Transcript Telaprevir
How to avoid a resistance issue with the first generation protease inhibitors ? O. Lada PHD Service d’Hépatologie et INSERM CRB3, AP-HP Hopital Beaujon, Paris, France. [email protected] Progress in the Treatment of Hepatitis C 70% 47% 35 18 6 90 % 63% 43% 23% 16% IFN PEG-IFN IFN+RBV PEG-IFN+RBV 1989 2010 DAAs 2011 - 20.. HBV HIV HCV Genome DNA RNA RNA Mutation rate +++ + +++ Daily viral production 1013 1010 1012 cccDNA Integrated c DNA None Single Multiple Multiple No No Yes Viral Reservoir Therapeutic strategy recovery Direct Acting Antivirals (DAA) drugs targets Asselah T et al. Liver International 2011 Targets for DAAs NS5A Inhibitors Protease Inhibitors NS3-4A Protease NS5A Polymerase Inhibitors NS5B Polymerase Asselah T et al. Liver International 2012 Resistance to specific HCV inhibitors Selection of viral variants bearing amino acid substitutions that alter the drug target and thereby confer reduced susceptibility to the drug Protease inhibitors monotherapy Median HCV RNA (Log10 IU/mL) Telaprevir 7 6 5 4 3 2 1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Study Time (days) Placebo Telaprevir 450 mg q8h Telaprevir 750 mg q8h Telaprevir 1250 mg q12h Reesink HW, et al. Hepatology. 2005;42:234A. Factors influencing viral resistance with DAA Viral Factors • Level of viral replication (1012/day) • Low fidelity of polymerase • Impact of mutations on fitness • Viral quasi-species • Half-life of infected hepatocytes Resistance Pharmacological Factors Host Factors • Drug potency • Genetic barrier • Pharmacokinetic • Compliance • Immune system • Replication space • Activity of protein kinase • Nuceos(t)ide transporters Emergence of resistance during antiviral therapy Sensitive variants HCV Replication Resistant variants Time Emergence of resistance during antiviral therapy Treatment HCV Replication Sensitive variants Resistant variants MUTATION(S) Time Emergence of resistance during antiviral therapy Treatment HCV Replication Sensitive variants Resistant variants Virological breakthrough Time of resistance PI Les Patterns RAVS... (Variants associés à lato résistance) HCV protease V36A/M T54A/S R155K/T TELAPREVIR A156S A156V/T V36A/M T54A/S R155K/T/Q V170A BOCEPREVIR V55A Adapted from Thibault V, GEMHEP_Nov.11 A156S Subtype impacts the genetic barrier to Nombre de changements de resistance nucléotides pour modifier un résidu en "RAV" Number of nucleotide substitutions needed according subtype Genotype 1b R155K Genotype 1a CGG-AAG R155K AGG-AAG R155K 1 step CGG-CAG Resistant variant according to the subtybe in patients treated with boceprevir Thibault-GEMHEP_Nov.11 Zeuzem et al. EASL 2011, Abst. 9 2 step Resistance and viral fitness (x43) (x780) 20 90 18 80 16 70 14 60 12 50 10 40 8 30 6 20 4 10 2 0 0 Boceprevir Telaprevir Adapted from Thibault V, GEMHEP_Nov.11 Sarrazin et al. GASTROENTEROLOGY 2007;132:1767–1777 Susser et al. HEPATOLOGY 2009;50:1709-1718.) Resistance level (Fold) Relative Fitness 100 Resistance and triple combination therapy Treatment failure with the triple combination of Peg-IFN, Ribavirin and a protease inhibitor is principally due to an insufficient antiviral response to Peg-IFN and ribavirin. This poor response favors the growth of resistant virus selected by telaprevir or boceprevir. Importance of the lead-in phase Pooled data from SPRINT-2, RESPOND-2 and PROVIDE trial (Boceprevir) % of SVR SVR rates according to lead-in Emergence of Resistance accordind to lead-in 68% <1log Reduction in HCV RNA at Week 4 Poordad et al. NEJM 2011 364;13, Bacon et al. NEJM 2011, 2011, Abst. 931. Thibault-GEMHEP_Nov.11 Vierling et al. AASLD 31% >1log Reduction in HCV RNA at Week 4 Zeuzem et al. EASL 2011. Importance of the lead-in phase Data from the 4 weeks lead-in arm of the REALIZE trial (Telaprevir) % of SVR SVR rates according to previous response and RNA decline at 4 week Reduction in HCV RNA at Week 4 Foster et al. EASL Thibault-GEMHEP_Nov.11 2011, Abst 6A. Role of IL28B genotype in preventing resistance? Nature 2009 100% 80% SVR (%) 80% 60% 40 % 40% 25% 20% 0% T/T T/C C/C IL28B-genotypes and triple therapy in naïve patient IL28B-CC 100% IL28B-nonCC 90% cEVR 82% 80% 80% 71% 73% 64% 68% 67% 60% 50% 40% 25% 28% 26% 20% 0% PR T12PR Telaprevir PR BOC/PR48 Bocepravir Jacobson et al, EASL 2011; Poordad et al, EASL 2011; Zeuzem et al, EASL 2011 PR IFN-lambda IFN-l SVR Rates by IL28B Genotype and Prior SVR Rates by IL28B Genotype and Prior Response Response (Telaprevir regimens) Prior relapsers Prior partial responders Prior null responders Pooled T12/PR48 (n=209) Pooled T12/PR48 (n=79) Pooled T12/PR48 (n=134) Pbo/PR48 (n=52) Pbo/PR48 (n=20) Pbo/PR48 (n=33) Patients achieving SVR (%) P=ns 100 88 85 80 71 63 58 60 40 33 40 30 20 31 29 20 20 20 0 7 6 0 n/a CC n/N= 85 51/58 CT 4/12 100/117 6/30 TT 29/34 3/10 CC 5/8 1/5 CT 33/57 2/10 TT 10/14 CC 0/5 4/10 CT 27/92 1/18 TT 10/32 1/15 Pol et al. EASL 2011 Conclusions • Importance of adherence • Cross resistance between telaprevir and boceprevir • Impact of subtype (1a/1b) on genetic barrier • Treatment failure to triple therapy is mainly due to a poor response to Peg-IFN and ribavirin. • Lead-in period could be useful • IL28B status is not significant to predict SVR in treatmentexperienced patients Treatment failure in Phase III trials Telaprevir trials Advance T12PR T8PR Realize Lead No -in lead-in Jacobson et al., AASLD 2010. Foster et al., AASLD 2010. Thibault-GEMHEP_Nov.11 Boceprevir trials Sprint-2 BOC/R GT BOC/P R48 Respond-2 BOC/R GT BOC/P R48 Poordard et al., N Eng J Med 2011. Bacon et al., , N Eng J Med 2011.