View
1
Download
0
Category
Preview:
Citation preview
HCV Resistance and
Remaining Challenges
Prof. Jean-Michel Pawlotsky, MD, PhD
National Reference Center for Viral
Hepatitis B, C and delta
Department of Virology & INSERM U955
Henri Mondor Hospital
University of Paris 12
Créteil, France
HCV Resistance
• Selection of preexisting HCV variants that are resistant to the specific drug, due to the presence of amino acid substitutions generally located within or in close vicinity to the target region, which grow according to their in vivo fitness and fill in the replication space
I
HCV Resistance to DAAs
Asp168
Ala156
Arg155
Thr54
Val36
(Pawlotsky J-M, Ther Adv Gastroenterol 2009;2: 205-219)
Amino Acid Substitutions
Associated with PI Resistance
Resistance and Fitness
In vivo
fitness
Resistance
(Kieffer T, et al. Hepatology 2007;46:631-9)
(Reesink HW, et al. Gastroenterology 2006;131:997-1002)
Telaprevir Resistance
-5
-4
-3
-2
-1
0
1
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Study Time (Days)
Med
ian
HC
V R
NA
Ch
an
ge
fro
m B
aselin
e (
Lo
g10
IU/m
L)
Placebo VX-950 450 mg q8h VX-950 1250 mg q12h
2’C-Me-ATP in the catalytic site
(Migliaccio et al., J Biol Chem 2003;278:49164-70)
HCV Resistance to 2’-C-Methyl Nucleoside Inhibitors
RdRp Resistance Mutations
(courtesy of Isabel Najera, Roche)
499
495
496
316
365
201
482
423
419
95
176
451
414
411448
142 96
282
499
495
496
316
365
201
482
423
419
95
176
451
414
411448
142 96
282
499
495
496
316
365
201
482
423
419
95
176
451
414
411448
142 96
282
FingersThumb
Palm
A
B
C
D
pol
Filibuvir (Pfizer) Resistance in IFN Null-Responders
(Mori et al., EASL 2010)
Thumb 2 domain
M423
Filibuvir
BMS-790052 Resistance in vitro
Subtype Sustitution EC50 Fold-changeReplication
level (% wt)
1b replicon
wt 2.6±0.3 1 100
L31V 61±15 24 144±47
Y93H 49±13 19 20±7
wt 5.9±3.7 1 100
1a replicon
M28T 4,100±360 360 31±23
Q30H 8,700±1,900 1,900 75±31
Q30R 7,300±1,100 1,100 41±16
L31M 2,100±610 610 55±15
L31V 20,000±6,000 6,000 117±29
Y93C 11,000±4,000 4,000 11±7
(Gao et al., Nature 2010;465:96-100)
Alisporivir Resistance in vitro
3’UTRNS3 NS4
A BNS5A
ANS5B5’UTR neo
HCV
IRES
EMCV
IRES
Domain I Domain II Domain III
36 213 250 342 356 447
R262Q R318WA241P D320E
A241P +
R262Q
A241P +
R318W
R262Q +
R318W
R318W +
D320E
A241P +
R262Q +
R318W
A241P +
R262Q +
R318W +
D320E
Fold-
change
vs wt
1.02 1.58 1.37 3.67 1.72 3.89
(Coelmont et al., EASL 2009)
II
Failure of the Triple Combination of PegIFN, Ribavirin and a PI to
Eradicate HCV
Treatment Failures on Triple Combination with a DAA
• Treatment-Naïve: 20-30%
• Treatment-experienced: 40-50%
Expected Higher Failure Ratesin Difficult-to-Treat Patients
• Advanced liver disease
• Liver transplant
• HIV coinfected
• Hemodialysis
• Immunosuppressed patients
• African Americans
• etc…
Treatment Failures on Triple Combination with a DAA
• Insufficient response to Peg-IFN and ribavirin
• Uncontrolled outgrowth of DAA-resistant HCV variants
SVR According to Lead-in (SPRINT-2, non-black)
29%
39%
82%
% o
f p
ati
en
ts
wit
h S
VR
0
10
20
30
40
50
60
70
80
90
100
BOC/RGT BOC/PR48
(Poordad et al., AASLD 2010)
82%
<1 log HCV RNA
decrease
≥1 log HCV RNA
decrease
SVR According to Lead-in (RESPOND-2, non-black)
33% 34%
79%
% o
f p
ati
en
ts
wit
h S
VR
0
10
20
30
40
50
60
70
80
90
100
BOC/RGT BOC/PR48
(Bacon et al., AASLD 2010)
73%
<1 log HCV RNA
decrease
≥1 log HCV RNA
decrease
Telaprevir Rollover Study 107
0
20
40
60
80
100
37%
55%
75%
97%
59%
Pati
en
ts W
ith
Un
dete
cta
ble
HC
V R
NA
(%
)
TOTAL
N=117
Prior
null-response
N=51
Prior partial
response
N=29
Prior
breakthrough
N=8
Prior
relapse
N=29
(Berg et al., EASL 2010)
REALIZE Trial-Telaprevir Arms
0
20
40
60
80
100
31%
57%
86%
65%
Pati
en
ts W
ith
Un
dete
cta
ble
HC
V R
NA
(%
)
TOTAL Prior
null-response
Prior partial
response
Prior
relapse
(Vertex press release, Sept 7, 2010)
Incidence of HCV resistance
(Hézode et al., N Engl J Med 2009;360:1839-50)
Arm Event N VL <LOD Wild-typeLow-level
resistance
High-level
resistance
T12PR24Breakthrough 4 - - - 4
Relapse 8 - 1 4 3
T12PR12Breakthrough 1 - 1 - -
Relapse 19 3 1 13 2
T12P12Breakthrough 19 2 - 9 8
Relapse 22 4 - 16 2
Long-Term Follow-Up After Treatment Failure (EXTEND)
100 100
Overall 36 155 156 36+15554
NS3 variant positions
9288 8589
0
20
40
60
80
100
% o
f sam
ple
s w
ith
no
dete
cta
ble
vari
an
t at
en
d o
f fo
llo
w-u
p
Median follow-up 22 months (range 5-35)
(Zeuzem et al., AASLD 2010)
Conclusions
• The administration of DAAs is always associated with the selection of resistant HCV variants
• In combination regimens, the antiviral effect of pegylated IFN and ribavirin prevents the growth of DAA-resistant variants and leads to viral eradication
• Treatment failure with the triple combination of pegylated IFN, ribavirin and a DAA is due to an insufficient antiviral response to IFN and ribavirin
• Treatment failure is characterized by the outgrowth of DAA-resistant HCV variants, as a result of virtual monotherapy with the DAA
• Prevention of treatment failure in patients with an insufficient response to pegylated IFN and ribavirin is based on:
• An accurate assessment of IFN responsiveness (lead-in phase, baseline parameters)
• Alternative options for true IFN null responders that must be assessed in prospective clinical trials
Conclusions
Recommended