Trithérapie (Boceprevir et Telaprevir)

Transcription

1 Trithérapie (Boceprevir et Telaprevir) GEMHEP Mardi 29 novembre 2011 Tarik Asselah MD, PhD Service d Hépatologie & INSERM U773, CRB3 Hôpital Beaujon, Clichy tarik.asselah@bjn.aphp.fr

2 Trithérapie (Boceprevir et Telaprevir) Introduction (DAAs) Patients G1 naïf Patients G1 traité Résistance Effets secondaires Conclusion

3 Hépatite C USA & Canada 4 M SOUTH AMERICA 10 M EUROPE 9 M FAR EAST EASTERN /ASIA MEDITERRANEAN 60 M 21.3M SOUTH EAST ASIA 32.3 M AFRICA 32 M AUSTRALIA 0.2 M Japan 2M 170 Millions de Porteurs chroniques du VHC WHO, 1999

4 Asselah T et al. Liver International 2009

5 Asselah T et al. Liver International 2012

6 Asselah T et al.al. GUT 2009 Asselah T et GUT 2009

7 Protease Inhibitors NS5A Inhibitors Polymerase Inhibitors NS3-4A Protease NS5A NS5B Polymeras e Asselah T et al. Liver International 2012

8 Trithérapie (Boceprevir et Telaprevir) Introduction (DAAs) Patients G1 naïf Patients G1 traité Résistance Effets secondaires Conclusion

9 Sprint 2 (Boceprevir) : Schéma de l essai Contrôle 48 P/R N = 363 Semaine 4 Semaine 28 Semaine 48 Semaine 72 PR lead-in PR + Placebo Suivi ARN-VHC indétectable entre S8-S24 Suivi BOC TGR* N = 368 PR lead-in PR + Bocéprévir ARN-VHC détectable entre S8-S24 PR + Placebo Suivi BOC/ N = 366 PR lead-in PR + Bocéprévir Suivi Poordad, et al. NEJM 2011

10 Sprint 2: Taux de RVS et de rechute (ITT) p < p < SVR* Relapse Rate p =0.004 p = /232 18/ /14 3/ Non-Black Patients Black Patients

11 Boceprevir : G1 naïf (sans cirrhose) Stop treatment at Week 28 if undetectable at Week 8 and 24 PR lead-in BOC + PR If detectable at Week 8 but undetectable at Week 24: BOC + PR* PR* Weeks HCV RNA Assess for RGT criterion If 100 IU/mL discontinue all drugs If detectable discontinue all drugs

12 Advance (telaprevir) : Schéma de l essai (control) (n=361) Pbo + PR PR Follow-up SVR T12PR (n=363) TVR + PR PR ervr+ Follow-up ervr PR SVR Follow-up Follow-up SVR T8PR (n=364) TVR + PR Pbo + PR PR ervr+ Follow-up ervr PR SVR Follow-up Follow-up SVR Weeks Jacobson IM, et al. N EJM 2011

13 Advance: Taux de RVS T12PR T8PR PR 100 P< Percent of patients with SVR n/n = P< / / /361 SVR

14 RVS selon la ervr T12PR T8PR PR 80 Percent of patients with SVR n/n = 189/ /207 28/29 82/151 79/ / week regimen 48-week regimen ervr+ ervr-

15 Telaprevir : G1 naïf Telaprevir Peg-IFN alfa + ribavirin Peg-IFN alfa + ribavirin if detectable at Week 4 or 12* Weeks HCV RNA: If >1000 IU/mL at Week 4 or 12: discontinue all drugs If detectable at Week 24 or 36: discontinue PR

16 Trithérapie (Boceprevir et Telaprevir) Introduction (DAAs) Patients G1 naïf Patients G1 traité Résistance Effets secondaires Conclusion

