UNIVERSITY OF SOUTH ALABAMA COLLEGE OF MEDICINE, MOBILE, AL. In general:

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1 HCV Retreatment of DAA Failures JORGE L. HERRERA, MD, MACG UNIVERSITY OF SOUTH ALABAMA COLLEGE OF MEDICINE, MOBILE, AL DAA Drug Classes NS3/4 (protease) inhibitors Telaprevir, boceprevir, simeprevir, paritaprevir Coming soon: grazoprevir NS5a Inhibitors Ledipasvir, dasabuvir, Daclatasvir Coming soon: Elbasvir, velpatasvir NS5b (polymerase) Sofosbuvir (nucleoside) Ombitasvir (non-nucleoside) In general: Resistance is shared among classes New generation drugs may overcome resistance within class Resistant mutants are sensitive to drugs from other classes Basis for multiple drug cocktails Copyright 2015 American College of Gastroenterology 1

2 Barrier to Resistance Drug Class Examples Barrier to Resistance Protease inhibitors Protease inhibitors 2 nd generation NS5a inhibitors Nucleoside NS5b inhibitors Non-nucleoside NS5b Inhibitors Telaprevir, boceprevir, simeprevir, paritaprevir ++ Grazoprevir +++ Ledipasvir, ombitasvir, daclatasvir ++ Sofosbuvir Dasabuvir + + = very low barrier to resistance = very high barrier to resistance Schaefer EA, et al. Gastroenterology 2012;142: Determinants of barrier to resistance Number of mutation needed to become resistant 1 st Generation protease inhibitors Genotype 1a 1 mutation Genotype 1b 2+ mutations Fitness of the resultant mutant Nucleoside polymerase inhibitor resistant mutant very unfit Protease inhibitor resistant mutant retain some fitness Non-nucleoside polymerase inhibitor mutants remain fit NS5a remain fit Copyright 2015 American College of Gastroenterology 2

3 Persistence of Resistance After Failure to Pr/O/D Genotype 1a patients Persistence assessed 48 weeks after discontinuation of therapy Resistance Mutation Percent Persisting at 48 wk NS3 9% NS5b (non-nucleoside) nucleoside) 57% NS5a 96% Informs decision making process on how to re-treat prior failures Krishnan P, et al. J Hepatol 2015;62:S220, Abstract O057 Resistant Variants are Selected During Therapy Resistant Baseline Antiviral Therapy variants expand X X Sensitive (wild) virus Resistant virus Pawlotsky JM. Clin Liv Dis 2003;7:45-66 Copyright 2015 American College of Gastroenterology 3

4 Patients naïve to DAA therapy Do Pre-existing existing RAV s Affect Outcome? DEPENDS ON THERAPY Genotype 1a Q80K and Simeprevir Q80K is a polymorphism that affects sensitivity to simeprevir Only affects genotype 1a Does it affect response to DAA combination therapy with simeprevir? Copyright 2015 American College of Gastroenterology 4

5 Genotype 1a - Cirrhosis Q80K Negatively Impacts SVR in Cirrhosis Treated with Simeprevir-Sofosbuvir Sofosbuvir Kwo P, et al. EASL 2015 Abstract LP14 Lawitz E, et al. EASL 2015, Abstract LP04 AASLD Guidance on Resistance Testing for SIM + SOF Therapy Genotype 1a Infection + compensated cirrhosis Test of Q80K if considering SOF + SIM therapy If Q80K present, consider alternate therapy Q80K testing not necessary for Genotype 1b Patients without cirrhosis Patients in whom other DAA s are considered Copyright 2015 American College of Gastroenterology 5

6 Effect of Pre-existing existing Mutations on Sofosbuvir/Ledipasvir Therapy Efficacy of sofosbuvir/ledipasvir in treatment- experienced subjects (no prior NS5a) Baseline resistance profiles: Protease Inhibitor (NS3/4) resistance polymorphisms 71% had baseline resistant mutants 98% of those achieved an SVR NS5a resistant polymorphisms 14% of subjects had baseline resistance it polymorphisms 89% achieved an SVR Among subjects that relapsed after therapy 23/37 (62%) had resistant polymorphisms Afdhal N, et al. NEJM 2014;370: Aviator Study No Impact of Baseline RAV s in G1a Patients Treated with Pr/O/D With RAV No RAV Copyright 2015 American College of Gastroenterology 6

7 Do we need to do pre- treatment resistance panels? As of today for patients never exposed to NS5a Resistance panel testing is not needed pre-therapy Except for 1a cirrhosis if simeprevir + sofosbuvir therapy is planned Presence of resistant variants associated with acceptable SVR rates What about advanced cirrhosis???? Future Resistance mutation analysis will be needed in NS5aexperienced patients Clinical Management of DAA Failures Copyright 2015 American College of Gastroenterology 7

8 Clinical Practice Scenarios Failed IFN + boceprevir, telaprevir or simeprevir IFN + sofosbuvir + ribavirin Sofosbuvir + ribavirin Sofosbuvir + simeprevir Sofosbuvir + ledipasvir Paritaprevir + ombitasvir + dasabuvir - + Level of Difficulty PEG-IFN +Telaprevir/Boceprevir/Simeprevir Failures 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Sofosbuvir + Ledipasvir for Prior Treatment Failure 93% 94% 100% 98% 40/43 62/66 58/58 49/50 12 weeks 24 weeks P+R P+R+PI Afdhal N, et al. NEJM 2014;370: Copyright 2015 American College of Gastroenterology 8

