Du 2010 Tp Biomarkers Output

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  • 1. 25 janv. 2010 Biomarkers of Liver Injury in a World without Gold Standards Thierry Poynard + AP-HP Groupe Hospitalier Pitié Salpêtrière, UPMC Liver Center, Université Paris 6, INSERM U680, Biopredictive France LiverCenter lundi 25 janvier 2010 1
  • 2. 25 janv. 2010 Population at risk of liver fibrosis, cirrhosis and hepatocellular carcinoma (Millions) No advanced fibrosis Advanced fibrosis Insulin resistance Alcool consumption Hepatitis B Hepatitis C Hemochromatosis 0 150 300 450 600 2 lundi 25 janvier 2010 2
  • 3. 25 janv. 2010 10 years of claims for diagnostic procedures 1993-2003: Severe Adverse Events and Deaths (French Insurance) Technic Severe Adverse Events Deaths ERCP 71 30 Liver Biopsy* 11 5 Ultrasound-Endoscopy 4 2 *1 death /8,000 biopsies if one claim out of 2 deaths Standard severe adverse events prevalence: 3/1,000 Poynard T. Rev Med Interne 2007 lundi 25 janvier 2010 3
  • 4. 25 janv. 2010 n=100 n=400.000 lundi 25 janvier 2010 4
  • 5. 25 janv. 2010 FibroMAX: HCV-HBV-ALD-NAFLD NashTest ActiTest AshTest FibroMAX FibroTest SteatoTest 5 lundi 25 janvier 2010 5
  • 6. 25 janv. 2010 Anticipated Frequently Asked Questions • Is the perfect fibrosis biomarker possible? No • There is a "gray zone" or "inaccurate zone" between intermediate stages? No • Is FibroTest better than non-patented biomarker?: ALT, Forns, APRI... Yes • Is liver biopsy still useful? Yes • Same performance of Fibrotest in HCV, HBV, ALD, NAFLD? Yes • Similar prognostic value of FibroTest vs biopsy? Yes • Fibrotest-ActiTest-SteatoTest-NashTest-AshTest better than FibroScan? Yes • Rational of FibroTest components? Yes • Are the authors credible due to their possible conflict of interest? Yes lundi 25 janvier 2010 6
  • 7. 25 janv. 2010 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 A • Haptoglobin Imbert Bismut 2001, Langlois 2006, Watanabe 2009 lundi 25 janvier 2010 7
  • 8. 25 janv. 2010 In Situ In Serum: FibroTest Liver Injury Alpha2Macroglobulin Total Bilirubin Gamma GT Apolipoprotein A1 Fibrotic Matrix Activated Stellate Cells Haptoglobin Imbert-Bismut, Lancet 2001 lundi 25 janvier 2010 8
  • 9. 25 janv. 2010 In Situ events: Fibrosis and serum ApoA1 decrease Trapping Apo A1 Down Regulation Paradis Cell Mol Biol 1996, Paradis Hepatology 1996, Mathurin Hepatology 1996. lundi 25 janvier 2010 9
  • 10. 25 janv. 2010 Haptoglobin Hemopexin lundi 25 janvier 2010 10
  • 11. 25 janv. 2010 lundi 25 janvier 2010 11
  • 12. 25 janv. 2010 Validated Fibrosis and Activity Biomarkers 400.000 prescriptions in 35 countries Used by 80% of French Hepatologists, first line FibroTest ActiTest Castera J Hepatol 2007 12 lundi 25 janvier 2010 12
  • 13. 25 janv. 2010 F0 Pas de Fibrose lundi 25 janvier 2010 13
  • 14. 25 janv. 2010 F1 Fibrose minime lundi 25 janvier 2010 14
  • 15. 25 janv. 2010 F2 Fibrose modérée lundi 25 janvier 2010 15
  • 16. 25 janv. 2010 F3 Fibrose importante lundi 25 janvier 2010 16
