1. How to Optimize Treatment of Genotype 4 Patients Rami MOUCARI MD, PhD Bellevue Medical Center – Saint Joseph University, Beirut, Lebanon

2. Case History A 40 years old man Hepatitis C Genotype 4 ALT 110 IU/L (N < 45 IU/L) AST 90 IU/L (N<35 IU/L) HBsAg (-), Anti-HBc Antibodies (-)HIV (-)

3. Geographical Origin: Lebanon Blood Transfusion 1988 Alcohol Consumption: 40g/day Weight: 84 kgHeight: 173 cm BMI: 28 kg/m 2 Waist Circumference: 98 cm Case History

4. Glucose: 5.6 mmol/L Insulin: 18 µU/mL IL28B Genotype ? Case History HOMA-IR= 4.4

5. HCV-4 Subtype: 4d HCV RNA : 940 000 IU/mL Liver Biopsy: A2 F3 (METAVIR) Steatosis 50% Sinusoidal Fibrosis Case History

8. Hepatitis C, Genotype 4 Subtype (4d) High Viral Load (> 800 000 IU/L) Middle East Caucasian patient (IL28B?) IR Severe Fibrosis & NASH Case History – Summary

9. TREATMENT REGIMEN Peginterferon Ribavirin STAT-C HOST FACTORS Age, gender, race insulin resistance Genetic factors (IL28B) DISEASE FEATURES Fibrosis, Steatosis, Co-infection (HBV, HIV) VIRAL FACTORS Genotype, Subtype Viral load HCV Response Factors Factors Influencing Response Moucari R. Hot Topics in Viral Hepatitis 2010

10. Maximizing Success Nowadays Host Factors: –Geographical Origin –Insulin Resistance Response-Guided Therapy –Viral Kinetics –IL28B Polymorphism New Drugs

11. Maximizing Success Nowadays Host Factors: –Geographical Origin –Insulin Resistance Response-Guided Therapy –Viral Kinetics –IL28B Polymorphism New Drugs

12. Geographical Origin EgypatianEuropean African 54.9 63.4 40.3 51.5 32.4 39.1 SVR (%) Roulot D et al. J Viral Hepat 2007;14:460-7 Moucari R et al. Gut 2009;58:1662-9 242 HCV-4 Patients: Egyptian (29%), European (55%), African (15%) 108 HCV-4 Patients: Egyptian (48%), European (30%), African (21%)

13. Geographical Origin & HCV-4 Subtypes Roulot D et al. J Viral Hepat 2007;14:460-7 Moucari R et al. Gut 2009;58:1662-9

14. Geographical Origin & HCV-4 Subtypes SVR (%) 59.8 34.9 Roulot D et al. J Viral Hepat 2007;14:460-7 242 HCV-4 Patients: Egyptian (29%), European (55%), African (15%)

15. Geographical Origin & IL28B Polymorphism Asselah T et al J Hepatol (in press)

16. Insulin Resistance & Viral Load 226 HCV-4 Patients Insulin Resistance & HCV-4 HOMA-IR > 3 (%) 500 Patients: G1 (59%) G2/3 (22%) G4 (19%) Moucari et al. Gastroenterology 2008;134:416-23 Moucari R et al. Gut 2009;58:1662-9 36.8 17.1

17. IR & Fibrosis in Chronic Hepatitis C Moucari et al. Gastroenterology 2008;134:416-423 500 Patients: G1 (59%) G2/3 (22%) G4 (19%)

18. IR & NASH in Chronic Hepatitis C  278 Consecutive CHC Patients  CHC (57%), CHC + Steatosis (34%), CHC + NASH (9%)  CHC + NASH: Higher METAVIR Fibrosis Stage Bedossa, Moucari et al. Hepatology 2007;46:380-387

19. IR and SVR Moucari R et al. Gut 2009;58:1662-9 SVR (%) 72 36 108 HCV-4 Patients: Egyptian (48%), European (30%), African (21%)

20. Pioglitazone and SVR 97 Egyptian Patients HCV-4 HOMA-IR > 2 PEG-RBV +/- Pioglitazone 30 mg/d SVR (%) Khattab M et al. Liver Int. 2010;30:447-54 60.4 38.7

21. Maximizing Success Nowadays Host Factors: –Geographical Origin –Insulin Resistance Response-Guided Therapy –Viral Kinetics –IL28B Polymorphism New Drugs

22. Definitions of Virological Response HCV RNA decrease (IU/mL) EOTR SVR 72 4 48 Weeks of therapy 0 12 Undetectable HCV RNA (<50 IU/mL) 0 RVR=undetectable HCV RNA at week 4 cEVR=no RVR but undetectable HCV RNA at week 12 >2 log 10 pEVR=no RVR and detectable HCV RNA, but >2 log 10 drop at week 12 24 RVR=rapid virological response; cEVR=complete early virological response; pEVR=partial early virological response