9 Grazoprevir (PI) + Elbasvir (NS5a) Ribavirin for Prior PI Failure (NS5a) + 79 patients (34 cirrhosis), prior failure to PEG + Ribavirin + either: Boceprevir Telaprevir Simeprevir 12 week therapy with grazoprevir, elbasvir and ribavirin SVR12 rates: Overall: 96% (76/79) Prior virologic failure: 95.5% 5% (63/66) Baseline NS3 RAVs: 91.2% (31/34) Baseline NS5a RAVs: 75% (6/8) Forns X, et al. J Hepatol 2015;63: Sofosbuvir Regimen Failures (NS5a-free regimens) Management of prior sofosbuvir failures PEG-IFN + Sofosbuvir + ribavirin i i Sofosbuvir + ribavirin Sofosbuvir-resistant mutants (S282T) are very rare Extremely unfit Do not survive Retreated with Sofosbuvir + ledipasvir + ribavirin 12 weeks SVR-12: 98% (44/45)* *The failure patient was a G3 patient that was misclassified Wyles D, et al. Hepatology 2015;61: Copyright 2015 American College of Gastroenterology 9

10 Is Ribavirin Needed in Sofosbuvir Failures? 14 patients, G1, prior failures to 24 weeks of sofosbuvir + ribavirin Re-treatment: Sofosbuvir + ledipasvir 12 weeks SVR-12: 100% Responses included 1 patient with detectable S282T mutation pre-therapy 7 with cirrhosis Osinusi A, et al. Ann Intern Med 2014;161: Telaprevir or Boceprevir + PEG-IFN or Simeprevir + Sofosbuvir Failures AASLD/IDSA Guidance No Cirrhosis Ledipasvir + sofosbuvir 12 weeks Consider ribavirin if a prior failure to sofosbuvir + simeprevir Cirrhosis Ledipasvir + sofosbuvir 24 weeks Consider ribavirin if a prior failure to sofosbuvir + simeprevir Ledipasvir + sofosbuvir + ribavirin 12 weeks Do not use if prior failure to sofosbuvir + simeprevir Copyright 2015 American College of Gastroenterology 10

11 NS5a-Experienced Patients LEDIPASVIR, DACLATASVIR, OMBITASVIR Resistance Analysis of Select NS5A Inhibitors in G1 HCV 1. Cheng G, et al. EASL 2012, Abstract Krishnan P, et al. Antimicrob Agents Chemother 2015;59: Yang G, et al. EASL Abstract NG T, et al. CROI 2014, Abstract 639 Copyright 2015 American College of Gastroenterology 11

12 Persistence of Treatment- Emergent NS5a RAVs Study of patients not achieving SVR after therapy with LDV without SOF NS5a RAVs persisted in majority of patients for 96 weeks Dvory-Sobol H, et al. EASL Abstract O059 Re-treatment of Sofosbuvir/Ledipasvir Failures Failed 8-12 weeks, re-treated with 24 weeks of ledipasvir + sofosbuvir 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 100% No NS5a RAV's SVR-12 60% 11/11 18/30 NS5a RAV's Present Lawitz E, et al. J Hepatol 2015;62:S192, Abstract O005 Copyright 2015 American College of Gastroenterology 12

13 Re-Treatment of LDV/SOF Failures Effect of Baseline RAVs NS5b variants (S282T) emerged during retreatment in 4/12 patients with virologic failure Lawitz E, et al. EASL 2015, Abstract O005 Re-Treatment of NS5a Containing Regimen Failures Data is very limited Persistence of NS5a resistant polymorphism is likely Particularly if prior treatment was >12 weeks Co-existence of NS3 resistant polymorphisms affects choice of therapy Pre-treatment resistance testing important Copyright 2015 American College of Gastroenterology 13

14 Treatment of Genotype 1 NS5a-Experienced Patients AASLD/IDSA Guidance If mild liver disease Defer treatment until data available Cirrhosis or need for urgent therapy Test for NS3 and NS5a resistance-associated variants (RAVs) RAV Testing Result Retreatment Regimen Duration No NS5a RAVs Ledipasvir/sofosbuvir + ribavirin 24 weeks NS5a but no NS3 RAVs Simeprevir + sofosbuvir + ribavirin 24 weeks NS5a and NS3 RAVs Refer to clinical trial Testing for Resistance is Commercially Available Resistance Panel Quest LabCorp NS NS5a NS5b Currently, testing is only available for genotype 1 Controversies How accurate are these tests? How many mutations are too many? Which mutations do we need to pay attention to? Copyright 2015 American College of Gastroenterology 14

15 Paritaprevir/Ombitasvir/Dasabuvir Failures Few data available Patients who have failed often have resistance to NS3 NS5a NS5b Defer therapy if mild liver disease Test for resistance if therapy needed now Design a sofosbuvir-based regimen Take Home Points 1. Fortunately, the majority of treated patients are cured! 2. Get it right the first time! 3. For the second time around Treatment is easy if failed a 1 st generation PI Options are good if failed sofosbuvir + ribavirin Use pre-treatment RAVs testing for failures to NS5a Non-nucleoside NS5b 4. Refer to the HCV guidance document for latest updates Copyright 2015 American College of Gastroenterology 15