Management of HCV in Prior Treatment Failure

Management of HCV in Prior Treatment Failure Arthur Y. Kim, MD Associate Professor of Medicine Harvard Medical School Boston, Massachusetts Learning Objectives After attending this presentation, learners will be able to: List treatment options for treatment experienced patients Describe the relevance of resistance associated substitutions Slide: 2 of 51 What we won t cover PEG-IFN experienced patients Every single possible re-treatment situation genotypes x presence or absence of cirrhosis x specific regimen exposure x presence or absence of resistance-associated substitutions x presence of absence of CKD 4-5 Slide: 3 of 51 Oklahoma City, Oklahoma, November 29, 2017 1

Slide: 4 of 51 Considerations for treatment failures after DAAs Was initial therapy appropriate / ideal? Was staging accurate? Is it needed again? Was adherence adequate? Were drug interactions present? Is this relapse or reinfection? What medication classes were used? Should I send resistance testing? If so, when? Case 69 y/o African-American gentleman with HIV / HCV co-infection HIV suppressed, CD4 568 cells/mm 3, TDF/FTC/rilpivirine Plt=135K, Cirrhosis by ultrasound, no decompensation, no varices, albumin 3.6 BMI 33, Cr 1.1, IL-28B T-T, No prior treatment 12 weeks of ledipasvir/sofosbuvir, week 4 HCV RNA is target detected but not quantifiable Reports good adherence, takes pills with HIV medication upon awakening, missed 2 doses (took 84 pills over 86 days). HIV RNA remains suppressed on treatment HCV RNA positive at week 4 post-treatment Slide: 5 of 51 He was eating more tomatoes during the last two months of treatment that caused heartburn, was taking TUMS at night What is the factor that likely most contributed to relapse? 1. Baseline resistance mutations 14% 14% 14% 14% 14% 14% 14% 2. HCV RNA at week 4 target detected 3. Cirrhosis 4. Genetic factors 5. HIV 6. Antacid use 7. Adherence issues Baseline resistance mutations HCV RNA at week 4 target detected Cirrhosis Genetic factors HIV Antacid use Adherence issues Slide 7 of 24 10 Oklahoma City, Oklahoma, November 29, 2017 2

Slide 9 of 24 Alternate scenario: the patient misses his SVR4 and SVR12 appointments, returns at week 16. HCV RNA is positive. Genotype is the same (1a). Is this more likely reinfection or relapse? 1. Reinfection 2. Relapse 50% 50% Reinfection Relapse 10 Is this relapse or reinfection? Long-term prospective follow-up of 1343 patients enrolled in phase III trials for PEG/RBV, mean f/u 47 months (range 10-87) Slide: 10 of 51 Swain, et al. Gastroenterology. 2011. Risk of Late Relapse or Reinfection with HCV after Achieving a SVR: A Systematic Review and Meta-analysis Re-infection more likely as we treat higher-risk populations Slide: 11 of 51 Simmons et al. Clin Infect Dis. 2016;62(6):683-694 Oklahoma City, Oklahoma, November 29, 2017 3

Slide: 12 of 51 Late Relapse Versus Hepatitis C Virus Reinfection in Patients With Sustained Virologic Response After Sofosbuvir-Based Therapies Across phase III trials of SOF and LDV/SOF, 12 of 3004 had detectable viremia after SVR12, 11 with same genotype/subtype 7 of 12 (58%) were re-infection, leaving 5 late relapses Sarrazin et al. Clin Infect Dis. 2017;64(1):44-52 Is this relapse or reinfection? Genotype /subtype Same, early Same Different, later Slide: 13 of 51 Likely relapse Treat as experienced Possible Reinfection Reinfection Evidence of acute? Treat as naive If the same genotype/subtype if detected, is it relapse or reinfection? Acute re-infection: Later onset Ongoing risk factors Higher ALT Dynamic HCV RNA Treatment Slide: 14 of 51 Original figure adapted from Svarovskaia, et al. Clin Infect Dis 2014: 59(12), 1666 1674 Oklahoma City, Oklahoma, November 29, 2017 4

Slide 16 of 24 What type of HCV resistance testing would you perform at this time? 1. NS3 20% 20% 20% 20% 20% 2. NS5A 3. NS5B 4. Both NS3 and NS5A testing 5. None NS3 NS5A NS5B Both NS3 and NS5A testing None 10 Case part 2 NS5A resistance testing: Mutation: Q30R NS3/4A resistance (2 years earlier): Mutation: I37V Agent Result Agent Result Daclatasvir Resistance Probable Boceprevir Sensitive Ledipasvir Resistance Probable Simeprevir Sensitive Ombitasvir Resistance Probable Telaprevir Sensitive Elbasvir Resistance Probable Slide: 17 of 51 Was resistance testing helpful? Slide: 18 of 51 Oklahoma City, Oklahoma, November 29, 2017 5

