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  • alleypat
    NATAP http://natap.org/ ... Hepatitis C Treatment Strategies-- 2 studies: (1) 72 weeks peg/RBV for genotype 1 not responding until 12 Week; (2) for genotypes
    Message 1 of 1 , Apr 27, 2007
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      Hepatitis C Treatment Strategies-- 2 studies: (1) 72 weeks peg/RBV for genotype 1 not responding until 12 Week; (2) for genotypes 2/3, 48 weeks peg + 1000/1200mg RBV for patients not achieving RVR instead of 24 weeks, 800 mg ribavirin

      Reported by Jules Levin
      EASL, April 2007, Barcelona

      In Genotype 1 Patients Who Clear HCV RNA At Week 12 (between week 8 and 12): SVR is Higher After 72 Weeks Than After 48 Weeks Treatment: Results of a Randomized Controlled Trial

      Reported by Jules Levin
      EASL, April 11-15, 2007
      Barcelona, Spain

      Alessandra Mangia from Italy looked at genotype 1 patients and reported patients who did not achieve HCV-RNA negativity until week 12 had higher SVR rates with 72 weeks of therapy than with 48 weeks of therapy (63% [n=33] vs 37% [n=7]). She said the results approached statistical significance, p=0.06. She said the main reason for failure was the high relapse rate in the 48 week group. The relapse rate was lower for the patients receiving 72 weeks (13%) than for patients receiving 48 weeks (26%). She said the rate of drop out was comparable between the two groups. The discontinuation rate was higher for patients receiving 72 weeks (23%) vs those receiving 48 weeks (16%). Of note, she said â?oa slower response was observed in older patientsâ?. She also said treatment duration was the only independent predictor I think she said in both the univariate & multivariate analysis (p=0.06). This was a prospective study of 694 treatment-naïve patients receiving â?ovariableâ? duration of therapy-- 24, 48, or 72 weeks peginterferon plus ribavirin (1000-1200mg/day), to better define, among genotype 1 patients without RVR (Rapid Viral Response, week 4), those who benefit from extended duration of therapy. In the variable treatment arm patients with an RVR stopped treatment at week 24; patients who were HCV RNA positive (PCR by 50 Iu/mL) at week 4 continued until week 48; and patients who were positive at week 8 continued treatment until week 72. 459 patients received â?ovariableâ? duration of therapy while 235 patients received standard 48 weeks therapy. Most study patients (60-65%) had fibrosis stage <3 and 75% <grade 3. In total 184 patients were HCV RNA negative at week 4, 122 in the variable group and 78% of these achieved SVR; 62 were HCV RNA negative at week 4 in the standard treatment group and 87% achieved SVR. 192 patients in total were HCV RNA negative at week week, 128 in the variable arm and 64 in the standard arm. 72% in the variable arm achieved SVR and 70% in the standard arm achieved SVR.


      48 Weeks & High Ribavirin Dose May Improve SVR Rates for Genotype 2/3, French study by Bernard Willems

      Reported by Jules Levin
      EASL, April 11-15, 2007
      Barcelona, Spain

      Several HCV studies presented with oral talks were of particular interest at EASL. Bernard Willems from France presented data suggesting that for genotype 2 & 3 patients who do not achieve a Rapid Viral Response (week 4), 48 weeks Peg/RBV with 1000/1200 mg RBV attains higher SVR rates and lower relapse rates than 24 weeks peg/RBV and than using 800 mg RBV. Willems presented data from a retrospective look at 2 early pivotal Pegasys/RBV studies to see if 48 weeks peg/RBV would be better than 24 weeks in genotype 2/3 patients if they do not achieve a RVR (week 4 response). In one study the SVR and relapse rates were better for genotype 2 & 3 patients who received 48 weeks and RBV 1000/1200 than for patients who received 24 weeks with either 800 or 1000/1200 mg RBV. But, in the second study the SVR was not better with 48 weeks. However, the results were not statistically significant, the numbers of patients in the analysis was small, and this examination was retrospective, so Willems concluded â?oformal prospective studies should be done before 48 weeks treatment duration can be recommended in these patientsâ?. I will report Willems full data set. (see slides from Willems talk below).

      â?oShould treatment with peginterferon plus ribavirin be intensified in patients with HCV genotype 2/3 without a rapid virologic response?â?

      Bernard Willems1, S.J. Hadziyannis2, T.R. Morgan3,
      M. Diago4, P. Marcellin5, D. Bernstein6, P.J. Pockros7, A. Lin8,
      M.L. Shiffman9, S. Zeuzem10

      1Hôpital Saint-Luc-Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada; 2Henry Dunand Hospital, Athens, Greece, 3VA Medical Center, Long Beach, USA; 4Hospital General Valencia, Spain; 5Hôpital Beaujon, France; 6North Shore University Hospital, Manhasset, USA; 7Scripps Clinic, La Jolla, USA; 8Roche, Nutley, USA; 9Virginia Commonwealth University Medical Center, Richmond, USA;
      10J.W. Goethe-University Hospital, Frankfurt, Germany

      BACKGROUND
      In the treatment of chronic hepatitis C, genotypes 2 and 3 are considered as â?oeasier to treatâ?.

      Patients with G2 or G3 who have a Rapid Virologic Response (RVR) achieve high rates of Sustained Virologic Response (SVR) with 12 to 16 weeks of treatment with pegylated interferon plus ribavirin.

      However, genotype 2/3 patients who do not achieve an RVR have a much lower SVR.1-3
      (RVR = HCV RNA <50 IU/mL at week 4)

      In the ACCELERATE trial (n=1469), the SVR rate was 90% in patients with RVR and only 49% in patients without RVR.4

      These patients may benefit from a more intensified treatment regimen (longer duration, higher ribavirin dose).

