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Hepatitis C Report From the 55th Annual Meeting of the AASLD*

This program discusses new agents for the treatment of Hepatitis C, including viramidine, albumin-interferon alpha, and NM283. It provides information on their effectiveness, dosing, and potential side effects.

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Hepatitis C Report From the 55th Annual Meeting of the AASLD*

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  1. http://clinicaloptions.com Sponsored by: Hepatitis C Report From the55th Annual Meeting of the AASLD* October 29 – November 2, 2004 Boston, Massachusetts * This program is not sanctioned by nor an official part of the conference. http://clinicaloptions.com/hepatitis

  2. About These Slides • Users are encouraged to include these slides in their own presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent. • These slides may not be published or posted online without permission from Clinical Care Options. • We are grateful to the following faculty members who aided the content creation of these slides: • Adrian M. Di Bisceglie, MD, Professor of Medicine and Chief of Hepatology at Saint Louis University School of Medicine, St. Louis, MO • Karen L. Lindsay, MD, Associate Professor of Medicine and Director, Hepatitis Research and Treatment Center at University of Southern California, Los Angeles, CA DisclaimerThe materials published on the iMedOptions Web site reflect the views of the authors, not those of iMedOptions LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials. http://clinicaloptions.com/hepatitis

  3. New Agents for the Treatment of HCV http://clinicaloptions.com/hepatitis

  4. New Agents for the Treatment of HCV • New Versions of Current Drugs • Viramidine (prodrug of ribavirin) • Preferentially taken up by the liver • Lower levels of ribavirin in the peripheral circulation http://clinicaloptions.com/hepatitis

  5. Use of Viramidine in Chronic Hepatitis C 24 Wks (genotype 2/3) 48 Wks (genotype 1/4/5/6) • Open-label phase 2 study Viramidine 400 mg BID + PegIFN 180 μg/wk (n = 47) Viramidine 600 mg BID + PegIFN 180 μg/wk (n = 43) Chronic HCV, treatment naiveStratified by genotype (N = 180) Follow-up for 24 wks after end of treatment Viramidine 800 mg BID + PegIFN 180 μg/wk (n = 45) RBV 1000/1200 mg QD + PegIFN 180 μg/wk(n = 45) Gish RG, et al. AASLD 2004. Abstract 519. http://clinicaloptions.com/hepatitis

  6. 400 600 800 1000-1200 400 600 800 1000-1200 Viramidine (mg BID) RBV (mg QD) Viramidine (mg BID) RBV (mg QD) Use of Viramidine in Chronic Hepatitis C • EOT response with viramidine comparable with RBV • Anemia significantly ↓ with viramidine compared with RBV 27 30 100 *P < .01 vs RBV 25 80 63 62 20 55 56 60 Patients with Hemoglobin < 10g/dL (%) Patients Achieving End-of-Treatment Response (%) 15 11 40 10 * * 20 2 5 0 0 0 Gish RG, et al. AASLD 2004. Abstract 519. http://clinicaloptions.com/hepatitis

  7. New Agents for the Treatment of HCV • New Versions of Current Drugs • Viramidine (prodrug of ribavirin) • Preferentially taken up by the liver • Lower levels of ribavirin in the peripheral circulation • Albumin-interferon alpha (fusion polypeptide) • Antiviral effects of interferon alfa • Long plasma half-life of albumin http://clinicaloptions.com/hepatitis

  8. Use of Albumin-Interferon Alpha in the Treatment of HCV • Phase 1/2, open-label, dose-escalation study enrolling 199 patients who received 1 dose ranging from 7 to 900 µg • Patients treated with 1 injection or 2 injections 14 days apart • 92% genotype 1 • All had failed interferon therapy • 47% of 78 patients given 120 to 900 μg had > 1 log reductions • Adverse events mild and transient • Pharmacokinetic data • Reduced clearance and extended half-life • Support every 2- to 4-wk dosing • May allow less frequent dosing than peginterferon Balan V, et al. AASLD 2004. Abstract 265. http://clinicaloptions.com/hepatitis

  9. New Agents for the Treatment of HCV • New Versions of Current Drugs • Viramidine (prodrug of ribavirin) • Preferentially taken up by the liver • Lower levels of ribavirin in the peripheral circulation • Albumin-interferon alpha (fusion polypeptide) • Antiviral effects of interferon alfa • Long plasma half-life of albumin • New Classes of Drugs • NM283 • Experimental oral NS5b polymerase inhibitor • Activity against flaviviruses in vitro and in HCV-infected chimps http://clinicaloptions.com/hepatitis

