HCV resistance
Understanding the
mechanism and Prevention
Fabien Zoulim
Hepatology department,
Hospices Civils de Lyon
INSERM U1052, Viral Hepatitis Team
Lyon University, France
Virologic monitoring of triple
therapy
Example of virologic breakthrough
DAA stopped + sequencing
10
HCV - RNA (UI/ml)
106
105
104
103
102
101
0
vBT
Confirmed v BT
0
2
4
6
8
10
12
N
N
N
N
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
DAA – Direct acting antiviral agents,
v BT – Virologic breakthrough
Example of virologic breakthrough
Importance of the timing of virologic monitoring
10
HCV - RNA (UI/ml)
106
105
104
103
102
101
0
vBT
Confirmed v BT
0
2
4
6
8
10
12
N
N
N
N
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
v BT – Virologic breakthrough
Example of virologic breakthrough
Importance of sequencing and mutation detection
10
HCV - RNA (UI/ml)
106
105
104
103
V36M
R155K
102
101
0
vBT
Confirmed v BT
0
2
4
6
8
10
12
N
N
N
N
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
v BT – Virologic breakthrough
Loss of telaprevir resistant variants after treatment
cessation
1.0
0.9
Médiane de retour des variants “sauvages” en
séquençage direct = 7 mois (IC95% : 5-8)
0.8
Probabilité
0.7
0.6
médiane
0.5
0.4
0.3
0.2
0.1
0.0
0
2
4
6
8
10
12
14
Suivi après l’échec thérapeutique (mois)
Sullivan J. et al. EASL 2011.
16
18
Loss of telaprevir resistant variants after treatment
cessation
1.0
0.9
1a
Probabilité
0.8
0.7
0.6
médiane
0.5
0.4
1b
0.3
0.2
0.1
0.0
0
2
4
6
8
10
12
14
16
Suivi après l’échec thérapeutique (mois)
Sullivan J. et al. EASL 2011.
18
Optimizing anti-HCV regimens to maximize
SVR and minimize resistance
 The drugs
 Antiviral potency
 Pharmacokinetics (intracellular concentration of the inhibitor)
 The virus
 Genetic barrier to resistance
 Fitness of resistant variants
 Cross-resistance
 The host
 Treatment adherence
 IFN response:
 Genetics / IL28B gene polymorphism & others
 ISGs expression
 The treatment regimen
 Treatment duration / Dosage of the drug /Dosing interval
 Side effects
IFN – Interferon, IL28 – Interleukin 28B, ISGs – Interferon stimulated genes,
SVR – Sustained virologic response
All-oral HCV treatment
GT-1
Site of action of BI compounds
NS3/4A Protease inhibitor
BI 201335
NS5B pocket I Polymerase inhibitor
BI 207127
Cross-resistance between polymerase and
protease inhibitors is unlikely
NS2–NS3
protease
C
Core
E1
E2
Envelope
p7
NS2
NS3
NS3 protease
NS4A
NS4B
NS5A
Serine protease
domain
Telaprevir; SCH 503034
T54
R1479*
(R1626)
Telaprevir; BI 201335
R155
Telaprevir; BI 201335; SCH 503034
A156
BI 201335
D168
Telaprevir
*nucleoside; †non-nucleoside
NS5B
S96
N142
NM283*
S282
HCV-796†
C316
M414
V36
M419
BI207127†
P495
T423
Sarrazin C, et al. Gastroenterol. 2007;132:1767–77; Tong X, et al. Antiviral Res. 2006;70:28–38; De Francesco R, et al. Nat.
