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How to Optimize Treatment of Genotype 4 Patients

This article discusses the factors that influence the treatment response in genotype 4 patients with hepatitis C. It explores the impact of geographical origin, insulin resistance, viral factors, and IL28B polymorphism on treatment outcomes. The goal is to maximize success in the treatment of genotype 4 patients.

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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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