VIRGIL was the first European surveillance network capable of addressing current and emerging antiviral drugs resistance developments in the field of influenza and viral hepatitis. Coordinated by Inserm (the French Institute for Health and Medical Research) and supported by a grant from the Priority 1 Life Sciences, Genomics and Biotechnology for Health programme in the 6th Framework Programme of the EU, the network's activities started in May 2004 with the initial task of integrating the fragmented European capacities and major expertise in the field into a single coherent Network of Excellence. VIRGIL initially gathers 60 organisations, including more than 60 academic laboratories and seven companies from 14 European countries and beyond.
VIRGIL is structured into seven integrated platforms centred on the patients with each focusing on a topic contributing towards the project objectives, from surveillance of resistant viruses in Europe, innovation in diagnostic tools, analysis of the virological mechanisms of antiviral treatment efficacy and resistance development and pharmacology to studies on host (patient-related) factors and the socio-economic impact of antiviral drug resistance. VIRGIL benefits from a central management unit that offers industrial partners a single contact point as well as integrated services for conducting large-scale European clinical trials. Finally, the network is also committed to training students and researchers within and outside of the participating organisations and to spreading VIRGIL's practices of excellence and the resulting knowledge throughout the medical community and the general population.
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. However, one of the consequences 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.
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:
In the first phase, three disease models were selected (influenza, hepatitis B, 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.
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 World Health Organization (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, United Kingdom), 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 (NIs1)." 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, United Kingdom). The objective is to allow each European country to autonomously develop the necessary skills to monitor resistant strains circulating in its territory.
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:
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 Jrme 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.
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.