13 janv. 2011                             Biomarkers of Liver Injury                        in a World without Gold Standa...
13 janv. 2011     The «Biopsist»                        2   Poynard J Hepatol 2010jeudi 13 janvier 2011
13 janv. 2011     The «Biopsist»     • Still recommends biopsy as the first-line estimate of liver injury                  ...
13 janv. 2011     The «Biopsist»     • Still recommends biopsy as the first-line estimate of liver injury     • Agrees that...
13 janv. 2011     The «Biopsist»     • Still recommends biopsy as the first-line estimate of liver injury     • Agrees that...
13 janv. 2011     The «Biopsist»     • Still recommends biopsy as the first-line estimate of liver injury     • Agrees that...
13 janv. 2011     The «Biopsist»     • Still recommends biopsy as the first-line estimate of liver injury     • Agrees that...
13 janv. 2011     The «Biopsist»     • Still recommends biopsy as the first-line estimate of liver injury     • Agrees that...
13 janv. 2011     The «Biopsist»     • Still recommends biopsy as the first-line estimate of liver injury     • Agrees that...
Biopsy first line                        If refused or not                           interpretable                         ...
13 janv. 2011     The "Biomarkerist"                          4   Poynard J Hepatol 2010jeudi 13 janvier 2011
13 janv. 2011     The "Biomarkerist"     • Recommends validated biomarkers as the first-line estimate of liver injury      ...
13 janv. 2011     The "Biomarkerist"     • Recommends validated biomarkers as the first-line estimate of liver injury     •...
13 janv. 2011     The "Biomarkerist"     • Recommends validated biomarkers as the first-line estimate of liver injury     •...
13 janv. 2011     The "Biomarkerist"     • Recommends validated biomarkers as the first-line estimate of liver injury     •...
13 janv. 2011     The "Biomarkerist"     • Recommends validated biomarkers as the first-line estimate of liver injury     •...
13 janv. 2011     The "Biomarkerist"     • Recommends validated biomarkers as the first-line estimate of liver injury     •...
13 janv. 2011     The "Biomarkerist"     • Recommends validated biomarkers as the first-line estimate of liver injury     •...
FibroTest             ActiTest                                    A la Parisienne                                        F...
13 janv. 2011     The «BioCocktailist» (1)                                6   Poynard J Hepatol 2010jeudi 13 janvier 2011
13 janv. 2011     The «BioCocktailist» (1)     • Recommends biomarker first and then biopsy if the       biomarker result i...
13 janv. 2011     The «BioCocktailist» (1)     • Recommends biomarker first and then biopsy if the       biomarker result i...
13 janv. 2011     The «BioCocktailist» (1)     • Recommends biomarker first and then biopsy if the       biomarker result i...
13 janv. 2011     The «BioCocktailist» (1)     • Recommends biomarker first and then biopsy if the       biomarker result i...
13 janv. 2011     The «BioCocktailist» (1)     • Recommends biomarker first and then biopsy if the       biomarker result i...
Sequentialist                                   Fibrotest or FibroScan FibroTest              ActiTest          First Line...
Biopsy has the same «Gray Zone»                     Bedossa Hepatology 2003                         25mm Biopsy         F4...
13 janv. 2011     The BioCocktailist (2)                              9   Poynard J Hepatol 2010jeudi 13 janvier 2011
13 janv. 2011     The BioCocktailist (2)           • «Discordantist»                               9   Poynard J Hepatol 2...
13 janv. 2011     The BioCocktailist (2)           • «Discordantist»                  • Performs two biomarkers and recomm...
13 janv. 2011     The BioCocktailist (2)           • «Discordantist»                  • Performs two biomarkers and recomm...
13 janv. 2011     The BioCocktailist (2)           • «Discordantist»                  • Performs two biomarkers and recomm...
A la Bordelaise                                   Fibrotest and FibroScan FibroTest              ActiTest           First ...
13 janv. 2011     Population at risk of liver fibrosis, cirrhosis and     hepatocellular carcinoma (Millions)              ...
13 janv. 2011     10 years of claims for diagnostic procedures 1993-2003:     Severe Adverse Events and Deaths (French Ins...
13 janv. 2011     10 years of claims for diagnostic procedures 1993-2003:     Severe Adverse Events and Deaths (French Ins...
13 janv. 2011     10 years of claims for diagnostic procedures 1993-2003:     Severe Adverse Events and Deaths (French Ins...
Fibrotic Liver                                        Disease                                          F0                 ...
Fibrotic Liver                                        Disease                                          F0       Reassure a...
Fibrotic Liver                                        Disease                                          F0       Reassure a...
Fibrotic Liver                                        Disease                                          F0       Reassure a...
Fibrotic Liver                                         Disease                                           F0       Reassure...
13 janv. 2011  Fibrosis biomarkers: 20 years history                                          Poynard SJG 2008            ...
13 janv. 2011  Fibrosis biomarkers: 20 years history                                          Poynard SJG 2008jeudi 13 jan...
Validated biomarkers                        FibroTest                          Fibroscan                                  ...
13 janv. 2011     FibroMAX: HCV-HBV-ALD-NAFLD                         17jeudi 13 janvier 2011
13 janv. 2011     FibroMAX: HCV-HBV-ALD-NAFLD                                    NashTest                   ActiTest      ...
13 janv. 2011     Anticipated Frequently Asked Questionsjeudi 13 janvier 2011
13 janv. 2011     Anticipated Frequently Asked Questions • Is the perfect fibrosis biomarker possible?   Nojeudi 13 janvier...
13 janv. 2011     Anticipated Frequently Asked Questions • Is the perfect fibrosis biomarker possible?                     ...
13 janv. 2011     Anticipated Frequently Asked Questions • Is the perfect fibrosis biomarker possible?                     ...
13 janv. 2011     Anticipated Frequently Asked Questions • Is the perfect fibrosis biomarker possible?                     ...
13 janv. 2011     Anticipated Frequently Asked Questions • Is the perfect fibrosis biomarker possible?                     ...
13 janv. 2011     Anticipated Frequently Asked Questions • Is the perfect fibrosis biomarker possible?                     ...
13 janv. 2011     Anticipated Frequently Asked Questions • Is the perfect fibrosis biomarker possible?                     ...
13 janv. 2011     Anticipated Frequently Asked Questions • Is the perfect fibrosis biomarker possible?                     ...
13 janv. 2011     Anticipated Frequently Asked Questions • Is the perfect fibrosis biomarker possible?                     ...
13 janv. 2011     Rational of FibroTest:                        Imbert Bismut 2001, Langlois 2006, Watanabe 2009, Ho 2010j...
13 janv. 2011     Rational of FibroTest:     • Alpha 2 macroglobulin:            key protein for Collagenase metabolism   ...
