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Hepatitis C Epidemiology, Natural History, Impact, and Viral Kinetics

Hepatitis C Epidemiology, Natural History, Impact, and Viral Kinetics. Kenneth E. Sherman, MD, PhD Gould Professor of Medicine Director, Division of Digestive Diseases University of Cincinnati Medical Center. Causes of Death in the United States, 2003. National Center for Health Statistics.

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Hepatitis C Epidemiology, Natural History, Impact, and Viral Kinetics

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  1. Hepatitis CEpidemiology, Natural History, Impact, and Viral Kinetics Kenneth E. Sherman, MD, PhD Gould Professor of Medicine Director, Division of Digestive Diseases University of Cincinnati Medical Center

  2. Causes of Death in the United States, 2003 National Center for Health Statistics

  3. Etiology of Chronic Liver Disease in the U.S. Bell BP et al. Hepatology 2001;34:468A

  4. Morphology Characteristics Hepatitis C Virus • Nucleic acid: ssRNA • Classification related to pestiviruses and flaviviruses • Serotypes: one with mulitple genotypes • In vivo replication: liver and lymphocytes

  5. HEPATITIS C VIRUSGenome 3’ 5’ Internal Ribosomal Entry Site RNA Binding Site Envelope Glyco-proteins Signal peptide Serine protease/ helicase RNA dependent RNA polymerase NONSTRUCTURAL PROTEINS

  6. HCV DIVERSITY • HCV replicates at high levels (>10 trillion virions/day • Lack of error correction leads to drift • Drift is observed in two forms • Quasispecies • Genotypes

  7. 7B 6B 11A 6A 8B 4A 9A 2C 5A 2A 1A 1C 2B 1B Patient 10% 3A 10A

  8. HCV Infection • 200,000,000 Chronic Infections Worldwide • At least 4 Million in US • Highly Associated With Development of • Cirrhosis • Hepatocellular Carcinoma • Leading Etiology for Liver Transplant in the United States

  9. Prevalence of HCV Infection in General Population Armstrong GL, Ann Intern Med 2006;144:705-714

  10. Current Hepatitis C Disease Burden, US New infections per year - 1985-1989 242,0001 - 2003 30,0002 Deaths from acute liver failure rare2 Persons ever infected (1.6%) 4.1 million3 - Persons undiagnosed 2.1 million4 Persons with chronic infection 3.2 million3 Estimated deaths from chronic disease/year = 8,000-10,0002 1Armstrong et al. Hepatology 2000;31:377-382 2 CDC. Hepatitis C Fact Sheet. Available at: www.cdc.gov. Accessed March 29, 2005 3 Armstrong et al. Ann Intern Med 2006;144:705-714. 4 Wasley AM et al. ISVHLD 2006, Paris

  11. Higher Estimates of HCV in US • NHANES (1988-1994) • 3.9 million infected • 2.7 active HCV infection • Excluded several high risk populations • Prevalence estimated in: • Homeless • Prisoners • Military • Nursing Home • Hospitalized Patients • New Estimate: 4.7-5.1 million infected and 3.4 million with Active Disease Edlin et. al. ,Hepatology Supp. Abs. #44, 2005

  12. Who Should be Screened? • Ever injected illegal drugs • Received clotting factors made before 1987 • Received blood/organs before July 1992 • Ever on chronic hemodialysis • Evidence of liver disease • HIV-positive • Healthcare and emergency personnel after exposure • Children born to HCV-positive women Based on increased risk for infection Based on need for exposure management

  13. Who Does Not Need Routine Screening? • Confirmed risk factor but prevalence low¹ • Health-care, emergency medical, public safety workers • History of STDs or multiple sex partners • Long-term steady sex partners of HCV-positive² • Individualize; counseling, testing partner may be beneficial • Unconfirmed and prevalence low³ • Intranasal cocaine or other non-injecting illegal drug users • History of tattooing, body piercing ¹ CDC. MMWR 1998;47(RR-19) ² Strader et al. Hepatology 2004;39:1147-1171 ³ Hwang et al. Hepatology 2006;44:341-351

  14. Tests for Hepatitis C • Enzyme Immunoassay (EIA) • Recombinant Immunoblot Assay (RIBA) • Qualitative HCV RNA • Quantitative HCV RNA • HCV Genotype

  15. HCV RNA levels in Sequential Serum Samples Gordon et. al., HEPATOLOGY, 1998

  16. Uninfected hepatocytes T Productively infected hepatocytes I Viral Dynamics of Hepatitis C Virus Infection Rate of production of target cells , pt Cell death  Viral load V Clearance of virionsc Cell death 

  17. Steady State • Terminology • Viral load, V, free virus particles in serum • p= Production • c= Clearance • pV= cV ergo EQUILIBRIUM Virus is being produced and cleared at the same rate • What does the viral load at steady state tell us? • Predicts progression in HIV • Predicts response to interferon based therapy for HCV

  18. STEADY STATE • Yields steady state (equilibrium) differential equation before therapy:

  19. INTERVENTION • INTERFERON • RIBAVIRIN • OTHER IMMUNE MODULATORS (e.g. Thymosin, Therapeutic Vaccines) • ANTIVIRALS • Serine Protease • Helicase • RNA Dependent RNA Polymerase • Fusion Inhibitors