Slide: 19 of 51 Key principles of HCV resistanceassociated substitutions (RASs) Viruses with RASs may exhibit variable fitness compared to wildtype RAS are present at baseline in the absence of drug exposure, but may or may not be detected RASs may impact treatment responses in select situations Resistance is NOT futile For newly approved regimens detection of RASs is most often NOT necessary Cirrhosis does not impact SVR rates for 12 weeks of EBR/GZR GZR EBR No cirrhosis Cirrhosis 100 75 94 97 97 94 96 100 AEs are similar between cirrhotic and non cirrhotic patients in these trials % SVR12 50 25 0 231/246 68/70 34/35 32/34 175/183 35/35 C-EDGE C-SALVAGE HIV C-EDGE Slide: 20 of 51 Zeuzem et al. Ann Intern Med 2015; Rockstroh et al. Lancet HIV 2015; Buti et al. CID 2016; Jacobson et al. AASLD 2015 EBR/GZR - RASs at NS5A positions 28, 30, 31, 93 associated with lower SVR for genotype 1a EBR GZR Baseline testing for NS5A resistance recommended if using this regimen for GT1a SVR12 Subjects With SVR12 Subjects with RAV Position RAVs (Population RAVs (1% ST NGS) Sequencing) 24 15/18 (83.3%) 4/4 (100.0%) 28 61/68 (89.7%) 29/33 (87.9%) 30 14/23 (60.9%) 4/10 (40.0%) 31 15/23 (65.2%) 5/13 (38.5%) 32 1/1 (100.0%) -- 38 9/9 (100.0%) -- 58 75/77 (97.4%) 48/49 (98.0%) 92 6/6 (100.0%) 3/3 (100.0%) 93 9/14 (64.3%) 5/8 (62.5%) } 28,30,31 } 93 Slide: 21 of 51 Jacobson et al AASLD 2015, San Francisco Oklahoma City, Oklahoma, November 29, 2017 6

Slide: 22 of 51 EBR/GZR - extension of therapy to 16 weeks and addition of RBV overcame resistance GZR EBR RBV Addition of RBV and extension of therapy to 16 weeks recommended with certain RASs Jacobson et al AASLD 2015, San Francisco Resistance Testing Assays Traditional approach is population sequencing, newer assays use ultrasdeep sequencing (next-generation sequencing, or NGS) Available: HCV NS5A drug resistance assay (LabCorp / Monogram Biosciences) NGS - 10% threshold for reporting HCV NS3 and NS5 HCV RNA genotype + resistance (Quest) RT-PCR with DNA sequencing For GT1 and GT3 Slide: 23 of 51 GT1 assays are subtype specific Adapted from David Wyles Core E1 E2 P7 NS2 NS3 NS4 NS5a NS5b Wild type Population sequencing May or may not go deep enough NGS goes very deep Sets threshold for reporting RAS Slide: 24 of 51 Oklahoma City, Oklahoma, November 29, 2017 7

Slide: 25 of 51 Differences in the barrier to resistance by drug class RAVs to one drug are generally cross resistant to other drugs within a class (but not always) Viral fitness of RAVs effects their persistence after discontinuation of therapy NS3/4A Protease Inhibitors NS5B Nucleos(t)ide NS5B Nonnucleoside Polymerase Polymerase Inhibitors Inhibitors NS5A Inhibitors Drugs in Class Simeprevir Paritaprevir Grazoprevir Voxilaprevir Glecaprevir Sofosbuvir Dasabuvir Ledipasvir Ombitasvir Daclatasvir Elbasvir Pibrentasvir Variable Barrier to resistance (1a lower barrier than 1b) Extremely High (1a=1b) Very low Variable (1a lower barrier than (1a lower barrier than 1b) 1b) Comments 2 nd and 3rd generation PIs have higher barrier, pangenotypic Single target Active site Allosteric Many targets Multiple antiviral Mechanism of Action Modified from Schaefer EA, et al. Gastroenterology. 2012 What do we mean by barrier to resistance? Mutations may produce strains of varying fitness to replicate A fit mutant strain An unfit mutant strain Proteas e inhibitor Sofosbuvir Slide: 26 of 51 Baseline RAS versus selected Core E1 E2 P7 NS2 NS3 NS4 NS5a NS5b NS3 RAS Compared to selected RAS, baseline RAS more likely to be: 1. Single variants 2. Variable prevalence within populations 3. Present regardless of other characteristics NS5 RAS Slide: 27 of 51 Oklahoma City, Oklahoma, November 29, 2017 8