17 Respond-2 (boceprevir) : schéma de l étude (control) n=80 Peg-IFN + RBV Pbo + Peg-IFN + RBV Follow-up Week 8 and 12 undetectable HCV RNA Follow-up BOC RGT n=162 Peg-IFN + RBV BOC + Peg-IFN + RBV Week 8 detectable HCV RNA + Week 12 undetectable HCV RNA Pbo + Peg-IFN + RBV Follow-up BOC44/ n=161 Peg-IFN + RBV BOC + Peg-IFN + RBV Follow-up Weeks SVR assessment 72 Bacon et al. NEJM 2011

18 Respond-2 (boceprevir): SVR Prior relapsers Prior partial responders SVR (%) BOC RGT BOC44/ BOC RGT BOC44/ n/n= 15/51 72/105 77/103 2/29 23/57 30/58

19 Boceprevir : G1 traités (sans cirrhose) Prior partial responders and prior relapsers without cirrhosis PR lead-in BOC + PR PR Prior null responders PR lead-in BOC + PR Weeks HCV RNA If 100 IU/mL discontinue all drugs If detectable discontinue all drugs

20 Realize (telaprevir): schéma de l étude (control) Pbo + Peg-IFN + RBV Peg-IFN + RBV n=132 Follow-up LI T12/ n=264 Pbo + Peg-IFN + RBV TVR + Peg-IFN + RBV Peg-IFN + RBV Follow-up T12/ n=266 TVR + Peg-IFN + RBV Pbo + Peg-IFN + RBV Peg-IFN + RBV Follow-up Weeks 48 SVR assessment 72 Zeuzem et al. NEJM 2011

21 Realize (telaprevir): SVR Prior relapsers * * Prior partial responders Prior null responders SVR (%) * * * * LI T12/ T12/ LI T12/ T12/ LI T12/ T12/ n/n= 15/68 124/ /145 4/27 27/48 30/49 2/37 25/75 22/72

22 Telaprevir : G1 traité Prior relapsers without cirrhosis Telaprevir + PR Prior partial and null responders Peg IFN alfa + Ribavirin Stop treatment at Week 24 if undetectable at Week 4 and 12* Peg IFN alfa + Ribavirin if detectable at Week 4 or 12 Telaprevir +PR Peg IFN alfa + Ribavirin Weeks HCV RNA If >1000 IU/mL at Week 4 or 12: discontinue all drugs If detectable at Week 24 or 36: discontinue PR

23 Durée pour tout patient avec cirrhose TVR + Peg-IFN + RBV Peg-IFN + RBV >1000 IU/mL: Stop 3 drugs >1000 IU/mL: Stop 3 drugs Detectable: Stop PR Detectable: Stop PR Peg-IFN + RBV BOC+ Peg-IFN + RBV 100 IU/mL: Stop 3 drugs Detectable: Stop 3 drugs INCIVO (telaprevir) EU SmPC; VICTRELIS (boceprevir) EU SmPC

24 Trithérapie (Boceprevir et Telaprevir) Introduction (DAAs) Patients G1 naïf Patients G1 traité Résistance Effets secondaires Conclusion

25 Caractéristiques des différentes classes d antiviraux directs Génotype Barrière génétique Inhibiteurs protéase G1 Faible Inhibiteurs polymérase nuc Inhibiteurs polymérase non nuc G1,G2,G3 G1 Elevée Faible Inhibiteurs NS5A G1, G4 Faible

26 PEG-IFN- + Ribavirin Fréquence de l échec thérapeutique PEG-IFN- 2a + ribavirin (Fried et al., 2002) 54% 48% 58% PEG-IFN- 2a + ribavirin (Hadziyannis et al., 2004) PEG-IFN- 2b + ribavirin (Manns et al., 2001) 24% 16% 18% Genotype 1 Genotypes 2/3 Manns et al., Lancet 2001; Fried et al., N Engl J Med 2002; Hadziyannis et al., Ann Intern Med 2004.

