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Teerha Piratvisuth MD. Prince of Songkla University

Pretreatment assessment of Chronic Hepatitis C and Compensated Cirrhosis and Indications for Therapy. Teerha Piratvisuth MD. Prince of Songkla University. Treatment of chronic hepatitis C and response rates. 41%. NGI <100 copies/ml. 33%. 16%. Sustained Virologic Response.

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Teerha Piratvisuth MD. Prince of Songkla University

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  1. Pretreatment assessment of Chronic Hepatitis C and Compensated Cirrhosis and Indications for Therapy Teerha Piratvisuth MD. Prince of Songkla University

  2. Treatment of chronic hepatitis C and response rates 41% NGI <100 copies/ml 33% 16% Sustained Virologic Response 6% McHutchison J. N Engl Med. 2000.

  3. Although all patients with chronic hepatitis C are potential candidates for antiviral therapy, careful pretreatment assessment and selection are mandatory to optimize the risk / benefit and cost / benefit ratio of therapy

  4. Pretreatment Assessment • Determine the activity and stage of the liver disease • Evaluate symptoms and QoL modification attributable to hepatitis C • Identify extrahepatic disease • Virological assessment : Genotype : Viral load • Identify co-morbidities that can influence the treatment decision • Identify contraindication to either Interferon or Ribavirin • Assess the motivation of the patients

  5. Determine Activity and Stage of the Liver Disease • Invasive : Liver Biopsy • Non-invasive

  6. Liver Biopsy remains the gold standard for assessing liver disease in patients with chronic hepatitis C Afdhal NH. et al. Am J Gastroenterol. 2004; 44: 1160-73.

  7. Liver Biopsy in Chronic Viral Hepatitis Benefits Risks Patient’s consent Physician’s skill Contraindications

  8. Risk of Complications of Liver Biopsy Severe complication 30% % 0.3% 0.03% Pain Death Piccinino F. et al. J Hepatol. 1986;2:165-73 Poynard T. et al. Semin Liver Dis 2000;20:47-55

  9. Pain after Liver Biopsy 40% % 15% Would not agree to have biopsy if they know how they would feel during and after the procedure Pain extended beyond the day of the biopsy Garcia G. et al. Am J Gastroenterology. 2001;96:3053-55

  10. Potential Limitations of Liver Biopsy % 60-90%* 15-30% 10-20% Underestimate of cirrhosis Agreement for the stage of fibrosis Sampling error (multiple biopsies) * Less agreement for the grade of inflammation Fontana RJ. et al. Hepatology 2002;36:S57-S64 Dienstag JL. et al. Hepatology 2002;36:S152-S160

  11. Liver Biopsy in 535 Patients with Chronic Viral Hepatitis % 81% 64% 60% 3.7% Knowledge of grade and stage were considered of value Treatment was not changed Additional diagnosis Andriulli A. et al. Dig Dis Sci 2001;46:1409-15

  12. Noninvasive methods and markers proposed for assessment of liver fibrosis Aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio AST to platelet ratio (APRI) Forns fibrosis index Fibro Test Glycocirrhotest Hyaluronan Metalloproteinase Procollagen III European Liver Fibrosis (ELF) index FibroScan

  13. AST / ALT ratio > 1 Sensitivity 78% Specificity 97% Combined with platelet < 130  109 / L Positive predictive values 97% Negative predictive values 86% Giannini E. et al. Arch Intern Med. 2003; 163: 218-24. AST / ALT Ratio: Diagnosis of Cirrhosis A Study of 252 patients with CH-C

  14. AST to Platelet Ratio Index (APRI) AST level ( /ULN)  100 APRI = Platelet count (10/L) Cut-off value <1.5 PPV NPV Fibrosis Ishak > 3 88% 86% Cirrhosis 57% 98% Wai CT. et al. Hepatology. 2003; 38(2): 512-26.

  15. Outline of initial reports of each major serum assay for hepatic fibrosis

  16. Outline of initial reports of each major serum assay for hepatic fibrosis

  17. Identify extrahepatic disease HCV and Associated Conditions • ESSENTIAL MIXED CRYOGLOBULINEMIA(EMC) • GLOMERULONEPHRITIS • LICHEN PLANUS • SJOGREN’S SYNDROME • PORPHYRIA CUTANEA TADA (PCT)

  18. Evaluate Viral Factors • HCV RNA Viral load • HCV Genotype • Co-infection - HBV - HIV

  19. Factors Predictive of Response to PEG IFN/RBV • Viral • Genotype 2/3 • Viral load • Baseline <1.3 million IU/mL • 12 weeks = 0 or decrease >2 logs • Host • Fibrosis F0–F1 estimated with Fibrotest • BMI <27 • Adherence: 80/80/80 Poynard TM, et al. Submitted. 2002.

  20. Peg IFN a-2b monotherapy in CH-C Peg IFN a -2b 1.0 mcg/kg/wk IFN a -2b 3.0 MU TIW 62% 47% 42% 38% 36% 28% 25% Sustained virological response (%) 21% 14% 8% 6% 2% <2 m. <2 m. ALL >2 m. ALL >2 m. Genotype 1 Genotype 2/3 Trepo C. et al. J Hepatol. 2000.

