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Hepatitis C Virus Infection Burden of Disease in United States <ul><li>New infections (cases)/year  1985-89 242,000      2...
1960  1970*  1980  1990  2000  2010  2020  2030 Year 4.0% 3.0% 2.0% 1.0% 0.0% Prevalence  of HCV Infection Predicted Futur...
Reducing the Burden of HCV-Related Liver Complications <ul><li>Prevent new infections: primary prevention </li></ul><ul><u...
Potential Screening Criteria for HCV in the General Population Armstrong.  Ann Intern Med , 2006;144:705. Screening Criter...
Established Risk Factors for Progression of Fibrosis and Cirrhosis Poynard T, Lancet 1997 349:825-32 Mathurin P, Hepatolog...
Newly-Recognized Risk Factors for HCV Disease Progression <ul><li>Menopausal status  </li></ul><ul><li>Cannabis </li></ul>...
Modifying Risk of Cirrhosis in Patients with HCV Summary <ul><li>Alcohol  </li></ul><ul><ul><li>Moderate to heavy use clea...
Burden of HCV Disease Summary <ul><li>Increasing number of persons with chronic HCV developing complications of cirrhosis ...
Early Data with Telaprevir: Important Principles Learned Kieffer.  Hepatology . 2007;46:631. Copyright © 2007.  Reprinted ...
Pharmacokinetics of PEG IFN PEG IFN-2b  PEG IFN-2a  IFN 3 Adapted from Glue.  Clin Pharmacol   Ther.  2000;68(5):556.   1....
SVR in Genotype 1  Non-US vs US Patients in Major Registration Trials http://www.hivandhepatitis.com/2005icr/aasld/docs/11...
IDEAL Study USA G1 N=3070 0 *  2  4  12  24  48  +4  +12  +24 Data on file Schering Corporation. *Time 0 = screening value...
IDEAL Final Results   USA G1 n=3070 Sulkowski. EASL 2008
SVR With Fixed-dose PEG IFN   -2a + Weight Adjusted RBV: All Genotypes 66% 36% Fried.  NEJM.  2002;347:975.
PEG IFN/RBV for 48 vs 72 Weeks in Patients With Detectable HCV at Week 4 of Treatment: Study Design 510 HCV Patients PEG I...
Peg-IFN/RBV for 48 vs. 72 Weeks in Patients with Detectable HCV at Week 4 of Treatment: SVR Comparisons SVR (%) Overall Ge...
REPEAT Trial: cEVR Was Predictive of SVR With an Expected Relapse PEG-2a + RBV * P <0.0001 † P =0.003 ‡ P <0.0001 Marcelli...
REPEAT Final Results 360 mcg 360 mcg 360 mcg 180 mcg 180 mcg 180 mcg Jensen. AASLD 2007.
SVR  (%) IFN 6 m IFN/RBV 6 m PEG/RBV 12 m IFN 12 m IFN/RBV 12 m 1991 1999 2001 2008 Evolution of Therapy of HCV Genotype 1...
Early Data with Telaprevir: Important Principles Learned Kieffer.  Hepatology . 2007;46:631. Copyright © 2007.  Reprinted ...
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Hepatitis C Virus Infection Burden of Disease in United States

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  • This figure shows the median HCV RNA curve for the 8 patients who got VX-950 and Peg-IFN. In the first 3 days the patterns of response are similar to the VX-950 alone group. At day 14 of dosing 5.5 log reduction in median HCV-RNA was observed. Different from the VX-950 alone group, all patients had a continuous HCV-RNA decline.
