Nouvelles thérapeutiques du VHC: progrès vers l éradication virale Fabien Zoulim Service d hépatologie, Hospices Civils de Lyon & Laboratoire des Hépatites, INSERM U1052 Université de Lyon, France
Prévalence mondiale du VHC < 1% 1-2,4% 2,5-4,9% 5-10% > 10% Données non disponibles OMS (97)
Distribution des génotypes du VHC Europe du nord Russie Amérique du nord Europe du sud Chine Japon Afrique centrale Asie du sud est Amérique du sud Afrique du sud Australie N elle Zélande Génotypes/sous types 1a 1b 2 3 4 5 6 Forns et Bukh (98)
Evolution de l infection aiguë vers la chronicité anti-hcv! Symptoms +/-! HCV RNA! Titer! ALT! Normal! 0! 1! 2! 3! 4! 5! 6! 1! 2! 3! 4! Years! Months! Time after Exposure!
Conséquences cliniques de l hépatite C Hépatite aigue Hépatite chronique Cirrhose Carcinome hépatocellulaire Fatigue chronique qualité de vie Dépression Vascularite Autoimmunité Cryoglobulinémie Lymphome B
Stade de Fibrose 0 Progression de l hépatite C Vitesse de progression 1 2 3 4 Rapide Intermediaire Lente 5-10 ans 15-30 ans >30 ans Cirrhose CHC 3%/an Decompensation 5%- 10%/an Mortalité «hépatique» 2%- 5%/an
Objectifs thérapeutiques pour HIV, HBV et HCV HIV HBV HCV Host cell Host cell Host cell HCV RNA Host DNA H Host DNA cccdna H Host DNA H Proviral DNA Integrated DNA Nucleus Nucleus Nucleus Lifelong suppression of viral replication Longterm suppression of viral replication Definitive viral clearance and SVR Kieffer et al. J Antimicrob Chemother 2010; Sorriano et al. J Antimicrob Chemother 2009; Clavel et al. New Engl J Med 2004; Zoulim &Locarnini Gastroenterology 2009; Sarrazin & Zeuzem Gastroenterology 2010
Combinaison d interferon alpha et de ribavirine: vers la guérison. Patients achieving SVR (%) 100 80 All genotypes Genotype 1 Genotypes 2 or 3 61-79 76-82 60 40 18-39 35-43 33-36 42-46 20 6-19 11-19 10-22 0 24 48 Weeks 78 Peg-IFN IFN + ribavirin IFN monotherapy Peg-IFN + ribavirin *Range of values reported; lower bar represents lower value;
Avenir des traitements anti-vhc Sustained Virological Responses Rates 100% 80% 60% 40% IFN 48 wk & Ribavirin Optimization and individualization PEG-IFN 48 wk & Ribavirin Direct antivirals 20% 0% IFN 24 wk IFN 48 wk 1990 1998 2000 2002 2007 2011
HCV: les enzymes cibles et le développement d inhibiteurs spécifiques Di Bisceglie et al., Hepatology 2002
Les principaux inhibiteurs spécifiques du VHC! Inhibiteurs de protéase 1 ère génération Approuvés: Telaprevir et Boceprevir! Inhibiteurs de protéase 2ème génération! Inhibiteurs nucléosidiques de polymérase! Inhibiteurs non nucléosidiques de polymérase! Inhibiteurs de NS5A! Inhibiteurs d entrée! Immunomodulateurs Réponse innée: agonistes de TLR Réponse adaptative: vaccinothérapie
Nouvelles cibles antivirales Receptor HCV Polymerase inhibitors IFN + RBV Endosome Entry Progeny genomes Release Exocytosis Uncoating Replication + - Assembly E1 - E2 Translation NS3/4A NS4B NS5B NS2 NS5A E1 E2 Core E1 - E2 Golgi Nucleus Protease inhibitors ER Racanelli V, et al. Trends Immunol 2003;24:456-64; Manns MP, et al. Nat Rev Drug Discov 2007;6:991-1000 Cytoplasm NS5A inhibitors Other viral and cellular targets IFN Interferon, RBV - Ribavirin
