Hepatitis C Nut and Bolts (2008) - Nevah-Rubin, Ilan

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Hepatitis C Nut and Bolts (2008) - Nevah-Rubin, Ilan

  1. 1. Hepatitis C
  2. 2. Characteristics RNA virus + sense 9.6 Kb in length Flaviviridae -> hepaciviridae -> HCV
  3. 4. HCV, HBV, HIV: Prevalence vs Undiagnosed Cases * Extrapolated from small population study. 1. American Liver Foundation. Hepatitis C Factsheet . Available at: www.liverfoundation.org. Accessed May 11, 2007. 2. NIAID. HIV Infection and AIDS: An Overview . 2005. Available at: www.niaid.nih.gov. Accessed May 14, 2007. 3. Lok A, et al. Hepatology . 2004;39:1-5. 4. Thompson MJ, et al. J Cancer Educ . 2002;17:222-226. * 3.5 M 2.5 M 1.5 M .5 M 0
  4. 5. Statistics <ul><li>170 Million infected worldwide </li></ul><ul><li>2.7-3 Million active infection nationwide </li></ul><ul><li>High medical costs - $600 Million </li></ul><ul><li>30K New infections/year </li></ul><ul><li>10K Deaths/year </li></ul><ul><li>Most important causes of Liver Disease </li></ul><ul><li>OLT </li></ul>
  5. 6. HCV Genotypes <ul><li>Hepatitis C virus </li></ul><ul><ul><li>RNA virus–high mutation rates </li></ul></ul><ul><ul><li>Evolved different genotypes </li></ul></ul><ul><li>6 known genotypes </li></ul><ul><ul><li>Genotype 1 (75%) </li></ul></ul><ul><ul><li>Genotype 2 (10%) </li></ul></ul><ul><ul><li>Genotype 3 (10%) </li></ul></ul><ul><li>The above 3 are the most common in the United States </li></ul><ul><li>Little difference in mode of transmission or natural history of infection among different genotypes </li></ul>Flamm SL. JAMA. 2003;289:2413-2417 . Distribution of HCV Genotypes 75% 10% 10% 5% Genotype 1 Genotype 2 Genotype 3 Other
  6. 7. Prevalence of HCV in Select Populations Alcoholics ~240,000 (11%–36%)5 HIV-infected ~300,000 (30%) 4 Living below poverty level ~940,000 (2.4%) 6 Incarcerated ~330,000 to 860,000 (16%–41%)1 Veterans ~280,000 (8%) 8 IDU ~300,000 (80%–90%)2,3 Homeless ~175,000 (22%) 7 Children (6 – 18 years old) ~100,000 (.1%) 9 <ul><li>Adapted from the following: </li></ul><ul><li>CDC. MMWR. 2003;52(RR-1):1-33. 2. Edlin B. Hepatol. 2002;36(5 suppl 1):S210-219. 3. NHSDA Report 2003. 4. Poles M, et al. Clin Infect Dis . 2000;31:154-161. 5. LaBrecque D, et al: Hepatitis C Choices . 2002:7-15. 6. Alter M, et al. N Engl J Med . 1999;341:556-562. 7. Nyamathi A, et al. J Gen Intern Med . 2002;17:134-143. 8. Bräu N, et al. Am J Gastroenterol . 2002;97:2071-2078. 9. Jonas M. Hepatol . 2002;36(5 suppl 1):S173-S178. 10. Armstrong GL, et al. Ann Intern Med. 2006;144:705-714. </li></ul>
  7. 8. Prevalence of HCV in Racial/Ethnic Populations <ul><li>Adapted from the following: </li></ul><ul><li>Armstrong GL, et al. Ann Intern Med . 2006;144:705-714. </li></ul><ul><li>US Census Bureau. Available at:: www.census.gov. Accessed March 21, 2007. </li></ul>In 2005, it was estimated that over 41 million Latinos lived in the United States. The Latino population is a diverse population. US census data show that the Latino population consists of nearly 64% Mexican Americans. 2 * * P < 0.005 for comparison with reference group (Non-Hispanic White) 1 1.5% 3% 1.3% 0 1 2 3 4 5 Prevalence of Antibodies to HCV Prevalence of Antibodies to HCV (%) Non-Hispanic White Non-Hispanic Black Mexican American
  8. 9. Hepatitis C Virus Infection Prevalence by Age 0 1.0 2.0 3.0 4.0 5.0 < 11 11-19 20-29 30-39 40-49 50-59 60-69 ≥ 70 Age Group Anti-HCV Positive (%) Alter MJ, et al. N Eng J Med. 1999;341:556-562 .
