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Du 2016 tp biomarkers
- 1. 7 févr. 2012 LiverCenter Non Invasive Biomarkers in chronic hepatitis C and B DU 2016 Thierry Poynard + AP-HP Groupe Hospitalier Pitié Salpêtrière, UPMC Liver Center, Université Paris 6, INSERM U680, Biopredictive France
- 2. Serum Biomarker Imaging Biomarker FibroTest FibroMax Choice Hepatologist Epidemiologist GP FibroScan Aixplorer
- 3. 2 Biomarkers of liver injury in chronic hepatitis • Unmet need • Historic • Methods and based evidence • Guidelines in practice 2
- 4. FRANCE FIBROSIS ICEBERG Biopsy: 2% (8 000 /yr) FibroTest: 10% (50 000/yr) Imaging: 10% (50 000/yr) No-estimate: 78% 0.25 Million Chronic Hepatitis C 0.25 Million Chronic Hepatitis B
- 5. USA FIBROSIS ICEBERG Biopsy: 1% (50 000 /yr) FibroSure: 1% (50 000 /yr) Imaging: 1% (50 000 /yr) No-estimate: 97% 3 Millions Chronic Hepatitis C 1 Million Chronic Hepatitis B
- 6. "META-analysis of histological data in VIRal hepatitis" Hepatology 1996 METAVIR THE METAVIR cooperative group. Inter- and intra-observer variation, Hepatology 1995
- 7. 7 févr. 20127 févr. 2012 Viral necrosis Activity Fibrosis Steatosis Alcohol Ash Nash Liver Injury
- 8. 8 7 févr. 2012 FibroMAX: HCV-HBV-ALD-NAFLD ActiTest FibroTest SteatoTest AshTest NashTest FibroMAX 7
- 9. 2 Biomarkers of liver injury in chronic hepatitis • Unmet need • Historic • Methods and based evidence • Guidelines in practice 2
- 10. 7 févr. 2012 Fibrosis biomarkers: 24 years history SJG 2008 n=100 n=1 million
- 11. 7 févr. 2012 Haptoglobin Alpha2Macroglobulin Apolipoprotein A1 Total Bilirubin Gamma GT In Situ In Serum: FibroTest Imbert-Bismut, Lancet 2001 Liver Injury Activated Stellate Cells Fibrotic Matrix
- 12. 7 févr. 2012 Rational of FibroTest: • Alpha 2 macroglobulin: key protein for Collagenase metabolism • Apolipoprotein A1 key protein for Collagen trapping • Haptoglobin: key protein for binding Free Hemoglobin oxidant • Total Bilirubin: specific marker of severe late Fibrosis • Gamma Glutamyl Transpeptidase: sensitive marker of early Fibrosis • No transaminases: to prevent inflammatory necrosis confusion (ActiTest) • Proteomic has blindly proved the major diagnostic value of • Apolipoprotein A1, A2M • Haptoglobin Paradis Cell Mol Biol 1996, Paradis Hepatology 1996, Mathurin Hepatology 1996, Imbert Bismut 2001, Langlois 2006, Watanabe 2009, Ho 2010
- 13. 2 Biomarkers of liver injury in chronic hepatitis • Unmet need • Historic • Methods and based evidence • Guidelines in practice 2
- 14. 7 févr. 2012 Period 1: 1991-2004 Optimistic Looking for a fibrosis biomarker with accuracy > 90%
- 15. 7 févr. 2012 Biopsy = Gold Standard Biopsy = 0% False Positive 0% False Negative
- 16. 7 févr. 2012 Liver Injury Serum biomarker Imaging biomarker
- 17. F4 F1 F0 Fibrotic Liver Disease F2 F3 Hemorrhage Liver failure Cancer FibroTest OK AUROC >80% FibroTest OK FibroScan OK AUROC >80% «Gray Zone»: Biopsy Imbert Bismut 2001, Castera 2005
- 18. 7 févr. 2012 Period 2: 2005-2009: Sceptic Standard statistical methods were inappropriate Period 3: 2010-2015 New methods