  • LB4 PEGYLATED INTERFERON ALFA-2A (40KD) PLUS RIBAVIRIN (RBV) IN PRIOR NON-RESPONDERS TO PEGYLATED INTERFERON ALFA-2B (12KD)/RBV: FINAL EFFICACY AND SAFETY OUTCOMES OF THE REPEAT STUDY Donald M. Jensen1, Bradley Freilich2, Pietro Andreone3, Adrian DiBisceglie4, Carlos E. Brandão-Mello5, K Rajender Reddy6, Antonio Craxi7, Antonio Olveira Martín8, Gerlinde Teuber9, Diethelm Messinger10, Greg Hooper11, Matei Popescu12, Patrick Marcellin13; 1Director, Center for Liver Diseases, University of Chicago Hospitals, Chicago, IL; 2Liver and Pancreas Institute of Kansas City, Kansas City, 64131, MO; 3Department of Internal Medicine and Gastroenterology, University of Bologna, Bologna, Italy; 4Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St. Louis, MO; 5Hospital Universitário Gaffree e Guinle, Rio de Janeiro, Brazil; 6Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA; 7GI &amp; Liver Unit, University of Palermo, Palermo, Italy; 8Hospital La Paz, Madrid, Spain; 9Department of Internal Medicine, Johann Wolfgang Goethe University Medical Centre, Frankfurt, Germany; 10IST GmbH, Mannheim, Germany; 11Roche, Welwyn, United Kingdom; 12Roche, Basel, Switzerland; 13Centre de Recherches Claude Bernard sur les Hépatites Virales, Hôpital Beaujon, Clichy, France Introduction: Treatment options are limited for patients (pts) who are previous non-responders to Peg-IFN/RBV. Intensified treatment with higher fixed-dose induction of Peg-IFN and/or longer treatment duration may increase SVR rates in these pts. REPEAT compared both strategies in prior non-responders to ≥ 12 wks of Peg-IFN α-2b (12KD, PegIntron®)/RBV. Methods: Eligible pts were randomized (2:1:1:2) to 1 of 4 regimens, Arms A and B Peg-IFN α-2a (40KD; PEGASYS®) 360 μg/wk for 12 wks then 180 μg/wk for a further 60 or 36 wks, respectively; Arms C and D Peg-IFN α-2a (40KD) 180 μg/wk for 72 or 48 wks, respectively. All pts received RBV (COPEGUS®; 1000/1200 mg/day). The primary endpoint was SVR (HCV RNA &lt;50 IU/mL 24 weeks post-therapy). Results: A total of 942 pts were randomized and dosed. Key baseline (BL) characteristics were similar across arms. For the protocol-defined primary analysis the SVR rate was higher for the 72-wk induction arm (Arm A: 16%) compared to the 48-wk non-induction arm (Arm D: 9%) [p=0.006, OR 2.0 (95% CI 1.21-3.31)]. Furthermore, SVR was higher for pooled 72-wk arms vs pooled 48- wk arms [p=0.0006, OR 2.22 (95% CI 1.40-3.52)]. Tolerability of induction and non-induction regimens of Peg-IFN α-2a were similar and overall the rate/type of AEs/SAEs were similar across arms. Discontinuation rates due to safety were lower for the 48-wks arms. Conclusion: In these difficult to cure pts with prior documented non-response to Peg-IFN α- 2b/RBV, re-treatment with fixed-dose induction and longer duration with Peg-IFN α-2a (40KD)/RBV provided the highest SVR rates and the lowest relapse rates. Re-treatment with 72-wks of Peg-IFN α-2a provided higher SVR rates than 48-wks, irrespective of induction.
  • This figure shows the median HCV RNA curve for the 8 patients who got VX-950 and Peg-IFN. In the first 3 days the patterns of response are similar to the VX-950 alone group. At day 14 of dosing 5.5 log reduction in median HCV-RNA was observed. Different from the VX-950 alone group, all patients had a continuous HCV-RNA decline.
  • Transcript of "Hepatitis C Virus Infection Burden of Disease in United States"

    1. 1. Hepatitis C Virus Infection Burden of Disease in United States <ul><li>New infections (cases)/year 1985-89 242,000 2005 20,000 </li></ul><ul><li>Persons with chronic infection 3.2 million (2.7-3.9 million)* </li></ul><ul><li>% Chronic liver disease = HCV-related 40% - 60% </li></ul><ul><li>Deaths from chronic HCV/year (2004) 12,000-41,000 (est./adj.) </li></ul><ul><li>% Liver cancer due to HCV 1993-96 11% 1996-99 21% 2006 48% </li></ul>. Armstrong GL et al. Ann Intern Med 2006;144:705-714 Davila JA et al, Gastroenterology 2004;127:1372-80 Wise et al, Hepatology 2008;47:1128-35 http:// digestive.niddk.nih.gov/ddiseases/pubs/chronichepc / . Accessed May 8, 2008. * Minimum, likely underestimates due to exclusion of prisoners, homeless, etc from NHANES IV
    2. 2. 1960 1970* 1980 1990 2000 2010 2020 2030 Year 4.0% 3.0% 2.0% 1.0% 0.0% Prevalence of HCV Infection Predicted Future Prevalence of HCV in the United States Armstrong et al, Hepatology, 2000;31:777-782 Total Infected Infected >20 Years HCC Cirrhosis
    3. 3. Reducing the Burden of HCV-Related Liver Complications <ul><li>Prevent new infections: primary prevention </li></ul><ul><ul><li>No vaccine </li></ul></ul><ul><ul><li>Risk behaviors reduction </li></ul></ul><ul><li>Preventing complications of liver disease in those with chronic infection = secondary and tertiary prevention </li></ul><ul><ul><li>Identifying infected individuals </li></ul></ul><ul><ul><li>Identify and reverse/eliminate factors which accelerate rate of fibrosis progression </li></ul></ul><ul><ul><li>Therapies to stabilize or reverse liver injury and fibrosis </li></ul></ul>