  • 17. 25 janv. 2010 F4 Fibrose sévère lundi 25 janvier 2010 17
  • 18. 25 janv. 2010 Message I: Appropriate methods • Imperfect Gold Standard • Spectrum bias • Analysis of discordances Bedossa Hepatology 2003, Poynard Clin Chem 2005, Poynard Clin Chem 2007, Poynard GCB 2008 lundi 25 janvier 2010 18
  • 19. 25 janv. 2010 Message II: Appropriate markers • Hepatologist: Must • GP and Screening: Simple • Industry: Rapid • Health Authorities: Surrogate Endpoint lundi 25 janvier 2010 19
  • 20. 25 janv. 2010 Fibrosis estimates: Profile A • “Biopsy is still the gold standard” • “Biomarkers on the market are not accurate enough” • “I steel need biopsy for all my patients” • “Biomarkers only if contra-indications of liver biopsy” 10 % Biopsy Biomarker 90 % lundi 25 janvier 2010 20
  • 21. 25 janv. 2010 N Engl J Med 2001 lundi 25 janvier 2010 21
  • 22. 25 janv. 2010 Risk of chronic liver disease If contra-indication Biomarker Biopsy lundi 25 janvier 2010 22
  • 23. 25 janv. 2010 Fibrosis estimates: Profile B • “Too many false positive/false negative for intermediate stages”, “Gray zone” • “Ok for the next generation of biomarkers when they will demonstrate 90% AUROCs for bridging fibrosis (F2)” • “Ok for cirrhosis biomarkers or elastography, as AUROCs = 90%” Biopsy Biomarker 50 % 50 % lundi 25 janvier 2010 23
  • 24. lundi 25 janvier 2010 24
  • 25. 25 janv. 2010 lundi 25 janvier 2010 25
  • 26. Biopsy has the same «Gray Zone» Bedossa Hepatology 2003 25mm Biopsy F4-F3 F2-F1 F1-F0 25% 25% 25% False Positive False Positive and Negative False Negative lundi 25 janvier 2010 26
  • 27. 25 janv. 2010 Fibrosis estimates: Profile C • “Still risk of severe adverse events for liver biopsy” • “Biopsy has same limitations for adjacent stages 10 % than validated biomarkers: there is no intermediate gray zone” • “No rational or evidence based for biopsy as first line test” 90 % • “Biopsy still necessary if biomarkers results at high risk of false positive/negative” Biopsy Biomarker lundi 25 janvier 2010 27
  • 28. 25 janv. 2010 Chronic Hepatitis B or C FibroTest ActiTest Fibroscan if FibroTest not applicable Advanced Fibrosis No Advanced Fibrosis Severe Activity No Severe Activity FibroTest Hepatologist every 2-4 years lundi 25 janvier 2010 28
  • 29. 25 janv. 2010 lundi 25 janvier 2010 29
  • 30. 25 janv. 2010 AUROC 5 mm = 0.75 AUROC 15 mm = 0.82 AUROC 25 mm = 0.89 “We showed that with 25-mm long biopsy specimens, only 75% were scored correctly and 65% for 15- mm biopsy specimens” Bedossa Hepatology 2003 lundi 25 janvier 2010 30
  • 31. 25 janv. 2010 Parkes et al review, J Hepatol 2006: An illustration of obsolete methodology using imperfect gold standard as a perfect gold standard • If the Parkes et al statements and conclusions were applied to 25 mm liver biopsy, which only scored correctly in 75% using perfect gold standard: • “The 25 mm liver biopsy have a place in assessment of fibrosis to rule-in or rule-out fibrosis, but in individual patients cannot differentiate the stages of fibrosis reliably. “ lundi 25 janvier 2010 31
