Pretreatment assessment of Chronic Hepatitis C and Compensated Cirrhosis and Indications for Therapy

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 Sustained Virologic Response 45 40 35 30 25 20 15 10 5 0 6% NGI <100 copies/ml 16% 33% IFN-2b 24 wk IFN-2b 48 wk IFN-2b + Riba 24 wk 41% IFN-2b + Riba 48 wk McHutchison J. N Engl Med. 2000.

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

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

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

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.

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

Risk of Complications of Liver Biopsy 30% 30% 20 10 0 Pain 0.3% 0.03% Severe Death complication Piccinino F. et al. J Hepatol. 1986;2:165-73 Poynard T. et al. Semin Liver Dis 2000;20:47-55

Pain after Liver Biopsy 40 % 40% 30 20 15% 10 0 Pain extended beyond the day of the biopsy Would not agree to have biopsy if they know how they would feel during and after the procedure Garcia G. et al. Am J Gastroenterology. 2001;96:3053-55

Potential Limitations of Liver Biopsy 100 % 80 60 40 20 0 10-20% Sampling error (multiple biopsies) 15-30% Underestimate of cirrhosis 60-90%* Agreement for the stage of fibrosis * 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

Liver Biopsy in 535 Patients with Chronic Viral Hepatitis 100 % 80 60 40 20 0 3.7% Additional diagnosis 60% 64% Knowledge of grade and stage were considered of value 81% Treatment was not changed Andriulli A. et al. Dig Dis Sci 2001;46:1409-15

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

AST / ALT Ratio: Diagnosis of Cirrhosis A Study of 252 patients with CH-C AST / ALT ratio > 1 Sensitivity 78% Specificity 97% Combined with platelet < 130 10 9 / L Positive predictive values 97% Negative predictive values 86% Giannini E. et al. Arch Intern Med. 2003; 163: 218-24.

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

Outline of initial reports of each major serum assay for hepatic fibrosis Number of patients Name (serum markers) Significant fibrosis Cutoff Sensitivity Specificity PPV NPV Indirect assays Wai et al. 2003 192 APRI (AST, platelets) Forns et al. 2002 476 Forns Index (age, GGT, cholesterol, platelet count) Ziol et al. 2005 327 FibroScan (hepatic elastography) Imbert-Bismut et al. 2001 134 FibroTest (α 2 -macroglobulin, α 2 -globulin, γ- globulin, apolipoprotein A 1, GGT and total bilirubin) Castera et al. 2005 183 Combined FibroScan and FibroTest Ishak >3 < 1.5 41% 95% 88% 64% Metavir >2 Metavir >2 Metavir >2 Metavir >2 < 4.2 94% 51% 40% 96% > 8.7 56% 91% 88% 56% 0.30 87% 59% 63% 85% NA NA NA NA

Outline of initial reports of each major serum assay for hepatic fibrosis Number of patients Name (serum markers) Significant fibrosis Cutoff Sensitivity Specificity PPV NPV Indirect assays Patel et al. 2004 402 FibroSpect (HA, TIMP-1 and α 2 -macroglobulin) Metavir >2 0.36 77% 73% 74% 76% Kelleher et al. 2005 95 SHASTA (HA, AST and albumin) Rosenberg et al. 2004 1,021 ELF (Propeptide III collagen, TIMP-1, HA ) Ishak >3 0.30 88% 72% 55% 94% Scheuer 3 or 4 0.102 90.5% 41% 99% 92%

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

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

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.

Peg IFN α-2b monotherapy in CH-C Peg IFN α -2b 1.0 mcg/kg/wk 50 IFN α -2b 3.0 MU TIW 47% 62% Sustained virological response (%) 45 40 35 30 25 20 15 10 5 0 38% 21% 14% 6% 8% 2% ALL >2 m. <2 m. 42% 36% 28% 25% ALL >2 m. <2 m. Genotype 1 Genotype 2/3 Trepo C. et al. J Hepatol. 2000.

