-1400 mg according to body weight) in HCV-2- or HCV-3-infected patients who achieved an early virologic response, defined as undetectable HCV RNA at weeks 4 and 8. Ninety-five of 122 patients (78%) fulfilled these early virologic response criteria, and 85 of the 95 patients achieved a sustained virologic response.16 Mangia et al observed a sustained virologic response rate of 89% in mainly HCV-2-infected patients who received peginterferon-α-2b (1.0 μg/kg once per week) plus ribavirin (1000-1200 mg according to body weight) for a total duration of 12 weeks if they were HCV RNA negative at week 4.17

      In conclusion, patients chronically infected with HCV-2 (independent from pretreatment viremia) and those infected with HCV-3 and a pretreatment HCV RNA level equal or below 800,000 IU/mL, who can achieve a rapid virologic response defined as HCV RNA below 600 IU/mL at week 4, can be treated for only 16 weeks with peginterferon-α-2a and ribavirin without compromising the chances for a sustained virologic response. The data of the present study are less conclusive for HCV-3-infected patients with a pretreatment viremia above 800,000 IU/mL, who achieve a rapid virologic response as well as for those patients who cannot achieve a rapid virologic response. Additional trials are required to optimize treatment duration in these patients.
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