- 19. 19 7 févr. 2012 • Sampling error Bedossa 2003 • Inter-observers variability Rousselet 2005 • Discordance studies Poynard 2004, Halfon 2006 • Prognostic studies Ngo 2006, Vergniol 2011 • Spectrum effect Poynard 2007, Lambert 2008 • Exceeding limits of biopsy Metha 2009 • Biopsy has a gray zone Poynard 2012 • Direct meta-analyses Poynard 2015 22 8 Key methodological issues: Biopsy is no more a perfect gold standard
- 20. Sampling error: AUROCs (F1 vs F2) of Biopsy vs Whole Liver according to length Bedossa Hepatology 2003 AUROC 15 mm = 0.82 AUROC 25 mm = 0.89 «We showed that with 25-mm long biopsy specimens, only 75% were scored correctly»
- 21. 7 févr. 2012 F0 F1 F2 F3 F4 Inter-Observers variability: Biopsy has lower inter-observers concordance for intermediate stages Rousselet, Hepatology 2005
- 22. 22 7 févr. 2012 Discordances studies: independent endpoints • 537 prospective cases hepatitis C • 154 (29%) discordances FibroTest/Biopsy • Error attributable • To FibroTest: 2% • To Biopsy: 18% 25 Poynard Clin Chem 2004, Halfon AJG 2006
- 23. F4.1 F1 F0 F2 F3 7 Stages Presumed by Biomarkers Decompensated F4.2 F4.3 Varices FibroTest 0.48 0.74 0.85 0.95 TE 7.1 9.5 20 50 CHC Poynard J Hepatol 2014 CHB Poynard J Hepatol 2014 12.5 0.58
- 24. F4.1 F1 F0 F2 F3 7 Stages Presumed by Biomarkers Decompensated F4.2 F4.3 Varices FibroTest 0.48 0.74 0.85 0.95 TE 7.1 9.5 20 50 CHC Poynard J Hepatol 2014 CHB Poynard J Hepatol 2014 12.5 0.58
- 25. 25 7 févr. 2012 • Sampling error Bedossa 2003 • Inter-observers variability Rousselet 2005 • Discordance studies Poynard 2004, Halfon 2006 • Prognostic studies Ngo 2006, Vergniol 2011 • Spectrum effect Poynard 2007, Lambert 2008 • Exceeding limits of biopsy Metha 2009 • Biopsy has a gray zone Poynard 2012 29 3/7 key methodological issues not well understood Biopsy is no more a perfect gold standard
- 26. F4 F1 F0 Fibrotic Liver Disease F2 F3 DANA=4 DANA=Difference between Advanced and non-advanced fibrosis stages Obuchowski measure=AUROCs Pair-wise comparison between all stages Black and White Spectrum FibroTest AUROC=0.98
- 27. F4 F1 F0 Fibrotic Liver Disease F2 F3 DANA=1 DANA=Difference between Advanced and non-advanced fibrosis stages Obuchowski measure=AUROCs Pair-wise comparison between all stages Gray Spectrum FibroTest AUROC=0.67
- 28. F4 F1 F0 Fibrotic Liver Disease F2 F3 DANA=2.5 DANA=Difference between Advanced and non-advanced fibrosis stages Obuchowski measure=AUROCs Pair-wise comparison between all stages FibroTest AUROC=0.85 Standard Spectrum
- 29. 7 févr. 2012 Hazardous AUROC Scores for defining test performance: AUROC Score* Biopsy (length) FibroTest (Spectrum) 0.90-1.00 Excellent 100mm F1 vs F2 F0 vs F4 0.80-0.90 Good 25 mm F1 vs F2 F01 vs F234 0.70-0.80 Fair 5 mm F1 vs F2 F0 vs F2 0.60-0.70 Poor 5 mm F0 vs F1 F1 vs F2 0.50-0.60 Fail *Sebastiani CCLM 2011, Bedossa Hepatology 2003, Poynard Clin Chem 2007
- 30. 7 févr. 2012 Hazardous AUROC Scores for defining test performance: AUROC Score* FibroTest Spectrum DANA 0.90-1.00 Excellent 50% F0 vs 50% F4 4 0.80-0.90 Good F01 vs F234 20% each stage 2.5 0.70-0.80 Fair 50% F0 vs 50% F2 2 0.60-0.70 Poor 50% F1 vs 50% F2 1 0.50-0.60 Fail Poynard Clin Chem 2007, Lambert Clin Chem 2008,
