Is HCV Resistance a reel issue at the tme of new DAA

Is HCV Resistance a reel issue at the tme of
new DAA combinaton?
Philippe HALFON
Marseille, France
Is HCV Resistance a reel issue at the tme of
new DAA combinaton?
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HCV Resistance :Basic concept
HCV Resistance assessement
Resistance issues in P+R+PI 1rst generation DAA
Resistance issues in P+R+2nd and other DAA
Resistance issues in IFN-free Regimen
Management of HCV resistance
Main HCV Resistance Mutatons to DAA
Based on In vitro assay ( Replicon) :
can we predicted the occurrence of drug
resistance mutatons?
In Vitro Resistance to DAA
14 days monotherapy (Replicon)
Potency IC 50 nM
1-10
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NS5 A Inhibitors
KEY is not li the In 0.01-0.1
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Non Nucleoside
Inhibitors ten
10-1000
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Protease Inhibitors
BMS
Nucleoside Inhibitors
Adapted from McCown et al. AAC 2008
10-100
Genetc
barrier
• Number and type of nucleotide
Changes required for a virus to aquire
clinical resistance to an antiviral
regimen
Viral
Fitness
•
Relative capacity of a viral variant
to replicate in a given environment
•
Some resistance mutations can
compromise viral enzyme function
and thus reduce viral replication
ability compared to wild –type in a
drug-free environment
Genetc Barrier for HCV
Direct Antviral Agents
High
Nucleos(t)ide
Analog Inhibitors
2 st generation
Protease
Inhibitors
n
Non Nucleos(t)ide
Analog Inhibitors
:
NS5 A
Inhibitors
1 st generation
Protease
Inhibitors
Low
Halfon P, Locarnini S, J Hepatol 2011
8
Importance of drug levels over time
Drug trough levels must be sufficient to suppress viral replication
HCV Resistance assessment :
No standardized assay and no RAVs clinical cut-of?
How to detect HCV Resistance?
“Detection depends on how carefully you
look for it”
Assays used to assess a patient’s
resistance profle
Genotypic assays
Phenotypic assays
Examine the genetc sequence of the
virus and identfy variants
Assess the drug concentraton required
to inhibit viral replicaton
in vitro by 50%
(IC50; enzyme/replicon assay)
Diferent assays have diferent levels of
Diferentto
assays
have
diferent
levels of
sensitvity
detect
resistant
variants
sensitvity to detect resistant variants
• Populaton sequencing: simple but may not
• detect
Populaton
sequencing:
simple
but may not
variants
at low levels
(<20%)
detect variants at low levels (<20%)
• Clonal sequencing: can detect variants at
• 5%Clonal
sequencing: can detect variants at
frequencies
5% frequencies
• Deep sequencing: can detect variants at
• very
Deep
cancostly
detect variants at
lowsequencing:
levels but are
very low levels but is costly
Outputs include fold change in sensitvity versus
a reference strain (e.g. wild-type)
Biological and/or clinical cut-ofs may allow
interpretaton of clinical significance
Halfon P and Locarnini S .J Hepatology 2011
Sarrazin C and Zeuzem S. Gastroenterology 2010;138:447–62
Clinical significance of RA minority mutants detecton
Sequencing : 15-20%
Pyrosequencing : 1-10 %
NGS : < 1%
Sarrazin et al. AASLD 2011
Magnitude of Treatment Failure using DAA
PR α-2a +Previr
100
PR+PI 2 gen, PR+NNI, PR+NI, PR+NS5A
IFN Free Regimen
SVR (%)
80
60
40
30-35
10-20
20
10
n/N =
0
PR α + PI
PR+DAA
IFN-Free
Triple therapy using First generation of protease
inhibitors + Peg-Ribavirine
100
Telaprevir-Boceprevir
SVR (%)
80
60
40
30-35
20
n/N =
0
PR α + PI
Failure to the treatment :
HCV Resistance or Treatment Discontinuation?
