10/21/2016. David L. Wyles, MD Chief, Division of Infectious Disease Denver Health Medical Center Denver, Colorado

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1 Drug Resistance-Associated Variants in Hepatitis C Virus Infection: Hype or Help? David L. Wyles, MD Chief, Division of Infectious Disease Denver Health Medical Center Denver, Colorado FORMATTED: 1/3/16 Atlanta, Georgia: October 2, 216 Financial Relationships With Commercial Entities Dr Wyles has received research grants awarded to his institution from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Inc, Merck & Co, Inc, and Tacere Therapeutics, Inc. He has also served as a consultant for Bristol-Myers Squibb, Gilead Sciences, Inc, AbbVie, and Merck & Co, Inc. (Updated 1/2/216) Slide 2 of 38 Learning Objectives After attending this presentation, participants will be able to: Compare and contrast the resistance potential of HCV infection and HIV infection Describe the available assays to screen for RAVs Describe the prevalence and impact of resistanceassociated variants (RAVs) on treatment regimens for hepatitis C virus (HCV) infection Slide 3 of 38 1

2 What is a RAV? Resistance Associated Variant Amino acid changes which result in a drug being less active (resistance) Viral protein specific: NS3, NS5A, NS5B Denoted: (consensus) Y93H (variant) position Resistance is quantified based on drug activity in vitro How much more drug do you need to get the same antiviral effect? Fold change in Effective Concentration 5% (FC EC5; 2x, 1x, x) Must be correlated with clinical outcomes Baseline RAVs- occur without prior drug exposure Polymorphisms (natural variations) in the viral nucleotide sequence Some happen to result in a change in the amino acid at key positions for DAAs Slide 4 of 38 Slide 5 of 38 Key HCV Resistance Concepts 1. HCV resistance associated variants (RAVs) can be present without drug exposure 2. HCV RAVs impact treatment response in specific situations 3. HCV resistance is NOT absolute 4. Patient characteristics are just as important as RAVs (if not more than) 5. Future regimens may obviate the need for most resistance testing HCV and HIV replication dynamics Slide 6 of 38 ~97% t 1/2 wks* ~3% Extrahepatic t 1/2 1 hrs Reservoir t 1/2 2.6 d >99% t 1/2.7 d <1% Long-lived Reservoir t 1/2 > 44 mo t 1/2 = 44.2 months ~ 7. d ~ 2. d t 1/2.75 hr t 1/2 1 hr eradication of 1 6 cells= 73.4 years *does not account for curing of infected hepatocytes Perelson A Science Markowitz M J Virol 23. Finzi D Nat Med Neumann A, Science Guo J. J Virol 23. Guedj J. PNAS 213. Siliciano J. Nat Med 23. 2

3 Slide 7 of 38 Virus characteristics and resistance potential HCV 1 12 virions/day Error prone viral polymerase (x2) No overlapping reading frames Moderate infected cell turnover Dynamic replication unit Cytoplasmic replication (t 1/2 ~1hrs) No latent reservoir Cure possible Viral Quasispecies HIV 1 1 virions/day Error prone viral polymerase Overlapping reading frames Rapid infected cell turnover (t 1/2 ~24hrs) Static replication unit Integrated proviral DNA Latently infected Tcells Control, not cure HIV-1 vs. HCV Genetic Diversity Slide 8 of 38 Stuart Ray Slide 9 of 38 Modeling the HCV resistance barrier Pre-existence of resistant variant explains their rapid emergence Not all variants will be fit enough to persist unless there is drug selective pressure Rong L et al. Science Transl Med 21. 3

4 Targets also impact resistance potential Protease structure: HCV and HIV contrast HCV: shallow and relatively featureless Limited options for optimizing inhibitor binding HIV: pocket within the homo-dimer Slide 1 of 38 HCV NS3/4A Serine protease HIV Aspartyl protease Tsantrizos YS et al. Agnew Chem Int Ed 23. Blundell TL et al. Nat Rev Drug Disc 22. Baseline minority variants impact HIV ART responses HIV NNRTI data: HR 2.5 ( ) for VF with minority NNRTI resistance Simen BB. JID 29 ACTG398 Slide 11 of 38 + NNRTI, + geno + NNRTI, - geno -NNRTI Halvas EK et al. JID 21. Slide 12 of 38 Baseline minority variants have a minimal impact on HCV treatment responses LDV/SOF EBR/GZR: TN GT1a Population EBR RAVs EBR RAVs No RAVS: 414/438 (95%) 5% No RAVS: 396/439 (9%) 1% / 14/ 389/ 31/ Population Sarrazin C. Gastro 216. Jacobson I. LB-22 AASLD