  21. PEG-IFN SVR in Patients With HCV Genotype 1 51 SVR (%) 41 40 29 n = 101 n = 118 n = 250 n = 271 PEG-IFN 180 mcg qw RBV800 mg/day RBV1000/1200 mg/day RBV800 mg/day RBV1000/1200 mg/day 24 Weeks 48 Weeks Hadziyannis SJ. EASL Annual Meeting. 2002.

  22. 24 weeks PEG-IFN alfa-2b Plus Ribavirin Treatment in HCV Genotypes 2 or 3 SVR 93% 81% 79% All patients n = 224 Genotype 2 n = 42 Genotype 3 n = 182 Zeuzem S. et al. J Hepatol 2004; 40: 993-9

  23. 24 weeks PEG-IFN alfa-2b Plus Ribavirin Treatment in HCV Genotypes 2 or 3 SVR 95% 90.9% 85.9% 69.9% Genotype 2 < 600,000 IU/mL n = 20 Genotype 2 > 600,000 IU/mL n = 22 Genotype 3 < 600,000 IU/mL n = 99 Genotype 3 > 600,000 IU/mL n = 83 Zeuzem S. et al. J Hepatol 2004; 40: 993-9

  24. Evaluate Host Factors • Alcohol drinking • BMI • Stage of liver disease • Iron load • Compliance Zeuzem S. et al. Ann Intern Med 2004; 140: 370-81. Lonardo A. et al. Gastroenterology. 2004; 126: 586-97. Adinolfi LE. et al. Hepatology. 2001; 33: 1358-64. Fargion S. et al. Am J Gastroenterol. 2002; 97: 1204-10.

  25. Probability of developing cirrhosis Marcellin F. et al. Hepatology. Nov 2002; 36(5) Suppl. 1: S47-S56.

  26. Progression of fibrosis by duration of infection Marcellin F. et al. Hepatology. Nov 2002; 36(5) Suppl. 1: S47-S56.

  27. Effect of patient compliance on the rate of sustained virological response (>80% of treatment with 1.5 mcg/kg)Peg-IFN-alfa-2b + > 10.6 mg/kg Ribavirin All patients 72% HCV Genotype 2, 3 94% HCV Genotype 1 63% HCV Genotype 1 and > 2million copies/mL. 54% % Sustained virologic response % McHutchison J.

  28. Contraindications to antiviral therapy

  29. Contraindications to antiviral therapy

  30. Indications for anti-HCV Therapy • Significant Liver Disease • fibrosis > F2 • activity > A 2 • Significant sympotms: Fatigue Syndrome • Extrahepatic diseases

  31. Studies that have investigated the effect of antiviral therapy for chronic hepatitis C on health-related quality of life (HRQL) and fatigue

  32. Studies that have investigated the effect of antiviral therapy for chronic hepatitis C on health-related quality of life (HRQL) and fatigue

  33. Rational for individualized care with Peg-Intron and Rebetol Teerha Piratvisuth MD. Prince of Songkla University

  34. Pretreatment assessment and individualized management of hepatitis C virus (HCV) patients Treat without biopsy Biopsy to treat No biopsy No therapy Individualize in clinical practice Young adults No co-factors Easy-to-treat (HCV-2/3) No contraindications Highly motivated Cirrhosis Middle-aged HCV-1 High viral load Co-factors Patient wants to know Doctor wants to know Elderly/children contraindication Long duration with “very low” ALT

  35. PEG-IFN SVR in Patients With HCV Genotype 1 51 SVR (%) 41 40 29 n = 101 n = 118 n = 250 n = 271 PEG-IFN 180 mcg qw RBV800 mg/day RBV1000/1200 mg/day RBV800 mg/day RBV1000/1200 mg/day 24 Weeks 48 Weeks Hadziyannis SJ. EASL Annual Meeting. 2002.

  36. 24 weeks PEG-IFN alfa-2b Plus Ribavirin Treatment in HCV Genotypes 2 or 3 SVR 95% 90.9% 85.9% 69.9% Genotype 2 < 600,000 IU/mL n = 20 Genotype 2 > 600,000 IU/mL n = 22 Genotype 3 < 600,000 IU/mL n = 99 Genotype 3 > 600,000 IU/mL n = 83 Zeuzem S. et al. J Hepatol 2004; 40: 993-9

  37. Flat based dosing with IFN -2b is associated with a decrease in SVR with increasing patient weightIFN-alfa-2b3MU TIW 48 weeks <55kg(n=40) 55-75kg (n=300) 75-95kg (n=334) >95kg (n=132) Patient weight McHutchison, JG. N Engl J Med. 1998;339:1485, Poynard T. Lancet. 1998;352:1426.