Resistance Emerges as a
Result of Treatment Failure
Activity of Peg-IFNα/RBV inadequate
to suppress NS3 inhibitor-resistant variants
Wild-type
virus
Mutant
NS3
inhibitor
Treatment Failure:
30%
~15% discontnuatons
Peg-IFN
+RBV
~15% virologic failure
●
~5% breakthrough
●
~10% relapse
McHutchison JG, et al. N Engl J Med 2009;360:1827–38
Hézode C, et al. N Engl J Med 2009;360:1839–50; Marcellin P, et al. Hepatol 2009;50(Suppl. 4):395A
Adapted from Kwo P, et al. J Hepatol 2009;50(suppl 1):S4
32
Resistant virus is rapidly selected with Telaprevir alone
CI50 x fold
WT
1
Telaprevir
T54A
6
V36A/M
7
R155K/T
7-29
36/155
57
A156V/T
>74
36/156
> 74
Treatment regimen :PEG-IFNα-2a + RBV
8
Log10 ARN-VHC (UI/ml)
Viral decrease
> 5 000 000 fold
6
Actvity of Peg-IFNα/RBV suppresses
NS3 inhibitor-resistant variants
4
2
Detection limit (100 UI/ml)
ARN-VHC LID (10 UI/ml)
0
0
10
20
50
100 days
Kieffer et al.Hepatology 2007
Low compliance
HCV resistance
• Important Side effects
• Treatment Duration 6 to 12 month
• High Pill burden
• Drug-drug Interaction
• Short therapeutic window : Ic 50/Cc 50
High fitness of the mutant not
compensated with the drug exposure
Barrier to resistance: Role of pharmacology
Clonal sequence analysis from subjects dosed with ABT-450 for 3 days
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Does Previous Response to PR infuence the selection of RAV during a
triple therapy PR+PI?
Peg-IFN treatment experienced patients can
be retreated
Prior PR response
PR
Emergence of RAV
Relapse
22%
14 %
Partial
15%
40 %
Null
5%
68 %
Previous response infuence the outcome of selection of RAV
Resistance Profles in Non SVR patients
Telaprevir Package Insert
Boceprevir Package Insert
Amino acid positons within the NS3/4A protease associated with
resistance mutatons to diferent NS3 protease inhibitors
V36A/M
Telaprevir
(linear)
T54A
V55A
Q80R/K
R155K/T/Q
A156S
A156V/T
*
D168A/V/T/
H
V170A
*
Boceprevir
(linear)
*
SCH900518
(linear)
BILN-2061
(macrocyclic)
ITMN191
(macrocyclic)
*
MK7009
(macrocyclic)
*
TMC435350
(macrocyclic)
*
*
*
BI-201335
(linear)
MK5172
(macrocyclic)
GS-9256
(macrocyclic)
ABT 450
(macrocyclic)
BMS-791325
(macrocyclic)
* Mutations associated with resistance in vitro only
HalfonP, Locarnini S et al J Hepatol 2011
Triple therapy using Peg-Ribavirine +
2nd of protease inhibitors, NS5A, and Nucleosides Inhibitors
100
SVR (%)
80
PR+PI 2 gen, PR+NNI, PR+NI, PR+NS5A
60
40
10-20
20
n/N =
0
PR+DAA
Potent PegIFN alfa/RBV+ DAA Regimens in Treatment-Naive Genotype 1
PR α-2a x 24/48 wks+ Simeprevir
Faldaprevir, Danoprevir, Asupnaprevir, ABT-450
PR x 48 wks + Daclatasvir (NS5A) x 48 wks
PR x24 wks+ Sofosbuvir (Nuc) x12 wks
SVR4, 12, or 24 (%)
100
83-88 [1
90 [3]
93[2]
80
60
40
20
n/N =
0
PR α-2a + PI 2nd
PR+NS5A
PR+Sof
Major caveats: G1a<G1b,CC<NonCC for PI
Do Baseline mutations polymorphism infuence
the SVR?
Diference between drugs within the same class
Patient do not be re-treated with the same medication in the same regimen
Wild type
Mutant
HCV RNA
Long term follow-up of patients with
resistant variants after failing Treatment
Return to
Pretreatment
state
Treatment
Years Post-Treatment
HCV Drag Resistance
Patient do not be re-treated with the same medication in the same regimen
but do patients be re-treated with HCV drugs from other DAA ?
Cross-Resistance
DAAs Compared with PEG-IFN/RBV
DAA class
HCV
Target
NS3
Protease
NS5A
NS5B
NS3
Linear
NS3
Macrocyclic
NS5A
inhibitor
NS5B
nucleoside
NS5B
Palm
NS5B
Thumb
NS5B
Finger
IFN
RBV
V36M
R
S
S
S
S
S
S
S
S
T54A
R
S
S
S
S
S
S
S
S
R155K
R
R
S
S
S
S
S
S
S
A156T
R
R
S
S
S
S
S
S
S
D168V
S
R
S
S
S
S
S
S
S
L28V
S
S
R
S
S
S
S
S
S
Y93H
S
S
R
S
S
S
S
S
S
S282T
S
S
S
R
S
S
S
S
S
C316Y
S
S
S
S
R
S
S
S
S
M414T
S
S
S
S
R
S
S
S
S
R422K
S
S
S
S
S
R
S
S
S
M423T
S
S
S
S
S
R
S
S
S
P495S
S
S
S
S
S
S
R
S
S
Variant
R = resistant = >4-fold increase in EC50; S = susceptble = <4-fold change in EC50; EC50 = 50% efectve concentraton (replicon
assay)
DAA = direct-actng antviral agent
Adapted from Kiefer T, et al. J Antmicrob Chemother 2010;65:202–12
IFN Free Regimen ?