  9. 11. HCV replication and infection Adapted from Pawlotsky JM, Gish RG. Antivir Ther 2006;11:397-408
  10. 12. Hepatitis C Virus Fate of Acute Infection 15% Chronic 85% Spontaneous resolution Alter MJ, et al. N Eng J Med. 1999;341:556-562 .
  11. 13. Natural History
  12. 14. Hepatitis C Virus Infection Natural History Stable 80% (68%) HCC Liver failure 25% (4%) Slowly progressive 75% (13%) Resolved 15% (15%) Acute HCV Cirrhosis 20% (17%) Chronic HCV 85% (85%) ETOH HIV Fe Hepatic viruses
  13. 15. Hepatitis C Virus Infection Population at Risk <ul><ul><li>Ever injected illegal drugs / intranasal cocaine use </li></ul></ul><ul><ul><li>Tattoo and Body piercing </li></ul></ul><ul><ul><li>Received clotting factors made before 1987 </li></ul></ul><ul><ul><li>Received blood/organs before July 1992 </li></ul></ul><ul><ul><li>Ever on chronic hemodialysis </li></ul></ul><ul><ul><li>Evidence of liver disease </li></ul></ul><ul><ul><li>Incarceration </li></ul></ul><ul><ul><li>Healthcare, emergency, public safety workers after needle stick/mucosal exposures to HCV-positive blood </li></ul></ul><ul><ul><li>Children born to HCV-positive women </li></ul></ul>Centers for Disease www.cdc.gov/ncidod/diseases/hepatitis/c/fact.htm Control and Prevention. Hepatitis C fact sheet.
  14. 16. Testing Strategies for HCV RF for HCV and/or Abn LFT’s Anti HCV (EIA) testing < 5% Chance of HCV Prior exposure to HCV HCV VL + Genotype RIBA NO HCV Exposed + Cleared Refer for evaluation and Tx. NO HCV HCV VL + Genotype positive negative
  15. 17. Hepatitis C Virus Diagnostic Testing Diagnostic Test Type Confirmation Screening Use 2-6 weeks 2-6 months Detection postexposure > 98% Variable Specificity > 98% > 95% Sensitivity Virus Virologic Antibodies Mode of detection Serologic Specifications
  16. 18. <ul><li>False positives </li></ul><ul><ul><li>Autoimmune disorders </li></ul></ul><ul><ul><li>Spontaneous resolution of viral infection </li></ul></ul><ul><li>False negatives </li></ul><ul><ul><li>Chronically immune suppressed </li></ul></ul><ul><ul><li>Transplant recipients </li></ul></ul><ul><ul><li>Chronic renal failure on dialysis </li></ul></ul><ul><ul><li>HIV positive </li></ul></ul>HCV Antibody Testing Limitations
  17. 19. Physical Exam <ul><li>Non Specific (Malaise / Weakness) </li></ul><ul><li>Chronic liver disease </li></ul><ul><ul><li>Palmar Erythema Temporal Wasting </li></ul></ul><ul><ul><li>Gynecomastia Spider Angiomas </li></ul></ul><ul><ul><li>Caput Medussa Dupuytren’s contracture </li></ul></ul><ul><ul><li>Clubbing Asterixis </li></ul></ul><ul><ul><li>Icterus Enlarged Parotid </li></ul></ul><ul><ul><li>Testicular atrophy HSM </li></ul></ul>
  18. 20. Extrahepatic Manifestations <ul><li>Autoimmune / Rheumatological </li></ul><ul><ul><li>Mixed Cryoglobulinemia, Sj ö gren and Arthritis </li></ul></ul><ul><li>Hematological </li></ul><ul><ul><li>NHL </li></ul></ul><ul><li>Endocrinological </li></ul><ul><ul><li>Thyroid and DM </li></ul></ul><ul><li>Dermatological </li></ul><ul><ul><li>PTC and Lichen Planus </li></ul></ul>
