1. How to optimize treatment of G4 patients?

2. 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 Treat? SOC response rate? Any possible treatment modification to improve response? Wait?

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

4. Peg-IFN = pegylated interferon alfa-2a 180 µg/wk; RBV = ribavirin 1,000 or 1,200 mg/day; NTX = nitazoxanide 500 mg bid 2404872 Weeks 126036 NTZ + Peg-IFN Follow-up NTX/IFN n=28 NTZ SVR Follow-up Control n=40 Peg-IFN + RBV SVR NTZ + Peg-IFN + RBV Follow-up NTZ SVR NTX/IFN/RBV n=28 Rossignol JF, et al. Gastroenterology. 2009 Mar;136(3):856-62. Epub 2008 Nov 19. Nitazoxanide in G-4 Improved virologic response in chronic hepatitis C G-4 treated with nitazoxanide, peginterferon, and ribavirin.

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

6. NTZ + Peg-IFN + RBV Follow-up NTZ SVR NTX/12 Wks n=50 NTX = nitazoxanide 500 mg bid 04872 Weeks -12 NTZ + Peg-IFN + RBV Follow-up NTX/4 Wks n=50 NTZ SVR Follow-up SOC n=25 Peg-IFN + RBV SVR -4 Nitazoxanide in G-4 NTX trial in National Liver Institute: G4 Naiive, NTX+PEG-IFN+RBV (4 vs 12 wk lead in) vs SOC

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

8. Nitazoxanide in G-4 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 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 MOH ongoing trial NTX 3 mths + SOC (100 pts) vs SOC (100 pts) EVR: NTX 76%, SOC 82% MOH ongoing trial NTX 3 mths + SOC (100 pts) vs SOC (100 pts) EVR: NTX 76%, SOC 82%

9. ■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. DAA for G4

10. 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 DAA for G4

11. 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 DAA for G4 Methods AASLD, 2011

12. DAA for G4 HCV RNA <LLQ and Detectable HCV RNA Undetectable Week 4 Percentage of Patients With Response 100 33 126n = Week 12 126n = Virologic Responses Through Week 12: AASLD, 2011

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

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?