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Tp Du Fibrosis Biomarkers
1. 16 janv. 2009
Biomarkers in a World
without Gold Standards
Thierry Poynard
AP-HP Groupe Hospitalier Pitié Salpêtrière,
UPMC Liver Center, Université Paris 6,
CNRS UMR 8149, Université Paris 5, Biopredictive France
LiverCenter
9. 16 janv. 2009
Top 10 FAQ
• Are the authors credible due to their possible conflict of interest?
• Is the perfect fibrosis biomarker possible?
• Are there a specific quot;gray zonequot; or quot;inaccurate zonequot; between intermediate
stages?
• Is the methodological quality of patented biomarkers better than non-
patented biomarker?
• Is the liver biopsy still useful?
• What are the normal values of a fibrosis marker?
• What is the diagnostic value of Fibrotest according to liver disease?
• What is the prognostic value of FibroTest vs biopsy ?
10. 16 janv. 2009
Biomarkers in Chronic Liver Disease
• New methodology
• Hepatitis B
• Hepatitis C
• Global screening
12. 16 janv. 2009
Message II: Appropriate markers
• Hepatologist: Must
• GP and Screening: Simple
• Industry: Rapid
• Health Authorities: Surrogate Endpoint
13. 16 janv. 2009
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”
Biopsy Biomarker
15. 16 janv. 2009
Risk of
chronic liver disease
If contra-indication
Biomarker
Biopsy
16. 16 janv. 2009
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
19. 16 janv. 2009
Fibrosis estimates: Profile C
• “Still risk of severe adverse events for liver biopsy”
• “Biopsy has same limitations for adjacent stages
than validated biomarkers: there is no
intermediate gray zone”
• “No rational or evidence based for biopsy as first
line test”
• “Biopsy still necessary if biomarkers results at
high risk of false positive/negative”
Biopsy Biomarker
20. 16 janv. 2009
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
21. 16 janv. 2009
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
23. 16 janv. 2009
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
24. 16 janv. 2009
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. “
26. 16 janv. 2009
Summary
• Biopsy has also a “Gray zone” for adjacent stages. To discriminate between
F1 and F2 (one stage difference) is more difficult than to discriminate between
F01 vs F234, and between F0123 vs F4
• Don’t mix “adjacent” stages (F1 vs F2 or F3 vs F4) and “intermediate” stages
(F1, F2, F3 vs F0, F4)
• Standardization of AUROCs according to prevalence of stages defining non-
advanced or advanced fibrosis (0.67-0.98)
• Standardization of AUROCs according to biopsy length
Bedossa Hepatology 2003, Poynard Clin Chem 2007, Poynard APT 2007
27. 16 janv. 2009
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
29. 16 janv. 2009
Spectrum bias: examples
• Relative accuracy of FibroTest for the diagnosis of fibrosis stages
• FibroTest in White vs non-White HBV patients
• FibroTest in HCV patients with normal ALT
Bedossa Hepatology 2003, Poynard Clin Chem 2005, Poynard Clin Chem 2007, Poynard GCB 2008
30. 16 janv. 2009
Biomarkers in Chronic Liver Disease
• New methodology
• Hepatitis B
• Hepatitis C
• Global screening
Bedossa Hepatology 2003, Poynard Clin Chem 2005, Poynard Clin Chem 2007, Poynard GCB 2008
31. 16 janv. 2009
FibroTest
• 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
37. 16 janv. 2009
Impact of HBV treatment on fibrosis (Biopsy) in HBV patients
Virological Responders with advanced baseline fibrosis
97 treated with adefovir,
9 treated with placebo (spontaneous clearance)
P<0.0001
3,00
2,25
1,50
0,75 Baseline
48 weeks
0
Adefovir Biopsy Placebo Biopsy
Poynard JVH 2008
38. 16 janv. 2009
Impact of HBV treatment on fibrosis (FibroTest) in HBV patients
Virological Responders with advanced baseline fibrosis
97 treated with adefovir,
9 treated with placebo (spontaneous clearance)
P<0.0001 P=0.02
0,70
Baseline
48 weeks
0,35
0
Adefovir FibroTest Placebo FibroTest
Poynard JVH 2008
39. 16 janv. 2009
Discordance Analysis in HBV patients
• The ratio between the number of discordant cases attributable to a
biopsy failure and to FT-AT failure in this subpopulation of patients with
incoherence between virological and histological response (worsening
fibrosis with virological response)
• Could be considered as an estimate of the overall ratio in the general
population including patients without incoherence
Poynard JVH 2008
39
40. 16 janv. 2009
Discordance Analyses in HBV
• 29% discordances of FibroTest estimated by the classical analysis
considering biopsy as the gold standard
• New method using discordant cases with incoherence between virological
response and histological response (n=29)
• Failure attributable to biopsy 66% (19/29) false positive median 11mm,
false negative median 7-mm
• Failure attributable to FT-AT 34% (10/29)
• If these estimates are true the real rates of patients misclassified using FT-AT
is 10% (34% of 29%)
Poynard JVH 2008
40
41. Kinetics of fibrosis according to baseline stages 16 janv. 2009
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
43. 16 janv. 2009
This definition had a 100% negative predictive value for liver related complications or death.