  19. 21. Laboratory Evaluation <ul><li>CBC </li></ul><ul><li>BMP </li></ul><ul><li>LFT’s </li></ul><ul><li>TFT’s </li></ul><ul><li>HIV </li></ul><ul><li>Viral Hepatitis </li></ul><ul><li>Genotype </li></ul><ul><li>Viral Load </li></ul><ul><li>Liver Biopsy </li></ul><ul><li>A1C </li></ul><ul><li>Hemochromatosis (Fe Studies) </li></ul><ul><li>A1-AT </li></ul><ul><li>Wilson’s Dz </li></ul><ul><li>Autoimmune </li></ul><ul><ul><li>ANA, RF, AMA </li></ul></ul>
  20. 22. Hepatitis C Virus Infection Liver Biopsy <ul><li>Only test that can accurately assess </li></ul><ul><ul><li>Severity of inflammation </li></ul></ul><ul><ul><li>Degree of fibrosis </li></ul></ul><ul><li>Determines the following </li></ul><ul><ul><li>Risk for developing cirrhosis in future </li></ul></ul><ul><ul><li>Need for therapy </li></ul></ul><ul><ul><li>Need for ongoing therapy when initial treatment has failed </li></ul></ul>
  21. 23. Liver Biopsy (Metavir)
  22. 24. Who to treat? Innocent until proven guilty Treatment until proven otherwise
  23. 25. Who to treat? <ul><li>Age 18 </li></ul><ul><li>Liver Enzyme elevation </li></ul><ul><li>Liver Biopsy (Stage dependant ?) </li></ul><ul><li>Compensated Liver Disease (Tbili, INR, Alb, Plt, HE, Ascites) </li></ul><ul><li>Hematologic parameters (Hb, WBC, Cr) </li></ul><ul><li>Controlled depression </li></ul>
  24. 26. Who NOT to treat? <ul><li>Major/Uncontrolled depressive disorder </li></ul><ul><li>Renal/Lung/Heart Transplant </li></ul><ul><li>Autoimmune Hepatitis </li></ul><ul><li>Uncontrolled hyperthyroidism </li></ul><ul><li>Pregnant – Unwilling to go contraception </li></ul><ul><li>Age under 3 </li></ul><ul><li>Hypersensitivity </li></ul><ul><li>Severe Disease: HTN, CHF, CAD, DM, COPD </li></ul>
  25. 27. Goals of Treatment <ul><li>Sustained Virological Response </li></ul><ul><li>Prevent the progression of Cirrhosis </li></ul><ul><li>Reduce Risk of HCC </li></ul>
  26. 28. Factors Associated With SVR <ul><li>Pretreatment or fixed </li></ul><ul><li>Genotype </li></ul><ul><li>HCV RNA level </li></ul><ul><li>Histology </li></ul><ul><li>Race </li></ul><ul><li>HIV coinfection </li></ul><ul><li>Steatosis / IR? </li></ul><ul><li>Body weight </li></ul><ul><li>Adherence </li></ul><ul><li>Dynamic factors </li></ul><ul><li>Rapid virologic response (HCV RNA negative at Wk 4) </li></ul><ul><li>Early virologic response </li></ul><ul><ul><li>Partial (HCV RNA decline of > 2 logs at Wk 12) </li></ul></ul><ul><ul><li>Complete (HCV RNA negative at Wk 12) </li></ul></ul>
  27. 29. SVR in Patients Who Achieved an RVR 90 282 257 9 GT 1 GT 2 GT 3 GT 4 100 86 86 88 Patients With an RVR RVR: HCV RNA negative (< 50 IU/mL) at Wk 4 Fried MW, et al. EASL 2008. Abstract 7. 0 20 40 60 80 100 SVR (%) n =
  28. 30. Calculating a Cure: Pretreatment Characteristics <ul><li>Likelihood of SVR depends on interactions of multiple factors </li></ul><ul><li>Can individual probabilities of SVR be estimated? </li></ul><ul><li>Data from 2 registration trials of pegIFN-2a + RBV used to identify important factors related to SVR </li></ul><ul><li>Modeling used to vary important baseline characteristics </li></ul>Foster GR, et al. Scand J Gastroenterol. 2007;42:247-255.
