Download - Du 2016 tp biomarkers
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7 févr. 2012
LiverCenter
Non Invasive Biomarkers in chronic hepatitis C and B
DU 2016
Thierry Poynard +
AP-HP Groupe Hospitalier Pitié Salpêtrière, UPMC Liver Center, Université Paris 6, INSERM U680, Biopredictive France
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Serum Biomarker Imaging Biomarker
FibroTest FibroMax
Choice Hepatologist
Epidemiologist GP
FibroScan Aixplorer
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Biomarkers of liver injury in chronic hepatitis
• Unmet need
• Historic
• Methods and based evidence
• Guidelines in practice
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FRANCE FIBROSIS ICEBERG
Biopsy: 2% (8 000 /yr) FibroTest: 10% (50 000/yr) Imaging: 10% (50 000/yr)
No-estimate: 78%
0.25 Million Chronic Hepatitis C 0.25 Million Chronic Hepatitis B
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USA FIBROSIS ICEBERG
Biopsy: 1% (50 000 /yr) FibroSure: 1% (50 000 /yr) Imaging: 1% (50 000 /yr)
No-estimate: 97%
3 Millions Chronic Hepatitis C 1 Million Chronic Hepatitis B
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"META-analysis of histological data in VIRal hepatitis"
Hepatology 1996
METAVIR
THE METAVIR cooperative group. Inter- and intra-observer variation, Hepatology 1995
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7 févr. 20127 févr. 2012
Viral necrosis Activity
Fibrosis Steatosis
Alcohol Ash
Nash
Liver Injury
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FibroMAX: HCV-HBV-ALD-NAFLD
ActiTest
FibroTest SteatoTest
AshTest
NashTest
FibroMAX
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Biomarkers of liver injury in chronic hepatitis
• Unmet need
• Historic
• Methods and based evidence
• Guidelines in practice
2
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7 févr. 2012
Fibrosis biomarkers: 24 years history
SJG 2008
n=100
n=1 million
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7 févr. 2012
Haptoglobin
Alpha2Macroglobulin
Apolipoprotein A1
Total Bilirubin
Gamma GT
In Situ In Serum: FibroTest
Imbert-Bismut, Lancet 2001
Liver Injury
Activated Stellate CellsFibrotic Matrix
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7 févr. 2012
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 A1, A2M
• HaptoglobinParadis Cell Mol Biol 1996, Paradis Hepatology 1996, Mathurin Hepatology 1996, Imbert Bismut 2001, Langlois 2006, Watanabe 2009, Ho 2010
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Biomarkers of liver injury in chronic hepatitis
• Unmet need
• Historic
• Methods and based evidence
• Guidelines in practice
2
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7 févr. 2012
Period 1: 1991-2004 Optimistic
Looking for a fibrosis biomarker with accuracy > 90%
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7 févr. 2012
Biopsy =
Gold Standard
Biopsy=
0% False Positive0% False Negative
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7 févr. 2012
Liver Injury
Serum biomarker Imaging biomarker
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F4
F1
F0
Fibrotic Liver Disease
F2
F3
Hemorrhage Liver failure Cancer
FibroTest OK AUROC >80%
FibroTest OK FibroScan OKAUROC >80%
«Gray Zone»: Biopsy
Imbert Bismut 2001, Castera 2005
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Period 2: 2005-2009: Sceptic
Standard statistical methods were inappropriate
Period 3: 2010-2015
New methods
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• Sampling error Bedossa 2003
• Inter-observers variability Rousselet 2005
• Discordance studies Poynard 2004, Halfon 2006
• Prognostic studies Ngo 2006, Vergniol 2011
• Spectrum effect Poynard 2007, Lambert 2008
• Exceeding limits of biopsy Metha 2009
• Biopsy has a gray zone Poynard 2012
• Direct meta-analyses Poynard 201522
8 Key methodological issues:Biopsy is no more a perfect gold standard
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Sampling error:AUROCs (F1 vs F2) of Biopsy vs Whole Liver according to length
Bedossa Hepatology 2003
AUROC 15 mm = 0.82 AUROC 25 mm = 0.89
«We showed that with 25-mm long biopsy specimens, only 75% were scored correctly»
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F0 F1 F2 F3 F4
Inter-Observers variability:Biopsy has lower inter-observers concordance for intermediate stages
Rousselet, Hepatology 2005
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Discordances studies: independent endpoints
• 537 prospective cases hepatitis C
