Evaluation of Liver Histology in Clinical

Trials for Chronic Viral Hepatitis

Zachary Goodman, M.D., Ph.D.Chief, Hepatic PathologyArmed Forces Institute of Pathology

Viral Replication

Chronic Viral HepatitisPresumed Pathogenesis

Immune Response

Tissue Damage

Scarring

HCC

Cirrhosis Death

Histologic Evaluation

Hepatitis• Acute

• Chronic

• Hepatocellular Injury– Apoptosis– Focal “necrosis”

• Inflammation– Parenchymal– Portal– Periportal

• Repair and Regeneration– +/- Scarring

Chronic HepatitisHistologic 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

Chronic HepatitisHistologic 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

Histology Activity Index(Knodell Score)

Periportal Injury 0-4

Confluent Necrosis 0-6

Parenchymal Injury 0-4

Portal Inflammation 0-4

Grade (Inflammation) 0-18

Stage (Fibrosis) 0-4

Mild = 1 Moderate = 3(< 50% circ.)

Marked = 4(> 50% circ.)

Periportal Injury(Interface hepatitis,

Piecemeal necrosis)

Mild = 1(<5 per 10X field)

Moderate = 3(5-20 per 10X field)

Marked = 4(>20 per 10X field)

Parenchymal Injury

Mild = 1 Moderate = 3 Marked = 4

Portal Inflammation

Histology Activity Index(Knodell Score)

Periportal Injury 0-4

Confluent Necrosis 0-6

Parenchymal Injury 0-4

Portal Inflammation 0-4

Grade (Inflammation) 0-18

Stage (Fibrosis) 0-4

None = 0 Portal Fibrosis = 1

Bridging Fibrosis = 3 Cirrhosis = 4

Fibrosis Scoring MethodsKnodell Metavir Ishak

None 0 0 0

Portal fibrosis (some) 1 1 1

Portal fibrosis (most) 1 1 2

Bridging (few) 3 2 3

Bridging (many) 3 3 4

Incomplete cirrhosis 4 4 5

Established cirrhosis 4 4 6

Chronic Viral HepatitisHistologic Evaluation

Grade (Activity, HAI score)– Correlates with ALT– Improves with successful therapy

Stage (Fibrosis)– Changes slowly– May improve with successful

therapy

Paired biopsies from each patient– Blinded as to treatment arm and

order Inflammation (same, better, worse) Fibrosis (same, better, worse)

Chronic Viral HepatitisRanked Assessment

Chronic HepatitisHistologic 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