Slide: 28 of 51 Baseline RAS versus selected Core E1 E2 P7 NS2 NS3 NS4 NS5a NS5b NS3 RAS NS5 RAS Selected RAS more likely to be: 1.Multiple variants 2.High prevalence within populations 3.More difficult to treat characteristics Kinetics of viral resistance Slide: 29 of 51 Pawlotsky Gastroenterology 2016 Viruses with RASs exhibit variable fitness compared to wildtype Significant sofosbuvir RASs are rare / super low frequency at baseline NS3 NS5A NS5B S282T rarely detected Disappears quickly Slide: 30 of 51 Svarovskaia, et al. Clin Infect Dis 2014: 59(12), 1666 1674 Oklahoma City, Oklahoma, November 29, 2017 9

Slide: 31 of 51 Viruses with RASs exhibit variable fitness compared to wildtype Variable at baseline (R155K ~1%) R155K 1a variants 1b variants NS3 NS5A NS5B V36A V36M Fitness varies by mutation and subtype V36A A156S/T Sullivan, et al. EASL. 2011 Viruses with RASs exhibit variable fitness compared to wildtype NS3 Variable at baseline NS5A Higher fitness NS5B Before LDV Treatment 84% (64/76) 16% (12/76) At Virologic Failure With LDV Treatment 1% 99% (72/73) Patients with NS5A RASs Patients without NS5A RASs NS5A RASs in patients who failed LDV treatment without SOF Positions 24, 28, 30, 31, 32, 58, 93 that confer >2.5-fold reduced susceptibility to LDV in vitro were included Patients With NS5A RAVs (%) 100 80 60 40 20 0 Majority of RASs Still Detected After 96 Weeks (>1% of Population) 98 100 98 100 VF Parent Study 95 86 62/63 58/58 42/43 45/45 52/55 50/58 Baseline FU-12 FU-24 FU-48 FU-96 Registry Study Slide: 32 of 51 Wyles, et al. Abstract O059, EASL 2015. Ability of RASs to persist is dependent on class Variable at baseline (R155K ~1%) NS3 NS5A NS5B Fitness varies by class Slide: 33 of 51 Black et al. EASL 2017 Oklahoma City, Oklahoma, November 29, 2017 10

Slide: 34 of 51 Additional factors matter! Ideally: Naive IL28B CC female sex lower BMI low fibrosis low HCV RNA No RAS Our case NS5A experienced IL28B TT male sex Higher BMI Cirrhosis HCV RNA Q30 RAS Develops 2.4 cm mass visualized on ultrasound c/w HCC, elevated AFB; Undergoes radiofrequency ablation; After cure of HCC, what would you treat with? 1. Defer treatment, first refer for liver transplant 17% 17% 17% 17% 17% 17% 2. SOF/VEL/RBV x 24 weeks 3. SOF/PrOD/RBV x 12 weeks 4. Glecaprevir / pibrentasvir x 16 weeks 5. SOF/VEL/VOX x 12 weeks 6. SOF/VEL/VOX/RBV x 12 weeks Defer treatment, first refer for liver transplant SOF/VEL/RBV x 24 weeks SOF/PrOD/RBV x 12 weeks Glecaprevir / pibrentasvir x 16 weeks SOF/VEL/VOX x 12 weeks SOF/VEL/VOX/RBV x 12 weeks Slide 36 of 24 10 Examples of salvage regimens before the newest approvals Off label: The kitchen sink sofosbuvir + simeprevir + RBV x 24 weeks paritaprevir/ritonavir/ombitasv ir/dasabuvir + sofosbuvir +/- RBV elbasvir/grazoprevir + sofosbuvir +/- RBV simeprevir + daclatasvir + sofosbuvir +/- RBV $19,377 Slide: 37 of 51 Taken from http://hcvguidelines.org, April 17, 2017 Oklahoma City, Oklahoma, November 29, 2017 11

