FibroTest in the diagnosis of HCV

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FibroTest in the diagnosis of HCV

• Publications on diagnostic performance

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In this Presentation
1. Diagnosis and clinical options

2. First validation Prospective Study

3. FibroTest in histological changes

4. FibroTest in HCV carriers with mixed cryoglobulinemia systemic vasculatis

5. Comparison and combination with other methods

6. Meta-analysis
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Diagnosis and clinical options
Positive serology
Poynard et al, Comp Hepatol 2004
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First validation study
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Imber-Bismut et al, Lancet 2001

• Biochemical markers of liver fibrosis in patients
  with hepatitis C virus infection a prospective
  study (n205)

Results
high negative predictive value (gt90 certainty of absence of F2, F3, or F4) was obtained for scores from zero to 020. 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 (gt90 certainty of presence of F2, F3, or F4) was obtained for scores from 080 to 100. Of these 50 patients with high scores (15 of total), there were five false positives two F1, A1, and three F1, A2.

• 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 15IQR.
• The lower error bar is the smallest observation
  that is 25th percentile minus 15IQR.
• Bonferroni allpairwise multiple comparison
  plt00001 between all stages.

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Imber-Bismut et al, Lancet 2001
Results
The ROC curves for the three indices were very similar The areas (SD) under the curves did not differ 5 factors 0851 (0370) 6 factors 0847 (0370) 10 factors 0837 (0370)
ROC curves of fibrosis indices combining five,
six, or ten biochemical factors, and age and sex
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
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FibroTest in histological changes
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DArondel JVHep 2006

• Utility of biomarkers to estimate the dynamics in
  the histological response in HCV to pegylated-IFN
  alpha-2b and ribavirin n96

Results
Baseline F2F3F4 sustained viral responders (n22)
FibroTest -ActiTest decrease (plt0.0001)
This improvement was significant even in virologic non-responders.

Conclusions
FibroTest and ActiTest are sensitive markers to histological changes during and after HCV treatment
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Poynard 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
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Poynard et al, Hepatology 2003 - Results
Results 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
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FibroTest in HCV carriers with mixed
cryoglobulinemia systemic vasculatis
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Sene 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)

Patients and methods 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 (95CI 0.75-0.90) vs 0.85 (95CI0.75-0.90) 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 (95CI 0.73-0.97) vs 0.71 (95CI0.60-0.80) p 0.055 correlated by METAVIR
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Sene D. et al, Clin Biochem 2006
Results FT/AT vsother biomarkers AUROC FibroTest AUC 0,83 APRI AUC 0,73 P0,01 Forns index AUC 0,77 P0,054 Age-platelet index AUC 0,0,72 P0,01 Platelet count AUC 0,66 P10-3
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
No vasculatis
Vasculatis
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Comparison and combination with other methods

• Hyaluronic acid, Historical index, Apri, FirboScan

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FibroTest versus other non invasive
markersPoynard 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

Study Design
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FibroTest versus other non invasive
markersPoynard et al, Comp Hepatol 2004 - Results
Conclusions
Better AUROC for FibroTest Lower than random 0.50 value (upper panel) (P lt 0.001). Higher then AUROCs of other fibrosis markers (lower panel) (P lt 0.05).
Diagnostic Value of FibroTest versus other non invasive markers
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FibroTest versus other non invasive
markersPoynard 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
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.
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
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 serum HCV viral load. AUROCs of ActiTest for the diagnosis of significant necrosis, according to serum HCV viral load.
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FibroTest versus BiopsyMyers 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

Patients and methods 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) 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) 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) 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
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 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 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 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
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Sebastiani et al, J Hepatol 2006

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

HEPATITIS C (AUC) HEPATITIS C (AUC) HEPATITIS C with NALT (AUC) HEPATITIS C with NALT (AUC)
APRI FT APRI FT
gtF2 0.69 0.81 0.69 0.70
F4 0.61 0.71
IN gtF2 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
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
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Sebastiani et al, J Hepatol 2006 Safe Biopsy

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

For significant fibrosis For cirrhosis
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Sebastiani et al, J Hepatol 2006 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 SAFE biopsy Fibropaca algorithm Fibropaca algorithm Leroy algorithm
gtF2 F4 gtF2 F4 gtF2 F4 gtF2 F4 gtF2
APRI Fibrotest sequential APRI Fibrotest sequential APRI Fibrotest Forns in parallel 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
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FibroTest versus Glycomics and FibroScan-
Castera et al, Gasteroenterol Clin Biol 2005

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

Patients and methods 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 F2, 0.92 for F3, 0.88 for F4) compared to other non-invasive methods like Fibroscan to Clinical Glycomics to a combination of both
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FibroTest versus FibroScan- 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
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Multi center validation study FibroTest versus
HA- 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 (n165)

Patients and methods 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 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 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 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
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 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 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 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
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Meta analysis
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Meta-analysis Poynard et al, clin chem 2007
FibroTest Meta-Analysis 30 Published
Studies 6.378 Patients 2001-2006 AUROC0.84
(0.83-0.86) for F2F3F4
The best you can obtain with 20mm biopsy is 0.90
Bedossa 2003