Resistance to DAAs: Real or over-estimated issue? P. Karayiannis

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1 Resistance to DAAs: Real or over-estimated issue? By P. Karayiannis

2 HEPATITIS C VIRION STRUCTURE: LIPO-VIRAL PARTICLE ApoB ApoE VLDL Core RNA Envelope E1 E2 Electron micrograph

3 9.6 kb HCV genome organisation Banerjee et al, openi.nlm.nih.gov

4 Ploss & Rice, EMBO Rep. 2009;10:

5 Stages of the HCV life cycle targeted by DAAs

In vivo In vitro RNA binding NS3 SERINE PROTEASE INHIBITORS AND RESISTANCE MUTATIONS HELICASE NTPase site Catalytic site Inhibitor BILN-2061

NA A156S/V/T V36A/M T54A R155K/T A156S/V/T A156V/T R109K NA A156S/T T54A V170A V36A/M, T54A, R155K/Q/T/M, A156S, V170A/T, F43C/S A156S/V Q41R,

6 In vivo In vitro RNA binding NS3 SERINE PROTEASE INHIBITORS AND RESISTANCE MUTATIONS HELICASE NTPase site Catalytic site Inhibitor BILN ,2 Telaprevir 2,3,7 (VX-950) SCH-6 4 Boceprevir (SCH ) ITMN Zinc PROTEASE NH 2 Membrane binding domain A156V/T R155Q D168A/V/Y NA A156S/V/T V36A/M T54A R155K/T A156S/V/T A156V/T R109K NA A156S/T T54A V170A V36A/M, T54A, R155K/Q/T/M, A156S, V170A/T, F43C/S A156S/V Q41R, F43S, S138T, D168A, S489L, V23A (NS4A) NA 2. Le Pogam S et al. J Virol. 2006;80: Le Pogam S, et al. J Infect Dis. 2010;202:

AH, amphipathic helix; hvap-a, human vesicle-associated membrane protein-associated protein A; LCS, low-complexity sequence;

7 NS5A: Domains and Function NS5A structure and function; proposed interaction sites with other cellular and viral proteins are summarized below the schematic diagram. AH, amphipathic helix; hvap-a, human vesicle-associated membrane protein-associated protein A; LCS, low-complexity sequence; PKR, protein kinase R. NS5A acts as a scaffold for other proteins in the viral replication complex. NS5A resistant variants are quite stable and long-lived Janardhan SV and Reau NS,Hepat Med. 2015; 7:

bound inhibitor and non-nucleoside inhibitor (NNI) sites 1 to 4.

8 DRUGS FOR FUTURE TREATMENT OF CHRONIC HCV INFECTION Target Drug Type Sofosbuvir (Sovaldi) RIBBON MODEL OF THE HCV POLYMERASE Active site with bound inhibitor and non-nucleoside inhibitor (NNI) sites 1 to 4. Palm, thumb and fingers coloured red, green and blue, respectively. Welsch et al, Gut 2012;61:36-46.

Hepatitis C virus genome and viral proteins targeted by DAAs Boceprevir (Victrelis) Telaprevir (Incivek) Simeprevir (Olisio) Asunaprevir* Paritaprevir/r* Danoprevir/r* Grazoprevir (MK-5172) GS-9451,

9 Hepatitis C virus genome and viral proteins targeted by DAAs Boceprevir (Victrelis) Telaprevir (Incivek) Simeprevir (Olisio) Asunaprevir* Paritaprevir/r* Danoprevir/r* Grazoprevir (MK-5172) GS-9451, TMC-435, BI , GS-9451, Daclatasvir (Daklinza) Ombitasvir Ledipasvir (GS5885)* Samatasvir Ombitasvir Elbasvir (MK-8742) Ravidasvir (PPI-668) Velpatasvir (GS-5816) Odalasvir (ACH-3102) GSK Nucleos(t)ide analogue Sofosbuvir (Sovaldi) Dasabuvir (Exviera)* Mericitabine (RG-7128) IDX-184 Non-nucleos(t)ide analogues Deliobuvir (BI ) Tegobuvir, Setrobuvir Filibuvir, VX-222, ABT-072, BMS Alisporivir SCY-635 * Approved for use in combinations Modified from Pos et al, Liver Intl 2014;34 (Suppl 1):18-23

10 Approved antivirals in the European Union in 2015 for the treatment of chronic HCV infection DAAs EASL Guidelines 2015 Approved combinations: LDV+SOF (Harvoni) OMV/PTV/r+DSV (Vikiera Pak) Effective combinations with high genetic barrier to resistance

11 Progress in therapy of chronic hepatitis C genotype 1 as shown by SVR rates with different antiviral regimens PI, first-generation protease inhibitor (telaprevir or boceprevir). NA, nucleotide analogue (sofosbuvir). Pawlotsky et al, Journal of Hepatology, Volume 62, Issue 1, Supplement, 2015, S87 - S99