  • 32. 25 janv. 2010 Poynard et al APT 2007 lundi 25 janvier 2010 32
  • 33. 25 janv. 2010 Imperfect Gold Standard: Summary • Entire liver is the perfect Gold Standard • Biopsy is an imperfect Gold Standard • Biopsy 25 mm has 25% false positive/ negative versus entire liver • Waiting for 90% AUROCs for bridging fibrosis biomarker is a dream in a world without Gold Standards Bedossa Hepatology 2003, Poynard Clin Chem 2005, Poynard Clin Chem 2007, Poynard GCB 2008 lundi 25 janvier 2010 33
  • 34. 25 janv. 2010 FibroTest: from blood donors to cirrhotics (n=1,570) 1.00 Fibrotest 0.67 0.33 0.00 Blood Donors F0 F1 F2 F3 F4 Poynard Clin Chem 2004, Comp Hepatol 2004 lundi 25 janvier 2010 34
  • 35. 25 janv. 2010 FibroTest accuracy for the diagnosis of advanced fibrosis • 38 Published Studies • 7.985 Patients • Standardized AUROC • 0.84 (0.83-0.86) The best you can obtain with 20mm biopsy is 0.90 Bedossa 2003 • Advanced Fibrosis Friedrich Rust et al Gastroenterology 2008, Halfon et al GCB 2008 lundi 25 janvier 2010 35
  • 36. 25 janv. 2010 FibroTest in Chronic Hepatitis B: 3,303 patients • Myers, J Hepatol 2003 n=209 • Poynard, Am J Gastro 2005 n=283 • Cales, Hepatology 2005 n=46 • Sebastiani, World J Gastro 2006 n=110 • Coco, JVH 2007 n=93 • Zhao Chines J Pract Int Med 2007 n=123 • Poynard, JVH 2008 n=924 • Ngo, 2008 PlosONE 2008 n=1,300 • Abstracts: Castera, J Hepatol 2006 n=154; Hilleret, J Hepatol 2006 n=184, lundi 25 janvier 2010 36
  • 37. Kinetics of fibrosis according to baseline stages 25 janv. 2010 In HBV patients treated with lamivudine 2 years n=283 FibroTest-FibroSURE 1.00 0.73 0.75 0.52 F2F3F4 P=0.01 0.50 0.25 F0F1 NS 0.00 Baseline 6 mo 12 mo 24 mo 44 Cirrhosis: 42 (95%) improvement at 24 months; Significant regression (>0.30) in 14/44 (32%) Dienstag et al Gastroenterol 2003. Poynard et al Am J G 2005 lundi 25 janvier 2010 37
  • 38. 25 janv. 2010 A New simple definition of low risk patients Ngo PlosONE 2008 lundi 25 janvier 2010 38
  • 39. 25 janv. 2010 A New simple definition of HBV Inactive Carrier Viral Load < Log5 + FibroTest<= 0.27 ActiTest <= 0.29 Ngo PlosONE 2008 lundi 25 janvier 2010 39
  • 40. 25 janv. 2010 Survival according to definition of inactive carrier based on FibroTest- ActiTest normal values in untreated patients FibroTest and Survival without Survival without Survival Paired Overall Survival ActiTest complications death Controls** Normal 99.6 % 100% 100% 100% n=289 (99.5-99.6) Not normal 91.2 % 94.7 % 91.2 % 98.4 % n=208* (84.2-98.1) (89.7-99.8) (84.2-98.1) (97.6-99.1) Both normal values: FibroTest <=0.27 and ActiTest <=0.29 * Survivals of patients with abnormal FibroTest and ActiTest were lower than those of normal FibroTest and ActiTest (p<0.005) ** Overall survivals of patients with abnormal FibroTest and ActiTest were lower to those in paired controls (p<0.005) Ngo PlosONE 2008 lundi 25 janvier 2010 40
