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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
Serum Biomarker Imaging Biomarker
FibroTest
FibroMax
Choice
Hepatologist
Epidemiologist
GP
FibroScan
Aixplorer
2
Biomarkers of liver injury in chronic hepatitis
• Unmet need

• Historic

• Methods and based evidence

• Guidelines in practice
2
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
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
"META-analysis of histological data in VIRal hepatitis"
Hepatology 1996
METAVIR
THE METAVIR cooperative group. Inter- and intra-observer variation, Hepatology 1995
7 févr. 20127 févr. 2012
Viral necrosis
Activity
Fibrosis Steatosis
Alcohol
Ash
Nash
Liver
Injury
8
7 févr. 2012
FibroMAX: HCV-HBV-ALD-NAFLD
ActiTest
FibroTest SteatoTest
AshTest
NashTest
FibroMAX
7
2
Biomarkers of liver injury in chronic hepatitis
• Unmet need

• Historic

• Methods and based evidence

• Guidelines in practice
2
7 févr. 2012
Fibrosis biomarkers: 24 years history
SJG 2008
n=100
n=1 million
7 févr. 2012
Haptoglobin
Alpha2Macroglobulin
Apolipoprotein A1
Total Bilirubin
Gamma GT
In Situ In Serum: FibroTest
Imbert-Bismut, Lancet 2001
Liver Injury
Activated Stellate Cells
Fibrotic Matrix
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

• Haptoglobin
Paradis Cell Mol Biol 1996, Paradis Hepatology 1996, Mathurin Hepatology 1996, Imbert Bismut 2001, Langlois 2006, Watanabe 2009, Ho 2010
2
Biomarkers of liver injury in chronic hepatitis
• Unmet need

• Historic

• Methods and based evidence

• Guidelines in practice
2
7 févr. 2012
Period 1: 1991-2004 Optimistic

Looking for a fibrosis biomarker with accuracy > 90%
7 févr. 2012
Biopsy
=
Gold Standard
Biopsy

=

0% False Positive

0% False Negative
7 févr. 2012
Liver
Injury
Serum biomarker Imaging biomarker
F4
F1
F0
Fibrotic Liver
Disease
F2
F3
Hemorrhage Liver failure Cancer
FibroTest OK
AUROC >80%
FibroTest OK 

FibroScan OK

AUROC >80%
«Gray Zone»: Biopsy
Imbert Bismut 2001, Castera 2005
7 févr. 2012
Period 2: 2005-2009: Sceptic

Standard statistical methods were inappropriate

Period 3: 2010-2015

New methods
19
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

• Direct meta-analyses Poynard 2015
22
8 Key methodological issues:

Biopsy is no more a perfect gold standard
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»
7 févr. 2012
F0 F1 F2 F3 F4
Inter-Observers variability:

Biopsy has lower inter-observers concordance for intermediate stages
Rousselet, Hepatology 2005
22
7 févr. 2012
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
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
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
25
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
29
3/7 key methodological issues not well understood

Biopsy is no more a perfect gold standard
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
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
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
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
7 févr. 2012
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,
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. Using
these 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)
32
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
29
3/7 key methodological issues not well understood

Biopsy is no more a perfect gold standard
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
34
7 févr. 2012
Exceeding limits of biopsy: 

>90% accuracy is impossible for advanced fibrosis
35
«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
7 févr. 2012
Misleading presentation using biopsy as Gold-Standard
Boursier Hepatology 2012
Mathematically impossible with biopsy as «Gold Standard
36
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
29
3/7 key methodological issues not well understood

Biopsy is no more a perfect gold standard
37
7 févr. 2012
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 »
37
FibroTest/FibroSure has a Gray Zone
Biopsy has a Gray Zone
41
7 févr. 2012
Review of fibrosis tests by Nguyen, Hepatology 2011
41
7 févr. 2012
Liver Biopsy Analysis Has a Low Level of
Performance for Diagnosis of Intermediate

Stages 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
7 févr. 2012
The gray zone of liver biopsy: 27,864 virtual biopsies
Area
Fibrosis
(Log)
25 mm Liver Biopsies
Poynard Clin Gastro Hepatol 2012
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
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.
Biopsy

n=27,864
Fibrotest

n=6500
Poynard Clin Gastro Hepatol 2012
7 févr. 2012
Biopsy is no more a perfect gold standard

FibroTest and Elastography have similar performance

2006: Approval Markers French Health Authorities HCV

2011: Guidelines EASL 2011
7 févr. 2012
Period 2: 2005-2009: Sceptic

Standard statistical methods were inappropriate

Period 3: 2010-2015

New methods
(c) BioPredictive 2008 - All Rights Reserved - No reproduction without written permission
Benefit/Risk must be evaluated for each change in the formula:
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
(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%
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
7 févr. 2012
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
7 févr. 2012
Period 3: 2010-2015

