Hepatitis C in Primary Care: - the way forward Dr Iain Brew GPSI Hepatitis C HMP Leeds
Hepatitis C in Primary Care: - the way forward I have received speaker and consultancy fees from:- • AbVie and Janssen
Twist or Stick? • Todays drugs • What is emerging • How do we get people onto therapy?
Twist or Stick? • Todays drugs • What is emerging • How do we get people onto therapy?
A bit of history…
Genotype 1 – Good Drugs on the market PegIFN / Ribavirin and Protease inhibitors 72 – 75* PR48 T12PR 158/361 659/903 n/N = Sherman KE, et al. Hepatology 2010;52(Suppl.):401A *p<0.001 vs PR48 in ADVANCE (75% versus 44%) Jacobson IM, et al. N Engl J Med 2011;364:2405-16; Sherman KE, et al. CROI 2011. Abstract 957
Telaprevir SVR rates by fibrosis stage in treatment-naïve patients F0 – F1 F2 F3 F4 SVR (%) PR48 T12PR PR48 T12PR PR48 T12PR PR48 T12PR n/N= 67/147 109/134 67/141 117/156 17/52 32/52 7/21 13/21 SVR, considered virologic cure, was defined as HCV RNA undetectable 24 weeks after Marcellin P, et al. J Hepatol 2011;54(Suppl 1):S183 last planned dose
Telaprevir SVR rates by fibrosis stage in treatment-naïve patients F0 – F1 F2 F3 F4 SVR (%) PR48 T12PR PR48 T12PR PR48 T12PR PR48 T12PR n/N= 67/147 109/134 67/141 117/156 17/52 32/52 7/21 13/21 SVR, considered virologic cure, was defined as HCV RNA undetectable 24 weeks after Marcellin P, et al. J Hepatol 2011;54(Suppl 1):S183 last planned dose
OPTIMIZE: telaprevir bid was non- inferior to q8h in terms of SVR Difference 1.5% (95% CI: – 4.9%, 12.0%) SVR12 (%) 274/369 270/371 T12(bid)/PR T12(q8h)/PR ITT analysis CI: confidence interval Buti M, et al. AASLD 2012:LB-8
SPRINT-2: SVR rates with boceprevir-based therapy versus PR alone * * PR48 BOC RGT BOC44/PR48 137/363 233/368 242/366 n/N = *p<0.001 for both boceprevir arms versus PR48 Adapted from Poordad F, et al. N Engl J Med 2011;364:1195 – 206
Boceprevir Response is Predictable At 4 weeks:- • < 1 log decline – low probability of response • > 1 log decline – high probability of response
Current Drugs - Problems • SIDE EFFECTS • Anaemia, skin rashes, odd tastes • Long duration of therapy
CUPIC Week 60 analysis: safety overview TVR CUPIC BOC CUPIC Outcomes, % N=299 N=212 Serious adverse event 53.8 44.3 Premature discontinuations 23.8 17.5 due to serious adverse events Death, n (%) 8 (2.7) 3 (1.4) Infections (grade 3/4) 9.7 2.4 Hepatic decompensation 4.7 4.2 EPO use 56.5 56.1 Transfusion 17.7 11.8 RBV dose reduction 27.8 23.6 Hézode C, et al. Unpublished data Updated 26 September 2013
Adverse events in cirrhotic patients with Peg and Riba 26 centres in Spain; 568 treatment-naïve patients with cirrhosis Treated with PR All patients Adverse event, n (%) (N=508) 59 (11.6) Ascites / encephalopathy / CPT 2 Variceal hemorrhage 19 (3.74) Development of HCC 31 (6.1) Any adverse event 89 (17.5) Liver-related mortality 29 (5.7) IFN safety in advanced liver disease is poor Fernández-Rodríguez CM, et al. Am J Gastroenterol 2010;105:2164 – 2172 CPT: carnitine palmitoyltransferase; IFN: interferon
Current Drugs - not perfect For G1 – reasonable efficacy, high side effects For G2/3 – good efficacy, moderate side effects In cirrhosis efficacy falls, side effects rise So DO NOT LET YOUR PATIENT GET CIRRHOSIS
Twist or Stick? • Todays drugs • What is emerging • How do we get people onto therapy?