27 HCV resistance NS2 NS3 proteinase NS3 protease C E1 E2 p7 NS2 NS3 4A NS4B NS5A NS5B Core Envelope Serine protease domain RNA-dependent RNA polymerase VX-950; SCH VX-950; BILN 2061 VX-950; BILN 2061; SCH BILN 2061 VX-950 T54 R155 A156 D168 V36 R1479 (R1626) Valopicitabine HCV-796 Nonnucleosides S96 N142 S282 C316 M414 M419 P495 T423 Sarrazin et al. Gastroenterology Tong et al. Antiviral Res De Francesco and Migliaccio. Nature Le Pogam et al. Virology Villano et al. Hepatology

28 Telaprevir Phase II/III : Résumé T12/PR (750 mg q8h) N=1346 Placebo/ N=764 Deaths N=0 a N=1 a,b Serious AEs 7% 3% AEs leading to permanent discontinuation of Telaprevir/Placebo AEs leading to permanent discontinuation of all study drugs at same time 14% 4% 8% 4% a Refers to the number of patients who died as a result of an AE with onset during the telaprevir/placebo treatment phase b This includes 1 patient who had a life-threatening AE that was not resolved at his last study visit. The patient died afterwards due to this AE Materials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM pdf

29 Boceprevir Phase III : résumé BOC RGT BOC44/ PR SPRINT-2 (naïve) 1,2 N=368 N=366 N=363 Deaths N=1 N=1 N=4 Serious AEs 11% 12% 9% Discontinued due to AEs 12% 16% 16% RESPOND-2 (experienced) 3 N=162 N=161 N=80 Deaths N=1 N=0 N=0 Serious AEs 10% 14% 5% Discontinued due to AE 8% 12% 2% 1. Poordad F, et al. N Engl J Med 2011;364: ; 2. Poordad F, et al. N Engl J Med 2011;364: (supplementary appendix); 3. Bacon BR, et al. N Engl J Med 2011;364:

30 Telaprevir Phase II/III : résumé Patients, % T12/PR (750 mg q8h) N=1346 Skin and subcutaneous tissue disorders Placebo/ N=764 Leading to discontinuation of all study drugs*(%) Pruritus (SSC) % Rash (SSC) % Gastrointestinal disorders Nausea <0.5 Diarrhea <0.5 Hemorrhoids 12 3 <0.5 Anorectal discomfort 8 2 <0.5 Anal pruritus 6 1 <0.5 Blood and lymphatic system disorders Anemia (SSC) % Materials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM pdf *Discontinuation of all study drugs in the T12/PR arms (analyzed within SSC for rash and anemia) SSC: special search category

31 Boceprevir Phase III : résumé Patients, % BOC RGT BOC44/ PR SPRINT-2 (naïve) 1 N=368 N=366 N=363 Anemia* Dysgeusia* Grade 3-4 neutropenia (500 to <750/mm 3 and <500/mm 3 ) RESPOND-2 (experienced) 2 N=162 N=161 N=80 Anemia* Dysgeusia* Dry skin** Grade 3-4 neutropenia (500 to <750/mm 3 and <500/mm 3 ) Rash *p<0.001 for boceprevir arms versus PR **p=0.009 (BOC RGT) and p=0.004 (BOC44/) versus PR p=0.01 (BOC RGT) and p=0.05 (BOC44/) versus PR 1. Poordad F, et al. N Engl J Med 2011;364: Bacon BR, et al. N Engl J Med 2011;364:

32 Conclusion (1) La trithérapie permet un gain de RVS d au moins 30 % chez les patients génotype 1. Réduction de la durée du traitement à 6 mois chez la majorité des patients. Peu ou pas de données dans les populations particulières: coinfectés VIH, cirrhotiques, greffés. Limites des futurs traitements : - Résistance - Effets secondaires - Coûts - Autres populations (autres génotypes )

33 Conclusion (2) Gestion des effets secondaires: suivi précoce attentif Interactions médicamenteuses: CYP dépendant Observance: prise toutes les 8 heures Risque de résistance: Nouvelles règles d arrêt de traitement: Durée de traitement en fonction de la réponse (ervr) Lead in phase: Traitement à la carte?

34 Amélioration des traitements 35 43% 47% - 63% 70% 6 16% 18 23% IFN PEG-IFN IFN + Riba PEG- IFN+Riba Manns et al. Lancet 2001 Fried et al. NEJM 2002 Hadziyannis et al. Annals of Internal Medicine 2004