  • 41. 25 janv. 2010 Summary: FibroTest-ActiTest in patients with chronic hepatitis B • Similar accuracy than in HCV, validated at baseline, during and after HBV treatment • Discordances are also due to biopsy failure in at least 50% of cases • More sensitive than biopsy • Same prognostic value than biopsy • Permitted a better definition of non active carrier 41 lundi 25 janvier 2010 41
  • 42. 25 janv. 2010 Analyses of Discordances Reference 25 mm Biopsy Surgical Biopsy • Failures of biopsy • Failures of FibroTest • Failures of elastography Discordance 30% between 2 estimates Reguev AJG 2003, Poynard Clin Chem 2004, Poynard APT 2007, Coco JVH 2007, Poynard PlosOne 2008 42 lundi 25 janvier 2010 42
  • 43. 25 janv. 2010 HCV: Stage transitions Interferon-Ribavirin: Advanced baseline fibrosis Low quality biopsy Discordant Cases 0/15 >= 25mm both 7/15 >= 15mm both Low quality biopsy 2/24 >= 25mm both SVR n=107 NR n=105 10/24 >= 15mm both 100 % 75 % Progression Stable 50 % Regression 25 % 0 % Fibrotest Biopsy Fibrotest Biopsy Poynard et al, Hepatology 2003 43 lundi 25 janvier 2010 43
  • 44. 25 janv. 2010 HCV n=416 Mean FibroTest (range 0.00-1.00) Baseline 12mo/EOT 24mo/EOF Slow increase = Slow decrease = Sensitivity Not related to activity 0,60 0,48 0,36 0,24 0,12 Control (n=304) 0 SVR (n=70) Vergniol et al JVH 2009 lundi 25 janvier 2010 44
  • 45. 25 janv. 2010 HCV n=416 Mean Liver Stiffness Measurements (range 0-75 kPa ) Baseline 12mo/EOT 24mo/EOF Too Early = No treatment No increase = necro-inflammatory activity Lack of sensitivity ? improvement ? 15 12 9 6 3 Control (n=304) 0 SVR (n=70) Vergniol et al JVH 2009 lundi 25 janvier 2010 45
  • 46. 25 janv. 2010 HCV n=92 Mean Fibrotest and Actitest Baseline 12 weeks 24 weeks 48 weeks Fibrosis Activity 1,00 0,80 0,60 0,40 0,20 Fibrotest 0 Actitest D’Arondel et al JVH 2006 lundi 25 janvier 2010 46
  • 47. 25 janv. 2010 HBV: Adefovir Trial Incoherence between Biopsy and Virological results False Positive False Negative Low quality biopsies Low quality biopsies Median 11mm Median 9mm Treated PCR Neg Placebo 100 % 75 % Progression Stable 50 % Regression 25 % 0 % Biopsy Biopsy 47 lundi 25 janvier 2010 47
  • 48. 25 janv. 2010 Oliveri WJG 2008 lundi 25 janvier 2010 48
  • 49. 25 janv. 2010 537 Prospective Cases Same day Biopsy and FibroTest Cause of errors in the 154 (29%) cases with discordant results 2% FT-AT vs 18% Biopsy (p<0.001) Poynard et al, Clin Chem 2004 49 lundi 25 janvier 2010 49
  • 50. 25 janv. 2010 Bedossa et al, Hepatology 2003 Poynard et al, Clin Chem 2004 Quality of Liver Biopsy: Pitie experience 1,773 biopsies: 16% > 25mm Median 15 mm lundi 25 janvier 2010 50
  • 51. 25 janv. 2010 FibroTest validation in “difficult to diagnose patients” • HIV-HCV: Myers 2003, Cacoub 2008 • Aged patients: Thabut 2006 • Children: de Ledinghen 2007, Friedrich 2008 • Renal insufficiency: Varaud 2005 • Vasculitis: Cacoub 2006 • Hemophiliac Mahor 2006 • Transplanted • Kidney: Varaud 2006 • Liver: Hamelet 2008 • Normal ALT Poynard 2006, 2008, Castera 2006 51 lundi 25 janvier 2010 51
