NonInvasive Liver Testing Noninvasive Liver Stiffness Testing Assessing

Non-Invasive Liver Testing

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

Fibro. Scan 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

Mechanical Shear Wave Induction 50 Hz Shear Wave

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

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

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

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

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

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

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

Stiffness Calculation Formula Measure Shear Wave Speed Vs (m/s) Calculate Equivalent Stiffness E (k. Pa) E = 3 p. VS 2 Elasticity (Stiffness) Liver Tissue Density Velocity of Shear Wave

Shear Wave Speed Examples D e p t h Slow D e p t h Fast Time 15

Primary Fibro. Scan Applications • Assess urgency of need for care • Guide DAA duration • Longitudinal testing • Disease progression rate • Therapeutic response

VCTE Cutoff Value References

Fibro. Scan Cutoff Value Reference Multiple Disease Groups F 3 F 4 Disease F 0 -F 1 F 2 Significant Fibrosis Cirrhosis HBV < 6. 0 > 9. 0 > 12. 0 HCV < 7. 0 > 9. 5 > 12. 0 HCV-HIV < 7. 0 < 10. 0 > 11. 0 > 14. 0 Cholestatic < 7. 0 > 7. 5 > 10. 0 > 17. 0 NAFLD/NASH < 7. 0 > 7. 5 > 10. 0 > 14. 0 Utilization of Fibro. Scan in Clinical Practice; Bonder et al, Current Gastroenterology Rep, 2014 16 -372

Fibro. Scan Cutoff Value Reference Multiple Disease Groups F 3 F 4 Disease F 0 -F 1 F 2 Significant Fibrosis Cirrhosis HBV < 6. 0 > 9. 0 > 12. 0 HCV < 7. 0 > 9. 5 > 12. 0 HCV-HIV < 7. 0 < 10. 0 > 11. 0 > 14. 0 Cholestatic < 7. 0 > 7. 5 > 10. 0 > 17. 0 NAFLD/NASH < 7. 0 > 7. 5 > 10. 0 > 14. 0 Utilization of Fibro. Scan 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≥F 3 4 546 HCV 0. 83 0. 95 [1] 9 2083 Multiple 0. 87 0. 96 [2] 38 8433 Multiple 0. 84 0. 94 [3] Diagnosis of cirrhosis AUROC F 4 REFERENCE Accuracy of Fibro. Scan, 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≥F 3 4 546 HCV 0. 83 0. 95 [1] 9 2083 Multiple 0. 87 0. 96 [2] 38 8433 Multiple 0. 84 0. 94 [3] Diagnosis of cirrhosis AUROC F 4 REFERENCE Accuracy of Fibro. Scan, 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 Liver Stiffness Fibrosis Hepatic Pressure Hepatic Inflammation 1 Alcohol 2 Hepatic Blood Pressure 3 1. Alanine aminotransferase-based Algorithms of Liver Stiffness Measurement by Transient Elastography (Fibro. Scan) for Liver Fibrosis in Chronic Hepatitis B; Chan et al; Journal of Viral Hepatitis, 2009, 16, 36– 44 2. 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 3. Effect of meal ingestion on liver stiffness in patients with cirrhosis and portal hypertension; Berzigotti, A. , et al; PLOS One, 2013. 8(3): p. e 58742

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 Significant Fibrosis Low Cirrhosis Low Stiffness Cirrhosis Stiffness Significant Fibrosis Cirrhosis DAA Qualified ? Stiffness Utilization of Fibro. Scan Testing in Hepatitis C Virus Management; Gastroenterology & Hepatology Volume 11, Issue 3, March 2015

DAA Prequalification in HCV Significant Fibrosis Low Cirrhosis Low Stiffness Cirrhosis Stiffness Significant Fibrosis Cirrhosis Stiffness DAA 12 Weeks Utilization of Fibro. Scan Testing in Hepatitis C Virus Management; Gastroenterology & Hepatology Volume 11, Issue 3, March 2015

DAA Prequalification in HCV Significant Fibrosis Low Cirrhosis Low Stiffness Significant Fibrosis Stiffness Cirrhosis Stiffness DAA 24 Weeks Utilization of Fibro. Scan Testing in Hepatitis C Virus Management; Gastroenterology & Hepatology Volume 11, Issue 3, March 2015

Practice Guideline Overview Fibro. Scan VCTE Listings Society Region Disease Guidance AASLD / IDSA 1 USA HCV First line test WHO 2 World HCV & HBV First line test EASL 3 Europe HCV & HBV First line test NICE 4 UK HBV First line test 1. 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/cg 165

Report Review

Fibro. Scan Operating Principle Controlled Attenuation Parameter CAP ™

CAP Liver Assessment Ultrasound Attenuation Rate Unit: d. B/M (decibels per meter)

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

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 VCTE Value

Slide Deck Complements of: Echosens North America, Inc 185 Alewife Brook Parkway Suite 410 Cambridge MA 02138 www. echosens. com