- 31. 7 févr. 2012 Hazardous Tables due to Spectrum Effect (October 2012) Ochi Hepatology 2012 Real-time tissue elastography cut-off values by stage in the training set were 2.47 for F1, 2.67 for F2, 3.02 for F3, and 3.36 for F4. Using these cut-off values, the diagnostic accuracy of hepatic fibrosis in the validation set was 82.6%-96.0% in all stages. The area under the receiver operating characteristic curve of elastic ratio better correlated than serum fibrosis markers in both early and advanced fibrosis stages. Conclusion: Real-time tissue elastography is useful in evaluating hepatic fibrosis and PH in patients with NAFLD. (HEPATOLOGY 2012;1271-1278)
- 32. 32 7 févr. 2012 • Sampling error Bedossa 2003 • Inter-observers variability Rousselet 2005 • Discordance studies Poynard 2004, Halfon 2006 • Prognostic studies Ngo 2006, Vergniol 2011 • Spectrum effect Poynard 2007, Lambert 2008 • Exceeding limits of biopsy Metha 2009 • Biopsy has a gray zone Poynard 2012 29 3/7 key methodological issues not well understood Biopsy is no more a perfect gold standard
- 33. Using 25 mm liver biopsy a perfect market cannot be validated Black shading represents the set of conditions under which the AUROC values exceed what has already been observed Metha J Hepatol 2009
- 34. 34 7 févr. 2012 Exceeding limits of biopsy: >90% accuracy is impossible for advanced fibrosis 35 «Comparison of 8 diagnostic algorithms for liver fibrosis in hepatitis C: New algorithms are more precise and entirely non-invasive». Boursier et al, Hepatology 2012
- 35. 7 févr. 2012 Misleading presentation using biopsy as Gold-Standard Boursier Hepatology 2012 Mathematically impossible with biopsy as «Gold Standard
- 36. 36 7 févr. 2012 • Sampling error Bedossa 2003 • Inter-observers variability Rousselet 2005 • Discordance studies Poynard 2004, Halfon 2006 • Prognostic studies Ngo 2006, Vergniol 2011 • Spectrum effect Poynard 2007, Lambert 2008 • Exceeding limits of biopsy Metha 2009 • Biopsy has a gray zone Poynard 2012 29 3/7 key methodological issues not well understood Biopsy is no more a perfect gold standard
- 37. 37 7 févr. 2012 Review of tests by Gebo, Hepatology 2002 « These panels of tests may have the greatest value in predicting fibrosis or cirrhosis » « Biochemical tests were best at predicting no or minimal fibrosis, or at predicting advanced fibrosis/cirrhosis, and were poor at predicting intermediate levels of fibrosis » 37
- 38. FibroTest/FibroSure has a Gray Zone
- 39. Biopsy has a Gray Zone
- 41. 41 7 févr. 2012 Review of fibrosis tests by Nguyen, Hepatology 2011 41
- 42. 7 févr. 2012 Liver Biopsy Analysis Has a Low Level of Performance for Diagnosis of Intermediate Stages of Fibrosis The gray anatomy of 27,869 virtual biopsies and 6,500 patients Poynard Clin Gastro Hepatol 2012 Poynard, BMC 2005, J Hepatol 2011
- 43. 7 févr. 2012 The gray zone of liver biopsy: 27,864 virtual biopsies Area Fibrosis (Log) 25 mm Liver Biopsies Poynard Clin Gastro Hepatol 2012
- 44. 7 févr. 2012 The gray zone of liver biopsy: 27,864 virtual biopsies Poynard Clin Gastro Hepatol 2012 Area Fibrosis (Log) 25 mm Liver Biopsies
- 45. Lower gray zone of FibroTest relative to biopsy Lower gray zone F2vsF1 for FibroTest vs Biopsy 58% lower F2vsF1 vs F1vsF0 41% lower F2vsF1 vs F4vsF3. Biopsy n=27,864 Fibrotest n=6500 Poynard Clin Gastro Hepatol 2012