Magnitude of Treatment Failure using IFN
Free Regimen ?
100
IFN Free Regimen
SVR (%)
80
60
40
20
10
n/N =
0
IFN-Free
Potent IFN -FreeDAA Regimens in Treatment-Naive Genotype 1
SVR4, 12, or 24 (%)
100
100[1]
100[2]
98[3]
15/15
25/25
77/79
85[4]
97[1]
94[4]
100[5
]
80
60
40
20
n/N =
0
2-3 DAAs + RBV
Sofosbuvir (Nuc) + Daclatasvir (NS5A)
+ RBV x 24 wks
Sofosbuvir (Nuc) + Ledispasvir (NS5A)
+ RBV x 12 wks
ABT-450/r (PI) + ABT-333 (NNI)
+ ABT-267 (NS5A) + RBV x 12 wks
Faldaprevir (PI) + Deleobuvir (NNI)
+ RBV x 24 wks (G1b)
28/29
15/16
2-3 DAAs, No RBV
Sofosbuvir (Nuc) + Daclatasvir (NS5A) x 24 wks
Daclatasvir (NS5A) + asunaprevir (PI) +
BMS 791325 (NNI) x 12 wks
Sofosbuvir (Nuc) +Simeprevir (PI)
Ribavirin-Free Regimen
IFN Free Regimen :
combination of drugs have to be robust
Clinical resistance occurs if drug levels are not sufficient to inhibit viral replication
Highly resistant viruses need very high drug levels (may not be achievable) to inhibit their
replication
• The modelling results show that the active tissue concentration of daclatasvir is 9% of
the concentration measured in plasma (95% CI 1%–29%).
• Using plasma concentrations as surrogates for clinical recommendations may lead to
substantial underestimation of the risk of resistance
How we manage Patients Who Did Not
Respond to PI Therapy ?
HVC Viral load (UI/mL)
6.106
Daclatasvir (NS5A)
+Asunaprevir (NS3 I)
+BMS-791325 (NNI)
Post Treatment
5.106
4.106
3.106
12 weeks
15 month
NS5A : H58P
NS3 : V36M (97,3%)
NS3 : V36M (95,2%),
R155K (99%)
R155S (0,31%)
NS5A : M28A,Q30R,H58P
NS3 : V36M (100%), R155K (96,7%)
NS5B : P495L
2.106
< 25 UI/ml détectable
< 25 UI/ml non détectable
1.106
SVR12
05/2012
08/2012
11/2013
High ftness of the R155K mutation persisting > 1 year
Options for Patients Who Did Not Respond to
PI Therapy
LONESTAR[2]
AI444-040[1]
100
100
100
95*
24 wks SOF +
daclatasvir
60
24 wks SOF +
daclatasvir +
RBV
40
SVR12 (%)
SVR12 (%)
95
80
80
12 wks
SOF/LDV
FDC + RBV
60
40
12 wks
SOF/LDV
FDC
20
20
n/N =
0
100
21/
21
19/
20
n/N =
0
21/
21
18/
19
*1 patient in triple-drug arm had missing data at Wk 12 posttreatment; this patient had undetectable
HCV RNA at Wks 4 and 24 posttreatment.
1. Sulkowski MS, et al. EASL 2013. Abstract 1417. 2. Lawitz E, et al. AASLD 2013. Abstract 215.
Resistant variants can be eliminated with a combination drug regimen
Adapted from Bartels DJ. , et al. J Infec Dis, 2008;198(6); 800-7
Maximize response, Minimize resistance
How Overcome virologic resistance?
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Adherence-friendly regimen
Shorter regimen
Minimal drug-drug interactions
Potent viral suppression
Good tolerability
Combination regimens
to HCV
DAASis:the threat
ResistanceResistance
to HCV DAAs:
What
what is the
threat level?
level?
Combinaison of DAA should suppress any replication
under antiviral pressure in majority of cases in the future
• HCV resistance have to be survey using IFN free
regimen combination, particulary with drugs without
high potency or , DDI or not well tolerated
• Investigation of NGS have to be explored using
combination of DAA
• Ribavirin will continue to have old bones in the future
of HCV therapy…

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