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HCV resistance Understanding the mechanism and Prevention

HCV resistance Understanding the mechanism and Prevention. Fabien Zoulim Hepatology department, Hospices Civils de Lyon INSERM U1052, Viral Hepatitis Team Lyon University, France. Virologic monitoring of triple therapy. Example of virologic breakthrough. DAA stopped + sequencing. 10 10 6

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HCV resistance Understanding the mechanism and Prevention

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  1. HCV resistanceUnderstanding the mechanism and Prevention Fabien Zoulim Hepatology department, Hospices Civils de Lyon INSERM U1052, Viral Hepatitis Team Lyon University, France

  2. Virologic monitoring of triple therapy

  3. Example of virologic breakthrough DAA stopped + sequencing 10 106 105 104 103 102 101 0 HCV - RNA (UI/ml) 0 N N 2 N N 4 Y Y 6 Y Y 8 Y Y 10 Y Y 12 Y Y vBT Confirmed v BT DAA – Direct acting antiviral agents, v BT – Virologic breakthrough

  4. Example of virologic breakthrough Importance of the timing of virologic monitoring 10 106 105 104 103 102 101 0 HCV - RNA (UI/ml) 0 N N 2 N N 4 Y Y 6 Y Y 8 Y Y 10 Y Y 12 Y Y vBT Confirmed v BT v BT – Virologic breakthrough

  5. Example of virologic breakthrough Importance of sequencing and mutation detection 10 106 105 104 103 102 101 0 HCV - RNA (UI/ml) V36M R155K 0 N N 2 N N 4 Y Y 6 Y Y 8 Y Y 10 Y Y 12 Y Y vBT Confirmed v BT v BT – Virologic breakthrough

  6. Loss of telaprevir resistant variants after treatment cessation 1.0 0.9 Médiane de retour des variants “sauvages” en séquençage direct = 7 mois (IC95% : 5-8) 0.8 0.7 0.6 médiane 0.5 Probabilité 0.4 0.3 0.2 0.1 0.0 0 2 4 6 8 10 12 14 16 18 Suivi après l’échec thérapeutique (mois) Sullivan J.et al.EASL 2011.

  7. Loss of telaprevir resistant variants after treatment cessation 1.0 0.9 1a 0.8 0.7 0.6 médiane Probabilité 0.5 0.4 1b 0.3 0.2 0.1 0.0 0 2 4 6 8 10 12 14 16 18 Suivi après l’échec thérapeutique (mois) Sullivan J. et al. EASL 2011.

  8. Optimizing anti-HCV regimens to maximize SVR and minimize resistance • The drugs • Antiviral potency • Pharmacokinetics (intracellular concentration of the inhibitor) • The virus • Geneticbarrier to resistance • Fitness of resistantvariants • Cross-resistance • The host • Treatmentadherence • IFN response: • Genetics / IL28B genepolymorphism & others • ISGs expression • The treatmentregimen • Treatmentduration / Dosage of the drug /Dosinginterval • Sideeffects IFN – Interferon, IL28 – Interleukin 28B, ISGs – Interferon stimulated genes, SVR – Sustained virologic response

  9. All-oral HCV treatmentGT-1

  10. Site of action of BI compounds NS3/4A Protease inhibitor BI 201335 NS5B pocket I Polymerase inhibitor BI 207127

  11. Cross-resistance between polymerase and protease inhibitors is unlikely NS2–NS3 protease NS3 protease E1 E2 NS5B C p7 NS2 NS3 NS4A NS4B NS5A Serine protease domain Core Envelope T54 R155 A156 D168 V36 S96 N142 S282 C316 M414 M419 P495 T423 R1479*(R1626) Telaprevir; SCH 503034 Telaprevir; BI 201335 NM283* Telaprevir; BI 201335; SCH 503034 HCV-796† BI 201335 Telaprevir BI207127† *nucleoside; †non-nucleoside 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

  12. BI 207127 + BI 201335 Combination: suppresses emergence of resistance BI 207127 X EC50 Long term selection of resistance in vitro is effectively suppressed by BI 201335 and BI 207127 combination BI 201335 X EC50 EC50 – Median estimated concentration