13 janv. 2011     Rational of FibroTest:     • Alpha 2 macroglobulin:              key protein for Collagenase metabolism ...
13 janv. 2011     Rational of FibroTest:     • Alpha 2 macroglobulin:               key protein for Collagenase metabolism...
13 janv. 2011     Rational of FibroTest:     • Alpha 2 macroglobulin:               key protein for Collagenase metabolism...
13 janv. 2011     Rational of FibroTest:     • Alpha 2 macroglobulin:               key protein for Collagenase metabolism...
13 janv. 2011     Rational of FibroTest:     • Alpha 2 macroglobulin:               key protein for Collagenase metabolism...
13 janv. 2011     Rational of FibroTest:     • Alpha 2 macroglobulin:               key protein for Collagenase metabolism...
13 janv. 2011     Rational of FibroTest:     • Alpha 2 macroglobulin:                key protein for Collagenase metabolis...
13 janv. 2011     Rational of FibroTest:     • Alpha 2 macroglobulin:                key protein for Collagenase metabolis...
13 janv. 2011 Novel biomarkers predict liver fibrosis in hepatitis C patients: alpha 2 macroglobulin, vitamin D binding pro...
13 janv. 2011                        Imbert-Bismut, Lancet 2001jeudi 13 janvier 2011
13 janv. 2011                    In Situ                              Imbert-Bismut, Lancet 2001jeudi 13 janvier 2011
13 janv. 2011                    In Situ             In Serum: FibroTest                              Imbert-Bismut, Lance...
13 janv. 2011                    In Situ                In Serum: FibroTest                  Liver Injury                 ...
13 janv. 2011                    In Situ                In Serum: FibroTest                  Liver Injury                 ...
13 janv. 2011                    In Situ                In Serum: FibroTest                  Liver Injury                 ...
13 janv. 2011                    In Situ                In Serum: FibroTest                  Liver Injury                 ...
13 janv. 2011                    In Situ                In Serum: FibroTest                  Liver Injury                 ...
13 janv. 2011                    In Situ                In Serum: FibroTest                  Liver Injury                 ...
13 janv. 2011                    In Situ                In Serum: FibroTest                  Liver Injury                 ...
13 janv. 2011                    In Situ                In Serum: FibroTest                  Liver Injury                 ...
13 janv. 2011      In Situ events: Fibrosis and serum ApoA1 decrease                                                      ...
13 janv. 2011                   Haptoglobin   Hemopexinjeudi 13 janvier 2011
13 janv. 2011jeudi 13 janvier 2011
13 janv. 2011     FibroTest accuracy for the diagnosis of advanced fibrosis     • 38 Published Studies     • 7.985 Patients...
Kinetics of fibrosis according to baseline stages                             13 janv. 2011                          In HBV...
13 janv. 2011                 A New simple definition of low risk patients                                 Ngo PlosONE 2008...
13 janv. 2011             A New simple definition of HBV Inactive Carrier                              Viral Load < Log5   ...
13 janv. 2011     Survival according to definition of inactive carrier based on FibroTest-     ActiTest normal values in un...
13 janv. 2011     Summary:     FibroTest-ActiTest in patients with chronic hepatitis B     • Similar accuracy than in HCV,...
13 janv. 2011                     FibroTest: from blood donors to cirrhotics (n=1,570)                        1.00        ...
13 janv. 2011     Validated Fibrosis and Activity Biomarkers     500.000 prescriptions in 35 countries     Used by 80% of ...
13 janv. 2011                             F0                        Pas de Fibrosejeudi 13 janvier 2011
13 janv. 2011                             F1                        Fibrose minimejeudi 13 janvier 2011
13 janv. 2011                              F2                        Fibrose modéréejeudi 13 janvier 2011
13 janv. 2011                               F3                        Fibrose importantejeudi 13 janvier 2011
13 janv. 2011                             F4                        Fibrose sévèrejeudi 13 janvier 2011
13 janv. 2011     FibroTest prognostic value among HCV cirrhosis stage     1,457 patients followed 5 years                ...
HCV Survival according to FibroTest classes                         N=537 NGO Clin Chem 2006, Ngo Clin Chem 2008jeudi 13 j...
13 janv. 2011  5 year Prognostic Value of FibroTest versus Biopsy Fibrosis Staging  Survival Without HCV Complications    ...
13 janv. 2011     Prognostic value     • FibroTest in HCV: Ngo, Clin Chem 2006     • FibroTest in HBV: Ngo, PlosOne 2008  ...
13 janv. 2011     FibroTest validation in “difficult to diagnose patients”     • HIV-HCV: 	         Myers 2003, Cacoub 2008...
13 janv. 2011                   ActiTest vs ALT accuracy for the diagnosis                of necro-Inflammatory histologica...
13 janv. 2011                   ActiTest vs ALT accuracy for the diagnosis                of necro-Inflammatory histologica...
13 janv. 2011                   ActiTest vs ALT accuracy for the diagnosis                of necro-Inflammatory histologica...
13 janv. 2011                   ActiTest vs ALT accuracy for the diagnosis                of necro-Inflammatory histologica...
13 janv. 2011                   ActiTest vs ALT accuracy for the diagnosis                of necro-Inflammatory histologica...
FibroTest Global Quality Estimates                         High Risk                   High Risk                  False Po...
13 janv. 2011     Three high-risk populations for false positive/negative                        • Tertiary center: 1.97% ...
FibroTest    Pro                               Cons    Simple                            Applicability 98% (Hemolysis)    ...
Première Ligne (99%)                           Deuxième Ligne                        si risque FP/FN (1%)                 ...
jeudi 13 janvier 2011
13 janv. 2011     Elastography     • 11 Published studies     • n=2,260     • Standardized AUROC     • Advanced Fibrosis  ...
13 janv. 2011                        Oliveri WJG 2008jeudi 13 janvier 2011
13 janv. 2011                            Pitfalls of Fibroscan                 3.1% Failures and Unreliable results 15.8%j...
13 janv. 2011                                                              Choice of FibroScan Cutoffs    F4 0.73         ...
13 janv. 2011   HCV n=92   Mean Fibrotest and Actitest                 Baseline               12 weeks   24 weeks         ...
13 janv. 2011     HCV n=416     Median % changes Fibrosis estimates (12-24 month)                                     Fibr...
13 janv. 2011     HCV n=416     Mean FibroTest (range 0.00-1.00)                        Baseline              12mo/EOT    ...
13 janv. 2011   HCV n=416   Mean Liver Stiffness Measurements (range 0-75 kPa )                        Baseline           ...
13 janv. 2011     Message I: Appropriate methods           • Imperfect Gold Standard           • Spectrum bias           •...