5 Slide 13 of 38 Clinical HCV Resistance For which regimen/circumstance is there a label recommendation to perform NS5A RAV testing? Slide 14 of 38 8% 1. All GT1a infections prior to PrOD 65% 2. All GT1a infections prior to EBR/GZR 8% 3. GT1 treatment experienced patients with cirrhosis prior to LDV/SOF 5% 4. GT1 treatment experienced patients with cirrhosis prior to SOF/VEL 5. RAV testing is not recommended in any label. 15% Slide 15 of 38 Resistance Characteristics of HCV Antiviral Classes Class Antiviral Potency Genotype Activity Resistance Barrier FDA Approvals NS3 Protease Inhibitors +++ to , 4 (± 2, 3, 6) Low to Moderate Simeprevir (213) Paritaprevir (214) Grazoprevir (216) NS5B Nucleotide Very High Sofosbuvir (213) NS5B Nonnucleoside ++ 1 Low Dasabuvir (214) NS5A Inhibitors , 4, 6 (± 2, 3) Low To Moderate Ledipasvir (214) Daclatasvir (215) Ombitasvir (214) Elbasvir (216) Velpatasvir (216) 5

6 Slide 16 of 38 Why NS3 PI resistance is not a big deal 1. Baseline RAVs are not a significant clinical issue RAVs at key PI positions are rare (<1%) without drug exposure No impact of Q8K with SOF + SMV at recommended durations 2. After failure selected PI RAVs are lost rather quickly Do they still have an impact, even if no longer detectable? 3. Non-PI options are available for sequencing of treatment Eliminates the issue of a persistent effect The saving grace with PI resistance? Slide 17 of 38 91% of nonsvr with resistance 1a: R155K +/- Q8K 1b: D168V Lenz O. EASL 214. Real World Data: Impact of prior PI therapy? Slide 18 of 38 PI failure= PEG/RBV + PI Resistance testing results not available Majority did not have baseline testing Prior PI failure was associated with a decreased SVR rate OR:.4 (.2-.9) SOF + SMV (± ) PI failure No PI Nelson D. ISVHLD 215. Jensen D. #45 AASLD

7 Slide 19 of 38 Overview of NS5A RAVs NS5A RAVs are the class with the most clinical significance GT 1a GT 3 Present in about 1-15% of patients without prior exposure More prevalent in GT 1b but of limited clinical significance The majority of time an NS5A inhibitor will still be used in a patient with NS5A RAVs Treatment extension and addition of RBV are key approaches to management of RAVs with currently available therapies A Word on NS5A Resistance Terminology The nomenclature of baseline NS5A resistance varies widely in the literature: RAPs resistance associated polymorphisms ANY nonconsensus amino acid at a site associated with resistance to ANY NS5A inhibitor Class RAVs resistance associated variants Specific amino acid substitutions associated with resistance to ANY NS5A inhibitor Drug-specific RAVs Specific amino acid substitutions associated with resistance to a particular NS5A inhibitor Different fold-change cut-offs have been used (2x, 5x, 1x, etc) Slide 2 of 38 Sarrazin C. J Hepatol. 216;64: Baseline NS5A RAVs: A Moving Target Slide 21 of 38 GT 1a GT 1b Jacobson I. #LB-22. AASLD