Emergence des résistances aux antiviraux (I) Hepatocytes All single HCV mutations likely to RNA be generated every day Resistant mutants less fit than wt Viral infection Viral replication Wild-type Resistant mutant
Emergence des résistances aux antiviraux (II) Hepatocytes HCV RNA All single mutations likely to be generated every day Viral infection Viral replication Wild-type Resistant mutant Antiviral treatment with DAA Resistant mutants more fit than wt DAA Direct acting antiviral agents, wt wild-type
Evolution des variants de la protéase NS3 pendant la monothérapie de telaprevir Sarrazin C, et al. Gastroenterology 2007;132:1767-77 NS3 Non structural protein 3
Peg-IFN & ribavirin inhibent la réplication des mutants de la protéase HCV Kieffer TL, et al. AASLD 2006 Peg-IFN Pegylated interferon, PI Protease inhibitor
Efficacité des trithérapies chez les patients naifs infectés par le génotype 1 du VHC
Efficacité antivirale précoce des trithérapies basées sur les inhibiteurs de protéase exemple du telaprevir 0 1 2 3 4 0 Time (weeks) 8 12 Median change from baseline (log 10 HCV RNA) 1 2 3 4 5 6 7 Non-responders to prior PR treatment who received T12/PR24 or T24/PR48 in PROVE3 (n=130) Relapsers after prior PR treatment who received T12/PR24 or T24/PR48 in PROVE3 (n=83) Null responders and partial responders to prior PR treatment who received T12/PR24 or T24/PR48 in roll-over Study 107 (n=79) Relapsers after prior PR treatment who received T12/PR24 or T24/PR48 in roll-over Study 107 (n=28) Treatment-naïve patients who received T12/PR in PROVE1 or PROVE2 (n=338) Poordad F, et al. J Hepatol 2010; 52(Suppl. 1):S121 S122
Réponse virologique soutenue: trithérapie à base de telaprevir versus bithérapie PR 100 80 74 79* SVR (%) 60 40 46 20 0 PR48 T12/PR n/n = 166/361 683/903 *p<0.0001 T12/PR vs PR48 (79% versus 46%) in ADVANCE SVR, considered virologic cure, was defined as HCV RNA <25 IU/mL at last observation within the Week 72 visit window. In case of missing data, the last HCV RNA data point from Week 12 of follow-up onwards was used INCIVO (telaprevir) EU SmPC
Réponse virologique soutenue: trithérapie à base de boceprevir versus bithérapie PR 100 SVR (%) 80 60 40 38 63 * 66 * 20 0 PR48 BOC RGT BOC44/PR48 n/n = 137/363 233/368 242/366 *p<0.001 for both boceprevir arms versus PR48 SVR was defined as undetectable HCV RNA at the last available value in the period at or after follow-up Week 24. If there was no such value, the follow-up Week value was carried forward VICTRELIS (boceprevir) EU SmPC
Réponse virologique soutenue: impact de la réponse virologique précoce et de la durée du traitement Exemple du telaprevir Treatment duration according to ervr status <20 weeks 18% n=100 ervr 22% n=118 ervr+* 60%* n=322 SVR (%) Eligible for 24 weeks and randomized to 24 or 48 weeks* 100 80 60 40 20 92 SVR rate Δ 4% (2-sided 95% CI = 2% to +11%) 88 64 23 48 weeks <20 weeks (due to premature treatment discontinuation) *Patients who achieved ervr (undetectable HCV RNA at Weeks 4 and 12) and completed the Week 20 visit were randomized to receive an additional 4 or 28 weeks of PR alone 65% of patients achieved an ervr (352/540); 322/352 were randomized and 30/352 patients discontinued before randomization at Week 20 0 ervr+ T12PR24 149/162 ervr+ T12PR48 140/160 ervr T12PR48 76/118 <20 weeks 23/100 Sherman KE, et al. N Engl J Med 2011;365:1014 24
