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Handout 1

  1. 1. Division of Gastroenterology Duke University Medical Center Hepatitis C Update Andrew Muir, MD Director of Hepatology
  2. 2. U .S. A. 4 M SOUTH AMERICA 10 M AFRICA 32 M EAST MEDITERRANEAN 20M SOUTH EAST ASIA 30 M AUSTRALIA 0.2 M SOURCE, WHO 1999 WEST EUROPE 9 M FAR EAST ASIA 60 M HCV 170 Million Carriers Worldwide, 3-4 MM new cases/year
  3. 3. Hepatitis C <ul><li>NHANES </li></ul><ul><ul><li>15 079 participants 1999 and 2002 </li></ul></ul><ul><li>Results </li></ul><ul><ul><li>HCV antibody + 1.6% (95% CI, 1.3% to 1.9%), </li></ul></ul><ul><ul><li>4.1 million (CI, 3.4-4.9 million) </li></ul></ul><ul><ul><li>Chronic infection 1.3% </li></ul></ul><ul><ul><li> 3.2 million (CI, 2.7-3.9 million) </li></ul></ul>Armstrong GL. Ann Intern Med 2006
  4. 4. HCV in the USA Prevalence, % <ul><ul><li>Armstrong GL, Ann Intern Med 2006; 144: 705-714 </li></ul></ul>Prevalence, %
  5. 5. Overlapping international epidemics 40 million 170 million 10 million HIV HCV
  6. 6. HIV/HCV - USA <ul><li>United States </li></ul><ul><li>30% of patients who are HIV-infected are co-infected with HCV </li></ul><ul><li>HIV </li></ul><ul><ul><li>2003 – approximately 1 million persons in the US with HIV/AIDS </li></ul></ul>Staples CT. Clin Infect Dis 1999 HCV + HIV
  7. 7. Transmission <ul><li>Drug use </li></ul><ul><li>Transfusion/blood products </li></ul><ul><li>Organ transplantation </li></ul>
  8. 8. Transmission <ul><li>Sexual </li></ul><ul><ul><li>< 5% heterosexual monogamous couples </li></ul></ul><ul><ul><ul><li>No recommendations for condom use </li></ul></ul></ul><ul><ul><li>increased with multiple partners </li></ul></ul><ul><ul><li>??? increased if HIV co-infection ??? </li></ul></ul><ul><li>Vertical (mother to child) </li></ul><ul><ul><li>HCV alone: 2-5% </li></ul></ul><ul><ul><li>HIV/HCV: 25% </li></ul></ul><ul><ul><ul><li>No treatment given teratogenic meds </li></ul></ul></ul>Mast EE. J Infect Dis 2005 Veronese L. Antimicrob Agents Chemother 2000
  9. 9. Transmission <ul><li>Transmission to patients </li></ul><ul><ul><li>New York endoscopy center </li></ul></ul><ul><ul><li>Oklahoma pain clinic </li></ul></ul><ul><ul><li>Nebraska oncology treatment center </li></ul></ul><ul><ul><li>Las Vegas ambulatory surgical center 2008 </li></ul></ul><ul><ul><li>Laurinburg, NC cardiology clinic 2008 </li></ul></ul><ul><ul><li>Miami FL, Murfreesboro TN VAMC 2009 </li></ul></ul>MMWR 2001, 2008 CLOSED
  10. 11. Diagnostic approach
  11. 12. Acute Hepatitis C Chronic Hepatitis 85 % Cirrhosis 20 % Di Bisceglie, Hepatology, 2000 Natural History <ul><ul><ul><li>Faster progression </li></ul></ul></ul><ul><ul><ul><li>older age at infection </li></ul></ul></ul><ul><ul><ul><li>alcohol </li></ul></ul></ul><ul><ul><ul><li>HIV infection </li></ul></ul></ul><ul><ul><ul><li>post-transplant </li></ul></ul></ul>20-30 years 20-50 years
  12. 13. Diagnosis <ul><li>Antibody tests </li></ul><ul><ul><li>3 generations </li></ul></ul><ul><ul><li>ELISA </li></ul></ul><ul><ul><li>positive 8-10 weeks </li></ul></ul><ul><li>HCV RNA </li></ul><ul><ul><li>PCR or branched DNA </li></ul></ul><ul><ul><li>documents viremia </li></ul></ul><ul><ul><li>response to treatment </li></ul></ul>