  • 52. 25 janv. 2010 FibroTest in the follow-up of liver transplanted patients: a pilot study Relapse/Reject n=8 P<0.001 No Relapse/Reject n=15 Before LT 24-72 h 7 days 2 weeks 4 weeks 24 weeks 48 weeks Hamelet EASL 2008 lundi 25 janvier 2010 52
  • 53. FibroTest Global Quality Estimates High Risk High Risk False Positive Negative False Positive Negative 0/954 (0%) 0/7494 (0%) FibroScan (Roulot et al 2008) 7.1 kPa 12.6% false positives ? High Risk High Risk False Positive Negative False Positive Negative 0.97% 1.97% lundi 25 janvier 2010 53
  • 54. Classical risk of errors New risk of errors lundi 25 janvier 2010 54
  • 55. 25 janv. 2010 Prognostic value • FibroTest in HCV: Ngo, Clin Chem 2006 • FibroTest in HBV: Ngo, PlosOne 2008 • FibroTest in ALD: Naveau, Hepatology 2008 • FibroTest in Mixed severe cirrhosis: Thabut, AASLD 2007 55 lundi 25 janvier 2010 55
  • 56. 25 janv. 2010 5 year Prognostic Value of FibroTest versus Biopsy Fibrosis Staging Survival Without HCV Complications AUROCs FibroTest 0.96 vs Biopsy 0.91 P=0.01 Pugh 0.80 P=0.006 APRI 0.82 P=0.03 Forns 0.86 P=0.04 N=537 NGO Clin Chem 2006 56 lundi 25 janvier 2010 56
  • 57. HCV Survival according to FibroTest classes N=537 NGO Clin Chem 2006 HBV Survival according to FibroTest classes lundi 25 janvier 2010 57
  • 58. 25 janv. 2010 lundi 25 janvier 2010 58
  • 59. 25 janv. 2010 AST/ALT Risk false positive lundi 25 janvier 2010 59
  • 60. 25 janv. 2010 Quality of Patented Liver Biomarkers Nb Nb Quality Test Studies Patients Score FibroTest 33 6,549 60/62 FibroSpect 4 463 30/62 FibroMeter 2 1,041 26/62 ELF 3 1,134 30/62 HepaScore 3 757 25/62 Poynard et al, Advances in Clinical Chemistry, 2008, GCB 2008 lundi 25 janvier 2010 60
  • 61. FibroTest! First Line! Reference Center FibroScan for! Confirmation ! Biopsy! If discordances! lundi 25 janvier 2010 61
  • 62. 25 janv. 2010 FibroMAX: HCV-HBV-ALD-NAFLD NashTest ActiTest AshTest FibroMAX FibroTest SteatoTest 62 lundi 25 janvier 2010 62
  • 63. 25 janv. 2010 SteatoTest for Steatosis 744 patients 140 controls GGT AUROC=0.66 SteatoTest AUROC=0.80 ALT AUROC=0.61 Poynard Comp Hepatol 2005 lundi 25 janvier 2010 63
  • 64. 25 janv. 2010 New concept in liver diseases • Biomarkers are for Hepatologists • the HDL-Cholesterol for Cardiologists • Using biomarkers validated for the frequent chronic liver diseases, • GP will screen advanced fibrosis for Hepatologists, • Who have good treatment, at least for HCV and HBV 64 lundi 25 janvier 2010 64
  • 65. 25 janv. 2010 Summary: Responses to Questions • Is the perfect fibrosis biomarker possible? • No as 25 mm has 25% False P/N • There is a "gray zone" or "inaccurate zone" between intermediate stages? • No as this is the same for 25 mm biopsy (Spectrum effect) • Is FibroTest better than non-patented biomarker?: ALT, Forns, APRI... • Yes higher performance and safety than ALT, Forns, APRI • Is liver biopsy still useful? • Yes but when everything else failed lundi 25 janvier 2010 65
  • 66. 100% France: 12,000,000 at Risk F0 F1 10% F2 Test F3 5% F4 0.1% Death 15,000/year lundi 25 janvier 2010 66