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
LiverCenter
jeudi 13 janvier 2011
2. 13 janv. 2011
The «Biopsist»
2 Poynard J Hepatol 2010
jeudi 13 janvier 2011
3. 13 janv. 2011
The «Biopsist»
• Still recommends biopsy as the first-line estimate of liver injury
2 Poynard J Hepatol 2010
jeudi 13 janvier 2011
4. 13 janv. 2011
The «Biopsist»
• Still recommends biopsy as the first-line estimate of liver injury
• Agrees that
2 Poynard J Hepatol 2010
jeudi 13 janvier 2011
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 2010
jeudi 13 janvier 2011
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 2010
jeudi 13 janvier 2011
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 2010
jeudi 13 janvier 2011
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 2010
jeudi 13 janvier 2011
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 2010
jeudi 13 janvier 2011
10. Biopsy first line
If refused or not
interpretable
Biomarkers
FibroTest ActiTest
jeudi 13 janvier 2011
11. 13 janv. 2011
The "Biomarkerist"
4 Poynard J Hepatol 2010
jeudi 13 janvier 2011
12. 13 janv. 2011
The "Biomarkerist"
• Recommends validated biomarkers as the first-line estimate of liver injury
4 Poynard J Hepatol 2010
jeudi 13 janvier 2011
13. 13 janv. 2011
The "Biomarkerist"
• Recommends validated biomarkers as the first-line estimate of liver injury
• Agrees that
4 Poynard J Hepatol 2010
jeudi 13 janvier 2011
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 2010
jeudi 13 janvier 2011
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 2010
jeudi 13 janvier 2011
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 2010
jeudi 13 janvier 2011
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 2010
jeudi 13 janvier 2011
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 2010
jeudi 13 janvier 2011
19. FibroTest ActiTest
A la Parisienne
Fibrotest 98%
First Line
If not interpretable
Fibroscan
If not interpretable <1%
Biopsy
jeudi 13 janvier 2011
20. 13 janv. 2011
The «BioCocktailist» (1)
6 Poynard J Hepatol 2010
jeudi 13 janvier 2011
21. 13 janv. 2011
The «BioCocktailist» (1)
• Recommends biomarker first and then biopsy if the
biomarker result is not convincing
6 Poynard J Hepatol 2010
jeudi 13 janvier 2011
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 2010
jeudi 13 janvier 2011
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 2010
jeudi 13 janvier 2011
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 2010
jeudi 13 janvier 2011
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 2010
jeudi 13 janvier 2011
26. Sequentialist
Fibrotest or FibroScan
FibroTest ActiTest First Line
If F1or F2
Biopsy
jeudi 13 janvier 2011
27. 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
jeudi 13 janvier 2011
28. 13 janv. 2011
The BioCocktailist (2)
9 Poynard J Hepatol 2010
jeudi 13 janvier 2011
29. 13 janv. 2011
The BioCocktailist (2)
• «Discordantist»
9 Poynard J Hepatol 2010
jeudi 13 janvier 2011
30. 13 janv. 2011
The BioCocktailist (2)
• «Discordantist»
• Performs two biomarkers and recommends
biopsy only in case of discordance.
