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How to optimize treatment of G4 patients?

How to optimize treatment of G4 patients?. Treat? SOC response rate? Any possible treatment modification to improve response? Wait?. Case: 26 Y male, HCV positive on pre-employment Transfused at age 3 for hemolysis due to G6PD deficiency ALT normal, RNA 2,500,000 IU/ml

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How to optimize treatment of G4 patients?

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  1. How to optimize treatment of G4 patients?

  2. Treat? • SOC response rate? • Any possible treatment modification to improve response? • Wait? • Case: • 26 Y male, HCV positive on pre-employment • Transfused at age 3 for hemolysis due to G6PD deficiency • ALT normal, • RNA 2,500,000 IU/ml • Fibroscan 7KPa, • Bx A1F1, • IL-28 CT

  3. Nitazoxanide in G-4 • NTX is a broad spectrum antiviral drug (a thiazolides) • Inhibitor of hepatitis C virus in replicon studies • Use as a single agent decreased virema • NTX synergistic with IFN • Studies in patients with G 4 suggest that NTX can improve response Korba BE, et al. Antivir Res. 2008;77:56-63. Rossignol JF, et al. Aliment Pharmacol Ther 2008; 28, 574–580

  4. SVR Controln=40 NTZ NTZ NTZ + Peg-IFN + RBV Peg-IFN + RBV NTZ + Peg-IFN Follow-up SVR NTX/IFN n=28 Follow-up SVR NTX/IFN/RBV n=28 Follow-up Weeks 0 12 24 36 48 60 72 Nitazoxanide in G-4 Improved virologic response in chronic hepatitis C G-4 treated with nitazoxanide, peginterferon, and ribavirin. Peg-IFN = pegylated interferon alfa-2a 180 µg/wk; RBV = ribavirin 1,000 or 1,200 mg/day;NTX = nitazoxanide 500 mg bid Rossignol JF, et al. Gastroenterology. 2009 Mar;136(3):856-62. Epub 2008 Nov 19.

  5. Nitazoxanide in G-4 Rossignol JF, et al. Gastroenterology. 2009 Mar;136(3):856-62. Epub 2008 Nov 19.

  6. Nitazoxanide in G-4 NTX trial in National Liver Institute: G4 Naiive, NTX+PEG-IFN+RBV (4 vs 12 wk lead in) vs SOC SVR SOCn=25 SVR NTX/12 Wks n=50 Follow-up Peg-IFN + RBV NTZ + Peg-IFN + RBV NTZ Follow-up SVR NTX/4 Wks n=50 NTZ NTZ + Peg-IFN + RBV Follow-up Weeks -12 0 48 72 -4 NTX = nitazoxanide 500 mg bid

  7. Nitazoxanide in G-4 • NTX lead in had no effect on viral load

  8. Nitazoxanide in G-4 • MOH ongoing trial • NTX 3 mths + SOC (100 pts) vs SOC (100 pts) • EVR: NTX 76%, SOC 82% • NTX addition to PEG-RBV did not increase virological response • NTX does NOT appear to be the solution to increase response in patients with G4

  9. DAA for G4 • Boceprevir and telaprevir are not indicated for treatment of HCV G4 • Daclatasvir (BMS-790052) is a highly selective HCV NS5A replication complex inhibitor with broad genotypic coverage in vitro. • Daclatasvir (BMS-790052) combined with pegylated interferon-alfa-2a (peg-alfa) and ribavirin (RBV) showed high rates of SVR in a phase 2a study.

  10. DAA for G4 BMS-790052, A NS5A Replication Complex Inhibitor, Combined with Peginterferon-Alfa-2a and Ribavirin in Treatment-Naive HCV-Genotype 1 or 4 Subjects: Phase 2b AI444010 Study Interim Week 12 Results C Hézode, GM Hirschfield, W Ghesquiere, W Sievert, M Rodriguez-Torres, S Shafran, PJ Thuluvath, HA Tatum, I Waked, G Esmat, EJ Lawitz, VK Rustgi, S Pol, N Weis, P Pockros, M Bourlière, L Serfaty, JM Vierling, MW Fried, O Weiland, MR Brunetto, GT Everson, S Zeuzem, PY Kwo, M Sulkowski, PD Yin, U Diva, EA Hughes, M Wind-Rotolo, S Schnittman AASLD, 2011

  11. DAA for G4 Methods • Randomized, blinded, controlled, Phase 2b clinical trial • Patients • HCV genotype 1 (n=365) or 4 (n=30) infection • Treatment naïve, aged 18–70 years • METAVIR stage F0–F4 • Treatment • BMS-790052 (Daclatasvir) 20 mg or 60 mg or placebo once daily in combination with • Weekly peg-alfa and RBV twice daily AASLD, 2011

  12. DAA for G4 Virologic Responses Through Week 12: 100 HCV RNA <LLQ and Detectable HCV RNA Undetectable 33 Percentage of PatientsWith Response Week 12 Week 4 n = 12 6 n = 12 6 AASLD, 2011

  13. DAA for G4 Virologic Responses Through Week 48: (single center data, unpubished) Percentage of PatientsWith Response n = 9 4 n = 9 ETR 4 9 SVR 24 n = 2 ETR

  14. Daclatasvir effective in G4 • GS-7977 (formerly PSI-7977) effective in all genotypes (including some patients G4) • DAAs (specially NS-5 inhibitors) appear to be the future for optimizing treatment for G4 • Wait?

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