Tp Du Fibrosis Biomarkers
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16 janv. 2009 LiverCenter 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
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Transcript of Tp Du Fibrosis Biomarkers
16 janv. 2009
LiverCenter
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
16 janv. 2009
TexteJanuary 2009
16 janv. 2009
3
Validated Fibrosis Biomarkers 350.000 in 35 countries
FibroTest ActiTest
16 janv. 2009
F0
Pas de Fibrose
16 janv. 2009
F1
Fibrose minime
16 janv. 2009
F2
Fibrose modérée
16 janv. 2009
F3
Fibrose importante
16 janv. 2009
F4
Fibrose sévère
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 "gray zone" or "inaccurate zone" 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 ?
16 janv. 2009
Biomarkers in Chronic Liver Disease
• New methodology
• Hepatitis B
• Hepatitis C
• Global screening
16 janv. 2009
Message I: Appropriate methods
• Imperfect Gold Standard
• Spectrum bias
• Analysis of discordances
Bedossa Hepatology 2003, Poynard Clin Chem 2005, Poynard Clin Chem 2007, Poynard GCB 2008
16 janv. 2009
Message II: Appropriate markers
• Hepatologist: Must
• GP and Screening: Simple
• Industry: Rapid
• Health Authorities: Surrogate Endpoint
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
16 janv. 2009
N Engl J Med 2001
16 janv. 2009
Risk of chronic liver disease
Biopsy
If contra-indicationBiomarker
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
16 janv. 2009
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
16 janv. 2009
Chronic Hepatitis B or C
FibroTest ActiTest
Advanced FibrosisSevere Activity
Hepatologist
Fibroscan if FibroTest not applicable
No Advanced FibrosisNo Severe Activity
FibroTest every 2-4 years
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
16 janv. 2009
16 janv. 2009
Bedossa Hepatology 2003
AUROC 5 mm = 0.75AUROC 15 mm = 0.82AUROC 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”
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. “
16 janv. 2009
Poynard et al APT 2007
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
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
16 janv. 2009
Message I: Appropriate methods
• Imperfect Gold Standard
• Spectrum bias
• Analysis of discordances
Bedossa Hepatology 2003, Poynard Clin Chem 2005, Poynard Clin Chem 2007, Poynard GCB 2008
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
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
16 janv. 2009
• 38 Published Studies
• 7.985 Patients
• Standardized AUROC
• 0.84 (0.83-0.86)
• Advanced Fibrosis
Friedrich Rust et al Gastroenterology 2008, Halfon et al GCB 2008
The best you can obtain with
20mm biopsy is 0.90 Bedossa 2003
FibroTest
16 janv. 2009
FibroTest in Chronic Hepatitis B: 3,303 patients
• Myers, J Hepatol 2003 n=209
• Poynard, Am J Gastro 2005 n=283
• Cales, Hepatology 2005 n=46
• Sebastiani, World J Gastro 2006 n=110
• Coco, JVH 2007 n=93
• Zhao Chines J Pract Int Med 2007 n=123
• Poynard, JVH 2008 n=924
• Ngo, 2008 PlosONE 2008 n=1,300
• Abstracts: Castera, J Hepatol 2006 n=154; Hilleret, J Hepatol 2006 n=184,
16 janv. 2009
Adefovir, 2 Registrational Trials: Results using FibroTest-ActiTest (Poynard JVH 2008)
• 462 patients included 304 Adefovir and 158 Placebo:
• Paired biopsy and FibroTest
• 924 estimates of liver injury
• F0 n=21
• F1 n=596
• F2 n=160
• F3 n=69
• F4 n=78
F49%F3
3%
F218%
F168%
F02%
16 janv. 2009
Fibrotest and Fibrosis Stages
Poynard JVH 2008
16 janv. 2009
ActiTest and Necro-Inflammatory features
Poynard JVH 2008
16 janv. 2009
ActiTest and Necro-Inflammatory Scoring System
Poynard JVH 2008
16 janv. 2009
0
0,75
1,50
2,25
3,00
Adefovir Biopsy Placebo Biopsy
Baseline48 weeks
Impact of HBV treatment on fibrosis (Biopsy) in HBV patientsVirological Responders with advanced baseline fibrosis
97 treated with adefovir, 9 treated with placebo (spontaneous clearance)
P<0.0001
Poynard JVH 2008
16 janv. 2009
0
0,35
0,70
Adefovir FibroTest Placebo FibroTest
Baseline48 weeks
P<0.0001 P=0.02
Impact of HBV treatment on fibrosis (FibroTest) in HBV patientsVirological Responders with advanced baseline fibrosis
97 treated with adefovir, 9 treated with placebo (spontaneous clearance)
Poynard JVH 2008
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
