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How to Optimize Treatment of Genotype 4 Patients

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

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How to Optimize Treatment of Genotype 4 Patients

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  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. Case History • Geographical Origin: Lebanon • Blood Transfusion 1988 • Alcohol Consumption: 40g/day • Weight: 84 kg Height: 173 cm • BMI: 28 kg/m2 • Waist Circumference: 98 cm

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

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

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

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

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

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

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

  11. 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

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

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

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

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

  16. 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

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

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

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

  20. Definitions of Virological Response RVR=undetectable HCV RNA at week 4 cEVR=no RVR but undetectable HCV RNA at week 12 pEVR=no RVR and detectable HCV RNA, but >2 log10 drop at week 12 HCV RNA decrease (IU/mL) 0 >2 log10 SVR EOTR Undetectable HCV RNA (<50 IU/mL) 24 48 72 4 12 0 Weeks of therapy RVR=rapid virological response; cEVR=complete early virological response; pEVR=partial early virological response

  21. SVR in patients achieving RVR Peginterferon alfa-2a 180 μg/wk plus RBV 1383 patients (G 1/4 48 weeks; G 2/3 24 weeks) RVR 100 100 88 86 86 80 60 SVR (%) 40 20 0 GT1 GT2 GT3 GT4 Fried MW et al. J Hepatol 2011;55:69-75

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

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

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

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

  26. IL28B Polymorphism & SVR: Impact of Geographical Origin Egyptian Italian 89 80 47 SVR(%) 28 29 14 De Nicola S et al. Hepatology (in press)

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

  28. Case History • Weight Loss & Physical Activity • Reduce Alcohol Consumption • Six Months Later: • Alcohol Intake: 20 g/day • Weight 78 kg, BMI 26 kg/m2 • Waist circumference 88 cm • Glucose: 4.8 mmol/L • Insulin: 12 µU/mL HOMA-IR= 2.5

  29. Case History • 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

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

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

  32. 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

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

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

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

  36. 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)

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

  38. 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

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

  40. 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

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