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HCV resistance Understanding the mechanism and Prevention Fabien Zoulim Hepatology department, Hospices Civils de Lyon INSERM U1052, Viral Hepatitis Team.

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Presentation on theme: "HCV resistance Understanding the mechanism and Prevention Fabien Zoulim Hepatology department, Hospices Civils de Lyon INSERM U1052, Viral Hepatitis Team."— Presentation transcript:

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

2 Novel targets for antiviral intervention using the HCV life cycle IFN + RBV Other viral and cellular targets Racanelli V, et a., Trends Immunol 2003;24:456-64; Manns MP, et al. Nat Rev Drug Discov 2007;6: IFN – Interferon, RBV - Ribavirin

3 Key concepts for HCV  Viral persistence but a curable disease !  Viral genome heterogeneity  Resistance to polymerase & protease inhibitors  Selection of resistant mutants  Key objective: suppress resistance

4 The main differences between HIV, HBV and HCV H H HBV Host cell cccDNA Host DNA Integrated DNA Nucleus H H HIV Host cell Proviral DNA Nucleus H H HCV Host cell Host DNA Nucleus HCV RNA Life-long suppression of viral replication Definitive viral clearance and SVR Long-term suppression of viral replication Kieffer TL, et al. J Antimicrob Chemother 2010;65:202-12; Garrido C, et al. J Antimicrob Chemother 2010;65;320-6; Clavel F, et al. New Engl J Med 2004;350:1023-5; Zoulim F, et al. Gastroenterology 2009;137: ; Sarrazin C, et al. Gastroenterology 2010;138: SVR – Sustained viral response

5 How does HCV resistance develop? High replication rate with errors during replication ~10 12 viruses produced per day ~1 mistake per virus produced High replication rate with errors during replication ~10 12 viruses produced per day ~1 mistake per virus produced Continual development of viral variants Drug-resistant variants exist before antiviral therapy Suppression of wild-type and susceptible variants Suppression of wild-type and susceptible variants Selection and expansion of drug-resistant mutants Selection and expansion of drug-resistant mutants Antiviral therapy

6 Resistance mutants Definitions of treatment failure Detection limit Relapse Null-Response Breakthrough Partial responder Treatment including DAA DAA – Direct acting antiviral agents

7 The virus and its environment  The infected hepatocytes  Virus replication in hepatocytes  Hepatocyte response to infection  Antiviral drugs  Potency of antivirals  Potency shift to mutant  Barrier to resistance  The virus  Fitness of the resistant mutants  Accumulation of compensatory mutations  Cross-resistance profile

8 Emergence of drug resistant mutants Resistant mutant Wild-type Hepatocytes HCV RNA Viral infectionViral replication All single mutations likely to be generated every day Resistant mutants less fit than wt

9 Emergence of drug resistant mutants Resistant mutant Wild-type Hepatocytes HCV RNA Viral infection Viral replication All single mutations likely to be generated every day Resistant mutants more fit than wt Antiviral treatment with DAA DAA – Direct acting antiviral agents, wt – wild-type

10 Antiviral drug resistance testing  Genotypic (sequence analysis) assays Detection of emerging mutants  Population sequencing  Clonal analysis  Ultradeep sequencing  HCV viral fitness assays Determination of fitness, infectivity and evolution of mutants Difficult to apply to clinical isolates  HCV phenotypic assays Determination of drug susceptibility and cross-resistance profile / Replicon system

11 Evolution of NS3 protease variants in patients treated with telaprevir monotherapy Sarrazin C, et al. Gastroenterology 2007;132: NS3 – Non structural protein 3

12 Towards the suppression of resistance Factors affecting the selection of resistant variants during antiviral treatment  Drug selective pressure:  Antiviral potency  Drug concentration at the site of replication  Genetic barrier to resistance:  Number of mutations required for loss of activity  Viral fitness: Relative rate of replication of resistant strains  IFN and ribavirin backbone to maintain antiviral pressure on resistant mutants IFN – Interferon

13 Peg-IFN & Ribavirin inhibit PI resistant mutant replication Kieffer TL, et al. AASLD 2006 Peg-IFN – Pegylated interferon, PI – Protease inhibitor

14 Failure of triple therapy is the result of the failure of IFN – Ribavirin to clear PI resistant mutants ! IFN – Interferon, PI – Protease inhibitor

15 Virologic monitoring of triple therapy

16 Example of virologic breakthrough 0NN0NN 2NN2NN 4YY4YY 6YY6YY 8YY8YY 10 Y 12 Y vBT Confirmed v BT HCV - RNA (UI/ml) DAA stopped + sequencing DAA – Direct acting antiviral agents, v BT – Virologic breakthrough

17 Example of virologic breakthrough 0NN0NN 2NN2NN 4YY4YY 6YY6YY 8YY8YY 10 Y 12 Y vBT Confirmed v BT HCV - RNA (UI/ml) Importance of the timing of virologic monitoring v BT – Virologic breakthrough

18 Example of virologic breakthrough 0NN0NN 2NN2NN 4YY4YY 6YY6YY 8YY8YY 10 Y 12 Y vBT Confirmed v BT HCV - RNA (UI/ml) Importance of sequencing and mutation detection V36M R155K v BT – Virologic breakthrough

19 Médiane de retour des variants “sauvages” en séquençage direct = 7 mois (IC95% : 5-8) Probabilité Suivi après l’échec thérapeutique (mois) médiane Sullivan J. et al. EASL Loss of telaprevir resistant variants after treatment cessation

20 a 1b Probabilité Suivi après l’échec thérapeutique (mois) médiane Sullivan J. et al. EASL Loss of telaprevir resistant variants after treatment cessation

