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