  13. 14. HCV Genotypes <ul><li>Genotype 1 </li></ul><ul><ul><li>Most common in USA </li></ul></ul><ul><ul><li>> 90% for African Americans </li></ul></ul><ul><ul><li>Requires 48 weeks of treatment </li></ul></ul><ul><ul><li>Lowest response rates </li></ul></ul><ul><li>Genotype 2 and 3 </li></ul><ul><ul><li>Less common in USA </li></ul></ul><ul><ul><li>24 weeks of treatment </li></ul></ul><ul><ul><li>Higher response rates </li></ul></ul>Simmonds P, Journal of Hepatology, 1999 1 6 3 4 5 2
  14. 15. <ul><li>Generally advisable </li></ul><ul><ul><li>If impacts management </li></ul></ul><ul><li>Should not be mandatory </li></ul><ul><li>Aids in decision making process </li></ul><ul><li>Prognosis – cirrhosis? </li></ul><ul><li>Don’t be fooled by normal liver enzymes </li></ul>Liver Biopsy
  15. 16. Stage 2-3 Stage 4 Stage 0 Stage 0 = no fibrosis Stage 1 = portal fibrosis Stage 2 = portal with septa Stage 3 = bridging fibrosis Stage 4 = cirrhosis (nodules)
  16. 17. Alternatives to liver biopsy <ul><li>FibroSURE® </li></ul><ul><li>α2- macroglobulin </li></ul><ul><li>haptoglobin </li></ul><ul><li>apolipoprotein A1 </li></ul><ul><li>bilirubin </li></ul><ul><li>γ- glutamyl transpeptidase [GGT] </li></ul><ul><li>FIBROSpect II® </li></ul><ul><li>hyaluronic acid </li></ul><ul><li>TIMP-1 </li></ul><ul><li>alpha-2 macroglobulin </li></ul>Fibroscan
  17. 18. Role of liver biopsy <ul><li>HCV mono-infected </li></ul><ul><ul><li>Establish degree of fibrosis </li></ul></ul><ul><ul><li>Consider watchful waiting if early fibrosis </li></ul></ul><ul><li>HIV-HCV co-infection </li></ul><ul><ul><li>Establish fibrosis </li></ul></ul><ul><ul><ul><li>Hepatocellular carcinoma screening if advanced fibrosis </li></ul></ul></ul><ul><ul><li>Rule out hepatotoxicity from HAART </li></ul></ul><ul><ul><li>Watchful waiting less clear of a role given faster natural history </li></ul></ul>
  18. 19. Treatment
  19. 20. HCV treatment 2009 <ul><li>Peginterferon alfa </li></ul><ul><ul><li>Self-administered subcutaneous injection </li></ul></ul><ul><ul><li>Weekly </li></ul></ul><ul><li>Ribavirin </li></ul><ul><ul><li>Capsule </li></ul></ul><ul><ul><li>Twice daily </li></ul></ul>
  20. 21. HCV Treatment – PEG-IFN + ribavirin SVR, % Manns Lancet 2001 Fried NEJM 2002
  21. 22. IDEAL study <ul><li>Peg 2a vs Peg 2b </li></ul><ul><li>Dose Peg 2b </li></ul><ul><ul><li>Standard 1.5 mcg/kg </li></ul></ul><ul><ul><li>Low dose 1.0 mcg/kg </li></ul></ul><ul><li>Funded by Schering (maker of Peg 2b) </li></ul><ul><li>118 sites </li></ul><ul><li>3070 patients </li></ul>SVR McHutchison JG NEJM 2009
  22. 23. Racial & Ethnic groups Muir et al. N Engl J Med. 2004 Rodriguez-Torres M et al. N Engl J Med. 2009 SVR, %
  23. 24. HIV/HCV treatment trials Peg-IFN alfa + ribavirin SVR, % Laguno M, AIDS 2004 Chung RT NEJM 2004 Torriani FJ NEJM 2004 Carrat F, JAMA 2004
  24. 25. Baseline Comparisons RIBAVIC APRICOT ACTG 5071 Spain No. patients 206 289 67 52 GT 1/4 52% 61% 78% 63% Cirrhosis 38% 16% 10% 30% African Am. NS 11% 33% NS Median CD4 482 530 474 560 On HAART 83% 84% 86% 88% HIV RNA (-) 67% 60% 60% 46% RBV dose 800 800 600-1000 800-1200 Factors? No Yes Yes Yes