  29. 31. Everyone Is Special Probability of Achieving an SVR 100 80 60 40 20 0 Patients Number 1 2 3 4 5 6 7 8 97 89 74 52 36 19 14 7 Foster GR, et al. Prediction of sustained virological response in chronic hepatitis C patients treated with peginterferon alfa-2a (40KD) and ribavirin. Scandinavian Journal of Gastroenterology. 2007;42(2):247-255. 9000 9000 9000 9000 1200 40 40 40 HCV RNA, IU/mL x 10 3 30 30 30 26 26 26 20 20 BMI 20 2 No 60 2 No 20 7 No 43 2 No 60 1 Yes 60 43 43 Age in years 1 2 2 ALT quotient No No No Cirrhosis
  30. 32. Genotype 1/4 VS. Pegasys 180 mcg/week Copegus 1000 / 1200 mg/day (75kg) PEG-intron 1.5 mcg/Kg/week Rebetol 1000 / 1200 mg/day (75kg)
  31. 33. Genotype 2/3 VS. Pegasys 180 mcg/week Copegus 800 mg/day PEG-intron 1.5 mcg/Kg/week Rebetol 800 mg/day
  32. 34. Current Therapy of Hepatitis C <ul><li>Based on HCV genotype </li></ul><ul><li>Genotype 1 </li></ul>48 weeks PEG IFN alpha 2a 180 ug per week and RBV 1000-1200mg per day OR PEG IFN alpha 2b 1.5ug/kg per week and Ribavirin 800-1400mg/day <ul><li>Genotype 2 or 3 </li></ul>24 weeks PEG IFN alpha 2a or 2b and Ribavirin 800mg/day
  33. 35. Definition: Viral Responses <ul><li>Sustained Virological Response (SVR) </li></ul><ul><li>End of Treatment Response (ETR) </li></ul><ul><li>Non-Responders (NR) </li></ul><ul><ul><li>Breakthrough and Null responders </li></ul></ul><ul><li>Relapser (R) </li></ul><ul><li>Rapid Virological Response (RVR) – 4wk </li></ul><ul><li>Early Virologcal Response (EVR) – 12wk </li></ul><ul><ul><li>cEVR </li></ul></ul><ul><ul><li>pEVR </li></ul></ul>
  34. 36. Definition: Viral Responses RVR cEVR pEVR 4 12 24 48 72 NR BT ETR SVR Rel >2log ↓ Undetectable HCV RNA <50IU/ml
  35. 37. Efficacy of current HCV combination therapy by genotype 1. Hadziyannis SJ, et al. Ann Intern Med 2004;140:346-355; 2. Fried MW, et al. N Engl J Med 2002;347:975-982; 3. Manns MP, et al. Lancet 2001;358:958-965; 4. Zeuzem S, et al. J Hepatol 2004;40:993-999 1 2 or 3 42–52% response rate 1–3 Genotype 76–93% response rate 1–4
  36. 38. Current Therapy of Hep C ?