  20. THE “PERFECT DRUG” If Production (P) is Stopped (P=0) Then…… or

  21. MOST DRUGS CANNOTBLOCK 100% of PRODUCTION • IFN partially blocks viral production (drug efficacy = ):

  22. Biphasic viral dynamic model Antiviral therapy Therapeutic Implications • When E < 1, biphasic: at the same e, therapeutic outcome relies on the 2nd decline phase (i.e., Infected cell death rate by individual’s immune activity). • Drug or dosing efficacy is a key parameter in the initial viral decline phase. • Estimated Time to Clearance is based upon the combination of E and the 2nd Phase Decline slope Phase 1: Inhibition of Production/Release Phase 2:Inhibition + /clearance of infected cells

  23. Model predictions on the effect of efficacy of inhibition of viral production • (A) Effect of efficacy on the kinetics of HCV clearance. • (B) Effect of efficacyon the time required to reduce viral load to clearance level. Tsiang et. al., HEPATOLOGY, 1999

  24. Coinfected patient treated with PEG-IFN + ribavirin Cleared at day 56, model predicted 64 days to clearance Case: Baseline log10 HCV VL = 6.85 ε = 0.961 λ2 = 0.014 Days to clear = 56

  25. Matched pair treated with PEG-IFN + r demonstrating a steep phase 1 slope for control, indicating lack of fit of a 2-phase model Case: Baseline log10 HCV VL = 6.75 ε = 0.723 λ2 = 0.028 Days to clear = never cleared (predicted = 492) Control: Baseline log10 HCV VL = 4.90 ε = 0.997 λ2 = 0.158 Days to clear = 3

  26. Model Failure

  27. NON-LINEAR MODELMean Fitted Curve Sherman et al., 10th CROI, 2002

  28. NON-LINEAR MODELMean Fitted Curve Sherman et al., 10th CROI, 2002

  29. HCV vs COINFECTEDPooled Model:14 days

  30. HCV vs COINFECTEDPooled Model: To Clearance Differential time to clearance= 62 days

  31. HOW DOES THIS HELP? • CHACTERIZES EFFECT OF INTERVENTION • PERMITS COMPARISONS • Different Agents • Different Population Groups • INTRODUCES PREDICTION CAPABILITY • CREATES HYPOTHETICAL FRAMEWORK THAT CAN BE TESTED

  32. PREDICTION OF RESPONSE& STOPPING RULES • Pretreatment • During Treatment: Negative Prediction of SVR • 24 Weeks • 12 Weeks (EVR or Early Viral Response) • 4 Weeks (RVR or Rapid Viral Response) • ? 1-3 days

  33. PEG IFN Alfa-2a + RBV Predictability Analysis Week 12 (N = 453) n = 25365% SVR Yes n = 390 86% n = 137 35% No SVR 2-log10 dropor neg HCV RNA SVR n = 23% n = 6314% No n = 61 97% No SVR Fried et al. N Engl J Med. 2002;347:975-982.

  34. Predictability of SVR Following PEG-IFN -2b + RBV Week 12 (N = 512) n = 273(70%) SVR Yes n = 388 (76%) No SVR n = 115 (30%) 2 log10 dropor neg HCV RNA n = 1(1%) SVR n = 124(24%) No SVR No n = 123 (99%) Davis GL. HEPATOLOGY 2002;36:S145-S151

  35. SOURCES OF VARIABILITY IN MODELING • Assay Variability • Different Agents (IFN alfa 2a vs IFN alfa 2b) • Sampling Times/Frequency • Patient Populations including Controls • Inclusion of Outliers in Analysis • Nonresponders • Rapid Responders • Missing data points

  36. WHY DOES A MODEL FAIL? • Fails to account for all parameters • Assumes clearance is constant • Assumes fixed rate of new hepatocyte formation • Assumes steady state of viral load prior to treatment • Assumes infected cell death rate is constant • Assumes one viral compartment • Does not permit selection for virus with different level of fitness

  37. FIBROTIC PROGRESSION Mild 15-33% Moderate Severe fibrosis Cirrhosis- mild Cirrhosis - severe 20-33% HCC 0 10 20 30 40 50 Years adapted from Afdhal, Sem Liver Disease, 2004

  38. Histologic Progression of HCV Normal Mild Chronic Hepatitis Cirrhosis Moderate Chronic Hepatitis

  39. Rates of Progression Degree of Fibrosis on Initial Liver Biopsy 100 75 Percent of Progression to Cirrhosis 50 25 0 5 10 15 20 Years

  40. HCV in Cirrhotic PatientsRisk of Decompensation and HCC Fattovich et al., Gastroenterology 1997; 112:463

  41. Predicted HCV-Related Mortality in the USA Hepatocellular carcinoma (HCC) 30,000 Non-HCC liver-related 20,000 10,000 5,000 0 1992 1995 1998 2001 2004 2007 2010 2013 2016 2019 Year Wong JB, et al. Am J Public Health. 2000;90:1562–1569.

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