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.

Progress in the Treatment of Hepatitis C HBVHIVHCV GenomeDNARNA Mutation rate++++ Daily viral production Viral ReservoircccDNAIntegrated c DNANone Therapeutic strategySingleMultiple recoveryNo Yes

Direct Acting Antivirals (DAA) drugs targets Asselah T et al. Liver International 2011

NS3-4A Protease NS5B Polymerase NS5A Protease Inhibitors Polymerase Inhibitors NS5A Inhibitors Asselah T et al. Liver International 2012 Targets for DAAs

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

Placebo Telaprevir 450 mg q8hTelaprevir 750 mg q8hTelaprevir 1250 mg q12h Study Time (days) Median HCV RNA (Log 10 IU/mL) Telaprevir Reesink HW, et al. Hepatology. 2005;42:234A. Protease inhibitors monotherapy

Pharmacological Factors Drug potency Genetic barrier Pharmacokinetic Viral Factors Level of viral replication (10 12 /day) Low fidelity of polymerase Impact of mutations on fitness Viral quasi-species Half-life of infected hepatocytes Host Factors Compliance Immune system Replication space Activity of protein kinase Nuceos(t)ide transporters Factors influencing viral resistance with DAA Resistance

Time HCV Replication Sensitive variants Emergence of resistance during antiviral therapy Resistant variants

Time HCV Replication Sensitive variants Resistant variants Treatment MUTATION(S) Emergence of resistance during antiviral therapy

Time HCV Replication Sensitive variants Resistant variants Virological breakthrough Treatment Emergence of resistance during antiviral therapy

Adapted from Thibault V, GEMHEP_Nov.11 Les RAVS... (Variants associés à la résistance) V36A/M T54A/S R155K/T/Q A156S V170A BOCEPREVIR V55A Patterns of resistance to PI HCV protease V36A/M T54A/S R155K/T A156S A156V/T TELAPREVIR

Thibault-GEMHEP_Nov.11 Nombre de changements de nucléotides pour modifier un résidu en "RAV" Zeuzem et al. EASL 2011, Abst. 9 Subtype impacts the genetic barrier to resistance Number of nucleotide substitutions needed according subtype R155K AGG-AAG R155K AGG-AAG 1 step R155K CGG-CAG R155K CGG-CAG R155K CGG-AAG R155K CGG-AAG 2 step Genotype 1a Genotype 1b Resistant variant according to the subtybe in patients treated with boceprevir

Relative Fitness Adapted from Thibault V, GEMHEP_Nov.11 Sarrazin et al. GASTROENTEROLOGY 2007;132:1767–1777 Susser et al. HEPATOLOGY 2009;50: ) Resistance level (Fold) Boceprevir Telaprevir (x43) (x780) Resistance and viral fitness Resistance and viral fitness

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.

68% 31% Emergence of Resistance accordind to lead-in <1log>1log Reduction in HCV RNA at Week 4 Zeuzem et al. EASL Thibault-GEMHEP_Nov.11 Poordad et al. NEJM ;13, Bacon et al. NEJM 2011, Vierling et al. AASLD 2011, Abst SVR rates according to lead-in Pooled data from SPRINT-2, RESPOND-2 and PROVIDE trial (Boceprevir) Importance of the lead-in phase % of SVR Reduction in HCV RNA at Week 4

Thibault-GEMHEP_Nov.11 Foster et al. EASL 2011, Abst 6A. SVR rates according to previous response and RNA decline at 4 week Data from the 4 weeks lead-in arm of the REALIZE trial (Telaprevir) Importance of the lead-in phase % of SVR Reduction in HCV RNA at Week 4

Role of IL28B genotype in preventing resistance?

Nature % 80% 0% 20% 40% 60% 80% 100% SVR (%) T/TC/C 40 % T/C

IL28B-genotypes and triple therapy in naïve patient

SVR Rates by IL28B Genotype and Prior Response Prior relapsers Patients achieving SVR (%) Prior partial responders Prior null responders CCCT TT CCCT TT CCCT TT Pooled T12/PR48 (n=209) Pbo/PR48 (n=52) Pooled T12/PR48 (n=79) Pbo/PR48 (n=20) Pooled T12/PR48 (n=134) Pbo/PR48 (n=33) 51/58 4/12100/117 6/3029/34 3/105/81/5 33/57 2/1010/14 0/5 4/1027/92 1/1810/32 1/15 n/N= n/a Pol et al. EASL 2011 SVR Rates by IL28B Genotype and Prior Response (Telaprevir regimens) P=ns

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 treatment- experienced patients Conclusions

Thibault-GEMHEP_Nov.11 Jacobson et al., AASLD Foster et al., AASLD Treatment failure in Phase III trials AdvanceRealizeSprint-2Respond-2 T12PRT8PRLead -in No lead-in BOC/R GT BOC/P R48 BOC/R GT BOC/P R48 Poordard et al., N Eng J Med Bacon et al.,, N Eng J Med Telaprevir trials Boceprevir trials