Specific targets for HCV treatment: protease, polymerase and NS5A inhibition NS5A C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B Protease Polymerase Kwong A, et al. Drug Discovery Today: Therapeutic Strategies 2006;3:211 – 220 Schmitz U, Tan SL. Recent Pat Antiinfect Drug Discov 2008;3:77 – 92
New Protease Inhibitors Simeprevir Faldaprevir
New Protease Inhibitors (With Peg + Riba) Eligible for RGT Eligible for RGT Eligible for RGT Eligible for RGT Overall SVR Overall SVR Overall SVR Overall SVR 87 79 – 86 81 – 86 84 79 63 – 66 Patients (%) 58 44 Boceprevir Telaprevir Faldaprevir Simeprevir 750 mg TID 1 800 mg TID 2,3 240 mg QD 4 150 mg QD 5 Duration of RGT (wk) 24 28 24 24 Results are for separate trials for each compound, not head-to-head studies, in treatment-naïve patients also receiving PegIFN/RBV Hatched regions indicate ranges of results 1. Incivo EU SmPC 2011; 2. Victrelis EU SmPC 2011; 3. Poordad F, et al. N Engl J Med 2011;364:1195 – 1206; QD, once daily; RGT, response-guided therapy; SVR, sustained virological response; 4. Sulkowski MS, et al. Manuscript in preparation; TID, three times daily 5. Fried M, et al. AASLD 2011. Abstract LB-5
New Protease Inhibitors (With Peg + Riba) Eligible for RGT Eligible for RGT Eligible for RGT Eligible for RGT Overall SVR Overall SVR Overall SVR Overall SVR 87 79 – 86 81 – 86 84 79 63 – 66 Patients (%) 58 44 Boceprevir Telaprevir Faldaprevir Simeprevir 750 mg TID 1 800 mg TID 2,3 240 mg QD 4 150 mg QD 5 Duration of RGT (wk) 24 28 24 24 Results are for separate trials for each compound, not head-to-head studies, in treatment-naïve patients also receiving PegIFN/RBV Hatched regions indicate ranges of results 1. Incivo EU SmPC 2011; 2. Victrelis EU SmPC 2011; 3. Poordad F, et al. N Engl J Med 2011;364:1195 – 1206; QD, once daily; RGT, response-guided therapy; SVR, sustained virological response; 4. Sulkowski MS, et al. Manuscript in preparation; TID, three times daily 5. Fried M, et al. AASLD 2011. Abstract LB-5
New Protease Inhibitors (With Peg + Riba) Eligible for RGT Eligible for RGT Eligible for RGT Eligible for RGT Overall SVR Overall SVR Overall SVR Overall SVR 87 79 – 86 81 – 86 84 79 63 – 66 Patients (%) 58 44 Boceprevir Telaprevir Faldaprevir Simeprevir 750 mg TID 1 800 mg TID 2,3 240 mg QD 4 150 mg QD 5 Duration of RGT (wk) 24 28 24 24 Results are for separate trials for each compound, not head-to-head studies, in treatment-naïve patients also receiving PegIFN/RBV Hatched regions indicate ranges of results 1. Incivo EU SmPC 2011; 2. Victrelis EU SmPC 2011; 3. Poordad F, et al. N Engl J Med 2011;364:1195 – 1206; QD, once daily; RGT, response-guided therapy; SVR, sustained virological response; 4. Sulkowski MS, et al. Manuscript in preparation; TID, three times daily 5. Fried M, et al. AASLD 2011. Abstract LB-5
New Protease Inhibitors (With Peg + Riba) • Once a day regimes • Far fewer drug:drug interactions • ‘User friendly’ – less anaemia, less side effects
New protease inhibitors Restricted to the US viral strains Early data in HIV encouraging Fewer DDIs (Not as good as they pretend they are)
NS5A Inhibitors Daclatasvir Ledipasvir
Daclatasvir + PR DCV arms SVR RGT criterion % of patients SVR: 75-87% 105 105 32/ 27/ 21/ 63/ 66/ 147 146 5/16 41 31 56 106 113 PDR <LLOQ Wk4 + <LOD Wk 12 G1a G1b PR48 DCV 20/PR DCV 60/PR PDR: protocol defined response Hézode et al, AASLD 2012 (SVR 12 analysis), abstract 755; TVR EU SmPC
NS5A Inhibitors Quirky Large variation in efficacy Good to work with
NS5B – Non Nucleotides R 7128 (Roche) MK 0608 (Merck) VCH 759 (ViroChem) GSK 625433 (GSK) HCV 796 (Wyeth) …and others Very unpredictable Generally G1 specific
Nucleotides Sofosbuvir
Sofosbuvir with PEG-IFN + RBV • NEUTRINO Phase III trial – Sofosbuvir plus PEG-IFN + RBV* for 12 weeks – Treatment naïve, GT1 (89%), 4, 5 or 6 (N=327) • 17% had compensated cirrhosis – Primary endpoint: SVR12 99 99 100 91 90 Patients achieving SVR (%) 80 60 40 20 0 Week 2 Week 4 Last† SVR12 *Dose administered according to body weight † Last observed measurement Lawitz et al. N Eng J Med 2013;368:1878 – 87
Sofosbuvir with PEG-IFN + RBV NEUTRINO Phase III trial • Genotype 1a SVR = 92% • Genotype 1b SVR = 82% • Peg/Riba/Telap • Genotype 1b = 79% *Dose administered according to body weight † Last observed measurement Lawitz et al. N Eng J Med 2013;368:1878 – 87
Nucleotides Fast Effective Cures all strains Side effect free (Too good to be true?)
Interferon Regimes 6-12 months • PI + Peg Riba • + Old PI (dirty, but cheap) • + New PI (clean, but expensive, ‘quirky’) 3 months • Sofosbuvir - + Peg Riba (expensive)
What about interferon free? Interferon is horrid… …so …can we go to interferon free?
Playing Tag (I) BI + + BMS Protease Inhibitor + Non – Nuc/NS5A
Co-Pilot: Virologic Outcomes • SVR12 in 94% of treatment-naive and 47% of treatment-experienced pts – Responses independent of IL28B genotype RVR 100 eRVR 95 95 93 93 90 90 SVR4 79 79 80 77 SVR12 Patients (%) 59 60 47 47 40 20 0 ABT-450/r 250/100 mg QD ABT-450/r 150/100 mg QD ABT-450/r 150/100 mg QD + ABT-333 + RBV + ABT-333 + RBV + ABT-333 + RBV Treatment naive Treatment naive Nonresponders (n = 19) (n = 14) (n = 17) Poordad F, et al. EASL 2012. Abstract 1399.
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