• 154 (29%) discordances FibroTest/Biopsy
• Error attributable
• To FibroTest: 2%
• To Biopsy: 18%
25
Poynard Clin Chem 2004, Halfon AJG 2006
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F4.1
F1
F0
F2
F3
7 Stages Presumed by Biomarkers
Decompensated
F4.2
F4.3
Varices
FibroTest
0.48
0.74
0.85
0.95
TE
7.1
9.5
20
50
CHC Poynard J Hepatol 2014 CHB Poynard J Hepatol 2014
12.5
0.58
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F4.1
F1
F0
F2
F3
7 Stages Presumed by Biomarkers
Decompensated
F4.2
F4.3
Varices
FibroTest
0.48
0.74
0.85
0.95
TE
7.1
9.5
20
50
CHC Poynard J Hepatol 2014 CHB Poynard J Hepatol 2014
12.5
0.58
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7 févr. 2012
• Sampling error Bedossa 2003
• Inter-observers variability Rousselet 2005
• Discordance studies Poynard 2004, Halfon 2006
• Prognostic studies Ngo 2006, Vergniol 2011
• Spectrum effect Poynard 2007, Lambert 2008
• Exceeding limits of biopsy Metha 2009
• Biopsy has a gray zone Poynard 2012
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3/7 key methodological issues not well understoodBiopsy is no more a perfect gold standard
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F4
F1
F0
Fibrotic Liver Disease
F2
F3
DANA=4
DANA=Difference between Advanced and non-advanced fibrosis stages
Obuchowski measure=AUROCs Pair-wise comparison between all stages
Black and White Spectrum
FibroTest AUROC=0.98
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F4
F1
F0
Fibrotic Liver Disease
F2
F3
DANA=1
DANA=Difference between Advanced and non-advanced fibrosis stages
Obuchowski measure=AUROCs Pair-wise comparison between all stages
Gray Spectrum
FibroTest AUROC=0.67
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F4
F1
F0
Fibrotic Liver Disease
F2
F3
DANA=2.5
DANA=Difference between Advanced and non-advanced fibrosis stages
Obuchowski measure=AUROCs Pair-wise comparison between all stages
FibroTest AUROC=0.85
Standard Spectrum
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7 févr. 2012
Hazardous AUROC Scores for defining test performance:
AUROC Score* Biopsy (length) FibroTest (Spectrum)
0.90-1.00 Excellent 100mm F1 vs F2 F0 vs F4
0.80-0.90 Good 25 mm F1 vs F2 F01 vs F234
0.70-0.80 Fair 5 mm F1 vs F2 F0 vs F2
0.60-0.70 Poor 5 mm F0 vs F1 F1 vs F2
0.50-0.60 Fail
*Sebastiani CCLM 2011, Bedossa Hepatology 2003, Poynard Clin Chem 2007
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Hazardous AUROC Scores for defining test performance:
AUROC Score* FibroTest Spectrum DANA
0.90-1.00 Excellent 50% F0 vs 50% F4 4
0.80-0.90 Good F01 vs F234 20% each stage 2.5
0.70-0.80 Fair 50% F0 vs 50% F2 2
0.60-0.70 Poor 50% F1 vs 50% F2 1
0.50-0.60 Fail
Poynard Clin Chem 2007, Lambert Clin Chem 2008,
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7 févr. 2012
Hazardous Tables due to Spectrum Effect (October 2012)
Ochi Hepatology 2012
Real-time tissue elastography cut-off values by stage in the training set were 2.47 for F1, 2.67 for F2, 3.02 for F3, and 3.36 for F4. Usingthese cut-off values, the diagnostic accuracy of hepatic fibrosis in the validation set was 82.6%-96.0% in all stages.
The area under the receiver operating characteristic curve of elastic ratio better correlated than serum fibrosis markers in both early and advanced fibrosis stages.
Conclusion: Real-time tissue elastography is useful in evaluating hepatic fibrosis and PH in patients with NAFLD. (HEPATOLOGY 2012;1271-1278)
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• Sampling error Bedossa 2003
• Inter-observers variability Rousselet 2005
• Discordance studies Poynard 2004, Halfon 2006
• Prognostic studies Ngo 2006, Vergniol 2011
• Spectrum effect Poynard 2007, Lambert 2008
• Exceeding limits of biopsy Metha 2009
• Biopsy has a gray zone Poynard 2012
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3/7 key methodological issues not well understoodBiopsy is no more a perfect gold standard
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Using 25 mm liver biopsy a perfect market cannot be validated
Black shading represents the set of conditions under which the AUROC values exceed what has already been observed
Metha J Hepatol 2009
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Exceeding limits of biopsy: >90% accuracy is impossible for advanced fibrosis
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«Comparison of 8 diagnostic algorithms for liver fibrosis in hepatitis C: New algorithms are more precise and entirely non-invasive».