  37. 39. Rapid Virologic Response (RVR) Ferenci P, et al. J Hepatol . 2005;43:425 . Patients with SVR (%) HCV RNA Status Week 4 Negative ≥2 log  <2 log  ≥2 log  <2 log  Week 12 Negative Negative Negative ≥2 log  ≥2 log  Week 24 Negative Negative Negative Negative Negative PEG IFN  -2a 180 mg + RBV 1000–1200 mg 91 72 60 48 43 0 20 40 60 80 100 *Negative predictive value = 74%; positive predictive value = 75%. 91 90 90 90 65 ETR SVR
  38. 40. Slow-to-Respond Patients: Extending Therapy RBV dose (mg/day) = Berg 800 Sanchez-Tapias 800 Ferenci 1000-1200 33 16 31 46 44 77 0 20 40 60 80 100 SVR (%) Berg T, et al. Gastroenterology. 2006;130:1086-1097. Sanchez-Tapias JM, et al. Gastroenterology. 2006;131:451-460. Ferenci P, et al. AASLD 2006. Abstract 390. 72 weeks 48 weeks
  39. 41. SVR rate 72 wks treatment in G1 pts with pEVR <ul><li>PegIFN alfa-2b 1.5 µg/kg/wk + RBV 800-1400 mg/day </li></ul><ul><li>HCV RNA positive at Wk 12 but HCV RNA negative at Wk 24 (N = 101 slow responders) </li></ul><ul><li>Continued treatment through 48 vs 72 wks </li></ul><ul><li>Baseline characteristics </li></ul><ul><ul><li>48% black </li></ul></ul><ul><ul><li>78% high HCV RNA </li></ul></ul><ul><ul><li>26% F3/4 fibrosis </li></ul></ul><ul><ul><li>34% BMI > 30 </li></ul></ul><ul><ul><li>18% high fasting glucose </li></ul></ul>Pearlman BL, et al. Hepatology. 2007;46:1688-1694.
  40. 42. SVR rate 72 wks treatment in G1 pts with pEVR Pearlman BL, et al. Hepatology. 2007;46:1688-1694. Response, % 48 Wks 72 Wks P Value EOT 45 48 NS SVR 18 38 .03 Relapse 59 20 .004 Treatment cessation 14 15 NS
  41. 43. ACCELERATE Trial: SVR G2/3 Pts With and Without an RVR Shiffman ML, et al. N Engl J Med. 2007;357:124-134. Patients infected with HCV genotype 2/3 (N = 1291) RVR: yes 67% (871 / 1291) SVR 378/461 370/410 55/205 105/215 0% 20% 40% 60% 80% 100% 0% 20% 40% 60% 80% 100% SVR 82% 27% 49% 90% 16 wks 24 wks 16 wks 24 wks RVR: no 33% (420 / 1291)
  42. 44. Influence of Cumulative RBV: Wks 1-12 on SVR in G1 Reddy KR, et al. AASLD 2005. Abstract 596. Cumulative RBV Exposure (Wks 1-12) SVR (%) 0 20 40 100 66 57 62 45 425 < 60% 60% to 79% 80% to 96% ≥ 97% Total 80 60 n = 325 56 44 0
  43. 45. Discontinuing RBV on G1 Patients Responding to Therapy *HCV RNA – negative (< 50 IU/L) patients at Week 24 randomized to continue treatment with/without RBV at Week 26. Bronowicki J, et al. Gastroenterology. 2006;131:1040-1048. PegIFN alfa-2a 180 µg/wk + RBV 800 mg/day (n = 173) PegIFN alfa-2a 180  g/wk + RBV 800 mg/day (N = 516) PegIFN alfa-2a 180 µg/wk (n = 176) Week 26 Follow-up Week 24: HCV RNA negative* Week 48 Week 72
  44. 46. Discontinuing RBV oif n Patients Responding to Therapy: SVR Bronowicki J, et al. Gastroenterology. 2006;131:1040-1048. Outcome % Treatment During Last 24 Wks P Value PegIFN alfa-2a + RBV (n = 173) PegIFN alfa-2a (n = 176) SVR (ITT) 68.2 52.6 .004 SVR (PP) 71.5 56.7 .006
  45. 47. Complication / Side Effect <ul><li>PEG-Interferon alfa 2 a/b </li></ul><ul><ul><li>Flu-like symptoms </li></ul></ul><ul><ul><li>Depression / Mood instability </li></ul></ul><ul><ul><li>Cytopenias (WBC / Plt) </li></ul></ul><ul><ul><li>Thyroid (hypo / hyper) </li></ul></ul><ul><ul><li>Alopecia </li></ul></ul><ul><ul><li>Nausea / Vomiting /Abdominal pain </li></ul></ul><ul><li>Ribavirin </li></ul><ul><ul><li>Hemolytic anemia </li></ul></ul><ul><ul><li>Rash </li></ul></ul>
