FibroTest in the diagnosis of HCV

FT in diagnostic of HCV

FibroTest in the FibroTest in the diagnosisdiagnosis of of HCVHCV

Publications on diagnostic performance


1.1. Diagnosis and clinical optionsDiagnosis and clinical options

2.2. First validation: Prospective StudyFirst validation: Prospective Study

3.3. FibroTest in histological changesFibroTest in histological changes

4.4. FibroTest in HCV carriers with mixed cryoglobulinemia systemic FibroTest in HCV carriers with mixed cryoglobulinemia systemic vasculatisvasculatis

5.5. Comparison and combination with other methodsComparison and combination with other methods

6.6. Meta-analysisMeta-analysis

In this PresentationIn this Presentation


Results interpretable no risk of false positive/negative

Not interpretable Risk of false

positive/negative*

Repeat Test or perform

elastography/ biopsyNo biopsy mandatory

Treatment TreatmentOr follow-up**

Follow-up** with FibroTest

Treatment Or follow-up

95% 5%

(For liver injuries Assessment)

Diagnosis and clinical optionsDiagnosis and clinical options

Positive serologyPositive serology

Poynard et al, Comp Hepatol 2004


First validation studyFirst validation study


Imber-Bismut et al, Lancet 2001Imber-Bismut et al, Lancet 2001

• Biochemical markers of liver fibrosis in patients with hepatitis C virus infection: a prospective study (n=205)

- The top and bottom of the box are the 25th and 75th percentiles. - The length of the box is thus the IQR. The line through the middle of the

box is the median. - The upper error bar is the largest observation 75th percentile plus

1·5IQR.- The lower error bar is the smallest observation that is 25th percentile

minus 1·5IQR. - Bonferroni allpairwise multiple comparison; p<0·0001 between all

stages.

Results

high negative predictive value (>90% certainty of absence of F2, F3, or F4) was obtained for scores from zero to 0·20. Of these 119 patients with low scores (35% of total) there were 13 false negatives: four F2, A0; six F2, A1; three F2, A2.

high positive predictive value (>90% certainty of presence of F2, F3, or F4) was obtained for scores from 0·80 to 1·00. Of these 50 patients with high scores (15% of total), there were five false positives: two F1, A1, and three F1, A2.


Imber-Bismut et al, Lancet 2001Imber-Bismut et al, Lancet 2001

ROC curves of fibrosis indices combining five, six, or ten biochemical factors, and age and sex

ResultsThe ROC curves for the three indices were very similar

The areas (SD) under the curves did not differ:

5 factors: 0·851 (0·370) 6 factors: 0·847 (0·370) 10 factors: 0·837 (0·370)

Conclusions A combination of basic serum markers could be used to substantially reduce the number of liver biopsies done in patients with chronic HCV infection


FibroTest in histological changesFibroTest in histological changes


D’Arondel JVHep 2006D’Arondel JVHep 2006

• Utility of biomarkers to estimate the dynamics in the histological response in HCV to pegylated-IFN alpha-2b and ribavirin n=96

0

0,2

0,4

0,6

0,8

1

baseline week12 week24 Follow up12

FIBROTEST ACTITESTResults

Baseline F2F3F4 sustained viral responders (n=22)

FibroTest -ActiTest decrease (p<0.0001)

This improvement was significant even in virologic non-responders.

Conclusions

FibroTest and ActiTest are sensitive markers to histological changes during and after HCV treatment


Poynard et al, Hepatology 2003Poynard et al, Hepatology 2003

• Biochemical Surrogate markers of liver fibrosis and activity in a randomized trial of Peginterferon Alfa-2B and ribavirin

Patients and methods

208 patients treated with IFN alpha & ribavirin 1.5mcg/kilo, 3/week during 48 weeks

144 patients treated with IFN alpha 3mU, 3/week during 48 weeks

Follow up at 24 weeks after treatment

Assessment with FibroTest ActiTest and biopsy at baseline and after treatment

Results See next slide

Conclusion FT could be used as surrogate marker for liver biopsy in patients with chronic hepatitis C, both for initial evaluation and for follow-up

Due to liver biposy risks and limitation and the improvmentof nin invasive markers of fibrosis, liver biopsy should no longer be mandatory


Poynard et al, Hepatology 2003 Poynard et al, Hepatology 2003 - Results- Results

Results

FibroTest vs METAVIR at Baseline

FibroTest vs METAVIR at follow up

ActiTest vs METAVIR at Baseline

ActiTest vs METAVIR at follow up

FibroTest vs Knodell score at Baseline

FibroTest vs Knodell score at follow up

ActiTest vs Knodell score at Baseline

ActiTest vs Knodell score at follow up


FibroTest in HCV carriers with mixed FibroTest in HCV carriers with mixed cryoglobulinemia systemic vasculatiscryoglobulinemia systemic vasculatis


Sene D. et al, Clin Biochem 2006Sene D. et al, Clin Biochem 2006

• Biochemical markers of liver fibrosis and activity as non invasive alternatives to liver biopsy in patients with CHC and mixed cryoglobulinemia vasculatis (MCV)


238 patients with HCV (50% male, mean age: 57y, 56% genotype1, 32% genotype 2-3, 12% genotype 4-5

Performed tests: Liver biopsy, FibroTest, Apri, Forns index Systemic vasculatis defined by the presence of skin purpura, and rheumatological,

neurological or renal involvement. 52% had serum cryoglobulin, 27% had serum inflammation and 11% had hemolysis.