Boursier et al, Hepatology 2012
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7 févr. 2012
Misleading presentation using biopsy as Gold-Standard
Boursier Hepatology 2012
Mathematically impossible with biopsy as «Gold Standard
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• Sampling error Bedossa 2003
• Inter-observers variability Rousselet 2005
• Discordance studies Poynard 2004, Halfon 2006
• Prognostic studies Ngo 2006, Vergniol 2011
• Spectrum effect Poynard 2007, Lambert 2008
• Exceeding limits of biopsy Metha 2009
• Biopsy has a gray zone Poynard 2012
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3/7 key methodological issues not well understoodBiopsy is no more a perfect gold standard
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Review of tests by Gebo, Hepatology 2002
« These panels of tests may have the greatest value in predicting fibrosis or cirrhosis »
« Biochemical tests were best at predicting no or minimal fibrosis, or at predicting advanced fibrosis/cirrhosis, and were poor at predicting intermediate levels of fibrosis »
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FibroTest/FibroSure has a Gray Zone
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Biopsy has a Gray Zone
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Review of fibrosis tests by Nguyen, Hepatology 2011
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7 févr. 2012
Liver Biopsy Analysis Has a Low Level of Performance for Diagnosis of IntermediateStages of Fibrosis
The gray anatomy of 27,869 virtual biopsies and 6,500 patients
Poynard Clin Gastro Hepatol 2012 Poynard, BMC 2005, J Hepatol 2011
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The gray zone of liver biopsy: 27,864 virtual biopsies
Area Fibrosis (Log)
25 mm Liver Biopsies
Poynard Clin Gastro Hepatol 2012
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7 févr. 2012
The gray zone of liver biopsy: 27,864 virtual biopsies
Poynard Clin Gastro Hepatol 2012
Area Fibrosis (Log)
25 mm Liver Biopsies
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Lower gray zone of FibroTest relative to biopsy
Lower gray zone F2vsF1 for FibroTest vs Biopsy
58% lower F2vsF1 vs F1vsF0 41% lower F2vsF1 vs F4vsF3.
Biopsyn=27,864
Fibrotestn=6500
Poynard Clin Gastro Hepatol 2012
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7 févr. 2012
Biopsy is no more a perfect gold standard
FibroTest and Elastography have similar performance
2006: Approval Markers French Health Authorities HCV2011: Guidelines EASL 2011
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Period 2: 2005-2009: Sceptic
Standard statistical methods were inappropriate
Period 3: 2010-2015
New methods
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(c) BioPredictive 2008 - All Rights Reserved - No reproduction without written permission
Benefit/Risk must be evaluated for each change in the formula:
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High Risk False Positive Negative
5/954 (0.52%)
High Risk False Positive Negative
38/7494 (0.51%)
FibroTest Global Quality Estimates
High Risk False Positive Negative 3349/345,695 (0.97%)
High Risk False Positive Negative
491/24,872 (1.97%)
FibroScan (Roulot et al 2008) >7.1 kPa= 12.6%: False Positives ?
Poynard BMC Gastro 2011, Roulot J Hepatol 2008
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(c) BioPredictive 2008 - All Rights Reserved - No reproduction without written permission
One Test, One formula
360,000 FibroTest for Quality Control
Risk of False positive/negative of FibroTest
• Tertiary center: 1.97%
• HIV co-infection: 1.77%
• Sub-Saharan origin: 2.61%
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7 févr. 2012
Which Fibrometer for patients with Hepatitis C ? Too many variants = Risk of false positive
FibroMeter Variant Year Components
FM-1G 2005 PLT, PI, AST, A2M, HA, Urea, Age
FM-2G V* 2008 + Gender
FM-3G 2008 Switch GGT/HA
FM-3G+ (CirrhoMeter) 2009 New formula for cirrhosis
FM-HICV 2010 AST, A2M, PI
CSF-Index 2011 Combined with LSM
SF-Index 2011 Combined with LSM
C-Index 2011 Combined with LSM
*ONLY one ( FM-2G V) is approved by Haute Autorité de Santé
PLT: platelet counts, PI prothrombin index, AST aspartate amino transferase, A2M alpha2 macroglobulin, HA hyaluronic acid
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7 févr. 2012
Biopsy vs Serum marker Main advantages/disadvantages
Serum Marker FibroTest
Less accurate for intermediate stages
No grey zone relatively to biopsy
Fibrosis only ActiTest/SteatoTest
Delays result proprietary tests 1-48h
False positive/hemolysis/inflammation/Gilbert
Yes but 0.97% (3349/345695; 0.94-1.00)
Nguyen Hepatology, 2011 Poynard BMC Gastro 2011
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Period 3: 2010-2015
Welcome in a world without perfect Gold Standard
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7 févr. 2012
Gold Standard
25 mm Biopsy 0%False PositiveFalse Negative
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Truth in the Absence of
Gold Standard
25 mm Biopsy 25%False PositiveFalse Negative
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7 févr. 2012
Area of fibrosis estimated by biopsy according to its length (mm) in subjects scoring METAVIR F0 (no fibrosis) on large surgical section.