  10. Use of NM283 in Genotype 1 HCV • Approximately 60% of patients with HCV genotype 1 do not achieve SVR with current therapy • First human dose-escalation study involving sequential cohorts exposed to increasing NM283 doses (50-800 mg) • 8 cohorts randomized to NM283 or placebo for 15 days • 95 HCV genotype 1-infected adults aged 18-65 years with • Compensated, noncirrhotic liver disease by prior liver biopsy • ALT < 5 x ULN and serum HCV RNA > 5 log10 copies/mL • 87% prior nonresponders to IFN treatment • 13% treatment naive Afdhal N, et al. AASLD 2004. Abstract LB-03. http://clinicaloptions.com/hepatitis

  11. Use of NM283 in Genotype 1 HCV 0.2 Placebo 0 50 mg QD 100 mg QD -0.2 200 mg QD -0.4 400 mg QD Mean HCV RNA Change from Baseline (log10 copies/mL) 200 mg BID -0.6 Dose Titration 100-800 mg -0.8 Dose Titration 400-800 mg + Antiemetic -1.0 800 mg QD -1.2 Treatment Period 1 2 3 4 5 8 11 15 16 17 22 Study Day Afdhal N, et al. AASLD 2004. Abstract LB-03. http://clinicaloptions.com/hepatitis

  12. Preliminary phase 2a trial of NM283 ± PegIFN alfa-2b 30 treatment-naive HCV genotype 1 pts randomized to Escalating dose (400 mg, 600 mg, 800 mg) of NM283 alone Escalating NM283 dose + PegIFN alfa-2b (1 μg/kg) on Days 8, 15, and 22 Superior response observed with combination therapy 9/12 given combination had > 2 log10 reduction at 4 wks 0 -0.4 -0.7 -0.8 -1.2 -1.6 -2.0 -2.4 -2.8 -2.7 NM 283 + Peg-IFN 2b NM283 + PegIFN NM283 Mean HCV Change from Baseline (log10 copies/mL) 0 4 8 12 16 20 24 28 Study Day 400 600 800 mg NM283 QD Peg-IFNa-2b Dosing Afdhal N, et al. AASLD 2004. Abstract LB-03. http://clinicaloptions.com/hepatitis

  13. Treatment of Genotype 1 HCV http://clinicaloptions.com/hepatitis

  14. 48 wks 72 wks 72-wk Peg-IFN + RBV for HCV Genotype 1 • Extending pegIFN alfa-2a + ribavirin from 48 to 72 wks • Similar SVR rates in unselected cohort of HCV infected pts • ↑ SVR, ↓ relapse rate in pts without rapid virologic response Unselected Population [1] HCV RNA positive pts at Wk 4 [2] 100 100 72 67 61 52 53 52 45 50 50 Patients (%) Patients (%) 32 0 0 EOT SVR EOT SVR 1. Berg T, et al. AASLD 2004. Abstract 169. 2. Sanchez-Tapias JM, et al. AASLD 2004. Abstract 126. http://clinicaloptions.com/hepatitis

  15. P = .006 P = .004 Weight-Based Ribavirin Dosing in Blacks Infected With HCV Genotype 1 • WIN-R: randomized, multicenter trial involving more than 5000 patients • 387 blacks infected with HCV genotype 1 randomized to PegIFN2b (1.5 μg/kg/wk) + • Fixed-dose (STD) RBV • Weight-based (WB) RBV • 800-1400 mg/day • WB RBV associated with • Higher likelihood of SVR • Higher rates of anemia • 47% vs 29% • Not treatment limiting 100 STD n = 188 WB n = 174 80 60 Patients with undetectable HCV RNA (%) 40 29 21 16 10 20 0 EOT SVR Jacobson I, et al. AASLD 2004. Abstract 125. http://clinicaloptions.com/hepatitis

  16. Treatment of Genotypes 2 and 3 HCV http://clinicaloptions.com/hepatitis

  17. Optimal Treatment for Genotypes 2 and 3 • Retrospective analysis from 2 randomized, prospective, multicenter, phase 3 studies • Patients treated with peginterferon alfa-2a (180 g/wk) plus • 800 mg/day RBV for 24 weeks • 800 mg/day RBV for 48 weeks • 1000-1200 mg/day RBV for 24 weeks • 1000-1200 mg/day RBV for 48 weeks • SVR rates in 4 groups were not significantly different Rizzetto M, et al. AASLD 2004. Abstract 198. http://clinicaloptions.com/hepatitis