      1. Mangia A, et al. N Engl J Med 2005; 352: 2609
      2. von Wagner M, et al. Gastroenterology 2005; 129: 522
      3. Yu M-L, et al. Gut 2007; 56: 553
      4. Shiffman M, et al. 41st EASL 2006; Abstract 734


      In patients infected with genotype 1:
      -- Patients with RVR (undetectable HCV RNA at week 4) achieve high rates of SVR (89%) with a shorter duration of 24 weeks1

      --Patients with cEVR (complete Early virologic Response: no RVR but undetectable HCV RNA at week 12) achieve high rates of SVR (67%) with the currently recommended regimen of 48 weeks2

      --Patients with pEVR (partial Early virologic Response: no RVR and detectable HCV RNA but a >2 log10 drop at week 12) achieve improved rates of SVR (>50%) with an extended treatment duration of 72 weeks3-5

      1. Jensen D, et al. Hepatology 2006; 43: 954
      2. Marcellin P, et al. 42nd EASL 2007 Abstract 613
      3. Sánchez-Tapias J, et al. Gastroenterology 2006; 131: 451
      4. Berg T, et al. Gastroenterology 2006; 130: 1086
      5. Ferenci P, et al. 57th AASLD 2006; Abstract 390

      STUDY OBJECTIVE
      To determine whether an intensified regimen of peginterferon alfa_2a (40KD) plus ribavirin may be beneficial in HCV genotype 2/3 patients who do not achieve an RVR.

      METHODS
      Data were retrospectively analysed from two randomised, multicentre phase III studies in which patients were treated with peginterferon alfa-2a (40KD) 180 ºg/wk plus ribavirin

      In NV15942, patients were randomised to 24 or 48 weeks of peginterferon alfa-2a (40KD) plus ribavirin 800 or 1000/1200 mg/day1

      In NV15801, patients received 48 weeks of peginterferon alfa-2a (40KD) plus ribavirin 1000/1200 mg/day2

      1. Hadziyannis S, et al. Ann Intern Med 2004; 140: 346
      2. Fried M, et al. N Engl J Med 2002; 347: 975

      PATIENTS
      -- Treatment naive
      -- Age â?¥18 years
      -- Quantifiable HCV RNA (>600 IU/mL) in serum
      -- Elevated serum ALT levels
      -- Liver biopsy consistent with a diagnosis of chronic hepatitis C
      Compensated liver disease

      PROPORTION OF GENOTYPE 2/3 PATIENTS WITH AN RVR
      A high proportion of genotype 2/3 patients achieved an RVR in each study:
      -- 74% (362/492) in NV15942 (HADZIYANNIS et al.)
      -- 58% (81/140) in NV15801 (FRIED et al.)

      In a multiple logistic regression analysis, significant independent factors associated with achieving an RVR were:
      -- Genotype 2 versus 3 (p<0.001)
      -- Non-US region versus US region (p<0.001)
      -- Low baseline viral load (HCV RNA <400 000 IU/mL) (p<0.005)

      Genotype 2/3 patients with an RVR: SVR and relapse rates
      (RVR = HCV RNA <50 IU/mL at week 4)
      In the NV15942 Hadziyannis study, among patients with an RVR, the SVR rates are 82% to 92%: 92% for 24w-800mg; 88% for 24w-1000/1200mg; 87% for 48w-800mg; 82% for 48w-1000/1200mg. The relapse rates were low, 2% to 7%. Willems said â?othere was no benefit in longer treatment or higher dose of RBVâ?. In the NV15801 study SVR rate is 78% and the relapse rate was 14% â?oeven if the patients received 48 weeks and high dose of RBVâ?.


      Genotype 2/3 patients without an RVR: SVR and relapse rates
      In the Hadziyannis study NV15942, the highest response rate was 76% SVR (4% relapse rate, the lowest) for patients receiving 48 w-1000/1200mg compared to 65% to 67% for patients receiving 24w-800mg, 24w-1000/1200mg, or 48w-800mg, but the difference was not statistically significant (p=0.46) â?owith the available sample sizeâ?. Willems said he calculated that almost 400 patients would have had to be in each treatment group to demonstrate a difference of 9%. In the second study (Fried NV15801), the SVR rate was 61% and the relapse rate was 19%, â?oeven if those patients received 48 weeks and high dose of ribavirin.


      Genotype 2/3 patients without an RVR: SVR and relapse rates
      The data is pooled from the 2 studies in this slide and then there is no difference in SVR rate (65-67%). The relapse rate is lower (13%) for patients receiving 48 weeks compared to 24 weeks treatment (24-26%).


      Genotype 2 patients without an RVR: SVR and relapse rates
      In this analysis of NV15942, â?othe best SVR rate and the lowest relapse rate was for patients receiving 48 weeks but the numbers are smallâ?.


      Genotype 3 patients without an RVR: SVR and relapse rates
      The best SVR rate and lowest relapse rate was with 48 weeks and the highest RBV dose, and again the numbers are small.


      Genotype 2/3 patients without an RVR: SVR rates across studies: Summary
      In the Accelerate trial patients received 24 weeks treatment and 800mg RBV. Patients without an RVR had 41% SVR.


      Willems concluded:
      Genotypes 2 and 3 are not necessarily â?oeasy-to-treatâ? genotypes.

      Patients who do not achieve an RVR demonstrate disappointing SVR rates with the recommended 24 weeks of treatment.

      This retrospective cross-study analysis does not permit a recommendation for intensifying treatment in all patients.

      However, an overall decrease in relapse rates with a longer duration could be observed.

      Formal prospective studies should be done before 48 weeks treatment duration can be recommended in these patients.




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