13 janv. 2011     Imperfect Gold Standard: Summary     • Entire liver is the perfect Gold Standard     • Biopsy is an impe...
13 janv. 2011jeudi 13 janvier 2011
13 janv. 2011                        Bedossa Hepatology 2003jeudi 13 janvier 2011
13 janv. 2011                        Bedossa Hepatology 2003jeudi 13 janvier 2011
13 janv. 2011    AUROC 5 mm = 0.75    AUROC 15 mm = 0.82    AUROC 25 mm = 0.89                         Bedossa Hepatology ...
13 janv. 2011    AUROC 5 mm = 0.75    AUROC 15 mm = 0.82    AUROC 25 mm = 0.89  “We showed that with 25-mm long  biopsy sp...
13 janv. 2011     T Poynard, F Charlotte, G LeNahour, M Munteanujeudi 13 janvier 2011
13 janv. 2011     Gold-validation of liver fibrosis estimates,     FibroTest (FT) and liver stiffness measurement (LSM),   ...
13 janv. 2011     Virtual biopsy     Digitized image (Aperio Scanner, TRIBVN, France)     Increasing length     5/10/15/20...
13 janv. 2011     Virtual biopsy     Digitized image (Aperio Scanner, TRIBVN, France)     Increasing length               ...
13 janv. 2011     Virtual biopsy     Digitized image (Aperio Scanner, TRIBVN, France)     Increasing length               ...
13 janv. 2011     Virtual biopsy     Digitized image (Aperio Scanner, TRIBVN, France)     Increasing length               ...
13 janv. 2011     Virtual biopsy     Digitized image (Aperio Scanner, TRIBVN, France)     Increasing length               ...
13 janv. 2011     Virtual biopsy     Digitized image (Aperio Scanner, TRIBVN, France)     Increasing length               ...
13 janv. 2011     Virtual biopsy     Digitized image (Aperio Scanner, TRIBVN, France)     Increasing length               ...
13 janv. 2011     Virtual biopsy     Digitized image (Aperio Scanner, TRIBVN, France)     Increasing length               ...
13 janv. 2011     Virtual biopsy     Digitized image (Aperio Scanner, TRIBVN, France)     Increasing length               ...
13 janv. 2011                                        Area            METAVIR     Nb virtual   Fibrosis by                 ...
13 janv. 2011     FibroMAX: HCV-HBV-ALD-NAFLD                         64jeudi 13 janvier 2011
13 janv. 2011     FibroMAX: HCV-HBV-ALD-NAFLD                                    NashTest                   ActiTest      ...
13 janv. 2011     SteatoTest for Steatosis     744 patients 140 controls     GGT AUROC=0.66          SteatoTest           ...
13 janv. 2011     HCV-GenoFibroTest     A better prediction of virological response                                     Li...
13 janv. 2011jeudi 13 janvier 2011
13 janv. 2011     FibroMAX: HCV-HBV-ALD-NAFLD                          68jeudi 13 janvier 2011
13 janv. 2011     FibroMAX: HCV-HBV-ALD-NAFLD                                      NashTest                    ActiTest   ...
13 janv. 2011     HCV-GenoFibroTest: Liver injury, Virus Resistance, Host     Genes for treatment Response and Tolerance  ...
13 janv. 2011     IL28b, ITPA, UGT1A1 and prognostic factors of treatment     response in patients with chronic hepatitis ...
13 janv. 2011     Sustained Virologic Response (SVR)                                                • Independent Factors ...
13 janv. 2011     AUROCs for SVR     Training population = 0.743 (0.655-0.810; P<0.0001 vs random), not different (P=0.88)...
13 janv. 2011     Sustained Virologic Response     according to HCV-GenoFibroTest Score                                   ...
HCV Geno-FibroTest                                                                                                Ref #123...
13 janv. 2011     New concept in liver diseases     • Biomarkers are for Hepatologists           • the HDL-Cholesterol for...
100%          France: 12,000,000 at Risk                                   F0                                   F1        ...
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Biomarkers of liver injury.pdf

  1. 1. 13 janv. 2011 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 LiverCenterjeudi 13 janvier 2011
  2. 2. 13 janv. 2011 The «Biopsist» 2 Poynard J Hepatol 2010jeudi 13 janvier 2011
  3. 3. 13 janv. 2011 The «Biopsist» • Still recommends biopsy as the first-line estimate of liver injury 2 Poynard J Hepatol 2010jeudi 13 janvier 2011
  4. 4. 13 janv. 2011 The «Biopsist» • Still recommends biopsy as the first-line estimate of liver injury • Agrees that 2 Poynard J Hepatol 2010jeudi 13 janvier 2011
  5. 5. 13 janv. 2011 The «Biopsist» • Still recommends biopsy as the first-line estimate of liver injury • Agrees that • Biopsy is not a perfect gold standard but still believes that it is the best estimate 2 Poynard J Hepatol 2010jeudi 13 janvier 2011
  6. 6. 13 janv. 2011 The «Biopsist» • Still recommends biopsy as the first-line estimate of liver injury • Agrees that • Biopsy is not a perfect gold standard but still believes that it is the best estimate • In cases where biopsy is contraindicated, validated biomarkers should be recommended. 2 Poynard J Hepatol 2010jeudi 13 janvier 2011
  7. 7. 13 janv. 2011 The «Biopsist» • Still recommends biopsy as the first-line estimate of liver injury • Agrees that • Biopsy is not a perfect gold standard but still believes that it is the best estimate • In cases where biopsy is contraindicated, validated biomarkers should be recommended. • Biopsy is not recommended for screening of large populations. 2 Poynard J Hepatol 2010jeudi 13 janvier 2011
  8. 8. 13 janv. 2011 The «Biopsist» • Still recommends biopsy as the first-line estimate of liver injury • Agrees that • Biopsy is not a perfect gold standard but still believes that it is the best estimate • In cases where biopsy is contraindicated, validated biomarkers should be recommended. • Biopsy is not recommended for screening of large populations. • He rarely admits that in case of discordance between a validated biomarker and a 25 mm biopsy, the biopsy could be a false-positive or a false-negative. 2 Poynard J Hepatol 2010jeudi 13 janvier 2011