  46. 48. Non-Responder / Relapser <ul><li>New Molecules (STAT-C) </li></ul><ul><li>Clinical Trials </li></ul><ul><li>Retreatment with different PEG molecule </li></ul><ul><li>Infergen (Consensus IFN)? </li></ul><ul><li>Induction Therapy? </li></ul>
  47. 49. Future Therapies <ul><li>Viral Entry Inhibitors </li></ul><ul><ul><li>HC Ig. and Monoclonal Ab. </li></ul></ul><ul><li>HCV RNA Translation Inh. </li></ul><ul><li>Post Translational Processing Inh. </li></ul><ul><ul><li>NS3-4A Serine Proteinase Inh. </li></ul></ul><ul><li>HCV Replication Inhibitors </li></ul><ul><ul><li>NS5B Polymerase Inh, Cyclophilin B Inh, NS5A Inh, Helicase Inh </li></ul></ul><ul><li>Virus Assembly and Release Inh </li></ul>
  48. 50. Targets for New Treatments 1) Virus Entry 2) Uncoating 3) Protein Synthesis 4) Cleavage 5) RNA Replication 6) Packaging 7) Maturation 8) Re-infection Adapted from: Pawlotsky JM, Gish RG. Future therapies for Hepatitis C. Antivir Ther. 2006;11:397-408.
  49. 51. <ul><li>Randomized, placebo-controlled, phase II trial </li></ul>PROVE 1: Telaprevir + PegIFN/RBV in Naive HCV GT1 TVR + PegIFN alfa-2a + RBV (n = 79) PegIFN alfa-2a + RBV TVR + PegIFN alfa-2a + RBV (n = 79) TVR + PegIFN alfa-2a + RBV (n = 17) PegIFN alfa-2a + RBV Treatment-naive patients infected with HCV genotype 1* (N = 250) Week 12 * Patients received TVR 1250-mg loading dose followed by 750 mg every 8 hrs or placebo based on the arm to which they were randomized. † Patients must achieve undetectable HCV RNA at Week 4 (< 10 IU/mL) and at last test before stopping therapy at 12 or 24 weeks. Week 24 Week 48 24-week † follow-up 24-week † follow-up Placebo + PegIFN alfa-2a 180  g/wk + RBV 1000/1200 mg QD (n = 75) EOT EOT SVR SVR McHutchison J, et al. EASL 2008. Abstract 4.
  50. 52. PROVE 1: Response Rates (ITT) *HCV RNA < 10 IU/mL. † P = .001 vs pegIFN/RBV/placebo 48 weeks. ‡ P = .02 vs pegIFN/RBV/placebo 48 weeks. ¶ Only subjects who met the RVR criterion and stopped at 12 or 24 total weeks of treatment. § Relapse denominator is the number of subjects with undetectable HCV RNA at completion of assigned treatment duration. McHutchison J, et al. EASL 2008. Abstract 4. Treatment, % Week 4 Undetectable* Week 12 Undetectable* SVR Relapse (n/N) § PegIFN/RBV/placebo 48 wks (n= 75) 11 45 41 23 (8/35) TVR/PegIFN/RBV 12 wks  pegIFN/RBV 36 wks (n = 79) 81 80 67 † 6 (3/51) TVR/pegIFN/RBV 12 wks  pegIFN/RBV 12 wks ¶ (n = 79) 81 68 61 ‡ 2 (1/41) TVR/pegIFN/RBV 12 wks ¶ (n = 17) 59 71 35 33 (3/9)
  51. 53. PROVE 1: AEs Associated With TVR <ul><li>Gastrointestinal events, skin events (rash, pruritus), and anemia more frequent in TVR treatment arms </li></ul><ul><ul><li>Moderate and severe rash more frequent in TVR-based treatment arms </li></ul></ul><ul><ul><li>Incidence and severity of other AEs similar to peginterferon alfa-2a and ribavirin alone </li></ul></ul><ul><li>Cumulative discontinuation due to AEs by Week 12 </li></ul><ul><ul><li>TVR treatment arms: 18% </li></ul></ul><ul><ul><li>Peginterferon alfa-2a and ribavirin only: 4% </li></ul></ul><ul><li>Hemoglobin levels lower in TVR arms for first 12 weeks </li></ul>McHutchison J, et al. EASL 2008. Abstract 4.
