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EASL and Liver Research at the European EASL and Liver Research at the European LevelLevel
The viRgil network of excellenceThe viRgil network of excellence
VIRGIL: COMBATING RESISTANCE TO ANTIVIRAL VIRGIL: COMBATING RESISTANCE TO ANTIVIRAL TREATMENTSTREATMENTS
April 17, 2005April 17, 2005 EASL, ParisEASL, Paris
Fabien ZoulimFabien ZoulimINSERM Unit 271, LyonINSERM Unit 271, Lyon
General General ObjectivesObjectives
TO ORGANISE THE EUROPEAN FIGHT AGAINST VIRAL DRUG TO ORGANISE THE EUROPEAN FIGHT AGAINST VIRAL DRUG RESISTANCERESISTANCE
WITH A COMPREHENSIVE AND INTEGRATED ULTRASTRUCTURE WITH A COMPREHENSIVE AND INTEGRATED ULTRASTRUCTURE
MODEL: 3 major viral diseases in EuropeMODEL: 3 major viral diseases in Europe– InfluenzaInfluenza
Annual epidemic outbreaksAnnual epidemic outbreaks– 114 000 hospitalizations / year114 000 hospitalizations / year– 21 000 Deaths / year21 000 Deaths / year
Anticipation for pandemic planning and viral resistanceAnticipation for pandemic planning and viral resistance– Chronic hepatitis Chronic hepatitis
Hepatitis B Hepatitis B – 15 million chronic carriers in Europe15 million chronic carriers in Europe
Hepatitis C Hepatitis C – 8-10 million chronic carriers in Europe8-10 million chronic carriers in Europe
Responsible for 2/3 of Responsible for 2/3 of cirrhosis and liver cancercirrhosis and liver cancer Treatment failureTreatment failure:50-60% patients:50-60% patients
HBV resistance to HBV resistance to therapytherapy
% o
f pat
ient
s
5%
13%
24%
0% 0%0
20
40
60
80
year 1
2%
42%
year 2
???7%
53%
year 3
???
70%
15%
year 4
???
LAM 1 FTC 2 LdT 3 ADV 5 4ETV
1 Lai et al. Clin Infect Dis. 2003;36:687-961 Lai et al. Clin Infect Dis. 2003;36:687-962 Schiffman ML et al. Hepatology 2004; 40:172A2 Schiffman ML et al. Hepatology 2004; 40:172A3 Lai CL, et al. Hepatology 2003; 38: 262A3 Lai CL, et al. Hepatology 2003; 38: 262A4 Colonno RJ, et al. Hepatology 2004; 40: 661A 4 Colonno RJ, et al. Hepatology 2004; 40: 661A
5 Xiong et al. EASL 20055 Xiong et al. EASL 20056 Angus et at Gastroenterology (2003)6 Angus et at Gastroenterology (2003)7. Villeneuve et al J. Hepatol.7. Villeneuve et al J. Hepatol.
HBV resistance to HBV resistance to nucleoside analogsnucleoside analogs
Allen Hepatology 1998, Delaney J Virol 2003, Angus Gastroenterology 2003, Allen Hepatology 1998, Delaney J Virol 2003, Angus Gastroenterology 2003, Villeneuve J Hepatol 2003, Lai AASLD 2003, Colonno HepDart 2003Villeneuve J Hepatol 2003, Lai AASLD 2003, Colonno HepDart 2003
845 a.a.
Terminal protein spacer Pol/RT RNaseH
A B C ED
1 183 349 692
YMDD
V173L
L180M M204I/V
GVGLSPFLLA
I(G) II(F)
(rt1) (rt 344)
LAM1 / FTC2
ETV *4 T184A/G/I/S S202G/I M250V
ADV 3 A181V N236T
LdT 5
M204I
Terminal protein spacer
Chronic hepatitis C Chronic hepatitis C Treatment response Treatment response and failureand failure
0%
10%
20%
30%
40%
50%
60%
70%
6%
Standard IFNa
monotherapy(24 weeks)
16-30%
Standard IFN-a
monotherapy(48weeks)
41-45%
IFN-a2b +Ribavirin
Peg-IFN-a2b/2a+ Ribavirin
54-56%
Manns, Lancet 2001; Fried NEJM 2002
HCV : the new targetsHCV : the new targetsand the resistance and the resistance problemproblem
Di Bisceglie et al., Hepatology 2002
Specific Specific ObjectivesObjectives
Improve the understanding, Improve the understanding,
diagnosis, surveillance, and diagnosis, surveillance, and
treatment of treatment of antiviral drug resistanceantiviral drug resistance
Improved benefit/cost Improved benefit/cost of viral disease of viral disease
managementmanagement
Integration of European research Integration of European research
excellence and capacitiesexcellence and capacities
viRgil NetworkviRgil NetworkA European CoverageA European Coverage
+ ISRAEL
60 scientific60 scientificteamsteams
12 European Member States12 European Member States55 institutions55 institutions
Steering CommitteeSteering CommitteeProject Management Project Management
TeamTeam
Governing BoardGoverning BoardScientific Advisory BoardScientific Advisory BoardPatients Advocay GroupsPatients Advocay Groups
7 7 PharmaceutiPharmaceuti
calcal companiescompanies/ Biotech/ Biotech•BioallianceBioalliance•BioMérieuxBioMérieux•LiverDocLiverDoc•RetroscreeRetroscreenn•RiotechRiotech•TripepTripep
viRgil Network viRgil Network composition composition
EC grant EC grant for integration: for integration: 9 M € / 4 years9 M € / 4 years
viRgil viRgil NetworkNetworkThe structureThe structure
Major strengthsMajor strengths
Complementarity/Excellence of the teamsComplementarity/Excellence of the teams Exchange of material, expertise, personelExchange of material, expertise, personel Centralized platforms for collaborative Centralized platforms for collaborative
