Massimo Puoti Dept. of Infectious Diseases AO Ospedale Niguarda Cà Granda
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1 Massimo Puoti Dept. of Infectious Diseases AO Ospedale Niguarda Cà Granda Innovative strategies in viral hepatitis : Hepatitis C: Interferon and/or Ribavirin free regimens 10th International Workshop on HIV & Hepatitis Co-infection, June 2014 Paris, France.
2 Innovative strategies in viral hepatitis : Hepatitis C: Interferon and/or Ribavirin free regimens Directly Acting Antivirals nomenclature Rationale for IFN free Regimens Strategies Sofosbuvir based regimens Multi-target sofosbuvir free regimens
3 Innovative strategies in viral hepatitis : Hepatitis C: Interferon and/or Ribavirin free regimens Directly Acting Antivirals nomenclature Rationale for IFN free Regimens Strategies Sofosbuvir based regimens Multi-target sofosbuvir free regimens
4 HCV targets for therapy entry inhibitors mabs anti-e2/cd81, PRO 206 Ezetimibe mirna ISIS (antisense) AVI (antisense) Heptazyme (ribozyme) VGX-410C (small molecules IRES inhibitor) TT 033 (sirna) eif2α phosphorilation inhibitors: Nitazoxanide Protease inhibitors Trasltion Receptors binding And endocytosis (+) RNA Translation and processing of polyprotein NS2 NS3 Drugs active on viral enzymes protease Drugs active on host cell enzymes Fusion and decapsidation NS3 protease Transport and release Virion assembly RNA replication C E1 E2 p7 NS2 NS3 4A NS4B NS5A NS5B Core Membrane Serine protease RNA-dipendent RNA domain polymerase Inhibitors of viral assembly and relaese : Celgosivir NS5A I Replication inhibitors: NS5B NNI, NI NS5A I Ciclophyllin B 1. Lindenbach BD & Rice CM. Unravelling hepatitis C virus replication from genome to function. Nature 2005;Moradpour D and Penin F. Curr Top Microbiol Immunol
5 Protease Inhibitors (-PREVIR)
6 HCV Polymerase Inhibitors (-BUVIR) Nucleos(t)ide inhibitors (NI) - Mericitabine - Sofosbuvir Non-nucleoside inhibitors (NNI) = allosteric inhibitors A Thumb I e.g. deleobuvir B Thumb II e.g. lomibuvir, filibuvir C Palm I e.g.dasabuvir setrobuvir D E Palm II e.g. nesbuvir, tegobuvir Bartenschlager R et al. Nat Rev Microbiol 2013;11: See also Scheel TK and Rice CM. Nat Med 2013;19:
7 HCV Nonstructural Protein 5A Bartenschlager R et al. Nat Rev Microbiol 2013;11:
8 HCV NS5A Inhibitors (-ASVIR) Prototype: daclatasvir Other examples: Ombitasvir, ACH2928, ACH3102, AZD7295, BMS824393, GS5816, GSK , ledipasvir, MK8742, PPI668, samatasvir Gao M et al. Nature 2010;465: Reviewed in Bartenschlager R et al. Nat Rev Microbiol 2013;11: , Pawlotsky JM. J Hepatol 2013;59: , and Gao M. Curr Opin Virol 2013;3:1-7.