Welcome in a world without perfect Gold Standard
7 févr. 2012
Gold Standard
25 mm Biopsy 0%

False Positive

False Negative
7 févr. 2012
Truth in the
Absence of
Gold Standard
25 mm Biopsy 25%

False Positive

False Negative
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
7 févr. 2012
Poynard J Hepatol 2011
Truth
FibroTest FibroScan
5-30 mm Biopsy
ALT
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
7 févr. 2012
FibroTest Se LSM Se Biopsie Se
Performance for Cirrhosis: Sensitivity
The standard cutoffs: 0.74 FibroTest, 14.5 kPa Stiffness
Poynard, J Hepatol 2011
7 févr. 2012
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
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
2
Biomarkers of liver injury in chronic hepatitis
• Unmet need

• Historic

• Methods and based evidence

• Guidelines in practice
2
Serum Biomarker Imaging Biomarker
FibroTest
FibroMax
Choice
Hepatologist
Epidemiologist
GP
FibroScan
SWE Aixplorer
Competitors
65
• AFEF, HAS
• EASL, AASLD
• WHO
Guidelines: HCV and HBV
7 févr. 20127 févr. 2012
FibroTest APRI FIB4TE
Imbert-Bismuth
Lancet
2001
Sandrin
Ultra Med Biol
2003
Wai
Hepatology
2003
Sterling
Hepatology
2006
• Applicability
• Variability
• False positive if activity
• False negative for cirrhosis
Fibroscan limitations
7 févr. 2012
Pitfalls of Fibroscan
3.1% Failures and Unreliable results 15.8%
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
7 févr. 2012
Oliveri WJG 2008
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
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
8-week $ 63,000 12-Week $ 94,500 24-week $ 189,000
$ 1125 per pill
FibroTest used to identify cirrhosis at baseline or for follow-up
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
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
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
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
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%
Higher Diagnostic and Prognostic performance of FibroTest
versus APRI in CHC
Poynard, Ann Int Med 2013
5 years prognostic value in chronic hepatitis B
FibroTest better biomarker
de Ledinghen APT 2013
LSM Not in intention to
diagnose
10 year Prognostic value FibroTest versus TE n= 2724

45% CHC, 24% CHB, NAFLD 10%, ALD 6%
Biomarke
r
Analytic
variability
Risk false
positive due to
Activity
Fasting Applicability Investment Cost
FibroTest < 7% no (ActiTest) no >95% 0 38€-200$
FibroScan Inter Observer yes yes 80 %
60,000€
200,000$
38€-350$ 
APRI
Hazard 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
2
Biomarkers of liver injury in chronic hepatitis
• Unmet need

• Historic

• Methods and based evidence

• Guidelines in practice
2
2016
Direct comparisons between APRI, FIB4, FibroTest and TE
n=185 comparisons: 99 Fibrosis n=12,725 / 86 Cirrhosis n=10,929
Houot APT 2016
FT better than TE
AUROC + 0.06
Fibrosis
Cirrhosis
FT = TE
AUROC + 0.00
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
FibroTest similar to biopsy for estimating fibrosis progression
Progression to cirrhosis in 2472 patients
Biopsy FibroTest
Poynard et al, J Hepatol 2012
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
23 sept. 2014
Survival without liver complications
n = 933
NS
SVR n=4

3 HCC

1 Cholangiocarcinoma

All F4 before SVR

2 F2 after
Poynard, J Hepatol 2013
Cirrhosis regression in SVR n=24/43 ( 56%)
FibroTest = 0.74
Poynard, J Hepatol 2013
Cirrhosis Occurrence in SVR n=15/128 (12%)
FibroTest = 0.74
Poynard, J Hepatol 2013
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
F4
F1
F0
France: 12,000,000 at Risk100%
5%
Death 15,000/year0.1%
Biomarker10% F2
F3
n= 1,016,557 (100 %) ActiTest
Poynard BmjOpen 2015
Fibrosis density
Birth-Year and Gender
Other
USA
France
n= 470,762
Serum Biomarker Imaging Biomarker
FibroTest
FibroMax
Choice
Hepatologist
Epidemiologist
GP
FibroScan
Aixplorer