Classical definition of inactive carrier with normal transaminases, 23% had presumed fibrosis, and 3
complications occurred during the follow-up.
Ngo PlosONE 2008
44. 16 janv. 2009
A New simple definition of HBV Inactive Carrier
Viral Load < Log5
+
ActiTest <= 0.29
FibroTest<= 0.27
Ngo PlosONE 2008
45. 16 janv. 2009
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
45
46. 16 janv. 2009
Biomarkers in Chronic Liver Disease
• New methodology
• Hepatitis B
• Hepatitis C
• Global screening
Bedossa Hepatology 2003, Poynard Clin Chem 2005, Poynard Clin Chem 2007
46
47. 16 janv. 2009
FibroTest
Elastography
• 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, Poynard et al SJG 2008
47
48. 16 janv. 2009
FibroTest: from blood donors to cirrhotics (n=1,570)
1.00
Fibrotest
0.67
0.33
0.00
F0 F1 F2 F3 F4
Blood
Donors
49. 16 janv. 2009
FibroTest Diagnostic Values: Stage by Stage Analysis
n=1570 Poynard, Comp Hepatol 2004; n=506 Halfon AJG 2006
Same diagnostic value for low, intermediate or elevated stages
1,00
0,75
0,50
0,25
0
AUROC
BDvsF0 F0vsF1 F1vsF2 F2vsF3 F3vsF4
50. 16 janv. 2009
AUROC Standardization of FibroTest
• Regression line permitted to calculate FT AUROC according to
differences observed between mean fibrosis of advanced fibrosis group
and that of non-advanced fibrosis group (DANA):
• AUROC = 0.582 + 0.105 x (DANA)
• For a standardized population with equal prevalence of each 5 fibrosis
stages of 20% and DANA = 2.5
• standardized FibroTest AUROC = 0.85
• Idem for a naturalistic prevalence of each stage
Poynard Clin Chem 2007
50
52. F2,4 vs F0,8
DANA = 1,6 F2 vs F1
AUROC = 0.70 DANA = 1
AUROC = 0.67
Sebastiani JVH 2008. Poynard JVH 2008
53. 16 janv. 2009
FibroTest AUROCs for the diagnosis of Advanced Fibrosis
in patients with elevated or normal ALT
Elevated ALT Normal ALT
P=0.02 NS NS
0,9 0,9
0,6 0,6
0,3 0,3
n=164 n=80 n=164 n=80 n=1833 n=493
0 0
Observed Standardized Standardized
Sebastiani JVH 2008, Poynard JVH 2008, Poynard BMC Gastroenterol 2007
54. 16 janv. 2009
Analyses of Discordances
• Failures of biopsy
• Failures of biomarkers
• Failures of elastography
Reguev AJG 2003, Poynard Clin Chem 2004, Poynard APT 2007, Coco JVH 2007
54
55. 16 janv. 2009
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
55
56. 16 janv. 2009
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
57. 16 janv. 2009
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
57
60. 16 janv. 2009
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
61. 16 janv. 2009
FibroTest before and after HCV Treatment
Estimates 72 weeks Anti-Fibrotic Impact
-31%
Baseline EOF
0,8
-26%
0,6
0,4
0,2
0
F01 NR n=58 F01 SVR n=119 F234 NR n=110 F234 SVR n=65
Poynard et al Hepatology, 2003
61
62. 16 janv. 2009
FibroTest ActiTest
Estimates of 72 wks anti-fibrotic and anti-activity impact in 22 SVR PEG-Riba
Baseline W12 W24 W48 EOF
0,8
-28%
0,6
-75%
0,4
0,2
0
FibroTest ActiTest
D’Arondel et al JVH, 2006
62
64. 16 janv. 2009
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
65. 16 janv. 2009
Fibrotest has better diagnostic and
prognostic value than APRI in patients
with chronic hepatitis C.
