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 kg Height: 173 cm BMI: 28 kg/m2

• 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 : 940 000 IU/mL • Liver Biopsy:

• A2 F3 (METAVIR)• Steatosis 50%• Sinusoidal Fibrosis

Case History

• 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

TREATMENT REGIMEN

Peginterferon Ribavirin

STAT-C

HOST FACTORSAge, gender, race insulin resistance

Genetic factors (IL28B)

DISEASE FEATURESFibrosis, Steatosis,

Co-infection (HBV, HIV)

VIRAL FACTORSGenotype, Subtype

Viral load

HCVResponse 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 OriginEgypatian European African

54.9

63.4

40.3

51.5

32.439.1

SV

R (

%)

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%)

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 SubtypesS

VR

(%

)

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%)

Geographical Origin& IL28B Polymorphism

Asselah T et al J Hepatol (in press)

< 800 000 IU/mL > 800 000 IU/mL

Serum HCV RNA

0

2

4

6

8

10

HO

MA

-IR

p=0.001

Insulin Resistance & Viral Load

226 HCV-4 Patients

Insulin Resistance & HCV-4

HO

MA

-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

IR & Fibrosis in Chronic Hepatitis C

Moucari et al. Gastroenterology 2008;134:416-423

F0-F1 F2 F3 F4

FIBROSIS (METAVIR)

0

3

6

9

12

15

HO

MA

-IR

500 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;46:380-387

IR and SVR

Moucari R et al. Gut 2009;58:1662-9

SV

R (

%)

72

36

108 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

SV

R (

%)

Khattab M et al. Liver Int. 2010;30:447-54

60.4

38.7

Maximizing Success Nowadays

• Host Factors:– Geographical Origin– Insulin Resistance

• Response-Guided Therapy– Viral Kinetics– IL28B Polymorphism

• New Drugs

Definitions of Virological Response

HC

V R

NA

dec

reas

e (I

U/m

L)

EOTR SVR

724 48Weeks 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 log10

pEVR=no RVR and detectable HCV RNA,

but >2 log10 drop at week 12

24

RVR=rapid virological response; cEVR=complete early virological response; pEVR=partial early virological response

SVR in patients achieving RVR

88 86 86

100

0

20

40

60

80

100

GT1

SV

R (

%)

RVR

GT2 GT4GT3

Fried MW et al. J Hepatol 2011;55:69-75

Peginterferon alfa-2a 180 μg/wk plus RBV1383 patients (G 1/4 48 weeks; G 2/3 24 weeks)

Short Treatment Duration in Rapid Respnders

SV

R(%

)

Lee SS et al. Aliment Pharmacol Ther 2012;35:37-47

84 84

74.2 73.3

48.8

39.5

Control (48 weeks) Individualized (24, 36 or 72 weeks)

236 Patients (G1, G4, G5 & G6)

SV

R(%

)

Kamal SM et al. Hepatology 2007;46:1732-40

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%)

77

33.6

43.4

73.3

18.5

54.8

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%

SV

R(%

)

(1) De Nicola S et al. Hepatology (in press) (2) Asselah T et al J Hepatol (in press)

87.581.8

4046.5

21.4

29.4

IL28B Polymorphism & SVR: Impact of Geographical Origin

SV

R(%

)

De Nicola S et al. Hepatology (in press)

89

80

47

28 29

14

Egyptian Italian

IL28B Polymorphism & SVR: Impact of RVR

SV

R(%

)

De Nicola S et al. Hepatology (in press)

100

7075

23

CC CT/TT

• 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

Case History

HOMA-IR= 2.5

• 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

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;53:1090-99

NS3/4A Protease Inhibitor Telaprevir

• Phase IIa• 24 Patients• Genotype 4• TVR (750 mg/8h) or

TVR + SOC or SOC• 15 days

Mea

n M

ax H

CV

RN

A D

eclin

e 1.4

3.5

2.0

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

NS5B Polymerase InhibitorMericitabine

• 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

cEV

R (

%)

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)

Cyclophilin Inhibitor Alisporivir

Flisiak R et al. Hepatology 2009;49:1460-68

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

Nitazoxanide

• Phase II

• 96 Patients

• Egyptians

• Genotype 4

• NTZ x 12w

NTZ+PEG/RBV

or

NTZ + PEG 36w

88

73

63

SV

R(%

)

Rossignol JF et al. Gastroenterology 2009;136:856-862

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