HBV lesions

Fibrosis

Hepatic fibrosis is a process of scarring through fibrous tissue deposit which results in the destruction of the parenchyma, with the ultimate progressive stage being cirrhosis.

The METAVIR score assesses fibrosis in chronic hepatitis B according to a 5-stage classification:

• F0 : no fibrosis
• F1 : portal and periportal fibrosis with no septum
• F2 : portal and periportal fibrosis with rare septum
• F3 : portal and periportal fibrosis with many septum
• F4 : cirrhosis

Necroinflammatory activity

The activity (or grade) estimates the lesions of portal inflammation and hepatocellular necrosis.

The METAVIR score assesses the activity according to a 4-grade classification:

• A0 : no activity
• A1 : minimal activity
• A2 : moderate activity
• A3 : severe activity

The 2 BioPredictive tests for these 2 lesions

FibroTest

FibroTest measures the hepatic fibrosis stage with a blood test.

FibroTest was evaluated in relation to liver biopsy in a large number of HBV patients (n=1,580) and has been used in over 350,000 patients (2008).

FibroTest retains the same diagnostic value independent of ethnic origin, sex or HBeAg or transaminases.

FibroTest has the same diagnostic value for the intermediate stages and the extreme stages.

The use of FibroTest was validated for the initial diagnosis of fibrosis, but also for the monitoring of patients, whether treated or untreated.
The French National Authority for Health (HAS) has not recommended the use of FibroTest as a first-line assessment tool for fibrosis with untreated chronic hepatitis B, as with hepatitis C; the reevaluation however according to the latest positive published results is scheduled in 2009.

See FibroTest in action

Interpretation of the FibroTest results

The FibroTest result is provided as a score of 0 to 1, proportional to the severity of the fibrosis, with a conversion to the METAVIR system (from F0 to F4). To facilitate the visual interpretation, the result must be accompanied by a colored graph with three classes of severity:

• Green (minimal or absent)
• Orange (moderate)
• Red (significant)

The conversion of FibroTest into stages according to the three most used histological classifications (METAVIR, Knodell and Ishak) is proposed in the following grid:

ActiTest

Using the same blood test, ActiTest measures the degree of necroinflammatory activity of viral origin (HBV and HCV).

ActiTest combines the markers of FibroTest with ALT.

ActiTest was validated in relation to liver biopsy in a large number of HBV patients (n=924).

The diagnostic value of ActiTest is the same for the intermediate grades and the extreme grades.

ActiTest retains the same diagnostic value independent of ethnic origin, sex or HBeAg.

The use of ActiTest was validated for the initial diagnosis, but also for the monitoring of treated or untreated patients.

See ActiTest in action

Interpretation of the ActiTest results

The ActiTest result is provided as a score of 0 to 1, proportional to the significance of the activity, with a conversion to the METAVIR system (from A0 to A3).

To facilitate the visual interpretation, the result must be accompanied by a colored graph with three classes of severity:

• Green (minimal or absent)
• Orange (moderate)
• Red (significant)

The conversion of ActiTest into grades according to the three most used histological classifications (METAVIR, Knodell and Ishak) is proposed in the following grid:

FibroTest and ActiTest instructions for use

The use of our invasive tests is very simple: the physician writes a FibroTest prescription(available on the website).
The patient goes to a nearby laboratory for the six-parameters blood test. FibroTest and ActiTest combine six serum markers with the age and sex of the patient:

• Alpha-2-macroglobulin
• Haptoglobin
• Apolipoprotein A1
• Gamma-glutamyl transpeptidase (GGT)
• Total bilirubin
• ALT

A prototype prescription is available on the website(download the prescription).

The ActiTest and FibroTest scores are provided together on a result sheet combining all the information. The laboratory (or the physician) connects to the BioPredictive website for calculation of the tests and prints the results sheet which is available immediately and is accompanied by an interpretation aid and precautions for use.

Precautions for use, safety

An expert system analyzes each FibroTest and its parameters in order to ensure their proper applicability. Over 95% of tests are interpretable and enable an effective diagnosis of fibrosis and activity. In less than 5% of cases, the expert system detects the profiles that are at risk of false positives or false negatives and clearly indicates them on the result sheet.