  9. 9. 13 janv. 2011 The «Biopsist» • Still recommends biopsy as the first-line estimate of liver injury • Agrees that • Biopsy is not a perfect gold standard but still believes that it is the best estimate • In cases where biopsy is contraindicated, validated biomarkers should be recommended. • Biopsy is not recommended for screening of large populations. • He rarely admits that in case of discordance between a validated biomarker and a 25 mm biopsy, the biopsy could be a false-positive or a false-negative. • He is typically the head of a Pathology unit. 2 Poynard J Hepatol 2010jeudi 13 janvier 2011
  10. 10. Biopsy first line If refused or not interpretable Biomarkers FibroTest ActiTestjeudi 13 janvier 2011
  11. 11. 13 janv. 2011 The "Biomarkerist" 4 Poynard J Hepatol 2010jeudi 13 janvier 2011
  12. 12. 13 janv. 2011 The "Biomarkerist" • Recommends validated biomarkers as the first-line estimate of liver injury 4 Poynard J Hepatol 2010jeudi 13 janvier 2011
  13. 13. 13 janv. 2011 The "Biomarkerist" • Recommends validated biomarkers as the first-line estimate of liver injury • Agrees that 4 Poynard J Hepatol 2010jeudi 13 janvier 2011
  14. 14. 13 janv. 2011 The "Biomarkerist" • Recommends validated biomarkers as the first-line estimate of liver injury • Agrees that • A biomarker is not a perfect test but believes that it is as accurate as a 25 mm long liver biopsy, with the same gray zones. 4 Poynard J Hepatol 2010jeudi 13 janvier 2011
  15. 15. 13 janv. 2011 The "Biomarkerist" • Recommends validated biomarkers as the first-line estimate of liver injury • Agrees that • A biomarker is not a perfect test but believes that it is as accurate as a 25 mm long liver biopsy, with the same gray zones. • In case of discordance between a biomarker and a 25 mm biopsy, he believes that the failure may be due to either the biomarker or the biopsy (50%/50%). 4 Poynard J Hepatol 2010jeudi 13 janvier 2011
  16. 16. 13 janv. 2011 The "Biomarkerist" • Recommends validated biomarkers as the first-line estimate of liver injury • Agrees that • A biomarker is not a perfect test but believes that it is as accurate as a 25 mm long liver biopsy, with the same gray zones. • In case of discordance between a biomarker and a 25 mm biopsy, he believes that the failure may be due to either the biomarker or the biopsy (50%/50%). • In order to be useful to clinicians, the biomarker of fibrosis must be available along with those of necrosis and steatosis. 4 Poynard J Hepatol 2010jeudi 13 janvier 2011
  17. 17. 13 janv. 2011 The "Biomarkerist" • Recommends validated biomarkers as the first-line estimate of liver injury • Agrees that • A biomarker is not a perfect test but believes that it is as accurate as a 25 mm long liver biopsy, with the same gray zones. • In case of discordance between a biomarker and a 25 mm biopsy, he believes that the failure may be due to either the biomarker or the biopsy (50%/50%). • In order to be useful to clinicians, the biomarker of fibrosis must be available along with those of necrosis and steatosis. • In case of non-interpretability of the biomarker, another biomarker should be recommended, and then if still not interpretable, a biopsy should be recommended as a third-line assessment. 4 Poynard J Hepatol 2010jeudi 13 janvier 2011
  18. 18. 13 janv. 2011 The "Biomarkerist" • Recommends validated biomarkers as the first-line estimate of liver injury • Agrees that • A biomarker is not a perfect test but believes that it is as accurate as a 25 mm long liver biopsy, with the same gray zones. • In case of discordance between a biomarker and a 25 mm biopsy, he believes that the failure may be due to either the biomarker or the biopsy (50%/50%). • In order to be useful to clinicians, the biomarker of fibrosis must be available along with those of necrosis and steatosis. • In case of non-interpretability of the biomarker, another biomarker should be recommended, and then if still not interpretable, a biopsy should be recommended as a third-line assessment. • He is typically the inventor of a biomarker. 4 Poynard J Hepatol 2010jeudi 13 janvier 2011
  19. 19. FibroTest ActiTest A la Parisienne Fibrotest 98% First Line If not interpretable Fibroscan If not interpretable <1% Biopsyjeudi 13 janvier 2011
  20. 20. 13 janv. 2011 The «BioCocktailist» (1) 6 Poynard J Hepatol 2010jeudi 13 janvier 2011
  21. 21. 13 janv. 2011 The «BioCocktailist» (1) • Recommends biomarker first and then biopsy if the biomarker result is not convincing 6 Poynard J Hepatol 2010jeudi 13 janvier 2011
  22. 22. 13 janv. 2011 The «BioCocktailist» (1) • Recommends biomarker first and then biopsy if the biomarker result is not convincing • 2 Subtypes: 6 Poynard J Hepatol 2010jeudi 13 janvier 2011
  23. 23. 13 janv. 2011 The «BioCocktailist» (1) • Recommends biomarker first and then biopsy if the biomarker result is not convincing • 2 Subtypes: • «Sequentialist» 6 Poynard J Hepatol 2010jeudi 13 janvier 2011
  24. 24. 13 janv. 2011 The «BioCocktailist» (1) • Recommends biomarker first and then biopsy if the biomarker result is not convincing • 2 Subtypes: • «Sequentialist» • Starts with one biomarker and recommends biopsy if the result belongs in what he calls a "gray zone"F1/ F2 6 Poynard J Hepatol 2010jeudi 13 janvier 2011