Morra R et al. Hepatology 2008
66. 16 janv. 2009
Association of marker with clinical endpoint
• Example for FibroTest in 537 HCV patients with 29 liver complications 5 yr**
Attributable
Se Sp Relative Risk
Proportion
FibroTest
0.97 0.75 68 0.98
>0.58
Biopsy F4 0.60 0.93 11 0.65
* Chakravarty FDA 2008, **Ngo et al Clin Chem 2007
66
67. 16 janv. 2009
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
67
71. FibroTest!
First Line!
Reference Center
FibroScan for!
Confirmation !
Biopsy!
If discordances!
72. 16 janv. 2009
Summary:
FibroTest-ActiTest in patients with chronic hepatitis C
• Most validated Biomarker, approved by health authorities
• Validated at baseline, during and after HCV treatment
• Validated in difficult to diagnose patients
• Discordances due to biopsy failure in at least 50% of cases
• More sensitive than biopsy ?
• Better prognostic value than biopsy ?
72
73. 16 janv. 2009
Biomarkers in Chronic Liver Disease
• New methodology
• Hepatitis B
• Hepatitis C
• Global screening
Bedossa Hepatology 2003, Poynard Clin Chem 2005, Poynard Clin Chem 2007
73
76. Insulin Resistance Diabetes 2
Obesity Hyperlipidemia
Arterial Hypertension
FibroTest SteatoTest NashTest Fibroscan if
FT non
applicable
Advanced Fibrosis No Fibrosis
Or NASH No NASH
FibroMAX
Hepatologist
Every 2-4 years
77. Heavy Drinker
Fibroscan if
FibroTest SteatoTest
FT non
AshTest
applicable
Advanced Fibrosis No Fibrosis
Or Steato-Hepatitis No Steato-Hepatitis
FibroMAX
Hepatologist
Every 2 years
78. 16 janv. 2009
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
78
79. 16 janv. 2009
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
79
80. 100% France: 12,000,000 at Risk
F0
F1
10% FibroTest
F2
F3
5% F4
0.1% Death 15,000/year
81. 16 janv. 2009
Presumed Liver Injury assessed by FibroMAX in 1909 Hyperlipidemic
patients according to the number of metabolic factors
0 1 2 3 4 5
100
75
50
25
0
Steatosis SteatoHepatitis Fibrosis
Ratziu et al APT 2006
81
82. 16 janv. 2009
Presumed Liver Fibrosis assessed by FibroTest in 1909 Hyperlipidemic
patients according to the number of metabolic factors
10,0
7,5
5,0
2,5
0
0 1 2 3 4 5
Ratziu et al APT 2006
82
83. 16 janv. 2009
Prospective screening of liver fibrosis
using FibroTest in 1.131 naive diabetic patients
1261 Diabetics preincluded
74 Excluded
20 by security algorithms
50 duplicates
4 not diabetics
1187 Diabetics included
56 with previous history 1131 without previous history
of liver disease of liver disease
21 not presumed 1068 not presumed
Advanced fibrosis Advanced fibrosis
35 presumed 63 presumed
Advanced Fibrosis Advanced Fibrosis
3 not reinvestigated 18 not reinvestigated
32 reinvestigated 45 reinvestigated
32 Confirmed fibrosis 32 Confirmed fibrosis 13 Unconfirmed
20 Cirrhosis 5 Cirrhosis (4 liver cancer) 4 False positive FibroTest
8 Many septa 10 Many septa 9 not classified
4 Few septa 17 Few septa
Jacqueminet et al CGH 2008
84. 16 janv. 2009
Prospective screening of liver fibrosis
using FibroTest in 7.500 subjects of a general population
Prevalence of presumed fibrosis
Prevalence of liver disease
among advanced fibrosis
84