Area of fibrosis >5.3%: 16.3% false positives 20mm biopsy for diagnosis of advanced fibrosis >16.5%: 0.3% false positives 20mm biopsy for diagnosis of cirrhosis.
Cirrhosis
Advanced fibrosis
Poynard J Hepatol 2012
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Poynard J Hepatol 2011
Truth
FibroTest FibroScan
5-30 mm Biopsy
ALT
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7 févr. 2012
Distribution of 1893 subjects according to the 16 possible combinations of the 4 tests' results: presumed advanced fibrosis (present=1) or not (=0)
16 combinations of 4 tests results Number of subjects
FibroTest LSM ALT Biopsy Observed Expected by model
0 0 0 0 621 615.5
0 0 0 1 186 191.1
...
1 1 1 1 276 277.0
Poynard, J Hepatol 2011
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FibroTest Se LSM Se Biopsie Se
Performance for Cirrhosis: Sensitivity
The standard cutoffs: 0.74 FibroTest, 14.5 kPa Stiffness
Poynard, J Hepatol 2011
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FibroTest Sp LSM Sp Biopsy Sp
Performance for Cirrhosis: Specificity
The standard cutoffs: for cirrhosis 0.74 for FibroTest, and 14.5 kilo-Pascal for stiffness (LSM)
Poynard, J Hepatol 2011
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7 févr. 2012
SWE Fibrotest 1 TE-M Fibrotest 2 TE-XL FibroTest 3
Poynard, J Hepatol 2013
Performances for diagnosis of Cirrhosis (HCV, HBV, NAFLD, ALD) of FibroTest, and Elastography: Transient M-XL probes and Share Wave
Latent Class Model: Best model for FibroTest with TE-XL or SWE (Likelihood ratio test 5.5, 6.9)
n = 322 simultaneous reliable tests
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2
Biomarkers of liver injury in chronic hepatitis
• Unmet need
• Historic
• Methods and based evidence
• Guidelines in practice
2
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Serum Biomarker Imaging Biomarker
FibroTest FibroMax
Choice Hepatologist
Epidemiologist GP
FibroScan SWE Aixplorer
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Competitors
65
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• AFEF, HAS
• EASL, AASLD
• WHO
Guidelines: HCV and HBV
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7 févr. 20127 févr. 2012
FibroTest APRI FIB4TE
Imbert-Bismuth Lancet 2001
Sandrin Ultra Med Biol
2003
Wai Hepatology
2003
Sterling Hepatology
2006
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• Applicability
• Variability
• False positive if activity
• False negative for cirrhosis
Fibroscan limitations
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7 févr. 2012
Pitfalls of Fibroscan
3.1% Failures and Unreliable results 15.8%
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23 sept. 2014
Performances for cirrhosis diagnosis
FibroTest Fibrosure Transient elastography
AUROC* 0.86 (0.71-0.92) 0.94 (0.93-0.95)
Applicability >95% 80 %
Afdhal, JVH Nov 2013 Chou, Ann Int Med 2013
Not in intention to diagnose
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7 févr. 2012
Oliveri WJG 2008
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7 févr. 2012
Choice of FibroScan Cutoffs
Castera 2005, Ketanneh 2007 Roulot 2008
For F2: 7.1 or 8.8 kPa ? 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 ?
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
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75
7 févr. 2012
Elasto-FibroTest® 1289 patients with CHC and 604 healthy volunteers
• For the diagnosis of cirrhosis Elasto-FibroTest has significantly higher performances than FibroTest or Fibroscan alone.
• For the diagnosis of advanced fibrosis (F234) no improvement in performance has been observed vs FibroTest alone, when a method without gold standard was used.