  25. 25. 13 janv. 2011 The «BioCocktailist» (1) • Recommends biomarker first and then biopsy if the biomarker result is not convincing • 2 Subtypes: • «Sequentialist» • Starts with one biomarker and recommends biopsy if the result belongs in what he calls a "gray zone"F1/ F2 • He seems to take the results of the biopsy in the gray zone as the truth without risk of false positive/ negative, even with small length (< 25mm) biopsies. 6 Poynard J Hepatol 2010jeudi 13 janvier 2011
  26. 26. Sequentialist Fibrotest or FibroScan FibroTest ActiTest First Line If F1or F2 Biopsyjeudi 13 janvier 2011
  27. 27. Biopsy has the same «Gray Zone» Bedossa Hepatology 2003 25mm Biopsy F4-F3 F2-F1 F1-F0 25% 25% 25% False PositiveFalse Positive and Negative False Negativejeudi 13 janvier 2011
  28. 28. 13 janv. 2011 The BioCocktailist (2) 9 Poynard J Hepatol 2010jeudi 13 janvier 2011
  29. 29. 13 janv. 2011 The BioCocktailist (2) • «Discordantist» 9 Poynard J Hepatol 2010jeudi 13 janvier 2011
  30. 30. 13 janv. 2011 The BioCocktailist (2) • «Discordantist» • Performs two biomarkers and recommends biopsy only in case of discordance. 9 Poynard J Hepatol 2010jeudi 13 janvier 2011
  31. 31. 13 janv. 2011 The BioCocktailist (2) • «Discordantist» • Performs two biomarkers and recommends biopsy only in case of discordance. • He finally believes in the result supported by the concordance between one of the biomarkers and biopsy. 9 Poynard J Hepatol 2010jeudi 13 janvier 2011
  32. 32. 13 janv. 2011 The BioCocktailist (2) • «Discordantist» • Performs two biomarkers and recommends biopsy only in case of discordance. • He finally believes in the result supported by the concordance between one of the biomarkers and biopsy. • The BioCocktailist is typically a friend of one "Biopsist" and two "Biomarkerists". 9 Poynard J Hepatol 2010jeudi 13 janvier 2011
  33. 33. A la Bordelaise Fibrotest and FibroScan FibroTest ActiTest First Line If discordance Biopsyjeudi 13 janvier 2011
  34. 34. 13 janv. 2011 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 11jeudi 13 janvier 2011
  35. 35. 13 janv. 2011 10 years of claims for diagnostic procedures 1993-2003: Severe Adverse Events and Deaths (French Insurance) Poynard T. Rev Med Interne 2007jeudi 13 janvier 2011
  36. 36. 13 janv. 2011 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 Poynard T. Rev Med Interne 2007jeudi 13 janvier 2011
  37. 37. 13 janv. 2011 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 2007jeudi 13 janvier 2011
  38. 38. Fibrotic Liver Disease F0 F1 F2 F3 F4 Hemorrhage Liver failure Cancer Poynard Lancet 1997jeudi 13 janvier 2011
  39. 39. Fibrotic Liver Disease F0 Reassure and follow F1 F2 F3 F4 Hemorrhage Liver failure Cancer Poynard Lancet 1997jeudi 13 janvier 2011
  40. 40. Fibrotic Liver Disease F0 Reassure and follow F1 Treatment of the cause F2 Prediction of response to treatment F3 F4 Hemorrhage Liver failure Cancer Poynard Lancet 1997jeudi 13 janvier 2011
  41. 41. Fibrotic Liver Disease F0 Reassure and follow F1 Treatment of the cause F2 Prediction of response to treatment F3 Prevention cirrhosis complications F4 Hemorrhage Liver failure Cancer Poynard Lancet 1997jeudi 13 janvier 2011
  42. 42. Fibrotic Liver Disease F0 Reassure and follow F1 Treatment of the cause F2 Prediction of response to treatment F3 Prevention cirrhosis complications F4 Hemorrhage Liver failure Cancer Cost Complications: 50-100 k€ Poynard Lancet 1997jeudi 13 janvier 2011
  43. 43. 13 janv. 2011 Fibrosis biomarkers: 20 years history Poynard SJG 2008 n=100 n=500.000jeudi 13 janvier 2011
  44. 44. 13 janv. 2011 Fibrosis biomarkers: 20 years history Poynard SJG 2008jeudi 13 janvier 2011
  45. 45. Validated biomarkers FibroTest Fibroscan Pinzani, Castera Lancet 2010jeudi 13 janvier 2011
  46. 46. 13 janv. 2011 FibroMAX: HCV-HBV-ALD-NAFLD 17jeudi 13 janvier 2011
  47. 47. 13 janv. 2011 FibroMAX: HCV-HBV-ALD-NAFLD NashTest ActiTest AshTest FibroMAX FibroTest SteatoTest 17jeudi 13 janvier 2011
  48. 48. 13 janv. 2011 Anticipated Frequently Asked Questionsjeudi 13 janvier 2011
  49. 49. 13 janv. 2011 Anticipated Frequently Asked Questions • Is the perfect fibrosis biomarker possible? Nojeudi 13 janvier 2011
  50. 50. 13 janv. 2011 Anticipated Frequently Asked Questions • Is the perfect fibrosis biomarker possible? No • There is a "gray zone" or "inaccurate zone" between intermediate stages? Nojeudi 13 janvier 2011
  51. 51. 13 janv. 2011 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... Yesjeudi 13 janvier 2011
  52. 52. 13 janv. 2011 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? Yesjeudi 13 janvier 2011
  53. 53. 13 janv. 2011 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? Yesjeudi 13 janvier 2011
  54. 54. 13 janv. 2011 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? Yesjeudi 13 janvier 2011
  55. 55. 13 janv. 2011 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? Yesjeudi 13 janvier 2011
  56. 56. 13 janv. 2011 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? Yesjeudi 13 janvier 2011
  57. 57. 13 janv. 2011 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? Yesjeudi 13 janvier 2011
  58. 58. 13 janv. 2011 Rational of FibroTest: Imbert Bismut 2001, Langlois 2006, Watanabe 2009, Ho 2010jeudi 13 janvier 2011
  59. 59. 13 janv. 2011 Rational of FibroTest: • Alpha 2 macroglobulin: key protein for Collagenase metabolism Imbert Bismut 2001, Langlois 2006, Watanabe 2009, Ho 2010jeudi 13 janvier 2011
  60. 60. 13 janv. 2011 Rational of FibroTest: • Alpha 2 macroglobulin: key protein for Collagenase metabolism • Apolipoprotein A1 key protein for Collagen trapping Imbert Bismut 2001, Langlois 2006, Watanabe 2009, Ho 2010jeudi 13 janvier 2011
  61. 61. 13 janv. 2011 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 Imbert Bismut 2001, Langlois 2006, Watanabe 2009, Ho 2010jeudi 13 janvier 2011