- 46. 7 févr. 2012 Biopsy is no more a perfect gold standard FibroTest and Elastography have similar performance 2006: Approval Markers French Health Authorities HCV 2011: Guidelines EASL 2011
- 47. 7 févr. 2012 Period 2: 2005-2009: Sceptic Standard statistical methods were inappropriate Period 3: 2010-2015 New methods
- 48. (c) BioPredictive 2008 - All Rights Reserved - No reproduction without written permission Benefit/Risk must be evaluated for each change in the formula:
- 49. High Risk False Positive Negative 5/954 (0.52%) High Risk False Positive Negative 38/7494 (0.51%) FibroTest Global Quality Estimates High Risk False Positive Negative 3349/345,695 (0.97%) High Risk False Positive Negative 491/24,872 (1.97%) FibroScan (Roulot et al 2008) >7.1 kPa= 12.6%: False Positives ? Poynard BMC Gastro 2011, Roulot J Hepatol 2008
- 50. (c) BioPredictive 2008 - All Rights Reserved - No reproduction without written permission One Test, One formula 360,000 FibroTest for Quality Control Risk of False positive/negative of FibroTest • Tertiary center: 1.97% • HIV co-infection: 1.77% • Sub-Saharan origin: 2.61%
- 51. 7 févr. 2012 Which Fibrometer for patients with Hepatitis C ? Too many variants = Risk of false positive FibroMeter Variant Year Components FM-1G 2005 PLT, PI, AST, A2M, HA, Urea, Age FM-2G V* 2008 + Gender FM-3G 2008 Switch GGT/HA FM-3G+ (CirrhoMeter) 2009 New formula for cirrhosis FM-HICV 2010 AST, A2M, PI CSF-Index 2011 Combined with LSM SF-Index 2011 Combined with LSM C-Index 2011 Combined with LSM *ONLY one ( FM-2G V) is approved by Haute Autorité de Santé PLT: platelet counts, PI prothrombin index, AST aspartate amino transferase, A2M alpha2 macroglobulin, HA hyaluronic acid
- 52. 7 févr. 2012
- 53. 7 févr. 2012 Biopsy vs Serum marker Main advantages/disadvantages Serum Marker FibroTest Less accurate for intermediate stages No grey zone relatively to biopsy Fibrosis only ActiTest/SteatoTest Delays result proprietary tests 1-48h False positive/hemolysis/ inflammation/Gilbert Yes but 0.97% (3349/345695; 0.94-1.00) Nguyen Hepatology, 2011 Poynard BMC Gastro 2011
- 54. 7 févr. 2012 Period 3: 2010-2015 Welcome in a world without perfect Gold Standard
- 55. 7 févr. 2012 Gold Standard 25 mm Biopsy 0% False Positive False Negative
- 56. 7 févr. 2012 Truth in the Absence of Gold Standard 25 mm Biopsy 25% False Positive False Negative
- 57. 7 févr. 2012 Area of fibrosis estimated by biopsy according to its length (mm) in subjects scoring METAVIR F0 (no fibrosis) on large surgical section. Area of fibrosis >5.3%: 16.3% false positives 20mm biopsy for diagnosis of advanced fibrosis >16.5%: 0.3% false positives 20mm biopsy for diagnosis of cirrhosis. Cirrhosis Advanced fibrosis Poynard J Hepatol 2012
- 58. 7 févr. 2012 Poynard J Hepatol 2011 Truth FibroTest FibroScan 5-30 mm Biopsy ALT
- 59. 7 févr. 2012 Distribution of 1893 subjects according to the 16 possible combinations of the 4 tests' results: presumed advanced fibrosis (present=1) or not (=0) 16 combinations of 4 tests results Number of subjects FibroTest LSM ALT Biopsy Observed Expected by model 0 0 0 0 621 615.5 0 0 0 1 186 191.1 ... 1 1 1 1 276 277.0 Poynard, J Hepatol 2011