Results

FT/AT vsBiopsy

FibroTest versus biopsy AUROC for F2F3F4 vs F0F1 was 0.83(0.04), without a difference between patients with and those without systemic vasculitis [0.81 (95%CI = 0.75-0.90) vs 0.85 (95%CI=0.75-0.90); p = 0.65] correlated by METAVIR

ActiTest versus biopsy ActiTest assessed by the AUROC (SE) for A2A3 vs A0A1 was 0.77 (0.05) slightly higher but without significative difference between patients with and those without systemic vasculitis [0.89 (95%CI 0.73-0.97) vs 0.71 (95%CI=0.60-0.80); p = 0.055] correlated by METAVIR


Sene D. et al, Clin Biochem 2006Sene D. et al, Clin Biochem 2006

Results

FT/AT vsother biomarkers

AUROC FibroTest: AUC= 0,83 APRI: AUC= 0,73 P=0,01 Forns index: AUC= 0,77 P=0,054 Age-platelet index: AUC= 0,0,72 P=0,01 Platelet count: AUC= 0,66 P≤10-3

Results

FT unaffected by vasculatis

Conclusion

FT is a reliable non invasve alternative to liver biopsy in HCVwith systemic vasculitis or serum non-septic inflammation and is more reliable than other non-invasive fibrosis markers (Forns, APRI, HA, age-platelet).

Diagnostic value of FT in patients with HCV-mixed cryoglobulinemia vasculitis similar to that of patients without this condition and to those found in previous studies

Vasculatis No vasculatis


Comparison and combinationComparison and combination with other methods with other methods

Hyaluronic acid, Historical index, Apri, FirboScan


FibroTest versus other non invasive markersFibroTest versus other non invasive markersPoynard et al, Comp Hepatol 2004Poynard et al, Comp Hepatol 2004

• Overview of the diagnostic value of biochemical markers of liver fibrosis (FibroTest, HCV FibroSure) and necrosis (ActiTest) in patients with chronic Hepatitis C

16 HCV publications:FT= Alternative to Biospy

1,570 subject data base

New Analysis/ Summary

Control group: 300 blood donors

FibroTest in different HCV genotypes FibroTest versus…

Genotypes: 1, 2, 3, 4-5-6 APRI, Forns, Hyaluronic acid

Study Design


FibroTest versus other non invasive markersFibroTest versus other non invasive markersPoynard et al, Comp Hepatol 2004 - ResultsPoynard et al, Comp Hepatol 2004 - Results

Conclusions

Better AUROC for FibroTest

Lower than random 0.50 value (upper panel) (P < 0.001).

Higher then AUROCs of other fibrosis markers (lower panel) (P < 0.05).

Diagnostic Value of FibroTest versus other non invasive markers


FibroTest versus other non invasive markersFibroTest versus other non invasive markersPoynard et al, Comp Hepatol 2004 - ResultsPoynard et al, Comp Hepatol 2004 - Results

Conclusion

No significant difference in the AUROC of FibroTest and ActiTest in HCV according to HCV genotype or viral load.

FibroTest-ActiTest is a good surrogate to liver biopsy for the assessment of HCV related liver fibrosis

AUROCs of FibroTest for the diagnosis of significant fibrosis, according to HCV genotypes.

AUROCs of ActiTest for the diagnosis of significant necrosis, according to HCV genotypes.

AUROCs of FibroTest for the diagnosis of significant fibrosis, according to serum HCV viral

load.

AUROCs of ActiTest for the diagnosis of significant necrosis, according to serum

HCV viral load.


FibroTest versus BiopsyFibroTest versus BiopsyMyers R.P et al, American Journal of Gastro 2002Myers R.P et al, American Journal of Gastro 2002

• Biochemical markers of liver Fibrosis: a comparison with historical features in patients with chronic Hepatitis C


211 patients, 52% male, median age of 28y, median duration of infection 18y Untreated HVC patients Biopsy and FibroTest tested for the diagnosis of clinically significant fibrosis (F2-F4)

Results

FibroTest vs METAVIR Historical index vs METAVIR AUROC F2-F4 AUROC A2-A3/ F2-F4

Conclusion FibroTest accurately predicts significant fibrosis in HCV infected patients Markers used are widely available Represents the most discriminative tool available for non-invasive prediction of fibrosis in HCV More accurate than historical features, the addition of which to the existing index was not helpful

Historical indexFibroTest Historical indexFibroTest


Sebastiani et al, J Hepatol 2006Sebastiani et al, J Hepatol 2006

HEPATITIS C

(AUC)

HEPATITIS C with NALT (AUC)