  62. 62. 13 janv. 2011 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 Imbert Bismut 2001, Langlois 2006, Watanabe 2009, Ho 2010jeudi 13 janvier 2011
  63. 63. 13 janv. 2011 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 Imbert Bismut 2001, Langlois 2006, Watanabe 2009, Ho 2010jeudi 13 janvier 2011
  64. 64. 13 janv. 2011 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) Imbert Bismut 2001, Langlois 2006, Watanabe 2009, Ho 2010jeudi 13 janvier 2011
  65. 65. 13 janv. 2011 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 Imbert Bismut 2001, Langlois 2006, Watanabe 2009, Ho 2010jeudi 13 janvier 2011
  66. 66. 13 janv. 2011 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, A2M Imbert Bismut 2001, Langlois 2006, Watanabe 2009, Ho 2010jeudi 13 janvier 2011
  67. 67. 13 janv. 2011 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, A2M • Haptoglobin Imbert Bismut 2001, Langlois 2006, Watanabe 2009, Ho 2010jeudi 13 janvier 2011
  68. 68. 13 janv. 2011 Novel biomarkers predict liver fibrosis in hepatitis C patients: alpha 2 macroglobulin, vitamin D binding protein and apolipoprotein AIjeudi 13 janvier 2011
  69. 69. 13 janv. 2011 Imbert-Bismut, Lancet 2001jeudi 13 janvier 2011
  70. 70. 13 janv. 2011 In Situ Imbert-Bismut, Lancet 2001jeudi 13 janvier 2011
  71. 71. 13 janv. 2011 In Situ In Serum: FibroTest Imbert-Bismut, Lancet 2001jeudi 13 janvier 2011
  72. 72. 13 janv. 2011 In Situ In Serum: FibroTest Liver Injury Fibrotic Matrix Activated Stellate Cells Imbert-Bismut, Lancet 2001jeudi 13 janvier 2011
  73. 73. 13 janv. 2011 In Situ In Serum: FibroTest Liver Injury Alpha2Macroglobulin Fibrotic Matrix Activated Stellate Cells Imbert-Bismut, Lancet 2001jeudi 13 janvier 2011
  74. 74. 13 janv. 2011 In Situ In Serum: FibroTest Liver Injury Alpha2Macroglobulin Total Bilirubin Fibrotic Matrix Activated Stellate Cells Imbert-Bismut, Lancet 2001jeudi 13 janvier 2011
  75. 75. 13 janv. 2011 In Situ In Serum: FibroTest Liver Injury Alpha2Macroglobulin Total Bilirubin Gamma GT Fibrotic Matrix Activated Stellate Cells Imbert-Bismut, Lancet 2001jeudi 13 janvier 2011
  76. 76. 13 janv. 2011 In Situ In Serum: FibroTest Liver Injury Alpha2Macroglobulin Total Bilirubin Gamma GT Fibrotic Matrix Activated Stellate Cells Imbert-Bismut, Lancet 2001jeudi 13 janvier 2011
  77. 77. 13 janv. 2011 In Situ In Serum: FibroTest Liver Injury Alpha2Macroglobulin Total Bilirubin Gamma GT Fibrotic Matrix Activated Stellate Cells Haptoglobin Imbert-Bismut, Lancet 2001jeudi 13 janvier 2011
  78. 78. 13 janv. 2011 In Situ In Serum: FibroTest Liver Injury Alpha2Macroglobulin Total Bilirubin Gamma GT Apolipoprotein A1 Fibrotic Matrix Activated Stellate Cells Haptoglobin Imbert-Bismut, Lancet 2001jeudi 13 janvier 2011
  79. 79. 13 janv. 2011 In Situ In Serum: FibroTest Liver Injury Alpha2Macroglobulin Total Bilirubin Gamma GT Apolipoprotein A1 Fibrotic Matrix Activated Stellate Cells Haptoglobin Imbert-Bismut, Lancet 2001jeudi 13 janvier 2011
  80. 80. 13 janv. 2011 In Situ events: Fibrosis and serum ApoA1 decrease Trapping Apo A1 Down Regulation Paradis Cell Mol Biol 1996, Paradis Hepatology 1996, Mathurin Hepatology 1996.jeudi 13 janvier 2011
  81. 81. 13 janv. 2011 Haptoglobin Hemopexinjeudi 13 janvier 2011
  82. 82. 13 janv. 2011jeudi 13 janvier 2011
  83. 83. 13 janv. 2011 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 Halfon et al GCB 2008jeudi 13 janvier 2011
  84. 84. Kinetics of fibrosis according to baseline stages 13 janv. 2011 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 2005jeudi 13 janvier 2011
  85. 85. 13 janv. 2011 A New simple definition of low risk patients Ngo PlosONE 2008jeudi 13 janvier 2011
  86. 86. 13 janv. 2011 A New simple definition of HBV Inactive Carrier Viral Load < Log5 + FibroTest<= 0.27 ActiTest <= 0.29 Ngo PlosONE 2008jeudi 13 janvier 2011
  87. 87. 13 janv. 2011 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 2008jeudi 13 janvier 2011
  88. 88. 13 janv. 2011 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 30jeudi 13 janvier 2011
  89. 89. 13 janv. 2011 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 2004jeudi 13 janvier 2011
  90. 90. 13 janv. 2011 Validated Fibrosis and Activity Biomarkers 500.000 prescriptions in 35 countries Used by 80% of French Hepatologists, first line FibroTest ActiTest Castera J Hepatol 2007 32jeudi 13 janvier 2011
  91. 91. 13 janv. 2011 F0 Pas de Fibrosejeudi 13 janvier 2011
  92. 92. 13 janv. 2011 F1 Fibrose minimejeudi 13 janvier 2011
  93. 93. 13 janv. 2011 F2 Fibrose modéréejeudi 13 janvier 2011
  94. 94. 13 janv. 2011 F3 Fibrose importantejeudi 13 janvier 2011
  95. 95. 13 janv. 2011 F4 Fibrose sévèrejeudi 13 janvier 2011
  96. 96. 13 janv. 2011 FibroTest prognostic value among HCV cirrhosis stage 1,457 patients followed 5 years De Ledhingen EASL 2010jeudi 13 janvier 2011
  97. 97. HCV Survival according to FibroTest classes N=537 NGO Clin Chem 2006, Ngo Clin Chem 2008jeudi 13 janvier 2011
  98. 98. 13 janv. 2011 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 40jeudi 13 janvier 2011
  99. 99. 13 janv. 2011 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 41jeudi 13 janvier 2011
  100. 100. 13 janv. 2011 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 42jeudi 13 janvier 2011
  101. 101. 13 janv. 2011 ActiTest vs ALT accuracy for the diagnosis of necro-Inflammatory histological activity grade in 1,250 patients with chronic hepatitis C * m (se) One test for all grades pairwise area under the ROC curves comparisonsjeudi 13 janvier 2011