    4. 4. Potential Screening Criteria for HCV in the General Population Armstrong. Ann Intern Med , 2006;144:705. Screening Criteria Persons age 20-50 y Risk factor history IDU 1.9 46.6 IDU or transfusion before 1992 7.3 53.1 IDU or transfusion before 1992 or ≥20 lifetime sex partners 21.0 76.1 Any illicit drug use or transfusion before 1992 or ≥20 lifetime sex partners 33.2 89.7 Risk factor history and ALT level Abnormal ALT level 12.0 62.6 Abnormal ALT level or injection drug use 13.3 82.8 Abnormal ALT level or injection drug use or transfusion before 1992 18.1 85.1 Abnormal ALT level or injection drug use or transfusion before 1992 or 30.0 93.5 ≥ 20 lifetime sex partners Abnormal ALT level or any illicit drug use or transfusion before 1992 or 40.7 98.6 ≥ 20 lifetime sex partners Persons age ≥60 y Risk factor history Transfusion before 1992 17.2 60.1 Risk factor history and ALT level Abnormal ALT level 5.1 56.7 Abnormal ALT level or transfusion before 1992 21.1 87.4 General HCV RNA–Positive Population Population Participants with Criteria, %
    5. 5. Established Risk Factors for Progression of Fibrosis and Cirrhosis Poynard T, Lancet 1997 349:825-32 Mathurin P, Hepatology 1998 27:868-72 Benhamou J, Hepatology 1999 30:1054-8 <ul><li>Male gender </li></ul><ul><li>Longer duration of infection </li></ul><ul><li>Age >40 years at time of infection </li></ul><ul><li>Alcohol excess </li></ul><ul><ul><li>>50 gm/day - men </li></ul></ul><ul><ul><li>>30 gm/day - women </li></ul></ul><ul><li>Persistently elevated ALT levels </li></ul><ul><li>HIV, HBV coinfections </li></ul><ul><li>Organ transplantation </li></ul>
    6. 6. Newly-Recognized Risk Factors for HCV Disease Progression <ul><li>Menopausal status </li></ul><ul><li>Cannabis </li></ul><ul><li>Insulin resistance </li></ul><ul><ul><li>Obesity, metabolic syndrome </li></ul></ul>
    7. 7. Modifying Risk of Cirrhosis in Patients with HCV Summary <ul><li>Alcohol </li></ul><ul><ul><li>Moderate to heavy use clearly bad </li></ul></ul><ul><ul><li>Limited data on impact of “social” use of alcohol </li></ul></ul><ul><ul><li>Abstinence is generally recommended </li></ul></ul><ul><li>Cannabis </li></ul><ul><ul><li>Daily use accelerates fibrosis progression </li></ul></ul><ul><ul><li>Unclear if less frequent use is harmful </li></ul></ul><ul><li>Insulin resistance and steatosis </li></ul><ul><ul><li>Independent contributors to fibrosis progression </li></ul></ul><ul><ul><li>Weight loss reduces fibrosis progression </li></ul></ul><ul><li>Menopausal status may be modifiable </li></ul><ul><ul><li>HRT may reduce risk of fibrosis progression </li></ul></ul>
    8. 8. Burden of HCV Disease Summary <ul><li>Increasing number of persons with chronic HCV developing complications of cirrhosis and HCC </li></ul><ul><li>Fibrosis progression is not linear </li></ul><ul><ul><li>Increase with age and post-menopausal status </li></ul></ul><ul><li>Several “modifiable” factors recognized </li></ul><ul><ul><li>Offers some opportunities to modify disease progression </li></ul></ul><ul><li>Estimating risk of fibrosis progression and liver complications is important </li></ul><ul><ul><li>Patients for whom treatment is deferred </li></ul></ul><ul><ul><li>Nonresponders </li></ul></ul>
    9. 9. Early Data with Telaprevir: Important Principles Learned Kieffer. Hepatology . 2007;46:631. Copyright © 2007. Reprinted by permission of Wiley-Liss, Inc, a subsidiary of John Wiley & Sons, Inc. -6 -5 -4 -3 -2 -1 0 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Study Time (days) HCV RNA Change from Baseline (Log 10 IU/mL) Telaprevir + PEG IFN alfa-2a N=8 Telaprevir N=8 PEG IFN alfa-2a + placebo N=4 Baseline Sequence analysis 15 <ul><li>Resistant mutations emerged within 4-7 days; subsequently </li></ul><ul><li>suppressed by PEG IFN + RBV </li></ul>
    10. 10. Pharmacokinetics of PEG IFN PEG IFN-2b PEG IFN-2a IFN 3 Adapted from Glue. Clin Pharmacol Ther. 2000;68(5):556. 1. Algranati. Hepatology . 1999;30(suppl 1):190A. 2. Modi. Hepatology . 2000;32(suppl 2):394A. 3. Kozlowski. BioDrugs . 2001;15(7):419-429. Hours 0 5 10 15 20 25 30 0 24 48 72 96 120 144 168 Mean Concentration (ng/mL) After first dose 1 At steady state 2 Concentration (pg/mL) Hours 0 200 400 600 800 1000 1200 0 24 48 72 96 120 144 168 0.5 mg/kg qw 7 1.0 mg/kg qw 1.5 mg/kg qw
    11. 11. SVR in Genotype 1 Non-US vs US Patients in Major Registration Trials http://www.hivandhepatitis.com/2005icr/aasld/docs/111805_a.html. Accessed May 8, 2008.