Réponse virologique soutenue: impact de la fibrose hépatique Exemple du boceprevir 100 No, minimal or portal fibrosis (F0 F2) Bridging fibrosis or cirrhosis (F3/F4) 80 67 * 67 * SVR (%) 60 40 38 38 41 52 ** 20 0 PR48 BOC RGT BOC44/PR48 PR48 BOC RGT BOC44/PR48 n/n= 123/328 213/319 211/313 9/24 14/34 22/42 *p<0.001 for both boceprevir arms vs PR48; p=1.00 for boceprevir vs PR48 **p=0.31 for boceprevir vs PR48 Adapted from Poordad F, et al. N Engl J Med 2011;364:1195 206
Efficacité des trithérapies chez les patients en échec de bithérapie IFN-ribavirine (VHC génotype 1)
Definitions de l échec à la bithérapie Peg-IFN/RBV HCV RNA level Breakthrough Null response Partial response Non-response Relapse 2 log 10 drop Detection limit Treatment 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 Weeks Adapted from Shiffman M. Curr Gastroenterol Rep 2006;8:46 52 Neumann A, et al. Science 1998;282:103 7; De Bruijne J, et al. Neth J Med 2008;66:311 22
Réponse virologique soutenue: telaprevir chez les rechuteurs, répondeurs partiels, et les répondeurs nuls 100 Prior relapsers 88 * 84 * Prior partial responders Prior null responders 80 SVR (%) 60 40 56 * 61 * 33 * 31 * 20 22 15 5 0 PR48 LI T12/ PR48 T12/ PR48 PR48 LI T12/ PR48 T12/ PR48 PR48 LI T12/ PR48 T12/ PR48 n/n= 15/68 124/141 122/145 4/27 27/48 30/49 2/37 25/75 22/72 *p<0.001 vs PR48 SVR, considered virologic cure, was defined as HCV RNA <25 IU/mL at last observation within the Week 72 visit window. In case of missing data, the last HCV RNA data point from Week 12 of follow-up onwards was used INCIVO (telaprevir) EU SmPC
Réponse virologique soutenue: boceprevir chez les rechuteurs et répondeurs partiels 100 Prior relapsers Prior partial responders SVR (%) 80 60 40 29 69 75 40 52 Prior null responders were excluded from RESPOND-2 20 7 0 PR48 BOC RGT BOC44/ PR48 PR48 BOC RGT BOC44/ PR48 n/n= 15/51 72/105 77/103 2/29 23/57 30/58 SVR was defined as undetectable HCV RNA at the last available value in the period at or after follow-up Week 24. If there was no such value, the follow-up Week 12 value was carried forward VICTRELIS (boceprevir) EU SmPC
Réponse virologique soutenue au telaprevir en fonction du stade de fibrose et du type d échec à la bithérapie Prior relapsers Prior partial responders Prior null responders 100 80 87 85 84 77 Pbo/PR48 Pooled T12/PR48 SVR (%) 60 40 32 56 34 41 42 20 0 18 20 13 14 7 10 6 0 0 n/n= 12/38 145/167 2/15 53/62 1/15 48/57 3/17 36/47 0/5 10/18 1/5 11/32 1/18 24/59 0/9 16/38 1/10 7/50 Stage No, minimal or portal fibrosis Bridging fibrosis Cirrhosis No, minimal or portal fibrosis Bridging fibrosis Cirrhosis No, minimal or portal fibrosis Bridging fibrosis Cirrhosis SVR was defined as HCV RNA <25 IU/mL at last observation within the Week 72 visit window. In case of missing data, the last HCV RNA data point from Week 12 of follow-up onwards was used Pol S, et al. Hepatology 2011;54(Suppl. S1):374A
