Evaluation of Liver Histology in Clinical Trials for Chronic Viral Hepatitis

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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

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Chronic Viral HepatitisPresumed Pathogenesis
Viral Replication
Histologic Evaluation
Tissue Damage
Immune Response
Scarring
Cirrhosis
Death
HCC
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Hepatitis

• Acute
• Chronic

• Hepatocellular Injury
• Apoptosis
• Focal necrosis
• Inflammation
• Parenchymal
• Portal
• Periportal
• Repair and Regeneration
• /- Scarring

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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

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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

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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

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Periportal Injury(Interface hepatitis, Piecemeal
necrosis)
Moderate 3 (lt 50 circ.)
Marked 4 (gt 50 circ.)
Mild 1
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Parenchymal Injury
Moderate 3 (5-20 per 10X field)
Mild 1 (lt5 per 10X field)
Marked 4 (gt20 per 10X field)
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Portal Inflammation
Mild 1
Moderate 3
Marked 4
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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

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Portal Fibrosis 1
None 0
Bridging Fibrosis 3
Cirrhosis 4
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Fibrosis Scoring Methods
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Chronic Viral HepatitisHistologic Evaluation

• Grade (Activity, HAI score)
• Correlates with ALT
• Improves with successful therapy
• Stage (Fibrosis)
• Changes slowly
• May improve with successful therapy

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Chronic Viral HepatitisRanked Assessment

• Paired biopsies from each patient
• Blinded as to treatment arm and order
• Inflammation (same, better, worse)
• Fibrosis (same, better, worse)

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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