Applicability and safety integrated in the tests

Applicability of
FibroTest : 95-99%

FibroTest is applicable in 95 to 99% of cases. It has been validated for the following diseases : (available scientific publications)

• Chronic hepatitis C
• Chronic hepatitis B
• Chronic hepatitis C or B with HIV co-infection
• Alcoholic liver diseases (steatosis and steatohepatitis)
• Steatosis and non-alcoholic steatohepatitis (diabetes, overweight, hypertriglyceridemia, hypercholesterolemia, hypertension)

The test is robust and validated, including for the following specific populations:

• Subjects over the age of 65 years
• Children
• Patients with renal insufficiency and patients with renal transplanation
• Hemophiliac
• Patients with chronic inflammatory disease
• General population

The tests are not applicable in only 1 to 5% of cases:

• Acute hepatitises, e.g., acute viral hepatitis A, B, C, D, E; drug-induced hepatitis
• Extrahepatic cholestasis, e.g., pancreatic cancer, gallstones
• Severe hemolysis, e.g., some cardiac valves
• Gilbert's syndrome with high unconjugated hyperbilirubinemia
• Acute inflammatory syndrome (the blood test just needs to be postponed)

These cases are detected by our safety mechanisms and are clearly indicated on the results sheet.

Reproducibility

Only the analyses performed in pre-analytical and analytical conditions and using the automated analyzers and reagents validated by our reference center are authorized by BioPredictive.

Tracibility

Our systems are declared with the French Committee on Technologies and Freedom (CNIL) and guarantee the anonymity of the provided information. The BioPredictive information system implements a tracibility device on all of its processes, thus assuring its quality management.

Use of FibroTest in the management of hepatitis B

The management of HBV and the therapeutic decisions depend on the degree of fibrosis and activity according to three classes of severity: green (minimal), orange (moderate) and red (significant).

The FibroTest and ActiTest scores can also predict the occurrence of complications (prognostic value) at 4 years. In a prospective study (n=1,074), no complications were observed at 4 years in patients with FibroTest less than or equal to 0.27 and ActiTest less than or equal to 0.29.

The use of FibroTest was validated for the initial diagnosis of fibrosis, but also for the monitoring of treated or untreated patients.

Comparison of FibroTest and liver biopsy

Biopsy is an imperfect tool; due to sampling errors, biopsy size (5 to 30 mm) and intra- and interobservor variability, it is now agreed that biopsy presents a mean error of 30%: it is called the "imperfect Gold Standard". The "perfect Gold Standard" of the liver is utopian, it would essentially be necessary to use the entire liver to rule out any possibility of diagnostic error.

Biopsy continues to present major inconveniences: 30% of patients complain of pain, 0.6% have been noted to have severe complications and even 0.03% deaths. Its use as a first-line tool is no longer suitable, and as its repeatability is very weak, biopsy is not practical for patient monitoring.

FibroTest is a non-invasive diagnostic test (simple blood test) which is very easily reproduced and has the same relevance as a 25 mm biopsy.

There is a mean discordance of 25% observed between FibroTest and biopsy. Half of these discordances are attributable to an error of the biopsy, often too small, and the other half to FibroTest.

In conclusion, FibroTest has the same diagnostic value as a 25 mm biopsy, while being noninvasive and easily repeatable.

Key figures of FibroTest

Bibliographic references

Here are several key references:

• Halfon et al, FibroTest-ActiTest as a non-invasive marker of liver fibrosis. Gastroenterol Clin Biol 2008;32:22-38
• Ngo et al,An accurate definition of the status of inactive hepatitis B virus carrier by a combination of biomarkers (Fibrotest-Actitest) and viral load. PlosOne 2008;3:e2573
• Poynard et al, Standardization of ROC curve areas for diagnostic evaluation of liver fibrosis markers based on prevalences of fibrosis stages. Clin Chem. 2007;53:1615-1622
• Poynard et al, Methodological aspects for the interpretation of liver fibrosis non-invasive biomarkers: a 2008 update. Gastroenterol Clin Biol 2008;32:8-21
• Poynard et al, Impact of adefovir dipivoxil on liver fibrosis and activity assessed with biochemical markers (FibroTest-ActiTest) in patients infected by Hepatitis B Virus J Vir Hep 2009; 16:203-13
• Gui HL et al, FibroTest-ActiTest for predicting liver fibrosis and inflammatory activity in Chinese patients with chronic hepatitis B. Zhonghua Gan Zang Bing Za Zhi. 2008;16:897-901

The complete list of publications is available on the website : liste des publications.