  52. 54. PROVE 2: TVR + PegIFN ± RBV in HCV G1 Naive Patients Treatment- naive patients infected with HCV genotype 1* (N = 323) TVR + PegIFN alfa-2a + RBV (n = 81) TVR + PegIFN alfa-2a + RBV (n = 82) TVR + PegIFN alfa-2a (n = 78) Week 12 *Patients received TVR 1250-mg loading dose followed by 750 mg every 8 hrs or placebo based on the arm to which they were randomized. Patients received 12 or 24 weeks regardless of whether RVR occurred. Week 24 Week 48 Placebo + PegIFN alfa-2a 180 µg/wk + RBV 1000-1200 mg QD (n = 82) PegIFN alfa-2a + RBV (n = 81) Week 36 Follow-up Follow-up Follow-up Dusheiko G, et al. EASL 2008. Abstract 58.
  53. 55. PROVE 2: Response Rates (ITT) Dusheiko G, et al. EASL 2008. Abstract 58. Treatment, % Week 4 Undetectable* Week 12 Undetectable* SVR ¶ Relapse (n/N) § PegIFN/RBV/placebo 48 wks (n = 82) 12 41 48 20 (9/45) TVR/pegIFN/RBV 12 wks  pegIFN/RBV 12 wks (n = 81) 69 † 73 † 68 ‡ 14 (8/56) TVR/pegIFN/RBV 12 wks (n = 82) 80 † 79 † 62 ¥ 29 (18/63) TVR/pegIFN 12 wks (n = 78) 51 62 36 48 (22/46)
  54. 56. PROVE 2: Adverse Events <ul><li>Skin events (rash, pruritus) more frequent in TVR treatment arms </li></ul><ul><ul><li>Rash most common reason for treatment discontinuation in TVR/pegIFN/RBV treatment arms: 7% (12 of 163) </li></ul></ul><ul><ul><ul><li>Macropapular rash which resolved after treatment discontinuation (median time to discontinuation: ~ 9 weeks) </li></ul></ul></ul><ul><li>Cumulative discontinuation due to AEs by Week 12 </li></ul><ul><ul><li>Both pegIFN/RBV/placebo 48 weeks and TVR/pegIFN 12 weeks: 10% </li></ul></ul><ul><ul><li>TVR/pegIFN/RBV 12 weeks: 12% </li></ul></ul><ul><ul><li>TVR/pegIFN/RBV 12 weeks  pegIFN/RBV 12 weeks: 16% </li></ul></ul><ul><li>All treatment arms experienced comparable mean decreases in hemoglobin levels in the first 12 weeks </li></ul><ul><ul><li>No incremental effect on neutrophil or platelet counts in TVR treatment arms </li></ul></ul>Dusheiko G, et al. EASL 2008. Abstract 58.
  55. 57. SPRINT-1: Boceprevir + PegIFN/RBV in Naive HCV G1 Kwo P, et al. EASL 2008. Abstract 995. PegIFN/RBV * PegIFN/RBV *+ Boceprevir † 48-week treatment arm PegIFN/RBV *+ Boceprevir † 48-week treatment arm PegIFN/low-dose RBV arm + Boceprevir † PegIFN/RBV * Follow-up Week 72 Week 48 Week 4 Week 28 Baseline Week 40: interim analysis Lead in No lead in *PegIFN alfa-2b 1.5 µg/kg/wk and weight-based RBV 800-1400 mg/day. † Boceprevir 800 mg TID.