9 HCV: Probability of the presence of viral variants Hepatitis C virus: Error rate during replication: Viral turnover: Number of nucleotide change Probability of generation after one round of replication Number of virions with nucleotide change(s) produced per day 0 91% 9.1 x ~9600 nucleotides ~ per copied nucleotide ~10 12 virions produced every day Number of all possible nucleotide mutants Fraction of all possible mutants created per day 1 8.7% 8.7 x x % 4.2 x x % 1.3 x x x HCV genome ~ 9600 nucleotides; the average number of changes per genome is per replication cycle - Before treatment, a new virion has a probability of 91% to carry an unmutated genome and 8.7% to carry one substitution Not all variants survive - Dead mutations (variants that can not replicate) - Immune sensitive mutations (variants eliminated by the immune system) Rong L, et al, Sci Transl Med 2010;2:30ra32; Neumann AU, et al. Science 1998;282:103 7 Domingo E, et al. Viral Hepatitis Rev 1996;2:247 61; Cuevas JM, et al. J Virol 2009;83:5760 4
10 Emergence of Pre-existing Resistant Variants During Treatment with DAA Baseline HCV RNA Drug Potency Viral breakthrough HCV RNA Intracellular drug concentrations IC50 of mutant viruses N of Mutations needed to reduce IC50 Fitness of mutant viruses X X X X X X X X X Resistance Barrier Before Treatment Time on Treatment with DAA Alone Resistant virus Sensitive virus
11 DAA Classes and Subclasses Drug Class Subclass Potency Resistance Barrier Protease inhinbitors (-PREVIR) NS5a Inhibitor (-ASVIR) 1 st Generation first wave i.e. Telaprevir/Boceprevir 1 st Generation 2 nd wave i.e. Faldaprevir/Simeprevir/Asunapre vir ABT450/r 2 nd Generation MK5172 ABT st Generation Daclatasvir, Ledipasvi,r Ombitasvir Medium- Low Medium High High Low Low High except HCVG3 Medium- High except HCV G3 & 1a NN Polymerase Inhibitors Nucleos/tides Polymerase inhibitors (-BUVIR) 2 nd Generation MK 8742 GS 5816 ABT530 Dasabuvir GS 9669 Deleobuvir BMS High Low- Medium High Low 1st Generation: Mericitabine Low High 2 nd Generation : Sofosbuvir High Lower in HCV G1b High
12 CONSEQUENCES OF HCV VARIABILITY AT POPULATION LEVEL: HCV GENOTYPES
13 HCV protein variability 47% amino acid of HCV PROTEASE NS3 are conserved among All HCVgenotypes Amino acid variability: 0% <1% 1-5% 5-10% 10-25% >25% 46.1% amino acid of HCV NS5A are conserved among All HCV-genotypes 54.8% amino acid of HCV POLYMERASE NS5B are conserved among All HCVgenotypes Amino acid variability: 0% <1% 1-5% 5-10% 10-25% >25% Cento et al., PLoS ONE 2012 Love et al., J Vir 2009 Di Maio et al., submitted 2013
14 DAA Classes and Subclasses: antiviral potency and resistance barrier according to HCV genotype Drug Class Subclass 1 b 1a st Generation first wave i.e. Telaprevir/Boceprevir Protease inhinbitors (-PREVIR) NS5a Inhibitor (-ASVIR) 1 st Generation 2 nd wave i.e. Faldaprevir/Simeprevir 2nd Generation MK5172 ABT st Generation Daclatasvir Ledipasvir Ombitasvir 2 nd Generation MK 8742 GS 5816 ABT 530 NN Polymerase Inhibitors (-BUVIR) Nucleos/tides Polymerase inhibitors (-BUVIR) Dasabuvir Deleobuvir 2 nd Generation : Sofosbuvir 14 High Moderate Low Very low
15 Innovative strategies in viral hepatitis : Hepatitis C: Interferon and/or Ribavirin free regimens Directly Acting Antivirals nomenclature Rationale for IFN free Regimens Strategies Sofosbuvir based regimens Multi-target sofosbuvir free regimens
16 Combo with PEGIFN + RBV of Telaprevir, Boceprevir, Simeprevir, Faldaprevir 1 Potent IFNα-ribavirin effect Median HCV RNA change from baseline (log 10 IU/mL) Wild-type, sensitive HCV DAA Monotherapy Triple Combo Resistant HCV -5 Time on treatment
17 Combo with PEGIFN + RBV + non anchor drugs i.e. Telaprevir, Boceprevir, Simeprevir, Faldaprevir Weak IFNα-ribavirin effect 1 Median HCV RNA change from baseline (log 10 IU/mL) Wild-type, sensitive HCV Predictive role of RVR and Response Guided Therapy DAA Monotherapy Triple Combo Resistant HCV -5 Time on treatment
