VIRGIL

EC contribution

: € 9 000 000

Duration

: 48 months and beyond

Starting date

: 01/05/2004

Instrument

: Network of Excellence

Keywords

: Antiviral, drug, resistance, hepatitis, influenza, flu, HCV, HBV, virus

Project Number

: LSHM-CT-2004-503359

Web-site

: -

Problem:

The development of new antiviral therapies over recent decades constitutes major progress in the treatment of viral infections with a considerable impact on life expectancy and quality for patients. In the case of highly contagious viruses such as influenza, antiviral drugs can also be used to control epidemics, and, in the case of the emergence of a pandemic virus could even contribute to slowing or preventing its propagation.

One of the consequences, however, of this success is the high frequency of drug resistance, which may be due to the patient (host), or to the virus, or to a combination of both. In particular, the emergence of resistant viral strains during treatment (Darwinian selection), in the absence of adequate follow-up, can lead to treatment failure, or even epidemic diffusion of the resistant strains. It has been estimated, for example, that after four years of hepatitis B antiviral therapy with lamivudine, 70% of patients present resistances. Rational and logical use of antiviral drugs is essential to minimise the clinical and epidemiological impact of resistance. Treatment strategies must therefore be adapted in real time to changes in viral populations. This monitoring requires a multidisciplinary approach, as it is based on epidemiology, clinical follow-up, diagnostics and basic research and involves public institutions as well as private laboratories.

Aim:

The resources and skills allowing control of the various aspects of resistance already exist in European private and public laboratories, but until recently they were fragmented, constituting a major obstacle to progress of knowledge. The primary goal of VIRGIL is to gradually integrate resources and skills dispersed throughout Europe to achieve common research objectives, including the study of the socio-economic dimension of antiviral drug resistance. VIRGIL was therefore designed to be a virtual institute organised into seven collaborative platforms able to deal with all aspects of antiviral drug resistance, regardless of the type of virus concerned (surveillance, diagnosis, basic virology and modelling, host-inherent factors, pharmacology, technological innovation, socio-economic impact). It currently comprises more than 70 laboratories, including six biotech small and medium enterprises (SMEs), in more than 16 Member States of the European Union and beyond.

The other goals of VIRGIL are to:

1. provide the pharmaceutical industry with centralised management and standardised computer tools to conduct large-scale clinical trials on viral hepatitis and influenza;
2. rationalise the use of antiviral drugs for the benefit of patients and health systems and to contribute to the development of new more effective and less expensive drugs;
3. transpose these concepts of excellence to other regions of the world, including developing countries where the viruses studied are endemic;
4. constitute the basis for a future European Virology Foundation.

In the first phase, three disease models were selected (influenza, hepatitis B and hepatitis C) for the development and testing of working tools. Chronic hepatitis (15 million people infected in Europe) is responsible for two thirds of all cases of cirrhosis and liver cancer, and 50% of patients present drug resistances. Influenza, with its annual epidemic waves, is responsible for 21 000 deaths per year in France and 114 000 hospitalisations. The network is also reactive and can respond to emergency situations such as influenza pandemics.

Expected results:

Less than three years after the creation of VIRGIL, the preliminary results obtained on antiviral drugs used to treat influenza and hepatitis B and C demonstrate the pioneer role in Europe of an integrated approach linking basic research and clinical research.

VIRGIL teams were the first to precisely characterise resistances to newly marketed antiviral drugs (adefovir, entecavir and multi resistant strains) for the treatment of hepatitis B. As a result of the links between VIRGIL and scientific societies such as EASL (European Association for the Study of the Liver), these results could be adopted by health authorities for the establishment of official guidelines. In the case of hepatitis C, several in vitro studies have identified synergies and antagonisms between antiviral molecules, new more effective interferons, as well as new viral targets for treatments. This will allow the design of clinical trials using combinations of these molecules whose synergy and absence of cross-resistance have been demonstrated in vitro.

VIRGIL has initiated a collaboration with the European Influenza Surveillance Scheme (EISS), and the WHO network of national influenza reference laboratories to study, over several consecutive seasons, the conditions of emergence of drug-resistant influenza viruses, in susceptible subgroups of the population (children, immunosuppressed patients).

The VIRGIL approach will allow combined analysis of the characteristics of resistance strains (genetics, morphological), their associated clinical features (symptoms, infectious property) and their epidemiological impact. Prof. Alan Hay, director of one of the four WHO world influenza reference centres (London, UK), says: 'By integrating the efforts of people working on various aspects of influenza, VIRGIL plays a key role in the real-time surveillance, study and diffusion of knowledge on resistance to Neuraminidase Inhibitors (NIs ).' According to him, this initiative arrives 'just at the time when knowledge on NI resistance needs to be developed'.

A training programme on NI resistance tests for directors of WHO national influenza reference centres has also been set up by the VIRGIL team directed by Dr Maria Zambon (Health Protection Agency, London, UK). The objective is to allow each European country to autonomously develop the necessary skills to monitor resistant strains circulating in its territory.

Apart from their immediate benefit on seasonal influenza, the skills and infrastructures developed in the context of this programme could be mobilised in the event of an influenza pandemic. The H5N1 virus continues to circulate in Asia and Africa, inducing numerous epizootic infections in wild and domestic birds, and the risk of emergence of a pandemic still remains high, according to the WHO. At the present time, all countries of the EU have set up stocks of oseltamivir. These drugs will only be useful if they are used rationally, and if the emergence of resistant viral strains is controlled by continuous surveillance set up throughout the EU according to a sufficiently dense network.

Making Europe an important place for the conduct of large-scale clinical trials

During its first two years of existence, VIRGIL has established a number of standardised criteria for data collection in clinical trials. This is a crucial step, as adoption of these criteria by all members of VIRGIL will allow comparison of the results obtained in various trials. This standardisation process has allowed:

1. the elaboration of an informed consent form to perform research on biological samples taken from hepatitis B or C patients. Translated into 10 languages and downloadable from VIRGIL's intranet site, this form was designed to ensure that this research strictly complies with the ethical requirements of current EU legislation;
2. the adoption by all members of VIRGIL of standardised definitions of primary and secondary drug resistance to hepatitis B and C antiviral drugs based on viral load cut-off values;
3. the design and development of on-line databases allowing standardised and secure exchange of information on patients (profile, composition of treatment, follow-up, primary or secondary resistance etc.). They will also allow selection of patients of interest as a function of the questions raised by particular studies.

Several clinical trials have been initiated on these databases by VIRGIL to characterise resistances of HBV to new molecules such as entecavir or tenofovir, and resistances of HCV to dual therapy with peg-interferon and ribavirin.

VIRGIL plans to develop centralised clinical trial services with major pharmaceutical groups and promote the integration of SMEs (biotechs) in the European economic tissue by linking them with various regions of excellence represented by VIRGIL's partners. According to Dr Jerome Weinbach, logistic coordinator of VIRGIL (INSERM Transfert, Paris), 'access to the international market is an essential condition for the sustainable growth of SMEs'. Installation of VIRGIL in the Rhne-Alpes competitiveness pole in France therefore constitutes a major advantage.

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