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Du 2016 tp biomarkers

  • 1. 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
  • 2. Serum Biomarker Imaging Biomarker FibroTest FibroMax Choice Hepatologist Epidemiologist GP FibroScan Aixplorer
  • 3. 2 Biomarkers of liver injury in chronic hepatitis • Unmet need • Historic • Methods and based evidence • Guidelines in practice 2
  • 4. 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
  • 5. 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
  • 6. "META-analysis of histological data in VIRal hepatitis" Hepatology 1996 METAVIR THE METAVIR cooperative group. Inter- and intra-observer variation, Hepatology 1995
  • 7. 7 févr. 20127 févr. 2012 Viral necrosis Activity Fibrosis Steatosis Alcohol Ash Nash Liver Injury
  • 8. 8 7 févr. 2012 FibroMAX: HCV-HBV-ALD-NAFLD ActiTest FibroTest SteatoTest AshTest NashTest FibroMAX 7
  • 9. 2 Biomarkers of liver injury in chronic hepatitis • Unmet need • Historic • Methods and based evidence • Guidelines in practice 2
  • 10. 7 févr. 2012 Fibrosis biomarkers: 24 years history SJG 2008 n=100 n=1 million
  • 11. 7 févr. 2012 Haptoglobin Alpha2Macroglobulin Apolipoprotein A1 Total Bilirubin Gamma GT In Situ In Serum: FibroTest Imbert-Bismut, Lancet 2001 Liver Injury Activated Stellate Cells Fibrotic Matrix
  • 12. 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 • Haptoglobin Paradis Cell Mol Biol 1996, Paradis Hepatology 1996, Mathurin Hepatology 1996, Imbert Bismut 2001, Langlois 2006, Watanabe 2009, Ho 2010
  • 13. 2 Biomarkers of liver injury in chronic hepatitis • Unmet need • Historic • Methods and based evidence • Guidelines in practice 2
  • 14. 7 févr. 2012 Period 1: 1991-2004 Optimistic Looking for a fibrosis biomarker with accuracy > 90%
  • 15. 7 févr. 2012 Biopsy = Gold Standard Biopsy = 0% False Positive 0% False Negative
  • 16. 7 févr. 2012 Liver Injury Serum biomarker Imaging biomarker
  • 17. F4 F1 F0 Fibrotic Liver Disease F2 F3 Hemorrhage Liver failure Cancer FibroTest OK AUROC >80% FibroTest OK FibroScan OK AUROC >80% «Gray Zone»: Biopsy Imbert Bismut 2001, Castera 2005
  • 18. 7 févr. 2012 Period 2: 2005-2009: Sceptic Standard statistical methods were inappropriate Period 3: 2010-2015 New methods
  • 19. 19 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 • Direct meta-analyses Poynard 2015 22 8 Key methodological issues: Biopsy is no more a perfect gold standard
  • 20. 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»
  • 21. 7 févr. 2012 F0 F1 F2 F3 F4 Inter-Observers variability: Biopsy has lower inter-observers concordance for intermediate stages Rousselet, Hepatology 2005
  • 22. 22 7 févr. 2012 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
  • 23. 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
  • 24. 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
  • 25. 25 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 29 3/7 key methodological issues not well understood Biopsy is no more a perfect gold standard
  • 26. 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
  • 27. 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
  • 28. 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
  • 29. 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
  • 30. 7 févr. 2012 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,
  • 31. 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. Using these 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)
  • 32. 32 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 29 3/7 key methodological issues not well understood Biopsy is no more a perfect gold standard
  • 33. 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
  • 34. 34 7 févr. 2012 Exceeding limits of biopsy: >90% accuracy is impossible for advanced fibrosis 35 «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
  • 35. 7 févr. 2012 Misleading presentation using biopsy as Gold-Standard Boursier Hepatology 2012 Mathematically impossible with biopsy as «Gold Standard
  • 36. 36 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 29 3/7 key methodological issues not well understood Biopsy is no more a perfect gold standard
  • 37. 37 7 févr. 2012 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 » 37
  • 39. Biopsy has a Gray Zone
  • 40.
  • 41. 41 7 févr. 2012 Review of fibrosis tests by Nguyen, Hepatology 2011 41
  • 42. 7 févr. 2012 Liver Biopsy Analysis Has a Low Level of Performance for Diagnosis of Intermediate Stages 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
  • 43. 7 févr. 2012 The gray zone of liver biopsy: 27,864 virtual biopsies Area Fibrosis (Log) 25 mm Liver Biopsies Poynard Clin Gastro Hepatol 2012
  • 44. 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
  • 45. 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. Biopsy n=27,864 Fibrotest n=6500 Poynard Clin Gastro Hepatol 2012