Slide: 38 of 51 Broad Cross-resistance With Early Generation NS5As Fold-change 1a 1b L31M/V Y93H/N M28T Q30R Y93H/N L31V >100x/ >1,000x/ 20x >100x >100x/-- Ledipasvir >100x >10,000 <3x >10,000x/ Ombitasvir >1000x >100x <10x 20x/50x >10,000x >100x >100x/ >1,000x/ Daclatasvir >100x >1000x <10x 20x/50x >1000x >10,000x >10x >1,000x/ Elbasvir 20x >100x <10x >100x/-- >1,000x >100x >100x/ Velpatasvir <10x <3x 20x/50x <3x/-- >1000x ACH-3102 30x 20x <10x >100x/>100x <3x/<3x Pibrentasvir <3x <3x <3x <10x/<10x <3x <3x/<3x MK-8408 <10x <10x <10x <10x <10x <10x Wang C. AAC 2012. Cheng G. #1172. EASL 2012; Zhao Y. #A845 EASL 2012. Yang G. EASL 2013; Ng T. #639 CROI 2014. Asante-Appiah E. AASLD 2014. Glecaprevir and pibrentasvir (G/P): Fixed-dose combination 3 pills once daily Slide: 39 of 51 Glecaprevir / pibrentasvir for re-treatment of NS5A failures - MAGELLAN 1 GLE PIB 12 versus 16 weeks, GT1,4-6 34% / 26% cirrhosis per group Baseline RAS NS5A only: 55% / 52% NS3+NS5A: 11% / 9% Overall SVR 89% vs 91% 12wks higher relapse w/ NS5A RAS Slide: 40 of 51 Dual NS3/NS5A - 55% relapse Poordad et al. EASL 2017 Oklahoma City, Oklahoma, November 29, 2017 12

Slide: 41 of 51 Glecaprevir / pibrentasvir for re-treatment of NS5A failures - MAGELLAN 1 GLE PIB Poordad et al. EASL 2017 Glecaprevir / pibrentasvir for re-treatment of NS5A failures - MAGELLAN 1 GLE PIB Slide: 42 of 51 Poordad et al. EASL 2017 Glecaprevir / pibrentasvir for re-treatment, GT1, package insert Slide: 43 of 51 Package insert, glecaprevir/pibrentasvir Oklahoma City, Oklahoma, November 29, 2017 13

Slide: 44 of 51 SOF/VEL/VOX for re-treatment of NS5A failures VOX VEL SOF POLARIS 1 GT 1-6 (30% GT3) 12 weeks of therapy vs placebo Including compensated cirrhosis (46%) 2.2% relapse 4 GT 3 relapse all 3a and ¾ had BL NS5A RAS No treatment emergent RAS all VF had cirrhosis (6 R, 1 VBT) Bourliere et al. NEJM 2017 POLARIS-1 Slide: 45 of 51 Bourlière et al. AASLD 2016 POLARIS-1 & 4- Integrated resistance analysis By # of RASs: Slide: 46 of 51 Sarrazin et al. EASL 2017 Oklahoma City, Oklahoma, November 29, 2017 14

Slide: 47 of 51 Resistance testing is generally not recommended for these regimens Taken from http://hcvguidelines.org, September 26, 2017 Slide: 48 of 51 When should one test for RASs? Slide: 49 of 51 http://hcvguidelines.org, September 26, 2017 Oklahoma City, Oklahoma, November 29, 2017 15

Slide: 50 of 51 When should one NOT test for RASs? http://hcvguidelines.org, September 26, 2017 When should one test for RASs? Wyles and Leutkemeyer, Topic Antiviral Med 2017, available on IAS-USA website Slide: 51 of 51 Slide: 52 of 51 Key principles of HCV resistance-associated substitutions (RASs) Viruses with RASs may exhibit variable fitness compared to wildtype Higher fitness last longer, lower fitness may be transient RAS are present at baseline in the absence of drug exposure, but may or may not be detected Possibility of transmission RASs may impact treatment responses in select situations Situation is often worse in presence of other treatment characteristics Resistance is NOT futile May be overcome by longer durations, addition of ribavirin, or later-generation agents For newly approved regimens detection of RASs is most often NOT necessary Oklahoma City, Oklahoma, November 29, 2017 16

Slide: 53 of 51 Take home points regarding re-treatment after DAA failure The most important factor in deciding upon re-treatment regimens is the class of prior treatment failure Resistance-associated substitutions are NOT futile May impact select situations Certain mutations may require longer treatment courses, ribavirin Ribavirin-free regimens are newly available approved for many retreatment considerations Management of HCV in Prior Treatment Failure Arthur Y. Kim, MD Associate Professor of Medicine Harvard Medical School Boston, Massachusetts Slide: 54 of 51 Oklahoma City, Oklahoma, November 29, 2017 17