23. SVR in patients achieving RVR 88 86 100 0 20 40 60 80 100 GT1 SVR (%) RVR GT2GT4GT3 Fried MW et al. J Hepatol 2011;55:69-75 Peginterferon alfa-2a 180 μg/wk plus RBV 1383 patients (G 1/4 48 weeks; G 2/3 24 weeks)

24. Short Treatment Duration in Rapid Respnders SVR(%) Lee SS et al. Aliment Pharmacol Ther 2012;35:37-47 84 74.2 73.3 48.8 39.5 Control (48 weeks) Individualized (24, 36 or 72 weeks) 236 Patients (G1, G4, G5 & G6)

25. SVR(%) Kamal SM et al. Hepatology 2007;46:1732-40 Short Treatment Duration in Rapid Respnders 378 Egyptian Patients – HCV-4

26. Extended Treatment Duration in Slow Responders 551 Patients: Genotype 1 (87%) – Genotype 4 (12%) RVR = 150 (27%) EVR= 289 (52%) 77 33.6 43.4 73.3 18.5 54.8 Ferenci P et al. Gastroenterology 2010;138:503-12

27. IL28B Polymorphism & SVR (1)112 patients: Egyptian 68% - Italian 32% (2)82 patients: Egyptian 51% - European 34% - African 13% SVR(%) (1) De Nicola S et al. Hepatology (in press) (2) Asselah T et al J Hepatol (in press) 87.5 81.8 40 46.5 21.4 29.4

28. IL28B Polymorphism & SVR: Impact of Geographical Origin SVR(%) De Nicola S et al. Hepatology (in press) 89 80 47 2829 14 EgyptianItalian

29. IL28B Polymorphism & SVR: Impact of RVR SVR(%) De Nicola S et al. Hepatology (in press) 100 70 75 23 CC CT/TT

30. Weight Loss & Physical Activity Reduce Alcohol Consumption Six Months Later: Alcohol Intake: 20 g/day Weight 78 kg, BMI 26 kg/m 2 Waist circumference 88 cm Glucose: 4.8 mmol/L Insulin: 12 µU/mL Case History HOMA-IR= 2.5

31. Peginterefron Alfa 2a 180 µ/week + Ribavirin 1200 mg/day Serum HCV RNA Week 4: 24 000 IU/L Week 12: <15 IU/L Week 24 < 15 IU/L Week 48 < 15 IU/L Case History

32. Maximizing Success Nowadays Host Factors: –Geographical Origin –Insulin Resistance Response-Guided Therapy –Viral Kinetics –IL28B Polymorphism New Drugs

33. STAT-C Poordad F & Khungar V. Am J Manag Care 2011;17(Suppl4):S123-30

34. Natural Variability of NS3 Protease in HCV-4 43 NS3 gene sequences were determined for 53 patients 70 HCV-4 sequences (27 HCV-4 reference sequences, European HCV) 87 HCV-1 GenBank NS3 sequences. Compared with HCV genotype 1, all HCV-4 NS3 protein presented V36L and C16T residue changes Akhavan S et al. JID 2009;200:524-7

35. NS3/4A Protease Inhibitor Danoprevir Imhof I & Simmonds P. Hepatology 2011;53:1090-99

36. NS3/4A Protease Inhibitor Telaprevir Phase IIa 24 Patients Genotype 4 TVR (750 mg/8h) or TVR + SOC or SOC 15 days Mean Max HCV RNA Decline 1.4 3.5 2.0 Benhamou Y et al. J Hepatol 2009;50(S1):S6

37. NS5B Polymerase Inhibitor Mericitabine Phase IIb 408 Patients G1 & G4 Triple therapy: –RG7128 (500 or 1000 mg) + SOC – 12 or 8 weeks 83 68 49 Jensen DM et al. Hepatology 2010;52(S1):360A cEVR (%)

38. NS5A Inhibitor – BMS790052 BMS-790052 is a potent inhibitor of HCV RNA replication BMS-790052 generated robust and rapid viral load declines in subjects with HCV-1 BMS-790052 inhibits hybrid replicons containing HCV genotype-4 NS5A genes with EC50s ranging from 7-13 pM. NS5A residue 30 was an important site for BMS- 790052-selected resistance in the hybrid replicons. Wang C et al. Antimicrob Agents Chemother (in press)

39. Cyclophilin Inhibitor Alisporivir Flisiak R et al. Hepatology 2009;49:1460-68

40. TLR-7 Agonist – ANA773 Phase Ib Study. 34 Patients. Genotypes: 1, 2, 3 & 4 Bergmann JF et al. Aliment Pharmacol Ther 2011;34:443-453

41. Nitazoxanide Phase II 96 Patients Egyptians Genotype 4 NTZ x 12w NTZ+PEG/RBV or NTZ + PEG 36w 88 73 63 SVR(%) Rossignol JF et al. Gastroenterology 2009;136:856-862

42. CONCLUSIONS HCV-4 is a heterogeneous genotype Host and Viral Factors play important role in response to SOC: Individualize Therapy STAT-C are promising but we need dedicated large trials in the future