8 Slide 22 of 38 Baseline versus selected RAVs Baseline Single variants Variable fold change Variable prevalence in viral population Any patient Selected Multiple variants High fold change High prevalence in viral population Difficult to treat populations Kitrinos K. #1949 EASL 214. Wyles D. Dvory-Sobol H. EASL 215. Cooper C CROI 216 Slide 23 of 38 Rate of selection of NS5A resistance upon virologic failure Varies by regimen and duration PI based Vedroprevir + tegobuvir + LDV: >99% GZR/EBR: 85% PrOD: 68% Nucleotide based SOF/LDV: 75% 8 weeks: 65% SOF/VEL: 93% (14/15; majority GT3 and with baseline RAVs) Nuc-based triple SOF/5816/9857 ( 6 weeks): % (n=15) SOF + GZR/EBR ( 8 weeks): 37% (n=3) Kitrinos K. #AASLD 214.Sulkowski M. Lancet 214. Lawitz E. Lancet 214. Sarrazin AASLD 214. Kowdley K. NEJM 213. Gane E. EASL 215. Poordad F. EASL 215. Zeuzem S. Ann Intern Med 215. Hezode C. #THU-216 EASL 216. Available Resistance Testing (US) Slide 24 of 38 Ultra-deep (or next-generation sequencing [NGS]) vs population (Sanger) sequencing What is broadly available: 1. HCV NS5A drug resistance assay NGS with 1% detection level reported 2. Hepatitis C viral RNA genotype 1/3 NS3/NS5 drug resistance assays RT-PCR with DNA sequencing Both assays now available for GT1 and GT3 HCV GT1 assays are subtype specific 1. HCV NS5A Drug Resistance Assay Product Label Hepatitis C Viral RNA Genotype 1/3 NS3 and/or NS5 Drug Resistance Assay Product Labels

9 Slide 25 of 38 Examples: NS5A resistance genotyping Slide 26 of 38 Durability of Treatment-Emergent NS5A RAVs Study assessing NS5A RAVS in pts failing LDV-containing regimens (non-sof) Wyles D, et al. EASL 215. Abstract O59. Slide 27 of 38 Broad Cross-Resistance With Early Generation NS5As Fold Change Genotype 1a Genotype 1b M28T Q3R L31M/V Y93H/N L31V Y93H/N Ledipasvir 2x > x > x/ > x/ > x > 1, > x/-- Ombitasvir > x > x < 3x > 1,x/ > x > 1,x < 1x 2x/5x Daclatasvir > x > x > x/ > x > x/ > 1,x < 1x 2x/5x Elbasvir 2x > x > 1x > x/ > x > x < 1x > x/-- Velpatasvir < 1x < 3x 2x/5x > x/ > x < 3x < 3x/-- ABT-53 < 3x < 3x < 3x < 1x/< 1x < 3x < 3x/< 3x MK-848 < 1x < 1x < 1x < 1x < 1x < 1x Wang C, et al. Antimicrob Agents Chemother. 212;56: Cheng G, et al. EASL 212. Abstract Zhao Y, et al. EASL 212. Abstract A845. Yang G, et al. EASL 213. Abstract Ng T, et al. CROI 214. Abstract 639. Asante-Appiah E, et al. AASLD 214. Abstract

10 Impact of Baseline NS5A RAVs LDV/SOF SVR12 by LDV RAV* status with guideline-recommended SOF/LDV treatment Slide 28 of 38 Naïve Experienced TN NC: 12wks TN Cirr: 12wks TE NC: 12wks TE Cirr: 12wks + R TE Cirr: 24wks RAVs No RAVs RAVs No RAVs *LDV RAVs at positions 24, 28, 3, 31, 32, 58, and 93 at 1% cutoff. Zeuzem S, et al. AASLD 215. Abstract 91. Impact of Baseline NS5A RAVs in Pts With GT1a HCV Treated With EBR/GZR Analysis of pts with GT1a HCV treated with GZP/EBR in phase II/III trials (naive/relapsers) Population Sequencing Next-Generation Sequencing (1% Level) EBR RAVs NS5A Class RAVs EBR RAVs NS5A Class RAVs Slide 29 of 38 No RAVS: 414/438 (95%) No RAVS: No RAVS: No RAVS: 5% 432/438 2% 396/439 1% 289/439 35% (8%) (9%) (65%) / 14/ 345/ 74/ 389/ 31/ 284/ 136/ EBR RAVs NS5A RAVs EBR RAVs NS5A RAVs Population Sequencing Next Generation Sequencing Patients without RAVs Patients with RAVs Jacobson I, et al. AASLD 215. Abstract LB-22. GZR/EBR Efficacy in GT1a HCV: Resistance is all that matters! Analysis of PEP* of TN pts with GT1a HCV treated with GZP/EBR in phase II/III trials Multivariable logistic regression model eor (95% CI) P value Slide 3 of 38 *PEP = pooled efficacy population. Zeuzem S, et al. AASLD 215. Abstract 7. 1