  • 46. 7 févr. 2012 Biopsy is no more a perfect gold standard FibroTest and Elastography have similar performance 2006: Approval Markers French Health Authorities HCV 2011: Guidelines EASL 2011
  • 47. 7 févr. 2012 Period 2: 2005-2009: Sceptic Standard statistical methods were inappropriate Period 3: 2010-2015 New methods
  • 48. (c) BioPredictive 2008 - All Rights Reserved - No reproduction without written permission Benefit/Risk must be evaluated for each change in the formula:
  • 49. 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
  • 50. (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%
  • 51. 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
  • 53. 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
  • 54. 7 févr. 2012 Period 3: 2010-2015 Welcome in a world without perfect Gold Standard
  • 55. 7 févr. 2012 Gold Standard 25 mm Biopsy 0% False Positive False Negative
  • 56. 7 févr. 2012 Truth in the Absence of Gold Standard 25 mm Biopsy 25% False Positive False Negative
  • 57. 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
  • 58. 7 févr. 2012 Poynard J Hepatol 2011 Truth FibroTest FibroScan 5-30 mm Biopsy ALT
  • 59. 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
  • 60. 7 févr. 2012 FibroTest Se LSM Se Biopsie Se Performance for Cirrhosis: Sensitivity The standard cutoffs: 0.74 FibroTest, 14.5 kPa Stiffness Poynard, J Hepatol 2011
  • 61. 7 févr. 2012 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
  • 62. 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
  • 63. 2 Biomarkers of liver injury in chronic hepatitis • Unmet need • Historic • Methods and based evidence • Guidelines in practice 2
  • 64. Serum Biomarker Imaging Biomarker FibroTest FibroMax Choice Hepatologist Epidemiologist GP FibroScan SWE Aixplorer
  • 66. • AFEF, HAS • EASL, AASLD • WHO Guidelines: HCV and HBV
  • 67. 7 févr. 20127 févr. 2012 FibroTest APRI FIB4TE Imbert-Bismuth Lancet 2001 Sandrin Ultra Med Biol 2003 Wai Hepatology 2003 Sterling Hepatology 2006
  • 68. • Applicability • Variability • False positive if activity • False negative for cirrhosis Fibroscan limitations
  • 69. 7 févr. 2012 Pitfalls of Fibroscan 3.1% Failures and Unreliable results 15.8%
  • 70. 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
  • 72.
  • 73.
  • 74. 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
  • 75. 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
  • 76. 8-week $ 63,000 12-Week $ 94,500 24-week $ 189,000 $ 1125 per pill
  • 77. FibroTest used to identify cirrhosis at baseline or for follow-up
  • 78. 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
  • 79. 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
  • 80. 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
  • 81. 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
  • 82. 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%
  • 83. Higher Diagnostic and Prognostic performance of FibroTest versus APRI in CHC Poynard, Ann Int Med 2013
  • 84. 5 years prognostic value in chronic hepatitis B FibroTest better biomarker de Ledinghen APT 2013 LSM Not in intention to diagnose
  • 85. 10 year Prognostic value FibroTest versus TE n= 2724 45% CHC, 24% CHB, NAFLD 10%, ALD 6%
  • 86. Biomarke r Analytic variability Risk false positive due to Activity Fasting Applicability Investment Cost FibroTest < 7% no (ActiTest) no >95% 0 38€-200$ FibroScan Inter Observer yes yes 80 % 60,000€ 200,000$ 38€-350$  APRI Hazard 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
  • 87. 2 Biomarkers of liver injury in chronic hepatitis • Unmet need • Historic • Methods and based evidence • Guidelines in practice 2
  • 88. 2016
  • 89. Direct comparisons between APRI, FIB4, FibroTest and TE n=185 comparisons: 99 Fibrosis n=12,725 / 86 Cirrhosis n=10,929 Houot APT 2016
  • 90. FT better than TE AUROC + 0.06 Fibrosis
  • 92. 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
  • 93. FibroTest similar to biopsy for estimating fibrosis progression Progression to cirrhosis in 2472 patients Biopsy FibroTest Poynard et al, J Hepatol 2012
  • 94. 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
  • 95. 23 sept. 2014 Survival without liver complications n = 933 NS SVR n=4 3 HCC 1 Cholangiocarcinoma All F4 before SVR 2 F2 after Poynard, J Hepatol 2013
  • 96. Cirrhosis regression in SVR n=24/43 ( 56%) FibroTest = 0.74 Poynard, J Hepatol 2013
  • 97. Cirrhosis Occurrence in SVR n=15/128 (12%) FibroTest = 0.74 Poynard, J Hepatol 2013
  • 98. 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
  • 99. F4 F1 F0 France: 12,000,000 at Risk100% 5% Death 15,000/year0.1% Biomarker10% F2 F3
  • 100.
  • 101. n= 1,016,557 (100 %) ActiTest Poynard BmjOpen 2015
  • 102. Fibrosis density Birth-Year and Gender Other USA France n= 470,762
  • 103. Serum Biomarker Imaging Biomarker FibroTest FibroMax Choice Hepatologist Epidemiologist GP FibroScan Aixplorer