SAFETY OF TELAPREVIR OR BOCEPREVIR IN COMBINATION WITH PEGINTERFERON ALFA/ RIBAVIRIN, IN CIRRHOTIC NON RESPONDERS FIRST RESULTS OF THE FRENCH EARLY ACCESS PROGRAM (ANRS CO20-CUPIC) C Hézode 1, C Dorival 2, F Zoulim 3, T Poynard 4, P Mathurin 5, S Pol 6, D Larrey 7, P Cacoub 4, V de Ledinghen 8, M Bourlière 9, PH Bernard 10, G Riachi 11, Y Barthe 2, H Fontaine 6, F Carrat 2, JP Bronowicki 12 for the CUPIC study group (ANRS CO 20) Hôpital Henri Mondor, Créteil 1, UMR-S 707, Paris 2, INSERM U871, Lyon 3, Hôpital de la Pitié-Salpêtrière, Paris 4, Hôpital Claude Huriez, Lille 5, Hôpital Cochin, Paris 6, Hôpital Saint-Eloi, Montpellier 7, Hôpital Haut-Lévèque, Pessac 8, Fondation Hôpital Saint Joseph, Marseille 9, Hôpital Saint André, Bordeaux 10, Hôpital Charles Nicolle, Rouen 11, Hôpital de Brabois, Nancy 12, France
CUPIC Patients! HCV genotype 1 patients! Compensated cirrhosis (Child Pugh A)! Non-responders Relapsers Partial responders ( >2 log 10 HCV RNA decline at Week 12) Null responders theoretically excluded! Treated in the French early access program
Treatment regimen Interim analysis Peg-IFN + RBV BOC(+(Peg$IFN(α$2b(+(RBV( Follow-up BOC:(800(mg/8h;((Peg$IFNα$2b:(1.5(µg/kg/week;((RBV:(800(to(1400(mg/day( TVR(+(Peg$IFN(α$2a(+( RBV(( Peg$IFN(α$2a(+(RBV( Follow-up TVR:(750(mg/8h;((Peg$IFNα$2a:(180(µg/week;((RBV:(1000(to(1200(mg/day( 0( 4( 8( 12( 16( Weeks( 36( 48( SVR(assessment( 72( h"p://www.afssaps.fr/var/afssaps_site/storage/original/applica6on/4b8c53711bab9d8f7d4c3f947caa90f6.pdfb h"p://www.afssaps.fr/var/afssaps_site/storage/original/applica6on/fa78af08e029caf9d82bcd9d3e77eb09.pdfbb
Telaprevir: preliminary safety findings Patients, n (% patients with at least one event) Telaprevir n=296 Serious adverse events (SAEs)* 144 (48.6%) Premature discontinuation Due to SAEs Death Septicemia, Septic shock, Pneumopathy, Oesophageal varices Bleeding, Encephalopathy, Lung carcinoma 77 (26.0%) 43 (14.5%) 6 (2.0%) Infection (Grade 3/4) 26 (8.8%) Asthenia (Grade 3/4) 14 (4.7%) Rash Grade 3 Grade 4 (SCAR) 20 (6.8%) 2 (0.7%) Pruritus (Grade 3/4) 11 (3.7%) Hepatic decompensation (Grade 3/4) 13 (4.4%) *407 SAEs in 144 patients; SCAR: severe cutaneous adverse reaction
Telaprevir: preliminary safety findings Patients, n (% patients with at least one event) Telaprevir (n=296) Anemia Grade 2 (8.0 <10.0 g/dl) Grade 3/4 (<8,0 g/dl) EPO use Blood transfusion Neutropenia Grade 3 (500 <1000/mm 3 ) Grade 4 (<500/mm 3 ) G-CSF use Thrombopenia Grade 3 (25 000 <50 000) Grade 4 (<25 000) Thrombopoïetin Use EPO:Bérythropoïé6ne;BBBGLCSF:BgranulocyteLcolonyBs6mula6ngBfactorB 58 (19.6%) 30 (10.1%) 168 (56.8%) 45 (15.2%) 12 (4.0%) 2 (0.7%) 7 (2.4%) 35 (11.8%) 4 (1.3%) 5 (1.7%)
% of patients with undetectable HCV RNA Telaprevir: preliminary efficacy data 100 80 60 40 20 0 85 86 86 53 145/276 224/265 219/254 177/205 Week 4 Week 8 Week 12 Week 16
Boceprevir: preliminary safety findings Patients, n (% patients with at least one event) Boceprevir (n=159) Serious adverse events (SAEs)* 61 (38.4%) Premature discontinuation Due to SAE 38 (23.9%) 12 (7.4%) Death Bronchopulmonary infection, Sepsis 2 (1.3%) Infection (Grade 3/4) 4 (2.5%) Asthenia (Grade 3/4) 9 (5.7%) Rash Grade 3 Grade 4 (SCAR) Pruritus (Grade 3/4) 1 (0.6%) Hepatic decompensation (Grade 3/4) 7 (4.4%) 0 0 *158 SAEs in 61 patients; SCAR: severe cutaneous adverse reaction