  102. 102. 13 janv. 2011 ActiTest vs ALT accuracy for the diagnosis of necro-Inflammatory histological activity grade in 1,250 patients with chronic hepatitis C ActiTest ALT Significance Obuchowski* Measure 0.848 (0.005) 0.834 (0.006) P= 0.008 * m (se) One test for all grades pairwise area under the ROC curves comparisonsjeudi 13 janvier 2011
  103. 103. 13 janv. 2011 ActiTest vs ALT accuracy for the diagnosis of necro-Inflammatory histological activity grade in 1,250 patients with chronic hepatitis C ActiTest ALT Significance Obuchowski* Measure 0.848 (0.005) 0.834 (0.006) P= 0.008 * m (se) One test for all grades pairwise area under the ROC curves comparisonsjeudi 13 janvier 2011
  104. 104. 13 janv. 2011 ActiTest vs ALT accuracy for the diagnosis of necro-Inflammatory histological activity grade in 1,250 patients with chronic hepatitis C ActiTest ALT Significance Obuchowski* Measure 0.848 (0.005) 0.834 (0.006) P= 0.008 * m (se) One test for all grades pairwise area under the ROC curves comparisonsjeudi 13 janvier 2011
  105. 105. 13 janv. 2011 ActiTest vs ALT accuracy for the diagnosis of necro-Inflammatory histological activity grade in 1,250 patients with chronic hepatitis C ActiTest ALT Significance Obuchowski* Measure 0.848 (0.005) 0.834 (0.006) P= 0.008 * m (se) One test for all grades pairwise area under the ROC curves comparisonsjeudi 13 janvier 2011
  106. 106. FibroTest Global Quality Estimates High Risk High Risk False Positive Negative False Positive Negative 5/954 (0.52%) 38/7494 (0.51%) FibroScan (Roulot et al 2008) >7.1 kPa= 12.6%: False Positives ? High Risk High Risk False Positive Negative False Positive Negative Poynard EASL 2010, Roulot J Hepatol 2008 3349/345,695 (0.97%) 491/24,872 (1.97%)jeudi 13 janvier 2011
  107. 107. 13 janv. 2011 Three high-risk populations for false positive/negative • Tertiary center: 1.97% • HIV co-infection: 1.77% • Sub-Saharan origin: 2.61% 45jeudi 13 janvier 2011
  108. 108. FibroTest Pro Cons Simple Applicability 98% (Hemolysis) Blood Precautions of use Accurate for F0F1F2F3F4jeudi 13 janvier 2011
  109. 109. Première Ligne (99%) Deuxième Ligne si risque FP/FN (1%) Troisième Ligne si discordancejeudi 13 janvier 2011
  110. 110. jeudi 13 janvier 2011
  111. 111. 13 janv. 2011 Elastography • 11 Published studies • n=2,260 • Standardized AUROC • Advanced Fibrosis • 0.89 (0.84-0.95) Friedrich Rust et al Gastroenterology 2008, Poynard et al SJG 2008 49jeudi 13 janvier 2011
  112. 112. 13 janv. 2011 Oliveri WJG 2008jeudi 13 janvier 2011
  113. 113. 13 janv. 2011 Pitfalls of Fibroscan 3.1% Failures and Unreliable results 15.8%jeudi 13 janvier 2011
  114. 114. 13 janv. 2011 Choice of FibroScan Cutoffs F4 0.73 Castera 2005, Ketanneh 2007 Roulot 2008 For F2: 7.1 or 8.8 kPa ? F2 0.48 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 ? F2 8.8 kPa F4 14.5 kPa No rationale for changing cutoff according to liver disease Poynard PlosOne 2008jeudi 13 janvier 2011
  115. 115. 13 janv. 2011 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 2006jeudi 13 janvier 2011
  116. 116. 13 janv. 2011 HCV n=416 Median % changes Fibrosis estimates (12-24 month) FibroTest Fibroscan 10% 5% 0% -5% -10% -15% -20% -25% Control (n=304) -30% NR (n=27) SVR (n=70) Vergniol et al JVH 2009jeudi 13 janvier 2011
  117. 117. 13 janv. 2011 HCV n=416 Mean FibroTest (range 0.00-1.00) Baseline 12mo/EOT 24mo/EOF Slow decrease = Not related to activity Slow increase = Sensitivity 0,60 0,48 0,36 0,24 0,12 Control (n=304) 0 SVR (n=70) Vergniol et al JVH 2009jeudi 13 janvier 2011
  118. 118. 13 janv. 2011 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 2009jeudi 13 janvier 2011
  119. 119. 13 janv. 2011 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 2008jeudi 13 janvier 2011
  120. 120. 13 janv. 2011 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 Standard Bedossa Hepatology 2003, Poynard Clin Chem 2005, Poynard Clin Chem 2007, Poynard GCB 2008jeudi 13 janvier 2011
  121. 121. 13 janv. 2011jeudi 13 janvier 2011
  122. 122. 13 janv. 2011 Bedossa Hepatology 2003jeudi 13 janvier 2011
  123. 123. 13 janv. 2011 Bedossa Hepatology 2003jeudi 13 janvier 2011
  124. 124. 13 janv. 2011 AUROC 5 mm = 0.75 AUROC 15 mm = 0.82 AUROC 25 mm = 0.89 Bedossa Hepatology 2003jeudi 13 janvier 2011
  125. 125. 13 janv. 2011 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 2003jeudi 13 janvier 2011
  126. 126. 13 janv. 2011 T Poynard, F Charlotte, G LeNahour, M Munteanujeudi 13 janvier 2011
  127. 127. 13 janv. 2011 Gold-validation of liver fibrosis estimates, FibroTest (FT) and liver stiffness measurement (LSM), using surgical samples and virtual biopsies T Poynard, F Charlotte, G LeNahour, M Munteanujeudi 13 janvier 2011
  128. 128. 13 janv. 2011 Virtual biopsy Digitized image (Aperio Scanner, TRIBVN, France) Increasing length 5/10/15/20/25/30mmjeudi 13 janvier 2011
  129. 129. 13 janv. 2011 Virtual biopsy Digitized image (Aperio Scanner, TRIBVN, France) Increasing length 22,119 virtual biopsies 5/10/15/20/25/30mmjeudi 13 janvier 2011
  130. 130. 13 janv. 2011 Virtual biopsy Digitized image (Aperio Scanner, TRIBVN, France) Increasing length 22,119 virtual biopsies 5/10/15/20/25/30mm 18 operated subjectsjeudi 13 janvier 2011
  131. 131. 13 janv. 2011 Virtual biopsy Digitized image (Aperio Scanner, TRIBVN, France) Increasing length 22,119 virtual biopsies 5/10/15/20/25/30mm 18 operated subjects •5,106 HCVjeudi 13 janvier 2011
  132. 132. 13 janv. 2011 Virtual biopsy Digitized image (Aperio Scanner, TRIBVN, France) Increasing length 22,119 virtual biopsies 5/10/15/20/25/30mm 18 operated subjects •5,106 HCV •4,572 ALDjeudi 13 janvier 2011