18 Combo with PEGIFN & RBV + anchor drug (Sofosbuvir) 1 Any IFNα-ribavirin effect Median HCV RNA change from baseline (log 10 IU/mL) Wild-type, sensitive HCV No Predictive role of RVR No Response guided therapy Anchor drug monother Triple Combo Resistant HCV -5 Time on treatment
19 Attain study: Telaprevir vs Simeprevir with PEGIFN + R in non responders to PEGIFN + Ribavirin Reddy KR et al APASL 2014
20 Retreatment of HCV Genotype-1 Infected Patients Who Failed Prior Therapy with Peg-interferon + Ribavirin Plus 1 or 2 Other Direct- Acting Antiviral Agents with Sofosbuvir Pol S et al EASL 2014
21 Contraindications to Pegylated Interferon and Ribavirin
22 Side effects: IFN free vs IFN containing Sofosbuvir For Treatment of Chronic Hepatitis C Infection Antiviral Drugs Advisory Committee Meeting Briefing Document 25 October 2013
23 Innovative strategies in viral hepatitis : Hepatitis C: Interferon and/or Ribavirin free regimens Key messages PEGIFN based therapies: Weak PEGIFN activity Lack of efficacy Insufficient results in cirrhosis and PEGIFN experienced Contraindications restriction of access to treatment Side effects low patients motivations, tolerability and adherence
24 Innovative strategies in viral hepatitis : Hepatitis C: Interferon and/or Ribavirin free regimens Directly Acting Antivirals nomenclature Rationale for IFN free Regimens Strategies Sofosbuvir based regimens Multi-target sofosbuvir free regimens
25 Genetic barrier to resistance can be sufficient with one anchor drug + Ribavirin according to genotype sensitivity to anchor drug Baseline Sofosbuvir + Ribavirin Anchor drug Sensitive virus Resistant virus
26 Sofobuvir + Ribavirin in HCV G Gane D et al. AASLD 2011 Jacobson IM et al. NEJM 2013 Zeuzem et al. The Liver Congress 2013 abstr Ruane PJ, et al. AASLD 2013 #1090
27 Sofosbuvir + Ribavirin in HCV G Sovaldi SPC
28 Cosmos Study Sofosbuvir + Simeprevir + RBV for w: ITT SVR 12 All 12 W 12 W + R w w +R F3-F4 naives F3-F4 Exp F3-F4 all F0-F2 exp Sulkowsky MS et al EASL 2014; Lawitz E et al EASL 2014
29 AI study Daclatasvir + Sofosbuvir + RBV: SVR 12 primary endpoint (mitt) for treatment-naive patients HCV G1 a HCV G2 HCV G3 GT1 GT2 GT3 a HCV RNA <LLOQ Patients, % HCV RNA <LLOQ Patients, % A LI b SOF, DCV + SOF C DCV + SOF E DCV + SOF + RBV G DCV + SOF H DCV + SOF + RBV DCV + SOF ± RBV DCV + SOF ± RBV 24 weeks 12 weeks 24 weeks SVR 12 rates were 98% in GT1a and 100% in GT1b SVR 24 rates ranged from % in GT1, and % in GT2/3 c a LI, One lead patient in; LLOQ had missing = lower data limit at of post quantitation treatment (25 week IU/mL), 12 but mitt, achieved modified SVR24, intent and to one treat who was lost to follow-up after achieving SVR4 b LI (lead in) with SOF was not included in subsequent trials c 93% and 88% were the percentage for the lead in arm. Sulkowski et al. N Engl J Med 2014;370:
30 AI study: SVR 12 primary endpoint (mitt) for GT1 patients who have experienced PI failure a HCV RNA <LLOQ Patients, % I DCV + SOF J DCV + SOF + RBV 24 weeks End of treatment (EOT) responses were 100%, with or without RBV a One patient with missing data at post treatment week 12, who achieved SVR 24 Sulkowski et al. N Engl J Med 2014;370:
31 The ION studies: LDV + SOF ± RBV in HCV GT 1 ION-1 1 Naive ION-2 2 EXP ION-3 3 No cirrhosis Patients achieving SVR (%) / / / / 102/ / wk 24-wk 12-wk 24-wk 8-wk 12-wk LDV + SOF achieved high SVR12 rates with or without RBV SVR12 rates were similar if patients were categorised by GT (GT 1a: %, GT 1b: %) or by cirrhosis (cirrhotic: %, non-cirrhotic: %) 108/ / 202/ / / 216 RBV-free With RBV 1. Afdhal N, et al. N Engl J Med 2014;ePub ahead of print; 2. Afdhal N, et al. N Engl J Med 2014;ePub ahead of print; 3. Kowdley KV, et al. N Engl J Med 2014;ePub ahead of print. LDV, ledipasvir
32 Ledipasvir and Sofosbuvir for Untreated HCV Genotype 1 Infection: Treatment Discontinuations, Adverse Events, and Hematologic Abnormalities. Afdahl A et al. NEJM 2014
