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How to avoid a resistance issue with the first generation protease inhibitors ? O. Lada PHD

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. Olivier.lada@inserm.fr. Progress in the Treatment of Hepatitis C. Direct Acting Antivirals (DAA) drugs targets.

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How to avoid a resistance issue with the first generation protease inhibitors ? O. Lada PHD

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  1. 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. Olivier.lada@inserm.fr

  2. Progress in the Treatment of Hepatitis C

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

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

  5. 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

  6. Protease inhibitors monotherapy Telaprevir 7 6 5 Median HCV RNA (Log10 IU/mL) 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.

  7. 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 • Host Factors • Compliance • Immune system • Replication space • Activity of protein kinase • Nuceos(t)ide transporters • Pharmacological Factors • Drug potency • Genetic barrier • Pharmacokinetic

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

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

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

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

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

  13. Resistance and viral fitness (x43) (x780) Resistancelevel (Fold) Relative Fitness 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.)

  14. 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.

  15. Importance of the lead-in phase Pooled data from SPRINT-2, RESPOND-2 and PROVIDE trial (Boceprevir) Emergence of Resistance accordind to lead-in SVR rates according to lead-in % of SVR 68% 31% <1log >1log Reduction in HCV RNA at Week 4 Reduction in HCV RNA at Week 4 Poordad et al. NEJM 2011 364;13, Bacon et al. NEJM 2011, Vierling et al. AASLD 2011, Abst. 931. Zeuzem et al. EASL 2011. Thibault-GEMHEP_Nov.11

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

  17. Role of IL28B genotype in preventing resistance?

  18. Nature 2009 100% 80% 80% SVR (%) 60% 40 % 40% 25% 20% 0% T/T T/C C/C

  19. IL28B-genotypes and triple therapy in naïve patient

  20. SVR Rates by IL28B Genotype and Prior Response SVR Rates by IL28B Genotype and Prior Response (Telaprevir regimens) Prior relapsers Prior partial responders Prior null responders P=ns Pooled T12/PR48 (n=134) Pbo/PR48 (n=33) Pooled T12/PR48 (n=209) Pbo/PR48 (n=52) Pooled T12/PR48 (n=79) Pbo/PR48 (n=20) Patients achieving SVR (%) n/a TT TT TT CC CT CC CT CC CT n/N= 4/12 100/117 3/10 5/8 1/5 2/10 10/14 4/10 27/92 1/15 51/58 6/30 29/34 33/57 0/5 1/18 10/32 Pol et al. EASL 2011

  21. 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 treatment-experienced patients

  22. Treatment failure in Phase III trials Boceprevir trials Telaprevir trials Advance Realize Sprint-2 Respond-2 T12PR T8PR Lead -in No lead-in BOC/RGT BOC/PR48 BOC/RGT BOC/PR48 Jacobson et al., AASLD 2010. Foster et al., AASLD 2010. Poordard et al., N Eng J Med 2011. Bacon et al., , N Eng J Med 2011. Thibault-GEMHEP_Nov.11

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