  56. 58. SPRINT-1: Undetectable HCV: Wks 4 / 12 of Boceprevir Therapy Kwo P, et al. EASL 2008. Abstract 995. 0 20 40 60 80 100 Undetectable* HCV RNA (%) 60 39 8 78 73 34 PegIFN/RBV lead-in  pegIFN/RBV + boceprevir (n = 103) PegIFN/RBV + boceprevir (n = 107) PegIFN/RBV (n = 104) *HCV RNA <15 IU/mL. Duration 4 4 -- Boceprevir Rx 12 12 -- (weeks) 8 4 4 Total Rx 16 12 12
  57. 59. SPRINT-1: Highest WHO Grade Anemia 28 Weeks of Treatment <ul><li>Epoetin-alfa treatment </li></ul><ul><ul><li>PegIFN/RBV lead-in arm  pegIFN/RBV + boceprevir: 48% </li></ul></ul><ul><ul><li>PegIFN/RBV + boceprevir: 45% </li></ul></ul><ul><ul><li>PegIFN/RBV: 25% </li></ul></ul>Kwo P, et al. EASL 2008. Abstract 995. Anemia Severity 0 20 40 60 80 100 Patients (%) Grade 0 23 21 45 Grade 1 Grade 2 Grade 3 Grade 4 50 54 46 27 25 10 1 0 0 0 0 0 PegIFN/RBV lead-in  pegIFN/RBV + boceprevir (n = 206) PegIFN/RBV + boceprevir (n = 226) PegIFN/RBV (n = 104)
  58. 60. STEALTH C-1: NTZ + PegIFN ± RBV in G4 HCV Patients <ul><li>Nitazoxanide (NTZ): broad-spectrum activity against parasites, anaerobic bacteria and viruses </li></ul>Rossignol JF, et al. EASL 2008. Abstract 68. 180 µg/week pegIFN alfa-2a; weight-based RBV 1000-1200 mg/day; 500 mg BID NTZ. NTZ NTZ + PegIFN NTZ + PegIFN + RBV PegIFN/RBV Follow-up Week 72 Week 48 Week 12 Baseline NTZ NTZ NTZ + PegIFN NTZ + PegIFN + RBV NTZ n = 40 n = 28 n = 28 n = 12 n = 12 IFN-naive patients IFN-experienced patients
  59. 61. STEALTH C-1: NTZ + PegIFN ± RBV in G4 HCV Patients <ul><li>77 patients completed NTZ lead in </li></ul><ul><ul><li>Week-12 HCV RNA reduction: 0.26 log 10 IU/mL ( P = .0032) </li></ul></ul><ul><li>RVR (IFN-naive patients) </li></ul><ul><ul><li>PegIFN + RBV: 38% </li></ul></ul><ul><ul><li>PegIFN + RBV + NTZ: 64% ( P = .048)* </li></ul></ul><ul><li>No increase in AEs noted in NTZ arms vs SOC </li></ul>Rossignol JF, et al. EASL 2008. Abstract 68. 0 20 40 60 80 100 SVR (%) P = .023 10 30 50 70 90 50 61 79 PegIFN + RBV PegIFN + NTZ PegIFN + RBV + NTZ P = NS IFN-Experienced Patients 8 25 N = 40 28 28 12 12 IFN-Naive Patients * 16 wks total therapy (12 weeks NTZ + 4 weeks PegIFN + RBV + NTZ)
  60. 64. Hepatitis C Future Communication and Education Research and Treatment State and Local Prevention Programs Surveillance & Screening High Risk population HCV
  61. 65. HCV Prevention and Detection <ul><li>Prevention </li></ul><ul><ul><li>Community Education </li></ul></ul><ul><ul><li>Awareness </li></ul></ul><ul><ul><ul><li>Risk Factors • Complications </li></ul></ul></ul><ul><li>Detection </li></ul><ul><ul><li>Testing high risk populations </li></ul></ul>

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