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) HBsAg (-), Anti-HBc Antibodies (-)HIV (-)

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

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

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

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

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

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

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

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

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

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

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

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: Moucari R et al. Gut 2009;58:

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

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:

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

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:

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

Definitions of Virological Response HCV RNA decrease (IU/mL) EOTR SVR 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 RVR=rapid virological response; cEVR=complete early virological response; pEVR=partial early virological response

SVR in patients achieving RVR 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)

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

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

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

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)

IL28B Polymorphism & SVR: Impact of Geographical Origin SVR(%) De Nicola S et al. Hepatology (in press) EgyptianItalian

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

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

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

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

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

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

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

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 Benhamou Y et al. J Hepatol 2009;50(S1):S6

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

NS5A Inhibitor – BMS BMS is a potent inhibitor of HCV RNA replication BMS generated robust and rapid viral load declines in subjects with HCV-1 BMS 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 selected resistance in the hybrid replicons. Wang C et al. Antimicrob Agents Chemother (in press)

Cyclophilin Inhibitor Alisporivir Flisiak R et al. Hepatology 2009;49:

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

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

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