  13. BI 201335 + BI 207127: SOUND-C1 400 mg TID BI 207127 +120 mg BI 201335 + RBV(n=15) 600 mg TID BI 207127 +120 mg BI 201335 + RBV(n=17) 100000000 10000000 1000000 100000 10000 1000 100 10 1 100000000 10000000 1000000 100000 10000 1000 100 10 1 GT-1a GT-1b GT-1a GT-1b GT-6e HCV RNA (IU/mL) HCV RNA (IU/mL) LLOQ LLOQ LLOD LLOD 0 4 8 12 16 20 24 28 32 36 40 44 0 4 8 12 16 20 24 28 32 36 40 44 Treatment day Treatment day BI 207127 400 mg/BI 201335/RBV BI 201335/ PegIFN/RBV BI 207127 600 mg/BI 201335/RBV BI 201335/ PegIFN/RBV LLOQ, lower limit of quantification; LLOD, lower limit of detection, GT - genotype Zeuzem S, et al. Gastroenterology 2011;141:2047-55

  14. SOUND-C2 trial Multi-centre, open-label, randomised phase IIb study in treatment-naïve, HCV genotype-1 (GT-1) patients; Including ~15% cirrhotics A(n=81) B(n=81) C(n=81) D(n=81) E(n=81) 1335 + 7127TID + RBV Follow-up 1335 + 7127TID + RBV Follow-up 1335 + 7127TID + RBV 1335 + 7127BID + RBV Follow-up 1335 + 7127TID no RBV Follow-up Day 1 Week 12 Week 16 Week 26 Week 40 Interim analysis Zeuzem S, et al. AASLD 2010. Abstract LB-15 GT – Genotype, RBV - Ribavirin

  15. Results: Antiviral activity; antiviral response assessment up to week 12 (5) patients with HCV RNA <LLOD at Week 12 by IL28 GT and viral subtype (per protocol analysis) 100 80 60 40 20 0 Proportion of patientswith HCV RNA <LLODat Week 12 (%) C/C Non-C/C C/C Non-C/C GT-1a GT-1b 1335 + 7127TID + RBV 22/25 39/61 24/26 79/92 1335 + 7127BID + RBV 6/7 10/22 10/11 32/36 1335 + 7127TID no RBV 3/3 2/9 7/7 13/20 LLOD – Lower limit of detection, IL28b Interleukin 28b, GT - genotype Zeuzem S, et al. AASLD 2010. Abstract LB-15

  16. Phase IIa study of BMS-790052 plus BMS-650032 for 24 weeks HCV GT-1b Japanese null responders BMS-790052 + BMS-650032 BMS-790052 60 mg QD + BMS-650032 200 mg BID Follow-up n=10 (GT-1b) Week 24 48 72 GT – Genotype Chayama K, et al. Hepatology. 2011;54(Suppl. S1): Abstract LB-4

  17. BMS-650032/BMS-790052: virologic response (in GT1b only) • One patient discontinued at Week 2; HCV RNA was undetectable after 24 weeks’ follow-up Proportion of patients with undetectable HCV RNA (%) 9/10 9/10 9/10 4/10 Week 4 EOT SVR24 Week 12 EOT – End of treatment, SVR – Sustained virologic response Chayama K, et al. Hepatology. 2011;54(Suppl. S1): Abstract LB-4

  18. Dual-oral / QUAD 2 direct acting antivirals quadruple SOC Standard of Care NSOC New Standard of Care Triple-oral 3 direct acting antivirals HCV HCV Protease Polymerase Inhibitor Inhibitor** HCV Protease PegIFN +/ - Ribavirin Inhibitor* PegIFN HCV Polymerase Ribavirin **1 Inhibitor Ribavirin HCV Polymerase HCV PegIFN Ribavirin Inhibitor 2*** Protease Inhibitor* HCV HCV Protease Polymerase Inhibitor‘ Inhibitor** Conclusions:Current and future HCV treatment regimens HCV NS5A inhibitor HCV NS5A inhibitor OR HCV NS5A inhibitor

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