  25. 26. Treatment milestones for genotype 1 Baseline viral load Week 12 HCV RNA Week 24 HCV RNA < 2 log reduction HCV RNA > 2 log reduction HCV RNA HCV RNA negative HCV RNA positive
  26. 27. Factors Predictive of Response <ul><ul><li>Genotype 2 or 3 </li></ul></ul><ul><ul><li>Absence fibrosis </li></ul></ul><ul><ul><li>Low viral load </li></ul></ul><ul><ul><li>Younger age </li></ul></ul><ul><ul><li>Female </li></ul></ul><ul><ul><li>Weight </li></ul></ul><ul><ul><li>Non-African American </li></ul></ul>McHutchison JG. NEJM 1998 Poynard T. Lancet. 1998 Manns MP. Lancet 2001
  27. 28. Prediction of response <ul><li>IDEAL trial </li></ul>
  28. 29. IDEAL on-treatment prediction of SVR McHutchison JG NEJM 2009 Low-Dose Peginterferon Alfa-2b + Ribavirin Standard-Dose Peginterferon Alfa-2b + Ribavirin Peginterferon Alfa-2a + Ribavirin Weeks to first undetectable HCV RNA level 2 38/42 (90.5) 43/45 (95.6) 37/44 (84.1) 4 33/41 (80.5) 64/72 (88.9) 62/83 (74.7) 12 234/292 (80.1) 227/300 (75.7) 250/355 (70.4) 24 77/157 (49.0) 68/156 (43.6) 72/203 (35.5)
  29. 30. Prediction of treatment response <ul><li>IDEAL study participants </li></ul><ul><li>Optional genetic component at enrollment </li></ul><ul><li>3070 patients </li></ul><ul><li>1604 IDEAL participants + 67 participants from Muir et al., 2004 </li></ul><ul><ul><li>Excluded if inadequate specimen, noncompliance </li></ul></ul><ul><li>1137 samples analyzed </li></ul><ul><li>Genome wide association study </li></ul>Ge et al. Nature 2009
  30. 31. Prediction of treatment response Ge et al. Nature 2009
  31. 32. Prediction of treatment response Ge et al. Nature 2009
  32. 33. Prediction of treatment response Ge et al. Nature 2009
  33. 35. Previously treated patients <ul><li>Relapse </li></ul><ul><ul><li>Negative end of treatment but then positive </li></ul></ul><ul><li>Nonresponder </li></ul><ul><ul><li>Never HCV RNA negative </li></ul></ul><ul><li>Retreat these patients? </li></ul><ul><ul><li>Low response rates </li></ul></ul><ul><ul><li>Maintenance therapy trials negative </li></ul></ul><ul><ul><li>Can you improve treatment from previous course? </li></ul></ul><ul><ul><ul><li>Compliance? </li></ul></ul></ul><ul><ul><ul><li>Alcohol? </li></ul></ul></ul><ul><ul><ul><li>Inappropriate dose reductions? </li></ul></ul></ul><ul><ul><li>Consider HCV trials of new agents </li></ul></ul>Ghany MG, Hepatology 2009
  34. 36. New therapies <ul><li>Protease inhibitors </li></ul><ul><ul><li>FDA approval 2011? </li></ul></ul><ul><li>Polymerase inhibitors </li></ul><ul><ul><li>Phase 2 trials in progress </li></ul></ul><ul><li>Alternatives to interferon alfa </li></ul><ul><li>No alternative therapies with FDA approval expected soon </li></ul>
  35. 37. Boceprevir <ul><li>Protease inhibitor </li></ul><ul><li>SPRINT-1 </li></ul><ul><li>Phase 2, RCT study </li></ul><ul><li>GT 1 patients </li></ul><ul><ul><li>Control group </li></ul></ul><ul><ul><li>Lead in with PEG/RBV </li></ul></ul>SVR rates in SPRINT-1 Kwo P, EASL 2009