12 Not All Direct-Acting Antivirals Have the Same Properties Characteristic Protease Inhibitor * Protease Inhibitor ** NS5A Inhibitor Nuc Polymerase Inhibitor Non-Nuc Polymerase Inhibitor Resistance profile Pangenotypic efficacy Antiviral potency Adverse events Good profile Average profile Least favorable profile *First generation. **Second generation. Feld JJ, CCO Hepatitis

13 Mutations conferring DAA resistance in NS3, NS5A and NS5B NS3 catalytic site D168 R155 Q80 F43 A156 American Society of Microbiology

14 Prevalence of the most important naturally occurring NS3 RAVs in DAA-naïve patients and persistence after treatment Amino acid site Amino acid changes Resistant to Prevalence of naturally occurring RAVs (%) in genotypes 1-4 Persistence of RAVs during Follow-up 1a 1b Wk24 Wk48 W96 V36 A,G,I, L,M BOC,FDV,TVR, nd nd nd F43 I,S,V ASV,SMV,PTV,VPR 0 0 nd nd nd T54 A,C,G,S FDV,TVR,BOC nd nd nd 50 V55 A, I BOC nd nd nd 50 Y56 H GZR, 0 0 nd nd nd Q80 K,L,N,R ASV,FDV,SMV,PTV nd nd nd 59 V107 I BOC nd nd nd S122 A,G,R SMV,VPR 0 0 nd nd nd R155 A156 D168 G,M,K,Q,T F, N, S, T, V A,E,G,H,I,N, V,Y ASV,BOC,DSV,DPV,FDV,SMV,PTV,T VR,VPR 0.9 n.o. nd nd nd ASV,BOC,DPV,FDV,GZV,SMV,PTV,T VR,VPR n.o. n.o. nd nd nd 59 ASV,BOC,DPV,FDV,GZV,SMV,PTV,T VR,VPR nd nd nd I/V170 A,F,T,V BOC nd nd nd Schneider & Sarrazin, Antiviral Res 2014;105:64-71.Krishman et al, EASL 2015, O057; Dvory-Sobol et al, EASL 2015, O059; Susser et al, EASL 2015, P0896; Dietz et al, EASL 2015, P0900; Farnik et al, EASL 2015, P0766.

15 Prevalence of the most important naturally occurring NS5A RAVs in DAA-naïve patients and persistence after treatment Amino acid site Amino acid change Resistant to Prevalence of naturally occurring RAVs (%) in genotypes 1-4 Persistence of RAVs during Follow-up 1a 1b PTW24 PTW48 PTW96 K24 N/G/R LDV <1-1.5 nd nd nd nd M28 T/A/G/V OBV,LDV,E BR,DCV, Q30 E/H/K/R OBV,LDV,E BR L31 M/V/F DCV,LDV,E BR, OBV H58 D, P, S DCV,LDV,E BR,OBV nd 8 (L28F) nd 82 (M28L) nd nd 90- (Q30A) (L31M) 50- (Q30R) 1 (L31M) 92- (L31M) 98, 96, <1 nd nd nd nd 66 A92 K/T LDV nd nd nd 66 Y93 H/N/C/S LDV,DCV,E BR, OBV nd (Y93H) 5-13 (Y93H) 66 Krishman et al, EASL 2015, O057; Dvory-Sobol et al, EASL 2015, O059; Susser et al, EASL 2015, P0896; Dietz et al, EASL 2015, P0900; Farnik et al, EASL 2015, P0766.

16 Prevalence of the most important naturally occurring NS5B RAVs in DAA-naïve patients and persistence after treatment Amino acid site Amino acid change Resistant to Prevalence of naturally occurring RAVs (%) in genotypes 1-4 Persistence of RAVs during Follow-up 1a 1b PTW24 PTW48 S282 T SOF nd C316 N DSV nd nd 7.9 S556 G DSV G558 R DSV 0 0 nd nd nd nd nd D559 G/N DSV 0 0 nd nd nd nd nd Dietz et al, EASL 2015, P0900

Patients (%) with SVR 12 Jacobson IM, et al. Lancet. 2014;384:403-13.