PEG-IFN SVR in Patients With HCV Genotype 1 SVR (%) 50 40 30 29 41 40 51 20 10 0 n = 101 n = 118 n = 250 n = 271 RBV 800 mg/day PEG-IFN 180 mcg qw RBV 1000/1200 mg/day RBV 800 mg/day 24 Weeks 48 Weeks RBV 1000/1200 mg/day Hadziyannis SJ. EASL Annual Meeting. 2002.

24 weeks PEG-IFN alfa-2b Plus Ribavirin Treatment in HCV Genotypes 2 or 3 SVR 100 80 81% 93% 79% 60 40 20 0 All patients n = 224 Genotype 2 n = 42 Genotype 3 n = 182 Zeuzem S. et al. J Hepatol 2004; 40: 993-9

24 weeks PEG-IFN alfa-2b Plus Ribavirin Treatment in HCV Genotypes 2 or 3 SVR 100 95% 90.9% 85.9% 80 69.9% 60 40 20 0 Genotype 2 < 600,000 IU/mL n = 20 Genotype 2 > 600,000 IU/mL n = 22 Genotype 3 Genotype 3 < 600,000 IU/mL > 600,000 IU/mL n = 99 n = 83 Zeuzem S. et al. J Hepatol 2004; 40: 993-9

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.

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

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

McHutchison J. 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 HCV Genotype 1 and > 2million copies/ml. 63% 54% % 0 20 40 60 80 100 Sustained virologic response %

Contraindications to antiviral therapy Absolute Decompensated (Child B-C) cirrhosis (outside the pretransplant setting) Sever portal hypertension (outside the pretransplant setting) Thrombocytopenia (<50,000) Neutropenia (<1,000) Severe depression Psychosis Seizures Autoimmune disease Pregnancy Uncontrolled diabetes Severe systemic diseases Hypersensitivity to interferon α Relative Thyroid disease Moderate depression Autoimmune markers Alcohol and drug addiction Renal impairment (for peginterferon alfa-2b) Psoriasis

Contraindications to antiviral therapy Absolute Relative Anemia (Hb < 10) Anemia (Hb < 12) Pregnancy Hemoglobinopathy End-stage renal failure Severe iron overload Hemolytic anemia Ischemic heart disease Ischemic vascular

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

Studies that have investigated the effect of antiviral therapy for chronic hepatitis C on health-related quality of life (HRQL) and fatigue Author (ref.) Treatment Study size Additional scales (Significant differences between SVRs and non-svrs) Bonkovsky 1999 Consensus n = 437 Improvement in IFN / IFN-α2b appetite, perception of health and sleep quality Ware 1999 IFN-α2b / ribavirin n = 324 (IFN relapsers) Improvement in HCV-related health distress McHutchison 2001 IFN-α2b / ribavirin n = 912 Improvements in work functioning and productivity

Studies that have investigated the effect of antiviral therapy for chronic hepatitis C on health-related quality of life (HRQL) and fatigue Author (ref.) Treatment Study size Additional scales (Significant differences between SVRs and non-svrs) Roudot-Thoraval 2001 Bernstein 2002 PegIFN-α2a / Rasenack 2002 IFN-α2a n = 63 Non-significant trend to improvement in fatigue (VAS) n = 1,441 Improvement in the IFN-α2a FSS PegIFN-α2a / IFNα2a n = 531 Improvement in the FSS Cacoub 2002 Not recorded n = 355 Improvement in fatigue severity onlocal scale Hassanein 2004 PegIFN-α2a / IFNα2a /ribavirin n = 1,221 Improvement in the FSS Wright 2004 IFN-α2b / ribavirin n = 126 (histologically mild disease)

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

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

PEG-IFN SVR in Patients With HCV Genotype 1 SVR (%) 50 40 30 29 41 40 51 20 10 0 n = 101 n = 118 n = 250 n = 271 RBV 800 mg/day PEG-IFN 180 mcg qw RBV 1000/1200 mg/day RBV 800 mg/day 24 Weeks 48 Weeks RBV 1000/1200 mg/day Hadziyannis SJ. EASL Annual Meeting. 2002.