9 Poynard J Hepatol 2010
jeudi 13 janvier 2011
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 2010
jeudi 13 janvier 2011
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 2010
jeudi 13 janvier 2011
33. A la Bordelaise
Fibrotest and FibroScan
FibroTest ActiTest First Line
If discordance
Biopsy
jeudi 13 janvier 2011
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
11
jeudi 13 janvier 2011
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 2007
jeudi 13 janvier 2011
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 2007
jeudi 13 janvier 2011
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 2007
jeudi 13 janvier 2011
38. Fibrotic Liver
Disease
F0
F1
F2
F3
F4
Hemorrhage Liver failure Cancer
Poynard Lancet 1997
jeudi 13 janvier 2011
39. Fibrotic Liver
Disease
F0
Reassure and follow
F1
F2
F3
F4
Hemorrhage Liver failure Cancer
Poynard Lancet 1997
jeudi 13 janvier 2011
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 1997
jeudi 13 janvier 2011
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 1997
jeudi 13 janvier 2011
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 1997
jeudi 13 janvier 2011
43. 13 janv. 2011
Fibrosis biomarkers: 20 years history
Poynard SJG 2008
n=100
n=500.000
jeudi 13 janvier 2011
44. 13 janv. 2011
Fibrosis biomarkers: 20 years history
Poynard SJG 2008
jeudi 13 janvier 2011
49. 13 janv. 2011
Anticipated Frequently Asked Questions
• Is the perfect fibrosis biomarker possible? No
jeudi 13 janvier 2011
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? No
jeudi 13 janvier 2011
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... Yes
jeudi 13 janvier 2011
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? Yes
jeudi 13 janvier 2011
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? Yes
jeudi 13 janvier 2011
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? Yes
jeudi 13 janvier 2011
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? Yes
jeudi 13 janvier 2011
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? Yes
jeudi 13 janvier 2011
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? Yes
jeudi 13 janvier 2011
58. 13 janv. 2011
Rational of FibroTest:
Imbert Bismut 2001, Langlois 2006, Watanabe 2009, Ho 2010
jeudi 13 janvier 2011
59. 13 janv. 2011
Rational of FibroTest:
• Alpha 2 macroglobulin: key protein for Collagenase metabolism
Imbert Bismut 2001, Langlois 2006, Watanabe 2009, Ho 2010
jeudi 13 janvier 2011
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 2010
jeudi 13 janvier 2011
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 2010
jeudi 13 janvier 2011
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 2010
jeudi 13 janvier 2011
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 2010
jeudi 13 janvier 2011
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 2010
jeudi 13 janvier 2011
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 2010
jeudi 13 janvier 2011
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 2010
jeudi 13 janvier 2011
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 2010
jeudi 13 janvier 2011
68. 13 janv. 2011
Novel biomarkers predict liver fibrosis in hepatitis C patients:
alpha 2 macroglobulin, vitamin D binding protein and apolipoprotein AI
jeudi 13 janvier 2011
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 2008
jeudi 13 janvier 2011
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 2005
jeudi 13 janvier 2011
85. 13 janv. 2011
A New simple definition of low risk patients
Ngo PlosONE 2008
jeudi 13 janvier 2011
86. 13 janv. 2011
A New simple definition of HBV Inactive Carrier
Viral Load < Log5
+
FibroTest<= 0.27 ActiTest <= 0.29
Ngo PlosONE 2008
jeudi 13 janvier 2011
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 2008
jeudi 13 janvier 2011
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
30
jeudi 13 janvier 2011
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 2004
jeudi 13 janvier 2011
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
32
jeudi 13 janvier 2011
91. 13 janv. 2011
F0
Pas de Fibrose
jeudi 13 janvier 2011
92. 13 janv. 2011
F1
Fibrose minime
jeudi 13 janvier 2011
96. 13 janv. 2011
FibroTest prognostic value among HCV cirrhosis stage
1,457 patients followed 5 years
De Ledhingen EASL 2010
jeudi 13 janvier 2011
97. HCV Survival according to FibroTest classes
N=537 NGO Clin Chem 2006, Ngo Clin Chem 2008
jeudi 13 janvier 2011
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
40
jeudi 13 janvier 2011
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
41
jeudi 13 janvier 2011
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
42
jeudi 13 janvier 2011
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
comparisons
jeudi 13 janvier 2011
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
comparisons
jeudi 13 janvier 2011
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
comparisons
jeudi 13 janvier 2011
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
comparisons
jeudi 13 janvier 2011
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
comparisons
jeudi 13 janvier 2011
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. 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%
45
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108. FibroTest
Pro Cons
Simple Applicability 98% (Hemolysis)
Blood Precautions of use
Accurate for F0F1F2F3F4
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109. Première Ligne (99%)
Deuxième Ligne
si risque FP/FN (1%)
Troisième Ligne
si discordance
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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 2008
jeudi 13 janvier 2011
124. 13 janv. 2011
AUROC 5 mm = 0.75
AUROC 15 mm = 0.82
AUROC 25 mm = 0.89
Bedossa Hepatology 2003
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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 2003
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126. 13 janv. 2011
T Poynard, F Charlotte, G LeNahour, M Munteanu
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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 Munteanu
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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
LiverCenter
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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 2011
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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 2011
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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 2011
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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 Gilbert's 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.
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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
75
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152. 100% France: 12,000,000 at Risk
F0
F1
10% F2 Biomarker
F3
5% F4
0.1% Death 15,000/year
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