  36. 38. Telaprevir <ul><li>Protease inhibitor </li></ul><ul><li>Phase 2, RCT study </li></ul><ul><li>260 GT 1patients </li></ul><ul><ul><li>Control group </li></ul></ul><ul><ul><li>Intervention groups </li></ul></ul><ul><ul><ul><li>Telaprevir only during 1 st 12 weeks </li></ul></ul></ul><ul><ul><ul><li>T12/PR12 </li></ul></ul></ul><ul><ul><ul><li>T12/PR24 </li></ul></ul></ul><ul><ul><ul><li>T12/PR48 </li></ul></ul></ul><ul><li>Issues </li></ul><ul><ul><li>Rash </li></ul></ul><ul><ul><li>Mutations </li></ul></ul><ul><ul><li>Anemia </li></ul></ul>SVR rates in PROVE 1 McHutchison JG, NEJM 2009
  37. 39. Telaprevir – prior relapsers <ul><li>PROVE3 </li></ul><ul><li>4 arms </li></ul><ul><ul><li>T12PR24 </li></ul></ul><ul><ul><li>T24PR48 </li></ul></ul><ul><ul><li>T24P24 (no RBV) </li></ul></ul><ul><ul><li>Control (PEG/RBV) </li></ul></ul>SVR rates in PROVE3, % Manns MP, EASL 2009
  38. 40. Telaprevir – prior nonresponders <ul><li>PROVE3 </li></ul><ul><li>4 arms </li></ul><ul><ul><li>T12PR24 </li></ul></ul><ul><ul><li>T24PR48 </li></ul></ul><ul><ul><li>T24P24 (no RBV) </li></ul></ul><ul><ul><li>Control (PEG/RBV) </li></ul></ul>SVR rates in PROVE3, % Manns MP, EASL 2009
  39. 41. Complementary and alternative therapies <ul><li>Milk thistle (Silybum marianum) from the aster family </li></ul><ul><li>Active extract is silymarin, found in the fruit </li></ul><ul><ul><li>Anti-oxidant properties </li></ul></ul><ul><li>Used in Europe for jaundice since the 16th century </li></ul><ul><li>Not anti-viral </li></ul><ul><li>Studies in progress </li></ul>
  40. 42. Complementary and alternative therapies <ul><li>Hepatotoxic herbal remedies </li></ul><ul><ul><li>Chaparral leaf germander </li></ul></ul><ul><ul><li>Jin bu huan </li></ul></ul><ul><ul><li>Kava kombucha mushroom </li></ul></ul><ul><ul><li>Margosa oil </li></ul></ul><ul><ul><li>Mistletoe </li></ul></ul><ul><ul><li>Pennyroyal </li></ul></ul><ul><ul><li>Pyrrolizidine alkaloids </li></ul></ul><ul><ul><li>Traditional Chinese herbs </li></ul></ul>Verma S. Clin Gastro Hep 2007
  41. 43. Recommendations for all patients <ul><li>Consideration of treatment </li></ul><ul><li>Avoid alcohol </li></ul><ul><li>Vaccination for Hep A and Hep B if no prior exposure </li></ul><ul><li>Cirrhosis </li></ul><ul><ul><li>Pneumococcal vaccination </li></ul></ul><ul><ul><li>Upper endoscopy to r/o varices </li></ul></ul><ul><ul><li>Hepatocellular carcinoma screening </li></ul></ul>
  42. 44. Alcohol & HCV <ul><li>No safe level of alcohol </li></ul><ul><li>Interventions typically aimed if abuse </li></ul><ul><li>Duke NIH study </li></ul><ul><ul><li>Wider range of alcohol use </li></ul></ul><ul><ul><li>Individual and group therapy </li></ul></ul>
  43. 45. Resouces <ul><li>American College of Physicians </li></ul><ul><ul><li>pier.acponline.org </li></ul></ul><ul><li>American Liver Foundation </li></ul><ul><ul><li>www.liverfoundation.org </li></ul></ul><ul><li>Centers for Disease Control </li></ul><ul><ul><li>www.cdc.gov </li></ul></ul><ul><li>NIDDK </li></ul><ul><ul><li>digestive.niddk.nih.gov </li></ul></ul><ul><li>Veterans Affairs HCV program </li></ul><ul><ul><li>www.hepatitis.va.gov </li></ul></ul>
  44. 46. Take home message

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