21 Optimizing anti-HCV regimens to maximize SVR and minimize resistance  The drugs  Antiviral potency  Pharmacokinetics (intracellular concentration of the inhibitor)  The virus  Genetic barrier to resistance  Fitness of resistant variants  Cross-resistance  The host  Treatment adherence  IFN response:  Genetics / IL28B gene polymorphism & others  ISGs expression  The treatment regimen  Treatment duration / Dosage of the drug /Dosing interval  Side effects IFN – Interferon, IL28 – Interleukin 28B, ISGs – Interferon stimulated genes, SVR – Sustained virologic response

22 All-oral HCV treatment GT-1

23 Site of action of BI compounds NS3/4A Protease inhibitor BI NS5B pocket I Polymerase inhibitor BI

24 Cross-resistance between polymerase and protease inhibitors is unlikely C E1E2 p7NS2NS3NS4ANS4BNS5A NS5B NS2–NS3 protease NS3 protease Serine protease domain CoreEnvelope T54 R155 A156 D168 V36 S96 N142 S282 C316 M414 M419 P495 T423 NM283* R1479 * (R1626) Telaprevir; BI BI Telaprevir; BI ; SCH Telaprevir; SCH HCV-796 † Telaprevir *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 BI †

25 BI BI Combination: suppresses emergence of resistance BI X EC 50 BI X EC 50 Long term selection of resistance in vitro is effectively suppressed by BI and BI combination EC 50 – Median estimated concentration

26 BI BI : SOUND-C HCV RNA (IU/mL) Treatment day LLOQ LLOD GT-1a GT-1b BI mg/ BI /RBV BI / PegIFN/RBV 400 mg TID BI mg BI RBV (n=15) HCV RNA (IU/mL) GT-1a GT-1b GT-6e Treatment day BI mg/ BI /RBV BI / PegIFN/RBV LLOQ LLOD 600 mg TID BI mg BI RBV (n=17) LLOQ, lower limit of quantification; LLOD, lower limit of detection, GT - genotype Zeuzem S, et al. Gastroenterology 2011;141:

27 SOUND-C1 trial Multi-centre, open-label, randomised phase Ib study in treatment-naïve, HCV genotype-1 (GT-1) patients 600 mg BI TID mg BI QD + RBV n = 15 n = 17 PegIFN alfa 2a/ RBV a 400 mg BI TID mg BI QD + RBV Day 1Week 4Week 24Week 48 PegIFN alfa 2a/ RBV a 120 mg BI QD + PegIFN alfa 2a/RBV Futility rules: Virological breakthrough (increase in HCV RNA by > 1 log, or HCV RNA ≥ 100 IU/mL after < 25 IU/mL) Lack of EVR (> 2 log decrease at Week 12) Lack of undetectable HCV RNA at Week 24 a Patients without eRVR (HCV RNA ≤ 25 IU/mL Week 4, undetectable Weeks 5 to 18) continued PegIFN/RBV up to Week 48 TID, three times daily; QD, once daily Follow-up Week 72 Zeuzem S, et al. AASLD Abstract LB-7 EVR – Early virologic response, eRVR – extended Rapid virologic response, PegIFN/RBV – Pegylated interferon/ribavirin

28 SOUND-C1 Virologic response a Includes patient #61102 switched to Peg/RBV; b Patient #41203 outstanding RVR, rapid virologic response (after 4 weeks of treatment); eRVR, HCV RNA < 25 IU/mL at Week 4 and undetected at Week 5 to 18; EoT, undetectable HCV RNA at the end of all treatment 17/174/1517/1711/15 RVReRVREoTSVR Proportion of patients (%) 400 mg TID600 mg TID 11/1512/1714 a /1516 b /17 Zeuzem S, et al. AASLD Abstract 249 EOT – End of treatment, SVR – Sustained virologic response

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

30 Results: Antiviral activity; antiviral response assessment up to week 12 (5) patients with HCV RNA

31 All-oral HCV treatment GT-1 BMS BMS

32  Phase IIa study of BMS plus BMS for 24 weeks  HCV GT-1b Japanese null responders 48Week72 Follow-up BMS mg QD + BMS mg BID 24 n=10 (GT- 1b) GT – Genotype Chayama K, et al. Hepatology. 2011;54(Suppl. S1): Abstract LB-4

33 BMS /BMS : virologic response (in GT1b only)  One patient discontinued at Week 2; HCV RNA was undetectable after 24 weeks’ follow-up Chayama K, et al. Hepatology. 2011;54(Suppl. S1): Abstract LB-4 Week 4 Week 12 EOTSVR24 Proportion of patients with undetectable HCV RNA (%) 4/10 9/10 EOT – End of treatment, SVR – Sustained virologic response

34 All-oral HCV treatment GT2/3 PSI-7977

35 8 PSI mg + PegIFN/RBV Week PSI mg + RBV 12 PSI + R 12 weeks n=10 PSI + PR 12 weeks n=10 4 PSI mg + RBV PSI mg + PegIFN/RBV PSI + PR 8 weeks n=10 PSI + PR 4 weeks n=10 PSI mg + RBV PSI RBV (GT-2/3) (n=10 per arm) phase II, randomized, open-label trial of PSI-7977 plus RBV, with or without PegIFN, in treatment-naïve HCV GT-2 and GT-3 patients; cirrhotics excluded Gane EJ, et al. AASLD Abstract 34

36 PSI RBV (GT-2/3) (n=10 per arm)  No viral breakthrough observed  PSI-7977 very well tolerated, with no attributable safety signal, no treatment discontinuations and no treatment emergent laboratory abnormalities 100 Gane EJ, et al. AASLD Abstract 34

37 PSI RBV (GT-2/3) (n=10 per arm) Gane EJ, et al. AASLD Abstract 34RBV - Ribavirin

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


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