Simeprevir Randomized 2:1; N = 264 PEG + RBV + PEG + RBV PEG + RBV stratified on IL28B and HCV1 subtype N =130 Placebo PEG + RBV + PEG + RBV 80

17 Patients (%) with SVR 12 Jacobson IM, et al. Lancet. 2014;384: Simeprevir + PEG + RBV for Treatment-Naïve HCV GT1 QUEST-1 Trial: Results QUEST 2: SVR12 for HCV 1a by Baseline Q80K Status Week Simeprevir Randomized 2:1; N = 264 PEG + RBV + PEG + RBV PEG + RBV stratified on IL28B and HCV1 subtype N =130 Placebo PEG + RBV + PEG + RBV 80 Simeprevir + PEG + RBV 85 PEG + RBV /60 16/30 73/86 19/43 1a (with baseline Q80K) 1a (without baseline Q80K) HCV Genotype Abbreviations: PEG = Peginterferon RBV = Ribavirin Q=glutamine, K=lysine

18 SVR12 (%) Impact of Treatment Exp, Q80K Depends on Cirrhosis (12 Wks SMV + SOF in GT1) No Cirrhosis (OPTIMIST-1 [1] ) Cirrhosis (OPTIMIST-2 [2] ) n/n = 0 150/ 155 All pts 112/ 115 Naive 38/ 40 Exp d 44/ 46 1a + Q80K 68/ 70 1a no Q80K 20 n/n = 0 86/ 103 All pts 44/ 50 42/ 53 25/ 34 Naive Exp d 1a + Q80K 35/ 38 1a no Q80K Treatment History HCV GT Treatment History HCV GT 1. Kwo P, et al. EASL Abstract LP Lawitz E, et al. EASL Abstract LP04. Slide credit: clinicaloptions.com

19 SVR12 (%) ION-2: DAAs Effective Against NS3 RAVs After Boceprevir or Telaprevir Treatment History Failure of pegifn/rbv 60 Failure of PI / 43 62/ 66 LDV/SOF 45/ 47 62/ 64 58/ 58 49/ 50 58/ 59 51/ 51 LDV/SOF + RBV LDV/SOF LDV/SOF + RBV 12 Wks 24 Wks Virologic failure: 1 breakthrough in 24-wk LDV/SOF + RBV due to nonadherence; 11 relapses (7 in 12-wk LDV/SOF, 4 in 12- wk LDV/SOF + RBV) 14% of pts had NS5A RAVs at baseline; 89% of these achieved SVR12; 71% of pts had NS3 RAVs at baseline; 98% of these achieved SVR12 Afdhal N, et al. N Engl J Med. 2014;370: Slide credit: clinicaloptions.com

20 Impact of Duration of LDV/SOF on SVR12 in Pts With Baseline NS5A Resistance SVR12 (%) SVR12 (%) NS5A RAVS with < x resistance n/n = n/n = 0 12/ / / 193 Treatment Naive Wks 12 Wks 24 Wks Treatment Experienced / 5 11/ / / 27 NS5A RAVS with > x resistance 44/ / Wks 24 Wks 7/ 7 8/ 8 6/ 6 24/ 25 95/ / 183 No NS5A RAVs Sarrazin C. AASLD Abstract Slide credit: clinicaloptions.com

21 SVR12 (%) Effect of Baseline NS5A Resistance-Associated Polymorphisms on SVR ION Phase 3 Program (ION-1, ION-2, ION-3) LDV/SOF±RBV No emergent NS5A RAVs: N = 6/21 Emergence of new NS5A RAVs: N = 15/21 Same baseline NS5A RAPs: N = 5/14 Emergence of new NS5A RAVs: N = 8/14 Lost NS5A RAPs: N = 1/ % SVR (n= 1198/1219) 77% No NS5A polymorphisms at baseline (n=1219) 23% NS5A polymorphisms at baseline (n=370) 96% SVR 96% SVR (n= 356/370) (N=356/370) RAP: resistance-associated polymorphism; RAV: resistance-associated variant Resistance-associated polymorphism: resistance-associated substitution present at baseline Resistance-associated variant: treatment-emergent resistance-associated substitution HARVONI Summary of Product Characteristics EMA, Gilead Sciences, December 2014 Data on file. Gilead Sciences, Inc. AASLD/IDSA/IAS USA. Recommendations for testing, managing, and treating hepatitis C. Accessed February 5, Kowdley et al, N Engl J Med 2014;370: ; Afdhal et al, N Engl J Med 2014;370: ; Afdhal et al, N Engl J Med 2014;370:

22 SVR12 (%) 24 Wks of LDV/SOF After Failure of 8-12 Wks of LDV/SOF-Based Therapy in GT1 Pts Results from single arm of prospective phase II trial 24 Wks GT1 HCV infected pts previously treated with LDV/SOFbased therapy (N = 41) LDV/SOF 90/400 mg QD NS5B variants with resistance to SOF emerged during retreatment in 33% of pts (4/12) with virologic failure S282T: n = 3 (out of 12) n/n = 0 29/ 41 15/ 22 14/ 19 All No Yes 24/ 30 5/ 11 8 Wks 12 Wks 11/ 11 No 18/ 30 Yes Cirrhosis Previous Tx Duration BL NS5A RAVs Lawitz E, et al. EASL Abstract O005. Sulkowski, CCO Hepatitis