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
16 janv. 2009Kinetics of fibrosis according to baseline stagesIn HBV patients treated with lamivudine 2 years
n=283
F0F1 NS
F2F3F4 P=0.01
0.00
0.25
0.50
0.75
1.00
Baseline 6 mo 12 mo 24 mo
FibroTest-FibroSURE
44 Cirrhosis: 42 (95%) improvement at 24 months; Significant regression (>0.30) in 14/44 (32%)
0.73
0.52
Dienstag et al Gastroenterol 2003. Poynard et al Am J G 2005
16 janv. 2009
HBV Survival according to FibroTest classes n= 1,300
FibroTest METAVIR
0.59-1.00 F3-F4
0.32-0.58 F1-F2, F2
0.00-0.31 F0-F1
Ngo PlosONE 2008
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
16 janv. 2009
A New simple definition of HBV Inactive Carrier
FibroTest<= 0.27 ActiTest <= 0.29
+
Ngo PlosONE 2008
Viral Load < Log5
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
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
16 janv. 2009
• 38 Published Studies
• 7.985 Patients
• Standardized AUROC
• 0.84 (0.83-0.86)
• Advanced Fibrosis
•
Friedrich Rust et al Gastroenterology 2008, Poynard et al SJG 2008
FibroTest
The best you can obtain with
20mm biopsy is 0.90 Bedossa 2003
47
Elastography
16 janv. 2009
FibroTest: from blood donors to cirrhotics (n=1,570)
0.00
0.33
0.67
1.00
F0 F1 F2 F3 F4
Fibr
otes
t
BloodDonors
16 janv. 2009
FibroTest Diagnostic Values: Stage by Stage Analysisn=1570 Poynard, Comp Hepatol 2004; n=506 Halfon AJG 2006Same diagnostic value for low, intermediate or elevated stages
BDvsF0 F0vsF1 F1vsF2 F2vsF3 F3vsF4
0
0,25
0,50
0,75
1,00
AUROC
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
16 janv. 2009
F2 vs F1
DANA = 1
AUROC = 0.67
F2,4 vs F0,8
DANA = 1,6
AUROC = 0.70
Sebastiani JVH 2008. Poynard JVH 2008
16 janv. 2009
FibroTest AUROCs for the diagnosis of Advanced Fibrosisin patients with elevated or normal ALT
0
0,3
0,6
0,9
Observed Standardized
P=0.02 NS
Sebastiani JVH 2008, Poynard JVH 2008, Poynard BMC Gastroenterol 2007
Elevated ALT Normal ALT
0
0,3
0,6
0,9
Standardized
n=1833 n=493n=164 n=80 n=164 n=80
NS
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
16 janv. 2009
537 Prospective Cases Same day Biopsy and FibroTestCause 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
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
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
16 janv. 2009
Security Algorithms: Apparently healthy Blood donors
952 Blood Donors
Security Algorithms
29 High Risk Profile (3%)False Positive/Negative
9 HR Gilbert (0.9%)4 HR Hemolysis (0.4%)
925 97% TestsEasy to Interpret
No F2F3F4
Poynard 2004, Imbert Bismut 2004
16 janv. 2009
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
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16 janv. 2009
Relapse/Reject n=8
No Relapse/Reject n=15
P<0.001
Before LT 24-72 h 7 days 2 weeks 4 weeks 24 weeks 48 weeks
FibroTest in the follow-up of liver transplanted patients: a pilot study
Hamelet EASL 2008
16 janv. 2009
FibroTest before and after HCV Treatment Estimates 72 weeks Anti-Fibrotic Impact
0
0,2
0,4
0,6
0,8
F01 NR n=58 F01 SVR n=119 F234 NR n=110 F234 SVR n=65
Baseline EOF
-26%
-31%
Poynard et al Hepatology, 200361
16 janv. 2009
FibroTest ActiTestEstimates of 72 wks anti-fibrotic and anti-activity impact in 22 SVR PEG-Riba
0
0,2
0,4
0,6
0,8
FibroTest ActiTest
Baseline W12 W24 W48 EOF
D’Arondel et al JVH, 2006
-28%
-75%
62
16 janv. 2009
16 janv. 2009
TestNbStudies
NbPatients
Quality 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
Quality of Patented Liver Biomarkers
16 janv. 2009
Fibrotest has better diagnostic and prognostic value than APRI in patients with chronic hepatitis C. Morra R et al. Hepatology 2008
16 janv. 2009
Association of marker with clinical endpoint
• Example for FibroTest in 537 HCV patients with 29 liver complications 5 yr**
* Chakravarty FDA 2008, **Ngo et al Clin Chem 2007
Se Sp Relative RiskAttributable Proportion
FibroTest >0.58
0.97 0.75 68 0.98
Biopsy F4 0.60 0.93 11 0.65
66
16 janv. 2009
• 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
Elastography
16 janv. 2009
Kettaneh et al. J Hepatol 2005
FibroTest vs FibroScan
68
16 janv. 2009
Choice of FibroScan Cutoffs
Castera 2005, Ketanneh 2007Roulot 2008
For F2: 7.1 or 8.8 kPa ? FibroScan false negatives ?Low negative predictive value
For F4: 12.5 or 14.5 kPa ?