    12. 12. IDEAL Study USA G1 N=3070 0 * 2 4 12 24 48 +4 +12 +24 Data on file Schering Corporation. *Time 0 = screening value Follow-up Sulkowski. EASL 2008 End point <ul><ul><li>n=960 </li></ul></ul><ul><ul><li>n=960 </li></ul></ul>Screening <ul><ul><li>n=960 </li></ul></ul>48 Weeks 24 Weeks PEG-IFN alfa-2b 1.0 mcg/kg/wk + ribavirin 800-1,400 mg/d PEG-IFN alfa-2b 1.5 mcg/kg/wk + ribavirin 800-1,400 mg/d PEG-IFN alfa-2a 180 mcg/wk + ribavirin 1,000-1,200 mg/d
    13. 13. IDEAL Final Results USA G1 n=3070 Sulkowski. EASL 2008
    14. 14. SVR With Fixed-dose PEG IFN  -2a + Weight Adjusted RBV: All Genotypes 66% 36% Fried. NEJM. 2002;347:975.
    15. 15. PEG IFN/RBV for 48 vs 72 Weeks in Patients With Detectable HCV at Week 4 of Treatment: Study Design 510 HCV Patients PEG IFN  -2a 180  g/wk plus RBV 800 mg/day for 4 weeks 326 With Detectable HCV-RNA 184 With Undetectable HCV RNA Group A 48 Weeks Total Treatment n=165 Group B 72 Weeks Total Treatment n=161 Group C 24 Weeks Total Treatment n=148 Group D 48 Weeks Total Treatment n=36 Adapted from S á nchez-Tapias. Gastroenterology 2006;131:451.
    16. 16. Peg-IFN/RBV for 48 vs. 72 Weeks in Patients with Detectable HCV at Week 4 of Treatment: SVR Comparisons SVR (%) Overall Genotype 1 Baseline HCV RNA  800,000 IU/mL Baseline HCV RNA >800,000 IU/mL Adapted from S á nchez-Tapias. Gastroenterology 2006;131:451. 48 Weeks 72 Weeks P =0.014 P =0.003 P =0.004 P =0.60 n= 165 n= 161 n= 149 n= 142 n= 96 n= 86 n= 69 n= 75
    17. 17. REPEAT Trial: cEVR Was Predictive of SVR With an Expected Relapse PEG-2a + RBV * P <0.0001 † P =0.003 ‡ P <0.0001 Marcellin. Presented at: AASLD 2005. Abstract 1174, LB04. 0 10 20 30 40 50 60 70 180 µg/wk n=469 360 µg/wk n=473 Patients (%) with HCV RNA (-) <600 IU/mL Patients (%) with HCV RNA (-) <50 IU/mL (%) 25% N=942 patients have reached Week 12 0 13% 42%* 20% † 1/3 relapse: expect 9% SVR and 15% with higher dose
    18. 18. REPEAT Final Results 360 mcg 360 mcg 360 mcg 180 mcg 180 mcg 180 mcg Jensen. AASLD 2007.
    19. 19. SVR (%) IFN 6 m IFN/RBV 6 m PEG/RBV 12 m IFN 12 m IFN/RBV 12 m 1991 1999 2001 2008 Evolution of Therapy of HCV Genotype 1 The number to beat is 40% and the time to beat is 12 months
    20. 20. Early Data with Telaprevir: Important Principles Learned Kieffer. Hepatology . 2007;46:631. Copyright © 2007. Reprinted by permission of Wiley-Liss, Inc, a subsidiary of John Wiley & Sons, Inc. -6 -5 -4 -3 -2 -1 0 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Study Time (days) HCV RNA Change from Baseline (Log 10 IU/mL) Telaprevir + PEG IFN alfa-2a N=8 Telaprevir N=8 PEG IFN alfa-2a + placebo N=4 Baseline Sequence analysis 15 <ul><li>Resistant mutations emerged within 4-7 days; subsequently </li></ul><ul><li>suppressed by PEG IFN + RBV </li></ul>
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