- 60. 7 févr. 2012 FibroTest Se LSM Se Biopsie Se Performance for Cirrhosis: Sensitivity The standard cutoffs: 0.74 FibroTest, 14.5 kPa Stiffness Poynard, J Hepatol 2011
- 61. 7 févr. 2012 FibroTest Sp LSM Sp Biopsy Sp Performance for Cirrhosis: Specificity The standard cutoffs: for cirrhosis 0.74 for FibroTest, and 14.5 kilo-Pascal for stiffness (LSM) Poynard, J Hepatol 2011
- 62. 7 févr. 2012 SWE Fibrotest 1 TE-M Fibrotest 2 TE-XL FibroTest 3 Poynard, J Hepatol 2013 Performances for diagnosis of Cirrhosis (HCV, HBV, NAFLD, ALD) of FibroTest, and Elastography: Transient M-XL probes and Share Wave Latent Class Model: Best model for FibroTest with TE-XL or SWE (Likelihood ratio test 5.5, 6.9) n = 322 simultaneous reliable tests
- 63. 2 Biomarkers of liver injury in chronic hepatitis • Unmet need • Historic • Methods and based evidence • Guidelines in practice 2
- 64. Serum Biomarker Imaging Biomarker FibroTest FibroMax Choice Hepatologist Epidemiologist GP FibroScan SWE Aixplorer
- 65. Competitors 65
- 66. • AFEF, HAS • EASL, AASLD • WHO Guidelines: HCV and HBV
- 67. 7 févr. 20127 févr. 2012 FibroTest APRI FIB4TE Imbert-Bismuth Lancet 2001 Sandrin Ultra Med Biol 2003 Wai Hepatology 2003 Sterling Hepatology 2006
- 68. • Applicability • Variability • False positive if activity • False negative for cirrhosis Fibroscan limitations
- 69. 7 févr. 2012 Pitfalls of Fibroscan 3.1% Failures and Unreliable results 15.8%
- 70. 23 sept. 2014 Performances for cirrhosis diagnosis FibroTest Fibrosure Transient elastography AUROC* 0.86 (0.71-0.92) 0.94 (0.93-0.95) Applicability >95% 80 % Afdhal, JVH Nov 2013 Chou, Ann Int Med 2013 Not in intention to diagnose
- 71. 7 févr. 2012 Oliveri WJG 2008
- 74. 7 févr. 2012 Choice of FibroScan Cutoffs Castera 2005, Ketanneh 2007 Roulot 2008 For F2: 7.1 or 8.8 kPa ? Patients: false negatives ? Low negative predictive value Healthy volunteers: 7.1 kPa 12.6% false positives ? For screening 7.1 kPa ? For patients 8.8 kPa ? No rationale for changing cutoff according to liver disease F2 8.8 kPa F4 14.5 kPa F4 0.73 F2 0.48 Poynard PlosOne 2008
- 75. 75 7 févr. 2012 Elasto-FibroTest® 1289 patients with CHC and 604 healthy volunteers • For the diagnosis of cirrhosis Elasto-FibroTest has significantly higher performances than FibroTest or Fibroscan alone. • For the diagnosis of advanced fibrosis (F234) no improvement in performance has been observed vs FibroTest alone, when a method without gold standard was used. 67 Poynard, CRHG 2012
- 76. 8-week $ 63,000 12-Week $ 94,500 24-week $ 189,000 $ 1125 per pill
- 77. FibroTest used to identify cirrhosis at baseline or for follow-up
- 78. Number of Studies Quality Consistency Precision Strength of evidence 32 Fair High High High Chou, Ann Int Med 2013 FibroTest is the most validated test in Chronic Hepatitis C: Strength-of-evidence domains and overall ratings
- 79. Results: Area under the ROC curves: Significant fibrosis 0.84 (0.78 – 0.88) Cirrhosis 0.87 (0.85 – 0.90) Am J Gastro 2013
- 80. APRI has lower performance than Fibrotest due to its high variability 1. Analytical variability: ULN-AST definitions 2. Interaction with non-fibrosis features • Activity and AST • Steatosis and AST