For F0: 7.1 kPa 12.6% false positives ? 8.8 kPa 3.6% false positives ?
For screening 7.1 kPa ?
For patients 8.8 kPa ?
No rationale for changing cutoff according to liver disease
F2 8.8 kPa F4 14.5 kPa
F4 0.73
F2 0.48
Poynard PlosOne 2008
16 janv. 2009
Poynard PlosOne 2008
FibroTest!First Line!
Reference Center FibroScan for!Confirmation !
Biopsy!If discordances!
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
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
16 janv. 2009
FibroMAX: HCV-HBV-ALD-NAFLD
ActiTest
FibroTest SteatoTest
AshTest
NashTest
FibroMAX
74
16 janv. 2009
SteatoTest for Steatosis744 patients 140 controls
SteatoTestGGT AUROC=0.66
ALT AUROC=0.61
AUROC=0.80
Poynard Comp Hepatol 2005
Insulin Resistance Diabetes 2 Obesity HyperlipidemiaArterial Hypertension
FibroTest SteatoTest NashTest
Advanced FibrosisOr NASH
No FibrosisNo NASH
Hepatologist FibroMAXEvery 2-4 years
Fibroscan if FT non
applicable
Heavy Drinker
FibroTest SteatoTestAshTest
Advanced FibrosisOr Steato-Hepatitis
No FibrosisNo Steato-Hepatitis
Hepatologist FibroMAXEvery 2 years
Fibroscan if FT non
applicable
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
16 janv. 2009
Insulin resistance
Alcool consumption
Hepatitis B
Hepatitis C
Hemochromatosis
0 150 300 450 600
No advanced fibrosis Advanced fibrosis
79
Population at risk of liver fibrosis, cirrhosis and hepatocellular carcinoma (Millions)
F4
F1
F0
France: 12,000,000 at Risk100%
5%
Death 15,000/year0.1%
FibroTest10% F2
F3
16 janv. 2009
Presumed Liver Injury assessed by FibroMAX in 1909 Hyperlipidemic patients according to the number of metabolic factors
0
25
50
75
100
Steatosis SteatoHepatitis Fibrosis
0 1 2 3 4 5
Ratziu et al APT 2006
81
16 janv. 2009
Presumed Liver Fibrosis assessed by FibroTest in 1909 Hyperlipidemic patients according to the number of metabolic factors
0
2,5
5,0
7,5
10,0
0 1 2 3 4 5
Ratziu et al APT 2006
82
16 janv. 2009
Prospective screening of liver fibrosis using FibroTest in 1.131 naive diabetic patients
Jacqueminet et al CGH 2008
74 Excluded20 by security algorithms
50 duplicates4 not diabetics
21 not presumedAdvanced fibrosis
3 not reinvestigated
32 Confirmed fibrosis20 Cirrhosis
8 Many septa4 Few septa
32 reinvestigated
35 presumedAdvanced Fibrosis
56 with previous historyof liver disease
1068 not presumedAdvanced fibrosis
18 not reinvestigated
32 Confirmed fibrosis5 Cirrhosis (4 liver cancer)
10 Many septa17 Few septa
13 Unconfirmed4 False positive FibroTest
9 not classified
45 reinvestigated
63 presumedAdvanced Fibrosis
1131 without previous historyof liver disease
1187 Diabetics included
1261 Diabetics preincluded
16 janv. 2009
Prevalence of presumed fibrosis
Prevalence of liver disease among advanced fibrosis
Prospective screening of liver fibrosis using FibroTest in 7.500 subjects of a general population
84
Reduce death due to cirrhosis by 50%