  18. EOT SVR 94% 79% 85% 75% 71% 29% 16-Wk vs 24-Wk Therapy for Genotypes 2/3 • A nonrandomized study also presented showed that 90% of patients with untreated genotype 2/3 HCV achieved SVR after 14 weeks of PegIFN 2b + RBV [2] • Randomized, multicenter study [1] 16-wk treatment (n = 71) Wk 4 HCV RNA (-) 24-wk treatment (n = 69) Untreated pts with HCV genotype 2 or 3 (N = 153) Peginterferon alfa-2a (180 g/wk) + Ribavirin 800-1200 mg/day 24-wk treatment (n = 13) HCV RNA (+) 1. von Wagner M, et al. AASLD 2004. Abstract LB-02. 2. Dalgard O, et al. AASLD 2004. Abstract 197. http://clinicaloptions.com/hepatitis

  19. Treatment of Acute HCV http://clinicaloptions.com/hepatitis

  20. Peginterferon alfa-2b in Acute HCV • Patients in early phase of acute HCV infection at high risk of spreading infection • 6 months of standard IFN reduces chronic infection rate • Efficacy of 3 months of peginterferon alfa-2b now evaluated • 43 patients enrolled in Italian, multicenter, open-label trial Calleri G, et al. AASLD 2004. Abstract 38. http://clinicaloptions.com/hepatitis

  21. Peg-IFN vs IFN + RBV in Acute HCV • 63 asymptomatic patients with acute genotype 1 or 4 HCV without spontaneous recovery enrolled • 12 or 24 wks of • PegIFNa-2b (1.5 mg/kg/wk) • IFNa-2b (3 MIU, 3x/wk) + RBV (1-1.2 mg/day) • Treatment began at 8, 12, or 20 wks • PegIFN superior to standard IFN + RBV • Earlier treatment initiation leads to ↑ SVR rate 12 wks 24 wks P = .05 P = .01 P = .02 100 80 60 Patients with SVR (%) 40 20 n= 5 6 5 5 4 5 5 5 5 5 5 5 0 IFN + RBV Peg- IFN IFN + RBV Peg- IFN IFN + RBV Peg- IFN Wk 8 onset Wk 12 onset Wk 20 onset Sanaa M, et al. AASLD 2004. Abstract 37. http://clinicaloptions.com/hepatitis

  22. Treatment of Nonresponders http://clinicaloptions.com/hepatitis

  23. Daily Consensus IFN + RBV in Nonresponders to Standard IFN + RBV Chronic HCV nonresponders to combination therapy (n = 120) End-of-treatment response Sustained response 100 80 CIFN (18 mg QD) CIFN (27 mg QD) 60 Patients (%) Wk 4 40 CIFN (9 mg QD) CIFN (18 mg QD) 20 Wk 12 0 CIFN (9 mg QD) + RBV (by weight) CIFN (9 mg QD) + RBV (by weight) CIFN (27/18 mg) + RBV CIFN (18/9 mg) + RBV Wk 48 Kaiser S, et al. AASLD 2004. Abstract 173. http://clinicaloptions.com/hepatitis

  24. Side Effects of HCV Infection and Treatment http://clinicaloptions.com/hepatitis

  25. Patients with chronic HCV often experience fatigue Ondansetron decreases fatigue in patients with chronic fatigue syndrome Effects on chronic HCV-related fatigue unknown HCV-infected, untreated pts with fatigue randomized to Ondansetron 4 mg BID Placebo Ondansetron significantly improved fatigue and depression Ondansetron Reduces Fatigue Ondansetron (n = 18) 160 Placebo (n = 18) 140 120 * 100 Mean (+/- SEM) Fatigue Impact Scale Total Score 80 60 ** 40 ** ** * P < .05 vs D0 20 Treatment ** P < .01 vs D0 0 0 15 30 60 Days Piche T, et al. AASLD 2004. Abstract 354. http://clinicaloptions.com/hepatitis

  26. Predicting Ribavirin-Associated Anemia in Transplant Patients • Best multivariate baseline predictor of RBV discontinuation in liver transplant recipients with HCV recurrence • RBV Anemia Risk Score for Hemoglobin/(CrCL/weight) • Concordance 0.73 (P = .0007) Hassan M, et al. AASLD 2004. Abstract 452. http://clinicaloptions.com/hepatitis