23 SVR12 (%) SVR12 With Elbasvir/Grazoprevir in GT1 HCV With vs Without Baseline NS5A RAVs Tx-naive or previous relapse, EBR/GZR for 12 wks: GT1b: high SVR12 rates (98% to %) regardless of EBR or NS5A class RAVs GT1a: SVR12 rates lower with EBR (58%) or NS5A class (86%) RAVs vs no RAVs (98%) Pts without RAVs GT1a, Previous Nonresponse Pts with RAVs by population sequencing GT1b, Previous Nonresponse n/n = / 61 EBR RAVs 29 2/ / / 14 NS5A class RAVs 51/ 51 EBR RAVs NS5A class RAVs EBR/GZR 12 Wks EBR/GZR + RBV 16/18 Wks 1/ 1 44/ 44 8/ / 28 EBR RAVs 4/ / 22 10/ 12 NS5A class RAVs 26/ 26 12/ 12 EBR RAVs 22/ 22 16/ 16 NS5A class RAVs EBR/GZR 12 Wks EBR/GZR + RBV 16/18 Wks Jacobson IM, et al. AASLD Abstract LB-22. Slide credit: clinicaloptions.com

24 SVR24 (%) AVIATOR: No Impact of Baseline RAVs in GT1a Pts Treated With OMV/PTV/RTV + DSV SVR24 (%) SVR24 (%) Treatment naive pts or null responders to previous pegifn/rbv All differences in SVR24 with vs without baseline RAVs were non-significant With RAV Without RAV / 122/ 200/ 12/ 192/ 3/ 201/ 1/ 203/ 4/ 200/ n/n = /1 218 n/n = n/n = 0 Q80K D168 0 M28V/T Q30R L31V Y93C/N/H 0 7/ 7 220/ 239 S556G 1/ 2 226/ 244 C316Y NS3 RAVs NS5A RAVs NS5B RAVs Krishnan P, et al. Antimicrob Agents Chemother. 2015;59: Slide credit: clinicaloptions.com

25 ASTRAL-1, SOF+Velpatasvir for 12 weeks in naïve and experienced GT1-6 patients Overall SVR 99% SVR rates similar across genotypes (97-%) Lower rates with GT1a and 1b SVR did not differ according to cirrhosis status or treatment history Presence of NS5A RAVs did not affect SVR12 rates 42% of patients had NS5A RAVs at baseline SVR12 in patients without RAVs was % vs 99% in those with Feld et al, NEJM 2015;epub or Abstract, AASLD 2015, LB2

26 GT1 Pts With NS5A Failure: Who Needs Resistance Testing? If previous failure of any NS5A inhibitors (including DCV + SOF, LDV/SOF, OMV/PTV/RTV + DSV) and minimal liver disease, deferral preferred pending further data If cirrhosis or other need for urgent treatment, test for NS3 and NS5A RAVs Applies to genotype 1a and 1b HCV infection NS3 and NS5A testing not required for: Previous failure of NS3/4A PIs (including simeprevir, boceprevir, telaprevir) Previous failure of NS5B inhibitors (sofosbuvir) Tx-naive pts (unless considering SMV + SOF in cirrhotic GT1a) AASLD/IDSA/IAS-USA. HCV Guidance. Slide credit: clinicaloptions.com

27 GT3 and GT4 HCV Infection: Resistance Testing Genotype 3 Treatment failures on daclatasvir should be tested for NS5A RAVs BOSON: Adding pegifn to SOF/RBV appears to help overcome virologic failure due to resistance in GT3 [1] Improved SVR12 vs SOF/RBV alone in both treatment-naive and treatment-experienced pts, with or without cirrhosis Genotype 4 Resistance testing should be performed if considering retreatment after LDV/SOF failure Use SMV/SOF/RBV for NS5A RAVs 1. Foster GR, et al. EASL Abstract LO5. Slide credit: clinicaloptions.com

28 Selecting Treatment Based on Resistance Testing Results If genotype 1a or 1b HCV infection and previous failure with any NS5A inhibitors and cirrhotic or other need for urgent treatment: RAV Testing Result Retreatment Regimen Duration No NS5A RAVs Ledipasvir/sofosbuvir + ribavirin 24 wks NS5A but no NS3 RAVs Simeprevir + sofosbuvir + ribavirin 24 wks NS5A and NS3 RAVs Retreatment in a clinical trial setting IFN? AASLD/IDSA/IAS-USA. HCV Guidance. Slide credit: clinicaloptions.com

Baseline and acquired viral resistance to DAAs: how to test and manage

Baseline and acquired viral resistance to DAAs: how to test and manage Round table discussion by Marc Bourliere, Robert Flisiak, Vasily Isakov, Mark Sulkowsky & Konstantin Zhdanov Prevalence of baseline