67
Poynard, CRHG 2012
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8-week $ 63,000 12-Week $ 94,500 24-week $ 189,000
$ 1125 per pill
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FibroTest used to identify cirrhosis at baseline or for follow-up
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Number of Studies Quality Consistency Precision Strength of
evidence
32 Fair High High High
Chou, Ann Int Med 2013
FibroTest is the most validated test in Chronic Hepatitis C: Strength-of-evidence domains and overall ratings
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Results:
Area under the ROC curves:
Significant fibrosis 0.84 (0.78 – 0.88) Cirrhosis 0.87 (0.85 – 0.90)
Am J Gastro 2013
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APRI has lower performance than Fibrotest
due to its high variability
1. Analytical variability: ULN-AST definitions
2. Interaction with non-fibrosis features
• Activity and AST
• Steatosis and AST
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Impact on performance: Obuchowski measure
Change in AUROCs between fibrosis stages
ULN 26 IU/L ULN >=30 IU/L
APRI 0,862 0,820
FibroTest 0,867 0,867
Significance 0,30 <0,0001
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High variability of APRI associated with ULN definitions:
Impact on diagnosis performance
• Range of AST-ULN in controls: 26-49 IU/L
• According gender, BMI and cholesterol
• Fibrosis prevalence in CHC: spectrum effect
• Clinically significant fibrosis (F2F3F4): 35-69%
• Cirrhosis (F4): 11-32%
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Higher Diagnostic and Prognostic performance of FibroTest versus APRI in CHC
Poynard, Ann Int Med 2013
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5 years prognostic value in chronic hepatitis B FibroTest better biomarker
de Ledinghen APT 2013
LSM Not in intention to diagnose
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10 year Prognostic value FibroTest versus TE n= 272445% CHC, 24% CHB, NAFLD 10%, ALD 6%
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Biomarker
Analytic variability
Risk false positive due to
ActivityFasting Applicability Investment Cost
FibroTest < 7% no (ActiTest) no >95% 0 38€-200$
FibroScan Inter Observer yes yes 80 % 60,000€ 200,000$ 38€-350$
APRIHazard of AST
Upper Limit Normal
yes no ? 0 7€-40 $
Castera Hepatology 2010, Afdhal JVH 2013, Chou Ann Int Med 2013, Poynard BMC Gastro 2011, Poynard Ann Int Med 2013
Pro and Con of the three «Standard of Care» biomarkers
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2
Biomarkers of liver injury in chronic hepatitis
• Unmet need
• Historic
• Methods and based evidence
• Guidelines in practice
2
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2016
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Direct comparisons between APRI, FIB4, FibroTest and TE n=185 comparisons: 99 Fibrosis n=12,725 / 86 Cirrhosis n=10,929
Houot APT 2016
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FT better than TE
AUROC + 0.06
Fibrosis
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Cirrhosis
FT = TE
AUROC + 0.00
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13
Three reasons to assess fibrosis stages in 2016
•Expensive IFN-free regimen, priority to severe fibrosis
•Cirrhosis could need longer treatment
•Viral cure is not fibrosis cure
Cohen, Science 2013, Afdahl NEJM 2014, Poynard J Hepatol 2013
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FibroTest similar to biopsy for estimating fibrosis progression
Progression to cirrhosis in 2472 patients
Biopsy FibroTest
Poynard et al, J Hepatol 2012
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Response is associated with longer treatment in cirrhosis stage* vs non-cirrhosis in experienced Genotype 1, treated by Sofosbuvir-Ledispasvir:
80
85
90
95
100
12 weeks 24 weeks
Cirrhosis No Cirrhosis
Afdahl NEJM 2014*cirrhosis stage defined by biopsy or FibroTest
n=22 n=22n=87 n=87
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23 sept. 2014
Survival without liver complications
n = 933NS
SVR n=43 HCC1 CholangiocarcinomaAll F4 before SVR2 F2 after
Poynard, J Hepatol 2013
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Cirrhosis regression in SVR n=24/43 ( 56%)
FibroTest = 0.74
Poynard, J Hepatol 2013
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Cirrhosis Occurrence in SVR n=15/128 (12%)
FibroTest = 0.74
Poynard, J Hepatol 2013
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Fibrosis Progression in 13 HBV Sustained Virological Responders with occurrence of HepatoCellular Carcinoma at 10 years
FibroTest = 0.74 = F4
Poynard, J Hepatol 2014
F1: Subsaharan female, BMI 37 kg/m2
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F4
F1
F0
France: 12,000,000 at Risk100%
5%
Death 15,000/year0.1%
Biomarker10% F2
F3
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n= 1,016,557 (100 %) ActiTest
Poynard BmjOpen 2015
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Fibrosis density Birth-Year and Gender
Other
USA
France
n= 470,762
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Serum Biomarker Imaging Biomarker
FibroTest FibroMax
Choice Hepatologist
Epidemiologist GP
FibroScan Aixplorer