11 Slide 31 of 38 SOF/VEL responses and baseline RAVs Hezode C. THU-216 EASL 216. Slide 32 of 38 RAVs in DAA experienced patients Slide 33 of 38 Baseline NS5A RAVs Are Associated With Retreatment Failure 8 8/12-wk SOF/LDVbased tx failures (n = 41) 71 Retreatment with SOF/LDV Wks SVR /41 5/5 4/5 2/6 11/11 18/3 Combined No RAVs RAVs Q3R or L31M Y93H/N M28T Lawitz E. #O5 EASL

12 Slide 34 of 38 Impact of Multiple Negative Predictors on Response Retrospective analysis of phase 2/3 studies of SOF + RBV ± PegIFN > 85 pts, genotypes 1, 2, and 3 HCV > Treatment experienced Cirrhosis HCV RNA* Male 75 kg 2 7/ 181/ 247/ 211/ 6/ 12/ 9/ Number of Negative Predictors IL28B non-cc NS5A RAVs? Foster GR, et al. EASL 214. Abstract 66. What Role Does RBV Play in Overcoming Resistance and Optimizing Retreatment? Slide 35 of 38 HIV coinfected SOF/LDV failures at 12 wks Male: 78% 1a: 78% HCV RNA: 6.4 (±.8) Black: % Non-CC: % Cirrhosis: 22% NS5A RAVs: 78% N = 9 SOF/LDV + RBV weeks 89 8 SVR12(%) /9 EOT SVR12 SVR12 Failure 55-yr-old male GT1a No cirrhosis L31M Cooper C. #573 CROI 216. Slide 36 of 38 Genotype 3 and RAVs 12

13 In which scenario do the AASLD/IDSA guidelines NOT recommend RAV testing for GT3? Slide 37 of 38 6% 1. Treatment experienced patients prior to SOF/VEL 1% 2. Treatment naïve cirrhotic patients prior to SOF/VEL 68% 3. Treatment experienced and cirrhotic patients prior to SOF/VEL 16% 4. RAV testing is never recommended with SOF/VEL Slide 38 of 38 SOF/VEL: Answer for GT3 Cirrhotics and those with Y93H? Wk Wk 12 Wk 24 N = 277 SOF/VEL N = 275 Overall SOF + RBV SVR12 SVR12 Treatment Experienced Noncirrhotic Cirrhotic TE TE SOF/VEL SOF/RBV Foster GR, et al. N Engl J Med. 215;373: NS5A RAVs and Responses to SOF/VEL Slide 39 of No RAVs SOF/VEL RAVs Foster GR, et al. N Engl J Med. 215;373:

14 When should you do RAV testing? Slide 4 of 38 Definitely Probably Maybe Who: All GT1a prior to EBR/GZR What: NS5A (EBR RAVs) M28, Q3, L31, and Y93 5-1% impacted Who: All GT1 DAA failure What: NS3 and NS5A Who: GT1a treatment experienced GT3 non-cirrhotic (SOF + DCV) GT3 TE or cirrhosis (SOF/VEL) What: NS5A (LDV RAVS or GT3 Y93H) Action: 1. Extend to 16 weeks AND 2. Add RBV OR 3. Consider other therapy Action: 1. Select non-cross resistant therapy 2. Add RBV (regardless) 3. Extend therapy hcvguidelines.org Action: 1. GT1a-consider RBV with LDV/SOF 24wks + RBV with F4 2. GT3- add RBV to SOF+DCV 3. GT3 TE or cirrhosis- add RBV to SOF/VEL Drug Resistance-Associated Variants in Hepatitis C Virus Infection: Hype or Help? David L. Wyles, MD Chief, Division of Infectious Disease Denver Health Medical Center Denver, Colorado FORMATTED: 1/3/16 Atlanta, Georgia: October 2,