Non-Invasive Liver Testing

Non-invasive Liver Stiffness Testing Assessing The Liver’s Mechanical Properties Stiffness Elasticity

FibroScan Operating Principle Vibration Controlled Transient Elastography VCTE™

VCTE Measurement Steps Mechanically induce a shear wave Measure shear wave speed Calculate stiffness

Mechanical Shear Wave Induction 5

Mechanical Shear Wave Induction 50 Hz Shear Wave 6

Shear Wave Speed Correlates to Stiffness Low speed = Low Stiffness High speed = High Stiffness

Shear Wave Speed Measurement Pulse Echo Ultrasound Ultrasound Pulse Shear Wave Ultrasound Echo

Shear Wave Speed Measurement Pulse Echo Ultrasound Shear Wave Speed Measurement Shear Wave Ultrasound Pulse Ultrasound Echo

Mathematical Reconstruction of Shear Wave Propagation 25 mm Time 65 mm Propagation Map Mathematical Reconstruction of Shear Wave Propagation Subcutaneous Tissue Liver Tissue Explored Region

Propagation Map Shear Wave Passes 25 mm Liver Tissue Time 25 mm 65 mm Subcutaneous Tissue Liver Tissue Shear Wave Passes 25 mm

Propagation Map Shear Wave Passes 65 mm Liver Tissue Time 25 mm 65 mm Subcutaneous Tissue Liver Tissue Shear Wave Passes 65 mm

Propagation Map Shear Wave Speed = D/T Liver Tissue Time 25 mm 65 mm Subcutaneous Tissue Liver Tissue Shear Wave Speed = D/T 40 mm Time ?

Stiffness Calculation Formula Measure Calculate Shear Wave Speed Vs (m/s) Equivalent Stiffness E (kPa) E = 3pVS2 Elasticity (Stiffness) Liver Tissue Density Velocity of Shear Wave

Shear Wave Speed Examples Slow Fast Depth Depth Time

Primary FibroScan Applications Assess urgency of need for care Guide DAA duration Longitudinal testing Disease progression Disease progression rate Therapeutic response

VCTE Cutoff Value References

Multiple Disease Groups FibroScan Cutoff Value Reference Multiple Disease Groups F3 F4 Disease F0-F1 F2 Significant Fibrosis Cirrhosis HBV < 6.0 > 6.0 > 9.0 > 12.0 HCV < 7.0 > 7.0 > 9.5 HCV-HIV < 10.0 > 11.0 > 14.0 Cholestatic > 7.5 > 10.0 > 17.0 NAFLD/NASH Utilization of FibroScan in Clinical Practice; Bonder et al, Current Gastroenterology Rep, 2014 16-372

Multiple Disease Groups FibroScan Cutoff Value Reference Multiple Disease Groups F3 F4 Disease F0-F1 F2 Significant Fibrosis Cirrhosis HBV < 6.0 > 6.0 > 9.0 > 12.0 HCV < 7.0 > 7.0 > 9.5 HCV-HIV < 10.0 > 11.0 > 14.0 Cholestatic > 7.5 > 10.0 > 17.0 NAFLD/NASH Utilization of FibroScan in Clinical Practice; Bonder et al, Current Gastroenterology Rep, 2014 16-372

VCTE Accuracy Validation Meta-Analysis VCTE Versus Biopsy Staged Fibrosis # Studies # Patients ETIOLOGY Diagnosis of significant fibrosis AUROC F≥F3 Diagnosis of cirrhosis AUROC F4 REFERENCE 4 546 HCV 0.83 0.95 [1] 9 2083 Multiple 0.87 0.96 [2] 38 8433 0.84 0.94 [3] Accuracy of FibroScan, Compared to Histology, in Analysis of Liver Fibrosis in Patients with HBV or HCV; A United States Multicenter Study; Clinical Gastroenterology & Hepatology 2015

VCTE Accuracy Validation Meta-Analysis VCTE Versus Biopsy Staged Fibrosis # Studies # Patients ETIOLOGY Diagnosis of significant fibrosis AUROC F≥F3 Diagnosis of cirrhosis AUROC F4 REFERENCE 4 546 HCV 0.83 0.95 [1] 9 2083 Multiple 0.87 0.96 [2] 38 8433 0.84 0.94 [3] Accuracy of FibroScan, Compared to Histology, in Analysis of Liver Fibrosis in Patients with HBV or HCV; A United States Multicenter Study; Clinical Gastroenterology & Hepatology 2015

