1. Evaluation of Liver Histology in Clinical Trials for Chronic Viral Hepatitis Zachary Goodman, M.D., Ph.D. Chief, Hepatic Pathology Armed Forces Institute of Pathology

2. Viral Replication Chronic Viral Hepatitis Presumed Pathogenesis Immune Response Tissue Damage Scarring HCC Cirrhosis Death Histologic Evaluation

3. Hepatitis Acute Chronic Hepatocellular Injury – Apoptosis – Focal “necrosis” Inflammation – Parenchymal – Portal – Periportal Repair and Regeneration – +/- Scarring

7. Chronic Hepatitis Histologic Grading & Staging for Therapeutic Trials Goal – To assess whether there is improvement in a cohort of patients treated with a new therapy in comparison to a control cohort

8. Chronic Hepatitis Histologic Grading & Staging for Therapeutic Trials Methods – Semiquantitative numerical scoring – Ranked assessment – Single pathologist – Paired biopsies from each patient – Blinded as to treatment arm and order

9. Histology Activity Index (Knodell Score) Periportal Injury0-4 Confluent Necrosis0-6 Parenchymal Injury0-4 Portal Inflammation0-4 Grade (Inflammation)0-18 Stage (Fibrosis)0-4

10. Mild = 1 Moderate = 3 (< 50% circ.) Marked = 4 (> 50% circ.) Periportal Injury (Interface hepatitis, Piecemeal necrosis)

12. Mild = 1 (<5 per 10X field) Moderate = 3 (5-20 per 10X field) Marked = 4 (>20 per 10X field) Parenchymal Injury

13. Mild = 1Moderate = 3Marked = 4 Portal Inflammation

14. Histology Activity Index (Knodell Score) Periportal Injury0-4 Confluent Necrosis0-6 Parenchymal Injury0-4 Portal Inflammation0-4 Grade (Inflammation)0-18 Stage (Fibrosis)0-4

15. None = 0 Portal Fibrosis = 1 Bridging Fibrosis = 3 Cirrhosis = 4

17. Fibrosis Scoring Methods

18. Chronic Viral Hepatitis Histologic Evaluation Grade (Activity, HAI score) – Correlates with ALT – Improves with successful therapy Stage (Fibrosis) – Changes slowly – May improve with successful therapy

19. Paired biopsies from each patient –Blinded as to treatment arm and order Inflammation (same, better, worse) Fibrosis (same, better, worse) Chronic Viral Hepatitis Ranked Assessment

22. Chronic Hepatitis Histologic Grading & Staging for Therapeutic Trials Primary Endpoint – Proportion of patients with 2 point improvement in HAI inflammation with no worsening of fibrosis score Other (Exploratory) Endpoints – Ranked assessment – Mean change in HAI – Other scoring systems