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How to Optimize Treatment of Genotype 4 Patients
Rami MOUCARI MD, PhD
Bellevue Medical Center – Saint Joseph University, Beirut, Lebanon
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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 (-)
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• 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
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• Glucose: 5.6 mmol/L
• Insulin: 18 µU/mL
• IL28B Genotype ?
Case History
HOMA-IR= 4.4
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• HCV-4 Subtype: 4d
• HCV RNA : 940 000 IU/mL • Liver Biopsy:
• A2 F3 (METAVIR)• Steatosis 50%• Sinusoidal Fibrosis
Case History
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• 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
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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
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Maximizing Success Nowadays
• Host Factors:– Geographical Origin– Insulin Resistance
• Response-Guided Therapy– Viral Kinetics– IL28B Polymorphism
• New Drugs
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Maximizing Success Nowadays
• Host Factors:– Geographical Origin– Insulin Resistance
• Response-Guided Therapy– Viral Kinetics– IL28B Polymorphism
• New Drugs
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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%)
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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
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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%)
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Geographical Origin& IL28B Polymorphism
Asselah T et al J Hepatol (in press)
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< 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
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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%)
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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
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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%)
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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
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Maximizing Success Nowadays
• Host Factors:– Geographical Origin– Insulin Resistance
• Response-Guided Therapy– Viral Kinetics– IL28B Polymorphism
• New Drugs
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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
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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)
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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)
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SV
R(%
)
Kamal SM et al. Hepatology 2007;46:1732-40
Short Treatment Duration in Rapid Respnders
378 Egyptian Patients – HCV-4
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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
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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
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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
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IL28B Polymorphism & SVR: Impact of RVR
SV
R(%
)
De Nicola S et al. Hepatology (in press)
100
7075
23
CC CT/TT
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• 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
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• 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
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Maximizing Success Nowadays
• Host Factors:– Geographical Origin– Insulin Resistance
• Response-Guided Therapy– Viral Kinetics– IL28B Polymorphism
• New Drugs
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STAT-C
Poordad F & Khungar V. Am J Manag Care 2011;17(Suppl4):S123-30
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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
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NS3/4A Protease Inhibitor Danoprevir
Imhof I & Simmonds P. Hepatology 2011;53:1090-99
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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
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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 (
%)
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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)
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Cyclophilin Inhibitor Alisporivir
Flisiak R et al. Hepatology 2009;49:1460-68
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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
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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
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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