24 weeks PEG-IFN alfa-2b Plus Ribavirin Treatment in HCV Genotypes 2 or 3 SVR 100 95% 90.9% 85.9% 80 69.9% 60 40 20 0 Genotype 2 < 600,000 IU/mL n = 20 Genotype 2 > 600,000 IU/mL n = 22 Genotype 3 Genotype 3 < 600,000 IU/mL > 600,000 IU/mL n = 99 n = 83 Zeuzem S. et al. J Hepatol 2004; 40: 993-9

Flat based dosing with IFN α-2b is associated with a decrease in SVR with increasing patient weight IFN-alfa-2b 3 MU TIW 48 weeks % Sustained virologic response 40% 30% 20% 10% 0% 33% <55kg (n=40) 19% 55-75kg (n=300) 13% 75-95kg (n=334) 9% >95kg (n=132) Patient weight McHutchison, JG. N Engl J Med. 1998;339:1485, Poynard T. Lancet. 1998;352:1426.

Distribution of patients by body weight 25 20 Too much drug, increased side effects Appropriate amount of therapy Too little drug, to maximize SVR % of patients 15 10 5 10.5 15.5 21.0 22.0 16.0 15.0 580-all 0 <60kg >60-70kg >70-80kg >80-90kg >90-100kg >100kg Manns, Lancet 2001, Data on file, Schering-Plough Corporation

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

Effect of Ribavirin dose mg/kg on virologic response (Logistic regression analysis) % Sustained virologic response 100% 80% 60% 40% 20% 0% Manns et al., Lancet 2001 Rebetol 10.6 mg/kg 800mg for 75kg PEG 1.5 mcg/kg PEG 0.5 mcg/kg 5 7 9 11 13 15 17 19 21 23 25 27 Ribavirin

Virologic Relapse Genotype 1 Genotype 2/3 0 % virologic relapse -10-20 -30 21 7 24 11 28 14 17 7-40 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

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

McHutchison J. 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 HCV Genotype 1 and > 2million copies/ml. 63% 54% % 0 20 40 60 80 100 Sustained virologic response %

Rationale for Using Early Viral Response Endpoint Drawbacks of Antiviral Therapy Only half respond Difficult to tolerate Requires close monitoring Expensive Thus, identifying those with the greatest chance of benefiting (or not) from therapy is desirable

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=107/380; 28%) NR (n=98/98; 100%) Davis GL. et al. Hepatology. Sep 2003; 38(3): 645-652.

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

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

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

Regression of Cirrhosis Following Treatment of Hepatitis C Fibrosis stage Before and After Treatment With PEG-IFN α2b + RBV No of patients 160 140 120 100 80 60 40 153 78 Reversion of cirrhosis 49% 41 46 41 stage 4 stage 3 stage 2 stage 1 normal 20 5 0 Before treatment After treatment Poynard T et al. Gastroenterology, 2002;122:1303

Impaired Virological Response in CH-C Patients with Advanced Liver Disease SVR 50 604 pts treated with IFN +/- Ribavirin 40 30 23% P < 0.001 20 11 % 10 0 Non-cirrhotic Cirrhotic Gastroenteral. 2004;126:1015

Peg-IFN-α-2b plus Ribavirin Therapy in CH-C with Cirrhosis or Pre-Cirrhosis SVR (%) 60 50 40 30 23% 20 10 0 Genotype 1 (n=13) Naive 57% Genotype 2, 3 (n=15) 43% Genotype 1 (n=14) 57% Genotype 2, 3 (n=7) Previously IFN treated Peg-IFN-α-2b: 1.5 or/µg/kg weekly Ribavirin: 800-1200 mg daily 33% Relapses (n=6) 0% Previously I/R treated Non-responder (n=19) Marrache F. et al. AASLD 2003

Histologic Benefit of PEG-IFN α monotherapy In CH-C Patients with Advanced Fibrosis. N = 184 patients Liver biopsy: a median of 593 days apart Cirrhosis 76% Extensive bridging fibrosis 24% 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 Everson G. et al. AASLD 2004

Peg-IFN / Ribavirin should always be considered in patients with child A cirrhosis Contraindication : severe PHT with endoscopic signs of high risk for bleeding : large splenomegaly with severe neutropenia and / or thrombocytopenia Alberti A. Barcelona. 2005.