clinical and pre-clinical studiesclinical and pre-clinical studies– New drugsNew drugs– New assaysNew assays
> Integration of activities> Integration of activities > More ambitious and larger scale projects> More ambitious and larger scale projects > Additional grants> Additional grants
Launching of Launching of viRgil activitiesviRgil activities
Kick-off meeting, June 27-29, 2004 in LyonKick-off meeting, June 27-29, 2004 in Lyon– Launching at the Rhône-Alpes region council Launching at the Rhône-Alpes region council
headquartersheadquarters– Press conferencePress conference– Internal meeting with the network membersInternal meeting with the network members
Management structure in placeManagement structure in place Website in place: Website in place: http://www.virgil-net.org/
– Intranet Intranet – ExtranetExtranet– Links with scientific societies (EASL, national Links with scientific societies (EASL, national
liver societies, etc…)liver societies, etc…)
ViRgil launching ViRgil launching Lyon, June 27-29Lyon, June 27-29
Common definition of viral drug Common definition of viral drug resistanceresistance
Common clinical record form toCommon clinical record form to– Collect clinical dataCollect clinical data– Collect samples for further biological Collect samples for further biological
studiesstudies– Identify patients for clinical studies Identify patients for clinical studies
The basis for The basis for clinical clinical researchresearch
“primary” treatment failure* “secondary” treatment failure *
Hepatitis B decline of HBV-DNA load in serum <
1log10 IU/ml after 12 weeks of
therapy compared to baseline value.
increase in viral load in serum during
therapy of at least 1log10 IU/ml
compared to the nadir value
Hepatitis C 1. decline < 2-log (IU/mL) of HCV RNA
load in serum at week 12 of therapy
in comparison to baseline value.
2. Patients with further treatment
until week 24 (“slow responder”) are
considered as non-responders if they
are not HCV RNA negative in serum
at week 24.
at least 1-log increase of viral load
(IU/mL) in serum determined at t wo
different time points during IFN-based
therapy after initial response.
viRgil definition of viral drug resistance
viRgil ready to start viRgil ready to start clinical studies !clinical studies !
Ongoing activities of the centralized Ongoing activities of the centralized
platforms platforms
Implementation of a clinical trial platform Implementation of a clinical trial platform
for European trials for European trials -> European clinical research infrastructure network (ECRIN)-> European clinical research infrastructure network (ECRIN)
Endorsement of viRgil activities by the Endorsement of viRgil activities by the
EASLEASL
PhysicianPhysician PhysicianPhysician
DatabaseDatabase
LiverLiverExpertExpert
PatientPatient
Follow upFollow up
DecisionSupport System
Best practiceBest practice
DDDoc
Consultation Consultation requestrequest ReportReport
Dissemination of Dissemination of knowledge activitiesknowledge activities
Endorsement/organization of several Endorsement/organization of several meetingsmeetings– 2004: Immunology, HBV, & HCV 2004: Immunology, HBV, & HCV
(Heidelberg) meetings(Heidelberg) meetings– 2005: HBV meeting (Heidelberg)2005: HBV meeting (Heidelberg)– 2005: « virology of hepatitis B » book2005: « virology of hepatitis B » book– 2005: Virgil antiviral drug resistance 2005: Virgil antiviral drug resistance
symposium (Lyon), BioVisionsymposium (Lyon), BioVision
VIRGIL International Workshopon Antiviral Drug Resistance
June 8, 2005
Lyon, France
http://www.virgil-net.org/
Interaction between partnersInteraction between partners– Exchange of material / methodologyExchange of material / methodology– Exchange of scientific personelExchange of scientific personel– Start of new collaborative studiesStart of new collaborative studies
Interaction with other European actionsInteraction with other European actions– Biosapiens networkBiosapiens network– ECRINECRIN
Already > 20 viRgil publications and patent Already > 20 viRgil publications and patent applicationsapplications
-> Infrastructure for clinical research on drug -> Infrastructure for clinical research on drug resistanceresistance
Dissemination Dissemination of knowledgeof knowledge
J Weinbach, PMJ Weinbach, PMINSERM-transfertINSERM-transfertF Zoulim, coordinatorF Zoulim, coordinatorINSERMINSERM
M MannsM MannsB LinaB Lina
J NeytsJ Neyts
S SchalmS SchalmJM CohenJM Cohen
JM PawlotskyJM PawlotskyM ZambonM ZambonW SpaanW Spaan
J OxfordJ Oxford
G PapeG PapeS LudwigS Ludwig
R BartenschlagerR BartenschlagerA HayA Hay
60 teams & 55 institutions
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