2005;436:953–60; Le Pogam S, et al. Virol. 2006;351:349–59; Villano S, et al. 57th AASLD 2006, Boston, MA, October 27–31, 2006
BI 207127 + BI 201335 Combination:
suppresses emergence of resistance
BI 201335 X EC50
BI 207127 X EC50
Long term selection of
resistance in vitro is
effectively suppressed
by BI 201335 and
BI 207127 combination
EC50 – Median estimated concentration
BI 201335 + BI 207127: SOUND-C1
400 mg TID BI 207127 +
120 mg BI 201335 + RBV
(n=15)
600 mg TID BI 207127 +
120 mg BI 201335 + RBV
(n=17)
100000000
10000000
1000000
100000
10000
1000
100
GT-1a
GT-1b
GT-6e
10000000
HCV RNA (IU/mL)
HCV RNA (IU/mL)
100000000
GT-1a
GT-1b
LLOQ
10
LLOD
1
1000000
100000
10000
1000
100
LLOQ
10
LLOD
1
0
4 8 12 16 20 24 28 32 36 40 44
Treatment day
BI 207127 400 mg/
BI 201335/RBV
BI 201335/
PegIFN/RBV
Zeuzem S, et al. Gastroenterology 2011;141:2047-55
0
4 8 12 16 20 24 28 32 36 40 44
Treatment day
BI 207127 600 mg/
BI 201335/RBV
BI 201335/
PegIFN/RBV
LLOQ, lower limit of quantification; LLOD, lower limit of detection,
GT - genotype
SOUND-C2 trial
Multi-centre, open-label, randomised phase IIb study in
treatment-naïve, HCV genotype-1 (GT-1) patients;
Including ~15% cirrhotics
A
(n=81)
1335 + 7127TID + RBV
B
Follow-up
1335 + 7127TID + RBV
Follow-up
(n=81)
1335 + 7127TID + RBV
C
(n=81)
D
(n=81)
1335 + 7127BID + RBV
Follow-up
1335 + 7127TID no RBV
Follow-up
E
(n=81)
Day 1
Week 12 Week 16
Week 26
Week 40
Interim analysis
Zeuzem S, et al. AASLD 2010. Abstract LB-15
GT – Genotype, RBV - Ribavirin
Results: Antiviral activity; antiviral response
assessment up to week 12 (5)
patients with HCV RNA <LLOD at Week 12 by IL28 GT and viral subtype
(per protocol analysis)
100
Proportion of patients
with HCV RNA <LLOD
at Week 12 (%)
100
92 91
88 86
80
100
86 89
65
64
45
60
22
40
20
0
C/C
Non-C/C
GT-1a
1335 + 7127TID + RBV 22/25
1335 + 7127BID + RBV 6/7
1335 + 7127TID no RBV 3/3
C/C
Non-C/C
GT-1b
39/61
24/26
79/92
10/22
10/11
32/36
2/9 limit of detection,
7/7
13/20
LLOD – Lower
IL28b Interleukin 28b,
GT - genotype
Zeuzem S, et al. AASLD 2010. Abstract LB-15
BMS-790052 + BMS-650032
 Phase IIa study of BMS-790052 plus BMS-650032
for 24 weeks
 HCV GT-1b Japanese null responders
n=10 (GT1b)
Week
BMS-790052 60 mg QD +
BMS-650032 200 mg BID
Follow-up
24
Chayama K, et al. Hepatology. 2011;54(Suppl. S1): Abstract LB-4
48
72
GT – Genotype
BMS-650032/BMS-790052:
virologic response (in GT1b only)
Proportion of patients with
undetectable HCV RNA (%)
 One patient discontinued at Week 2; HCV RNA was undetectable after
24 weeks’ follow-up
4/10
9/10
9/10
9/10
Week 4
Week 12
EOT
SVR24
EOT – End of treatment, SVR – Sustained virologic response
Chayama K, et al. Hepatology. 2011;54(Suppl. S1): Abstract LB-4
Conclusions:
Current and future HCV treatment regimens
SOC
NSOC
Dual-oral / QUAD
Standard of Care
New Standard of
Care
2 direct acting antivirals
quadruple
HCV
Protease
Inhibitor
PegIFN
PegIFN
HCV
Polymerase
Inhibitor**
+/ - Ribavirin
HCV
NS5A inhibitor
Ribavirin
Ribavirin
HCV
Protease
Inhibitor*
PegIFN
Ribavirin
HCV
Protease
Inhibitor‘
HCV
Polymerase
Inhibitor**
OR
HCV
NS5A inhibitor
Triple-oral
3 direct acting antivirals
HCV
Protease
Inhibitor*
HCV
Polymerase
Inhibitor **1
HCV
Polymerase
Inhibitor 2***
HCV
NS5A inhibitor