Liver Stiffness Influencers Fibrosis Hepatic Blood Pressure 3 Hepatic Pressure Alcohol 2 Hepatic Inflammation 1 Alanine aminotransferase-based Algorithms of Liver Stiffness Measurement by Transient Elastography (FibroScan) for Liver Fibrosis in Chronic Hepatitis B; Chan et al; Journal of Viral Hepatitis, 2009, 16, 36–44 Effect of Alcohol on Liver Stiffness Measured by Transient Elastography; Bardou-Jacquet et al; World Journal of Gastroenterology, 2013 Jan 28, 19(4); 516-522 Effect of meal ingestion on liver stiffness in patients with cirrhosis and portal hypertension; Berzigotti, A., et al; PLOS One, 2013. 8(3): p. e58742

Meal Restriction Recommendation Fast > 3 hours prior to testing Drinking water is acceptable Food intake increases liver stiffness in patients with chronic or resolved hepatitis C virus infection; Mederacke, I., et al; Liver International, 2009. 29(10): p. 1500-6. Liver Stiffness Is Influenced by a Standardized Meal in Patients With Chronic Hepatitis C Virus at Different Stages of Fibrotic Evolution; Arena et al; Hepatology, Volume 58, No 1, 2013

DAA Prequalification in HCV 27/04/2017 DAA Prequalification in HCV Low Significant Fibrosis Cirrhosis Stiffness Low Significant Fibrosis Cirrhosis Stiffness Significant Fibrosis Cirrhosis Stiffness DAA Qualified ? Utilization of FibroScan Testing in Hepatitis C Virus Management; Gastroenterology & Hepatology Volume 11, Issue 3, March 2015 January 6, 2010

DAA Prequalification in HCV 27/04/2017 DAA Prequalification in HCV Low Significant Fibrosis Cirrhosis Stiffness Low Significant Fibrosis Cirrhosis Stiffness Significant Fibrosis Cirrhosis Stiffness DAA 12 Weeks Utilization of FibroScan Testing in Hepatitis C Virus Management; Gastroenterology & Hepatology Volume 11, Issue 3, March 2015 January 6, 2010

DAA Prequalification in HCV 27/04/2017 DAA Prequalification in HCV Low Significant Fibrosis Cirrhosis Stiffness Low Significant Fibrosis Cirrhosis Stiffness Significant Fibrosis Stiffness DAA 24 Weeks Utilization of FibroScan Testing in Hepatitis C Virus Management; Gastroenterology & Hepatology Volume 11, Issue 3, March 2015 January 6, 2010

Practice Guideline Overview FibroScan VCTE Listings Society Region Disease Guidance AASLD / IDSA1 USA HCV First line test WHO2 World HCV & HBV EASL3 Europe NICE4 UK HBV Recommendations for Testing, Managing and Treating Hepatitis C; When & In Whom to Initiate Antiviral Therapy, AASLD & IDSA Practice Guidelines; www.hcvguidelines.org 2. WHO Guidelines for Screening, Care and Treatment of Persons with Hepatitis C Infection; ISBN 978 92 4 154875 5 3. EASL Clinical Practice Guidelines : Noninvasive Tests for Evaluation of Liver Disease Severity and Prognosis; Journal of Hepatology 2015 4. Diagnosis and Management of Chronic Hepatitis B in Children, Young People & Adults; guidance.nice.org.uk/cg165

Report Review

FibroScan Operating Principle Controlled Attenuation Parameter CAP™

Ultrasound Attenuation Rate CAP Liver Assessment Ultrasound Attenuation Rate Unit: dB/M (decibels per meter)

Ultrasound Attenuation Rate Example Signal Intensity 75 % 50 % 25 % 0 % 50 mm 40 mm 30 mm Depth Below Skin

Ultrasound Attenuation Normal Liver Tissue Low Attenuation Rate

Ultrasound Attenuation Fatty Liver Tissue High Attenuation Rate

Ultrasound Attenuation Rate Steatosis Correlate Low attenuation rate = Low Steatosis High attenuation rate = High Steatosis

CAP Value VCTE Value

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