  133. 133. 13 janv. 2011 Virtual biopsy Digitized image (Aperio Scanner, TRIBVN, France) Increasing length 22,119 virtual biopsies 5/10/15/20/25/30mm 18 operated subjects •5,106 HCV •4,572 ALD •3,240 NAFLDjeudi 13 janvier 2011
  134. 134. 13 janv. 2011 Virtual biopsy Digitized image (Aperio Scanner, TRIBVN, France) Increasing length 22,119 virtual biopsies 5/10/15/20/25/30mm 18 operated subjects •5,106 HCV •4,572 ALD •3,240 NAFLD •2,988 HBVjeudi 13 janvier 2011
  135. 135. 13 janv. 2011 Virtual biopsy Digitized image (Aperio Scanner, TRIBVN, France) Increasing length 22,119 virtual biopsies 5/10/15/20/25/30mm 18 operated subjects •5,106 HCV •4,572 ALD •3,240 NAFLD •2,988 HBV •1,548 PBCjeudi 13 janvier 2011
  136. 136. 13 janv. 2011 Virtual biopsy Digitized image (Aperio Scanner, TRIBVN, France) Increasing length 22,119 virtual biopsies 5/10/15/20/25/30mm 18 operated subjects •5,106 HCV •4,572 ALD •3,240 NAFLD •2,988 HBV •1,548 PBC •4,665 controlsjeudi 13 janvier 2011
  137. 137. 13 janv. 2011 Area METAVIR Nb virtual Fibrosis by Fibrotest LSM Stage biopsies Image Analysis Mean (95%CI) F0 780 3.8 (3.5-4.0) 0.00-0.27 0.0-5.0 F1 137 5.0 (4.5-5.3) 0.28-0.48 5.1-8.8 F2 768 7.1 (8.0-8.5) 0.49-0.58 8.9-12.0 F3 270 9.1 (7.9-10.1) 0.59-0.74 12.1-14.5 F4 1734 18.2 (16.5-17.6) 0.75-1.00 14.6-75.0jeudi 13 janvier 2011
  138. 138. 13 janv. 2011 FibroMAX: HCV-HBV-ALD-NAFLD 64jeudi 13 janvier 2011
  139. 139. 13 janv. 2011 FibroMAX: HCV-HBV-ALD-NAFLD NashTest ActiTest AshTest FibroMAX FibroTest SteatoTest 64jeudi 13 janvier 2011
  140. 140. 13 janv. 2011 SteatoTest for Steatosis 744 patients 140 controls GGT AUROC=0.66 SteatoTest AUROC=0.80 ALT AUROC=0.61 Poynard Comp Hepatol 2005jeudi 13 janvier 2011
  141. 141. 13 janv. 2011 HCV-GenoFibroTest A better prediction of virological response LiverCenterjeudi 13 janvier 2011
  142. 142. 13 janv. 2011jeudi 13 janvier 2011
  143. 143. 13 janv. 2011 FibroMAX: HCV-HBV-ALD-NAFLD 68jeudi 13 janvier 2011
  144. 144. 13 janv. 2011 FibroMAX: HCV-HBV-ALD-NAFLD NashTest ActiTest AshTest FibroMAX FibroTest SteatoTest 68jeudi 13 janvier 2011
  145. 145. 13 janv. 2011 HCV-GenoFibroTest: Liver injury, Virus Resistance, Host Genes for treatment Response and Tolerance Genotype Viral Load IL28B Viral Resistance ITPA HCV- ActiTest GenoFibroTest UGT1A1 FibroTest SteatoTest 69jeudi 13 janvier 2011
  146. 146. 13 janv. 2011 IL28b, ITPA, UGT1A1 and prognostic factors of treatment response in patients with chronic hepatitis C Jean Marc Costa, Mona Munteanu, Yen Ngo, Vincent Thibault, Moussalli Joseph, Vlad Ratziu, Yves Benhamou, Jean Dominique Poveda and Thierry Poynard. Clinics and Research in Hepatology and Gastroenterology, 2011 LiverCenterjeudi 13 janvier 2011
  147. 147. 13 janv. 2011 Sustained Virologic Response (SVR) • Independent Factors (OR; P value) 100 • Genotype 2/3 (5.7 <0.0001) 63% 75 47% 50 • IL28B CC (4.8 <0.0001) 25 0 SVR • FibroTest low (4.2 0.03) Training Validation • ActiTest high (3.9 0.03) • Viral load <5.8 Log (1.9 0.03) Costa CRHG 2011jeudi 13 janvier 2011
  148. 148. 13 janv. 2011 AUROCs for SVR Training population = 0.743 (0.655-0.810; P<0.0001 vs random), not different (P=0.88) than Validation population = 0.753 (0.616-849; P=0.0007 vs random). Costa CRHG 2011jeudi 13 janvier 2011
  149. 149. 13 janv. 2011 Sustained Virologic Response according to HCV-GenoFibroTest Score 100% 75% SVR 50% 94% 44% 61% 25% 19% 0-0.25 (n=42) 0.25-0.50 (n=90) 0% 0.50-0.75 (n=69) 0.75-1 (n=35) HCV-GenoFibroTest Score Costa CRHG 2011jeudi 13 janvier 2011
  150. 150. HCV Geno-FibroTest Ref #123456 Internal reference : TEST http://www.biopredictive.com/ Patient Biomarkers Hepatitis C Birth date 1935-09-22 Sample date 2009-05-06 HCV Viral Load 250000 Sex Female Alpha2 3.12 g/l HCV Genotype Genotype 2 Macroglobulin IL28B Genotype C/C Apolipoprotein A1 1.82 g/l Bilirubin 13.00 Ämol/l Haptoglobin 1.18 g/l Gamma GT 149.00 IU/l ALT 47.00 IU/l Tests results FibroTest ActiTest HCV Geno-FibroTest FibroTest assesses the ActiTest assesses activity Chance of sustained fibrosis of the liver (inflammation in chronic virological response. viral hepatitis C or B) Score: 0.72 Score: 0.41 Score: 0.14 (F3) (A1-A2) (SVR ++) F3: advanced fibrosis A1-A2: minimal activity SVR ++: very good response Precautions of use and interpretability Å The reliability of results is dependent on compliance with the preanalytical and analytical conditions recommended by BioPredictive. Å The Tests have to be deferred for: acute hemolysis, acute hepatitis, acute inflammation, extra hepatic cholestasis. Å The advice of a specialist should be sought for interpretation in chronic hemolysis and Gilberts syndrome. Å The Test interpretation is not validated in liver transplant patients. Å Isolated extreme values of one of the components should lead to caution in interpreting the results. Å In case of discordance between a biopsy result and a Test, it is recommended to seek the advice of a specialist. The causes of these discordances could be due to a flaw of the Test or to a flaw in the biopsy: i.e. a liver biopsy has a 33% variability rate for one fibrosis stage Å FibroTest is interpretable for chronic hepatitis B and C, alcoholic and non alcoholic steatosis. Å ActiTest is interpretable for chronic hepatitis B and C. Å HCV Geno-FibroTest is interpretable when FibroTest is interpretable and when the IL28b genotype is interpretable. C/C : good response, C/T : intermediate response, T/T : poor response.jeudi 13 janvier 2011
  151. 151. 13 janv. 2011 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 75jeudi 13 janvier 2011
  152. 152. 100% France: 12,000,000 at Risk F0 F1 10% F2 Biomarker F3 5% F4 0.1% Death 15,000/yearjeudi 13 janvier 2011

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