33 SOF/LDV in patients who failed Sofosbuvir + Ribavirin SOF/RBV (SPARE Study) 17 relapsers Hypothesis: combining SOF with a second DAA may effectively suppress HCV replication and improve odds of achieving SVR Wk 0 Wk week follow up SOF/LDV (400/90mg) n = 14 SVR 12 NIAID SYNERGY STUDY 3 participants did not participate -1 developed hepatocellular cancer -1 opted for telaprevir triple therapy -1 declined participation Osinusi A et al. EASL 2014
34 Treatment Response On SOF/LDV of SOF/RBV failures n / N 14/14 14/14 14/14 14/14 14/14 14/14 Osinusi A et al. EASL 2014
35 Sofosbuvir + Ledipasvir +.. reducing treatment duration adding more drugs Kohli A et al CROI 2014
36 Sofo + GS5816 (2 nd gen NS5AI) FDC: one pill fits all? Everson GT et al EASL 2014
37 Innovative strategies in viral hepatitis : Hepatitis C: Interferon and/or Ribavirin free regimens Sofosbuvir based IFN free regimens: Sofosbuvir + Ribavirin Effective in HCV G w in HCV G2 24 week in HCV G3 & 4 Execption HCV G3 experienced cirrhotics Low efficacy in HCV G1 somewhat more is needed Sofosbuvir + PI/NS5a Universal efficacy wity Simeprevir in a small Phase II study in HCV G1 Optimal duration? Is ribavirin needed? Universal efficacy with Daclatasvi in HCV G1, 2, 3 Optimal Duration? Is Ribavirin needed? Sofosbuvir + Ledipasvir Large Phase IIII study: 12 w in cirrhotics 8 weeks in non cirrhotics No difference between naives and experienced Ribavirin is not needed les side effects Effective in Sofosbuvir experienced 12 weeks Ribavirin free schedule is insufficient in CTP B cirrhosis + PI/NNPOLi treatment for only 6 weeks Sofosbuvir + GS5816 one pill for all
38 Innovative strategies in viral hepatitis : Hepatitis C: Interferon and/or Ribavirin free regimens Directly Acting Antivirals nomenclature Rationale for IFN free Regimens Strategies Sofosbuvir based regimens Multi-target sofosbuvir free regimens
39 Genetic barrier to resistance can be increased in HCV G1 by combination drug regimens No relationship with IFN sensitivity no IFN related side effects Sensitive virus Resistant virus Baseline NN-NS5B in + NS5A + PI + RBV Anchor drug Sofosbuvir + NS5A / PI + RBV
40 SAPPHIRE-I: GT1, treatment-naive, non-cirrhotic patients Treated with 3D + RBV for 12 w SVR12 rates by HCV GT1 subtype Treatment-naive, non-cirrhotic SVR12 (%) n N GT1a patient experienced virologic failure; 7 patients relapsed; Error bars: 95% CI. Feld JJ, et al. New Engl J Med 2014; 370:
41 PEARL-III: GT1b, treatment-naive, non-cirrhotic patients treated with 3D + RBV SVR12 rates Treatment-naive, non-cirrhotic SVR12 (%) n N * 1 patient with virologic rebound emergence of NS5A Y93H; 2 patients were lost to follow-up, but subsequently achieved an SVR24; Error bars: 95% CI. Ferenci P, et al. EASL Abstract 1299 [late breaker poster].
42 SAPPHIRE-II: GT1, treatment-experienced, non-cirrhotic patients treated with 3D + RBV SVR12 rates by HCV GT1 subtype and by prior P/R response SVR12 (%) SVR12 (%) n N n N One patient achieved SVR12, but was unable to be subgenotyped; Error bars: 95% CI. Zeuzem S, et al. New Engl J Med 2014; 370:
43 PEARL-II: HCV GT1b, treatment-experienced, noncirrhotic patients SVR12 rates GT1b Treatment-experienced, non-cirrhotic SVR12 (%) n N AbbVie press release 2014 [Accessed ].
44 ABT450/r + Ombitasvir + RBV in HCV G4 Hezode C et al. EASL 2014
45 Safety of Ribavirin free treatment
46 DCV + ASV+ BMS Everson GT et al CROI 2014
47 DCV + ASV+ BMS Everson GT et al CROI 2014
48 Sensitive virus Resistant virus Genetic barrier to resistance can be increased in HCV G1 by combination drug regimens according to HCV subtype 2nd gen NS5A + 2nd gen PI HCV G1a Baseline HCV G1b Anchor drug
49 2nd generation PI + 2nd Generation NS5A I Phase II studies with MK MK 8742
50 Innovative strategies in viral hepatitis : Hepatitis C: Interferon and/or Ribavirin free regimens Key messages 3D Combos 3 D Abbvie 12 weeks in non cirrhotics with Ribavirin in HCV G1a, maybe 24 weeks in cirrhotics 2D Abbvie 12 w w/o Ribavirin in HCVG4 non cirrhotics BMS promising results from phase II study 2 Generation PI + 2 Generation NS5aI Impressibve results from phase II study in HCV G1 even in difficult to treat patients Potential one pilll for all schedule
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