  38. Distribution of patients by body weight Appropriate amount of therapy Too little drug, to maximize SVR Too much drug, increased side effects 15.5 21.0 22.0 16.0 15.0 10.5 580-all Manns, Lancet 2001, Data on file, Schering-Plough Corporation

  39. Peg-IFN-alfa-2b + ribavirin Sustained Virologic Response by Weight <65kg 65-85kg >85kg 62% 57% 55% 49% 49% 48% 47% 46% 41% 3MIU + riba 1000-1,200mg Peg 0.5 mcg/kg + Peg 1.5 mcg/kg + riba1000-1,200mg riba 800mg Data on file, Schering-Plough Corporation

  40. PEG 0.5 mcg/kg Effect of Ribavirin dose mg/kg on virologic response(Logistic regression analysis) Rebetol 10.6 mg/kg 800mg for 75kg PEG 1.5 mcg/kg Ribavirin Manns et al., Lancet 2001

  41. Virologic Relapse Intron A+Rebetol 1,000-1,200 mg PEG 1.5 +Rebetol 800 mg PEG 1.5 +Rebetol <10.6 mg/kg PEG 1.5 +Rebetol >10.6 mg/kg Data on file Schering-Plough Corporation

  42. Sustained Virologic ResponseOptimal ribavirin Dosing Optimal ribavirin >10.6 mg/kg Peg-IFN-alfa-2b 1.5 IFN-alfa-2b 3 MU Overall 47% 61% Genotype 1 34% 48% Genotype 2/3 81% 88%

  43. Early Virological Response HCV RNA negative or > 2 log decrease at 12 weeks (n=380/478 with HCV RNA available; 79%) Yes No SVR (n=273/380; 72%) SVR (n=0/98) NR (n=98/98; 100%) NR (n=107/380; 28%) Davis GL. et al. Hepatology. Sep 2003; 38(3): 645-652.

  44. Cost Benefits of EVR • If lack of EVR is used as the basis to stop treatment, 23% of cost of treatment saved versus no stopping • Genotype 1: 24-28% savings • Genotype 2 or 3: 0-5% savings • Savings similar to week 24 qualitative PCR

  45. CHRONIC HEPATITIS C HCV genotype determination Genotype 2 or 3 Genotype 1 (and 4, 5 or 6) Peginterferon + ribavirin 800 mg 24 weeks Liver biopsy >A2F2 < A1F1 HCV RNA detection at the end of treatment and 24 weeks later (lower limit of detection of the assay < 50 IU/mL) Peginterferon + ribavirin 1000-1200 mg 48 weeks Follow-up without treatment HCV RNA quantification at baseline and at week 12 (genotype 1) End-of-treatment virological response Sustained virological response > 2 log HCV RNA decrease or HCV RNA (-) at week 12 < 2 log HCV RNA decrease at week 12 Continue until week 48 Stop treatment Enroll in trials of other therapies HCV RNA detection at the end of treatment and 24 weeks later (lower limit of detection of the assay < 50 IU/mL) End-of-treatment virological response Sustained virological response

  46. Impact of IFN on Cirrhosis IFN No IFN P-Value HCC 4.4 23 <0.001 Decompensation 11 38 <0.001 Survival 82 63 <0.001 Cumulative Probability At 4 Years (%) Predictors of survival: IFN therapy, albumin >3.4 g/dL Serfaty L. et al. Hepatology, 1998;27:1435

  47. Regression of Cirrhosis Following Treatment of Hepatitis C Fibrosis stage Before and After Treatment With PEG-IFN 2b + RBV Reversion of cirrhosis 49% No of patients Poynard T et al. Gastroenterology, 2002;122:1303

  48. Impaired Virological Response in CH-C Patients with Advanced Liver Disease SVR 604 pts treated with IFN +/- Ribavirin P < 0.001 23% 11 % Cirrhotic Non-cirrhotic Gastroenteral. 2004;126:1015

  49. Peg-IFN--2b: 1.5 or/g/kg weekly Ribavirin: 800-1200 mg daily Peg-IFN--2b plus Ribavirin Therapy in CH-C with Cirrhosis or Pre-Cirrhosis SVR (%) 57% 57% 43% 33% 23% 0% Non-responder (n=19) Genotype 1 (n=14) Genotype 2, 3 (n=7) Relapses (n=6) Genotype 2, 3 (n=15) Genotype 1 (n=13) Naive Previously IFN treated Previously I/R treated Marrache F. et al. AASLD 2003

  50. Table 1. Change from Baseline (post-base) for Fibrosis and Activity By subgroup Subgroup Stage/Grade N Mean P-value All Patients Fibrosis stage 184 -.4293 P<.0001 Activity grage 184 -.1304 P=.0039 SVR Fibrosis stage 40 -1.000 P<.0001 Activity grage 40 -.6500 P<.0001 Non-SVR Fibrosis stage 144 -.2708 P<.0001 Activity grage 144 .0139 P=.7562 Histologic Benefit of PEG-IFN  monotherapyIn CH-CPatients with Advanced Fibrosis. Cirrhosis 76% N = 184 patients Extensive bridging fibrosis 24% Liver biopsy: a median of 593 days apart Everson G. et al. AASLD 2004

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