  27. Effects of Antiviral Therapy on Portal Hypertension http://clinicaloptions.com/hepatitis

  28. Low-dose PegIFN Decreases Risk of Variceal Bleeding • COPILOT (Colchicine vs PEG-IFN Long Term) Study • Randomized, controlled, multicenter, 2-year interim analysis • Patients with advanced fibrosis or cirrhosis who had failed interferon-based therapy • Clinical outcome at 2 years Afdhal N, et al. AASLD 2004. Abstract 171. http://clinicaloptions.com/hepatitis

  29. Antiviral Therapy Improves Portal Vein Pressure • Prospective study of 18 chronic HCV patients treated with PegIFN alfa-2b (1.5 g/kg/wk) + RBV (800-1200 mg/day) • Stage 3/4 fibrosis (METAVIR) • Hepatic venous pressure gradient (HVPG) > 5 mm Hg • Clinically compensated disease • Compared with 30 untreated controls • Mean % HVPG change • Treated -21 ± 27% vs untreated +33 ± 12% • Absolute HVPG reduction in treated patients • 3.6 ± 3.5 mm Hg (P < .001) • HVPG improvement seen in responders and nonresponders Rincon D, et al. AASLD 2004. Abstract 189. http://clinicaloptions.com/hepatitis

  30. Potential Mechanism of Interferon Resistance http://clinicaloptions.com/hepatitis

  31. Hyperinsulinemia Diminishes Antiviral Capacity of Interferon • Obesity and fatty liver in HCV infection associated with metabolic syndrome and failure of IFN treatment • Impact of insulin level on IFN antiviral activity examined • HCV replicon (hepatoma cell line stably expressing HCV RNA) • IFN resulted in rapid, sharp, stable decrease in HCV RNA • IFN induced PKR and IRF-1 protein expression • Insulin prevented IFN-mediated HCV suppression • Effects of insulin (100 µU/mL) mediated through PI3K pathway • Insulin blocked interferon-stimulated phosphorylation of 3 JAK-STAT pathway molecules Sanyal AJ, et al. AASLD 2004. Abstract 39. http://clinicaloptions.com/hepatitis

  32. Diagnosing Fibrosis http://clinicaloptions.com/hepatitis

  33. Background • Liver biopsy is the standard approach for assessment of HCV-related histologic lesions • Limited by sampling error (33% discordance) • Limited by risk of adverse events • FibroTest and transient elastography (FibroScan) are noninvasive alternatives to liver biopsy • FibroTest evaluates serologic markers of fibrosis • α2-macroglobulin, apolipoprotein A1, haptoglobin, γ-glutamyl-transpeptidase, and total bilirubin levels • Transient elastography measures liver stiffness http://clinicaloptions.com/hepatitis

  34. FibroScan vs FibroTest • Liver stiffness measurements by FibroScan comparable to use of serologic markers for detecting fibrosis in chronic hepatitis C patients • Combination of FibroScan + serologic markers may be a reasonable alternative to liver biopsy in most HCV patients APRI, AST to platelet ratio index; AUROC, area under the receiver operating characteristic curve Castera L, et al. AASLD 2004. Abstract 1183. http://clinicaloptions.com/hepatitis

  35. HCV/HIV-Coinfected Patients http://clinicaloptions.com/hepatitis

  36. PegIFN + RBV in HIV/HCV coinfection • Faster liver disease progression in HCV/HIV-coinfected patients vs monoinfected patients • Greater morbidity and mortality from liver disease • Should treat HCV aggressively • 3 randomized controlled trials in HCV/HIV-coinfected patients • Better SVR with PegIFN + RBV vs standard IFN + RBV 1. Chung RT, et al. N Engl J Med. 2004;351:451-459. 2. Torriani FJ, et al. N Engl J Med. 2004;351:438-450. 3. Pol S, et al. AASLD 2004. Abstract 351. http://clinicaloptions.com/hepatitis

  37. Death and Cirrhosis Rates in HCV Monoinfected vs Coinfected Patients • Prospective cohort study in HAART era (since 1997) • Deaths and cirrhosis occur with a similar frequency in monoinfected and HCV/HIV-coinfected patients Monto A, et al. AASLD 2004. Abstract 1212. http://clinicaloptions.com/hepatitis

  38. For a unique and easy-to-use comprehensive overview of AASLD, visithttp://clinicaloptions.com/AASLD • Get Expert Analyses, Capsule Summaries and Free Powerpoint slides on the following topics: • Treatment of HBV • Treatment of HCV • Epidemiology and Prevention • Side Effects and Treatment of HIV Coinfection • Diagnostics and New Drugs • Free, online CME credits Available http://clinicaloptions.com/hepatitis

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