- 81. Impact on performance: Obuchowski measure Change in AUROCs between fibrosis stages ULN 26 IU/L ULN >=30 IU/L APRI 0,862 0,820 FibroTest 0,867 0,867 Significance 0,30 <0,0001
- 82. High variability of APRI associated with ULN definitions: Impact on diagnosis performance • Range of AST-ULN in controls: 26-49 IU/L • According gender, BMI and cholesterol • Fibrosis prevalence in CHC: spectrum effect • Clinically significant fibrosis (F2F3F4): 35-69% • Cirrhosis (F4): 11-32%
- 83. Higher Diagnostic and Prognostic performance of FibroTest versus APRI in CHC Poynard, Ann Int Med 2013
- 84. 5 years prognostic value in chronic hepatitis B FibroTest better biomarker de Ledinghen APT 2013 LSM Not in intention to diagnose
- 85. 10 year Prognostic value FibroTest versus TE n= 2724 45% CHC, 24% CHB, NAFLD 10%, ALD 6%
- 86. Biomarke r Analytic variability Risk false positive due to Activity Fasting Applicability Investment Cost FibroTest < 7% no (ActiTest) no >95% 0 38€-200$ FibroScan Inter Observer yes yes 80 % 60,000€ 200,000$ 38€-350$ APRI Hazard of AST Upper Limit Normal yes no ? 0 7€-40 $ Castera Hepatology 2010, Afdhal JVH 2013, Chou Ann Int Med 2013, Poynard BMC Gastro 2011, Poynard Ann Int Med 2013 Pro and Con of the three «Standard of Care» biomarkers
- 87. 2 Biomarkers of liver injury in chronic hepatitis • Unmet need • Historic • Methods and based evidence • Guidelines in practice 2
- 88. 2016
- 89. Direct comparisons between APRI, FIB4, FibroTest and TE n=185 comparisons: 99 Fibrosis n=12,725 / 86 Cirrhosis n=10,929 Houot APT 2016
- 90. FT better than TE AUROC + 0.06 Fibrosis
- 91. Cirrhosis FT = TE AUROC + 0.00
- 92. 13 Three reasons to assess fibrosis stages in 2016 •Expensive IFN-free regimen, priority to severe fibrosis •Cirrhosis could need longer treatment •Viral cure is not fibrosis cure Cohen, Science 2013, Afdahl NEJM 2014, Poynard J Hepatol 2013
- 93. FibroTest similar to biopsy for estimating fibrosis progression Progression to cirrhosis in 2472 patients Biopsy FibroTest Poynard et al, J Hepatol 2012
- 94. Response is associated with longer treatment in cirrhosis stage* vs non-cirrhosis in experienced Genotype 1, treated by Sofosbuvir- Ledispasvir: 80 85 90 95 100 12 weeks 24 weeks Cirrhosis No Cirrhosis Afdahl NEJM 2014*cirrhosis stage defined by biopsy or FibroTest n=22 n=22n=87 n=87
- 95. 23 sept. 2014 Survival without liver complications n = 933 NS SVR n=4 3 HCC 1 Cholangiocarcinoma All F4 before SVR 2 F2 after Poynard, J Hepatol 2013
- 96. Cirrhosis regression in SVR n=24/43 ( 56%) FibroTest = 0.74 Poynard, J Hepatol 2013
- 97. Cirrhosis Occurrence in SVR n=15/128 (12%) FibroTest = 0.74 Poynard, J Hepatol 2013
- 98. Fibrosis Progression in 13 HBV Sustained Virological Responders with occurrence of HepatoCellular Carcinoma at 10 years FibroTest = 0.74 = F4 Poynard, J Hepatol 2014 F1: Subsaharan female, BMI 37 kg/m2
- 99. F4 F1 F0 France: 12,000,000 at Risk100% 5% Death 15,000/year0.1% Biomarker10% F2 F3
- 101. n= 1,016,557 (100 %) ActiTest Poynard BmjOpen 2015
- 102. Fibrosis density Birth-Year and Gender Other USA France n= 470,762
- 103. Serum Biomarker Imaging Biomarker FibroTest FibroMax Choice Hepatologist Epidemiologist GP FibroScan Aixplorer