Boceprevir: preliminary safety findings Patients, n (% patients with at least one event) Anemia Grade 2 (8.0 <10.0 g/dl) Grade 3/4 (<8,0 g/dl) EPO use Blood transfusion Neutropenia Grade 3 (500 <1000/mm 3 ) Grade 4 (<500/mm 3 ) G-CSF use Thrombopenia Grade 3 (25 000 <50 000) Grade 4 (<25 000) Thrombopoïetin Use EPO:Bérythropoïé6ne;BBBGLCSF:BgranulocyteLcolonyBs6mula6ngBfactorB Boceprevir (n=159) 36 (22.6%) 16 (10.1%) 105 (66.0%) 17 (10.7%) 7 (4.4%) 1 (0.6%) 6 (3.8%) 10 (6.3%) 1 (0.6%) 3 (1.9%)
Boceprevir: preliminary efficacy data % of patients with undetectable HCV RNA 80 60 40 20 0 1 71 61 37 2/155 55/149 88/144 89/126 Week 4 Week 8 Week 12 Week 16
Conclusions! La tolérance des trithérapies à base de telaprevir ou boceprevir est mauvaise chez les patients cirrhotiques en échec de bithérapie,mais est associée à un taux élevé de réponse virologique sous traitement.! Taux de SAEs élevé (38.4 to 48.6%)! Taux élevé d arrêt de traitement par SAE (7.4 to 14.5%)! Les patients cirrhotiques doivent être traités avec prudence et surveillés dans des centres de référence du fait d un taux important d anémie répondant mal l EPO! Les taux de SVR dans cette population sont en attente dans le cadre de l étude de cohorte.
Vers le développement de combinaisons d inhibiteurs sans interferon! Combinaisons d antiviraux directs Élévation de la barrière de résistance Prévention des résistances et ELIMINATION virale! Traitement de courte durée 24, 12, voire 8 semaines! Spécifique du génotype ou pangénotypique!! Points à résoudre: Interactions médicamenteuses Place de la ribavirine
Importance du profil de résistance croisée pour le choix des combinaisons d inhibiteurs spécifiques NS2 NS3 protease NS3 protease C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B Core Envelope Serine protease domain Telaprevir; SCH 503034 Telaprevir; BI 201335 Telaprevir; BI 201335; SCH 503034 BI 201335 Telaprevir T54 R155 A156 D168 V36 R1479 * (R1626) NM283* HCV-796 S96 N142 S282 C316 M414 M419 BI 207127 P495 *nucleoside; non-nucleoside T423 Sarrazin C, et al. Gastroenterol. 2007;132:1767 77; Tong X, et al. Antiviral Res. 2006;70:28 38; De Francesco R, et al. Nat. 2005;436:953 60; Le Pogam S, et al. Virol. 2006;351:349 59; Villano S, et al. 57th AASLD 2006, Boston, MA, October 27 31, 2006
Combinaison d un IP et d un Ipol BI 207127 + BI 201335: prévention des resistances BI 207127 X EC 50 BI 201335 X EC 50 + Long-term selection of resistance in vitro is effectively suppressed by BI 201335 and BI 207127 combination EC 50 Median estimated concentration
Preliminary Study of Two Antiviral Agents for Hepatitis C Genotype 1 Lok AS et al. N Engl J Med 2012;366:216-224 Lok AS, et al. New Engl J Med 366(3): 216-224 January 19, 2012
Conclusion - L avenir des traitements anti-vhc SOC Standard of Care NSOC New Standard of Care Dual-oral / QUAD 2 direct acting antivirals quadruple Triple-oral 3 direct acting antivirals PegIFN HCV Protease Inhibitor +/ - Ribavirin HCV Polymerase Inhibitor HCV Protease Inhibitor PegIFN Ribavirin or NS5A inhibitor HCV Polymerase Inhibitor 1 Ribavirin HCV Protease Inhibitor PegIFN HCV Protease Inhibitor Ribavirin HCV Polymerase Inhibitor HCV Polymerase Inhibitor 2 or NS5A inhibitor