1. Hadziyannis SJ et al. EASL. 2002. Peginterferon alfa-2a (40KD) (PEGASYS ® ) in combination with ribavirin (RBV): efficacy and safety results from a phase III, randomized, double-blind, multicentre study examining effect of duration of treatment and RBV dose Professor Stephanos J. Hadziyannis Department of Medicine and Hepatology Henry Dunant Hospital Athens, Greece

2. Hadziyannis SJ et al. EASL. 2002. Previous clinical studies with pegylated IFNs only investigated 48 weeks No prospective studies of the efficacy and safety of ribavirin doses have been conducted Therefore no evidence-based recommendation could be made Background

3. Hadziyannis SJ et al. EASL. 2002. Study Aims To compare the efficacy and safety of the combination of PEGASYS ® and ribavirin given for 24 weeks vs. 48 weeks To compare the efficacy and safety of two different daily doses of ribavirin (low dose 800 mg vs. ‘standard’ dose of 1000/1200 mg) taken with PEGASYS ®

4. Hadziyannis SJ et al. EASL. 2002. Study Design (1) Treatment-free follow-up of 24 weeks for all patients PEGASYS ® 180 µg sc qw + ribavirin 800 mg qd, 24 weeks PEGASYS ® 180 µg sc qw + ribavirin 1000/1200 mg qd, 24 weeks PEGASYS ® 180 µg sc qw + ribavirin 1000/1200 mg qd, 48 weeks PEGASYS ® 180 µg sc qw + ribavirin 800 mg qd, 48 weeks A : B : D : C : Total 1284 patients randomized and treated

5. Hadziyannis SJ et al. EASL. 2002. Study Design (2) Randomization stratified by HCV genotype (1 vs. non-1) and viral titre (low vs. high, defined as  or >2 million copies/mL, respectively) and by geographic region Pre-planned distribution of genotypes – Genotype non 1 and 1 LVT 1:1:1:1 – Genotype 1 HVT1:1:4:4 Treatment duration blinded until week 24 Ribavirin dose blinded throughout study

6. Hadziyannis SJ et al. EASL. 2002. Undetectable serum HCV RNA at the end of a 24-week treatment-free follow-up period (COBAS AMPLICOR ® HCV Test v2.0, sensitivity 50 IU/mL) Primary Endpoint

7. Hadziyannis SJ et al. EASL. 2002. Main Inclusion Criteria Quantifiable HCV RNA in serum (AMPLICOR HCV MONITOR ® Test, v2.0) Elevated serum ALT levels Liver biopsy consistent with chronic HCV infection No previous interferon or ribavirin treatment

8. Hadziyannis SJ et al. EASL. 2002. Main Exclusion Criteria Decompensated liver disease Coinfection with HIV or HBV Anaemia or expected inability to tolerate anaemia Significant co-morbid medical conditions

9. Hadziyannis SJ et al. EASL. 2002. Patient Characteristics 800 1000/ 1200 800 1000/ 1200 Male (%)68666366 Age (mean, y)414243 Weight (mean, kg)7877 24 weeks 48 weeks HCV RNA titre (mean, x10 6 copies/mL) 5.05.57.26.1 Genotype 1 (%)49426962 Cirrhosis/ bridging fibrosis (%) 2125 26

10. Hadziyannis SJ et al. EASL. 2002. Results: SVR Genotype 1 24 weeks48 weeks SVR (%) 29% 41% 40% 51% n=101n=118n=250n=271 PEGASYS ® RBV 800 PEGASYS ® RBV 1000/1200 PEGASYS ® RBV 800 PEGASYS ® RBV 1000/1200

11. Hadziyannis SJ et al. EASL. 2002. Results: SVR Genotype 1 Low Viral Titre 24 weeks48 weeks SVR (%) 41% 51% 53% 61% n=51n=71n=60n=85 PEGASYS ® RBV 800 PEGASYS ® RBV 1000/1200 PEGASYS ® RBV 800 PEGASYS ® RBV 1000/1200

12. Hadziyannis SJ et al. EASL. 2002. Results: SVR Genotype 1 High Viral Titre 24 weeks48 weeks SVR (%) 16% 26% 35% 46% n=50n=47n=190n=186 PEGASYS ® RBV 800 PEGASYS ® RBV 1000/1200 PEGASYS ® RBV 800 PEGASYS ® RBV 1000/1200

13. Hadziyannis SJ et al. EASL. 2002. Results: SVR Genotype Non-1 SVR (%) 24 weeks48 weeks 78% 73% 77% n=106n=162n=111n=165 PEGASYS ® RBV 800 PEGASYS ® RBV 1000/1200 PEGASYS ® RBV 800 PEGASYS ® RBV 1000/1200

14. Hadziyannis SJ et al. EASL. 2002. Sustained Virologic Response: Effect of Cirrhosis SVR (%) 61% 65% 50% n=436n=321n=115 All patientsNon-cirrhoticsCirrhotics Treatment: PEGASYS ® + RBV 1000/1200 mg for 48 weeks

15. Hadziyannis SJ et al. EASL. 2002. % Due to Adverse EventDue to Lab Abnormality 3.7% 0.9% 1.0% 12.4% 2.7% 0 5 10 15 20 25 30 Rate of Withdrawal From Treatment 3.5% 14.2% 1.9% PEGASYS ® + RBV 800 mg, 24 weeks PEGASYS ® + RBV 1000/1200 mg, 24 weeks PEGASYS ® + RBV 800 mg, 48 weeks PEGASYS ® + RBV 1000/1200 mg, 48 weeks

16. Hadziyannis SJ et al. EASL. 2002. Ribavirin Discontinuations for Adverse Events / Lab Abnormalities 24 weeks48 weeks Discontinuations (%) 7% 6% 18% 19% PEGASYS ® RBV 800 PEGASYS ® RBV 1000/1200 PEGASYS ® RBV 800 PEGASYS ® RBV 1000/1200

17. Hadziyannis SJ et al. EASL. 2002. 24 weeks48 weeks PEGASYS ® RBV 800 PEGASYS ® RBV 1000/1200 PEGASYS ® RBV 800 PEGASYS ® RBV 1000/1200 3% 7% 9% 10% % Serious Adverse Events 3%4%3% Treatment-related SAEs 1%

18. Hadziyannis SJ et al. EASL. 2002. Summary (1) Overall SVR of 61% in patients treated for 48 weeks with PEGASYS ® and RBV 1000/1200 mg Overall safety profile similar to previous studies

19. Hadziyannis SJ et al. EASL. 2002. Summary (2) Genotype 1 – 51% SVR achieved with 48 weeks treatment, 1000/1200 mg RBV – Shorter duration and/or lower RBV dose leads to reduction in efficacy

20. Hadziyannis SJ et al. EASL. 2002. Summary (3) Genotype non-1 – SVR 78% 24 weeks with 800 mg RBV – Increasing duration and/or dose of RBV gave no increase in efficacy Shorter treatment associated with fewer SAEs and withdrawals for safety Lower dose RBV associated with fewer – SAEs (24 weeks) – RBV dose modifications – Large decreases in haemoglobin

21. Hadziyannis SJ et al. EASL. 2002. Study Countries Norway UK Sweden Canada Ireland Denmark Belgium Finland USA Netherlands France Mexico GermanyTaiwan Brazil Portugal Spain Australia Italy New Zealand Greece 21 Countries