APRI FT APRI FT

>F2 0.69 0.81 0.69 0.70

F4 0.61 0.71

• Stepwise combination algorithms of non-invasive markers to diagnose significant fibrosis in chronic hepatitis C

Conclusions Fibrotest presents with the best accuracy in all the subgroups of patients with chronic liver disease

Combination of markers should reduce the need for liver biopsy and ultimately health expenses

IN >F2 FibroTest APRI

Classified cases % 100 51

SE % 65 83.5

SP % 80.6 77.1

PPV% 80 86.6

NPV% 66.7 72.5

Accuracy% 72.6 81.2


Sebastiani et al, J Hepatol 2006 Sebastiani et al, J Hepatol 2006 – Safe Biopsy– Safe Biopsy

• Sequential Algorithms for Fibrosis Evaluation (SAFE BIOPSY) Stepwise modelling aimed to achive accuracy> 95%

For significant fibrosis For cirrhosis

APRI

No Fibrosis(low accuracy)

Significant fibrosis(high accuracy)

Unclassified

FIBROTEST

F2-F3-F4(high accuracy)F0-F1

(low accuracy)

>94% accuracy Liver biopsy not needed

Liver biopsy needed

APRI

Cirrhosis(low accuracy)Unclassified

FIBROTEST

F4(high accuracy)

F0-F1(high accuracy)

>95% accuracy Liver biopsy not needed

LiverLiver biopsybiopsy neededneeded

F2-F3 (low accuracy)

No cirrhosis(high accuracy)


Sebastiani et al, J Hepatol 2006 Sebastiani et al, J Hepatol 2006 – Biopsy and cost reduction– Biopsy and cost reduction

• Sequential Algorithms for Fibrosis Evaluation (SAFE BIOPSY) INTERIM ANALYSIS ON 2035 HCV CASES

SAFE BIOPSY for

SIGNIFICANT FIBROSIS

SAFE BIOPSY for

CIRRHOSIS

Accuracy (%) 90 93

Saved biopsies (%) 47 82

Saved cost (%) 45 80

SAFE biopsy

Fibropaca algorithm

Leroy algorithm

>F2 F4 >F2 F4 >F2

APRI + Fibrotest sequential

APRI + Fibrotest + Forns in parallel

APRI + Fibrotest in

parallel

Accuracy (%)

90 91.2 87.6 94 93.5

Saved biopsies (%)

43.8 79.1 51.7 76.2 29.2

Reduced cost (%)

52.2 70.9 34.6 59.1 15


FibroTest versus Glycomics and FibroScanFibroTest versus Glycomics and FibroScan- Castera et al, Gasteroenterol Clin Biol 2005- Castera et al, Gasteroenterol Clin Biol 2005

• “Clinical glycomics”: independant validation and comparison with Fibroscan and FibroTest for the assessment of fibrosis in CHC


211 CHC patients (57 males, mean age 53) Exams (on same day): Liver biopsy, FirboScan, FibroTest and profile of

glycosylation of serum proteins to obtain the GlycoMarker (GM)

Results (Auroc)

Conclusion FibroTest had an excellent diagnostic values (0.84 for F≥2, 0.92 for F≥3, 0.88 for F=4) compared to

other non-invasive methods like Fibroscan to “Clinical Glycomics” to a combination of both


FibroTest versus FibroScanFibroTest versus FibroScan- Castera et al, Gastroenterology 2005- Castera et al, Gastroenterology 2005

• Prospective comparison of transient elastography, FibroTest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C.

Conclusions Recommend algorithm (from author)

From this first study, Fibroscan seemed able to assess liver fibrosis with a performance similar to that of FibroTest.

The combined use of Fibroscan and FibroTest to evaluate liver fibrosis could avoid a biopsy procedure in most patients with chronic hepatitis C


Multi center validation study: FibroTest versus HAMulti center validation study: FibroTest versus HA- Poynard et al, J viral Hepat 2002- Poynard et al, J viral Hepat 2002

• Biochemical markers of liver fibrosis in patients infected by hepatitis C virus: longitudinal validation in a randomized trial (n=165)


244 patients from 15 university hospitals, Positive HCV serology, never treated with elevated ALT Group 1: 3mU IFN alpha thrice weekly (24 weeks) Group 2: 6mU IFN alpha daily for 12 days and weekly for 22 weeks

Liver biopsies performed before and 72 weeks after Comparison Biopsy, FibroTest and hyaluronic acid

Results

FibroTest vs METAVIR Hyaloronic acid vs METAVIR AUROC FT (0,74) AUROC HA (0,65)

Conclusion Validation in an external population Greater diagnostic value than HA FT could be used as surrogate marker of the impact of HCV treatment on fibrosis progression


Meta analysisMeta analysis


Meta-analysis – Poynard et al, clin chem 2007Meta-analysis – Poynard et al, clin chem 2007

FibroTest Meta-Analysis

30 Published Studies

6.378 Patients

2001-2006

AUROC=0.84 (0.83-0.86)

for F2F3F4

The best you can obtain with 20mm biopsy is 0.90 Bedossa 2003

FibroTest in the diagnosis of HCV

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