hépatite c_résistance aux traitements.ppt
DESCRIPTION
JM PawlotskyTRANSCRIPT
Hépatite C: RésistanceHépatite C: Résistanceaux Traitementsaux Traitements
Prof. Jean-Michel PawlotskyProf. Jean-Michel Pawlotsky
CNR des Hépatites B, C et deltaCNR des Hépatites B, C et deltaLaboratoire de Virologie & INSERM U635Laboratoire de Virologie & INSERM U635
HHôpital Henri Mondorôpital Henri MondorUniversité Paris XIIUniversité Paris XII
CréteilCréteil
HCV Resistance
• HCV resistance to IFN- therapy
• HCV resistance to ribavirin ?
• HCV resistance to specific antiviral molecules
I
HCV resistance to IFN-Therapy
Incidence of Peg-IFN-RibavirinTreatment Failures
2%2%
00
1515
3030
4545
606054%54%
48%48%
58%58%
24%24%
16%16% 18%18%
Genotype 1 Genotypes 2/3Genotype 1 Genotypes 2/3
PEG-IFN-PEG-IFN-αα2a+ribavirin 2a+ribavirin (Fried et al)(Fried et al)
PEG-IFN-PEG-IFN-αα2a+ribavirin 2a+ribavirin (Hadziyannis et al)(Hadziyannis et al)
PEG-IFN-PEG-IFN-αα2b+ribavirin 2b+ribavirin (Manns et al)(Manns et al)
(Manns et al, Lancet 2001 ; Fried et al, N Engl J Med 2002 ; Hadziyannis et al, Ann Intern Med 2004) (Manns et al, Lancet 2001 ; Fried et al, N Engl J Med 2002 ; Hadziyannis et al, Ann Intern Med 2004)
TreatmentTreatmentFailureFailure
TreatmentTreatmentScheduleSchedule
TreatmentTreatmentFailureFailure
HostHostFactorsFactors
TreatmentTreatmentScheduleSchedule
TreatmentTreatmentFailureFailure
DiseaseDiseaseCharacteristicsCharacteristics
HostHostFactorsFactors
TreatmentTreatmentScheduleSchedule
TreatmentTreatmentFailureFailure
Viral FactorsViral FactorsDiseaseDiseaseCharacteristicsCharacteristics
HostHostFactorsFactors
TreatmentTreatmentScheduleSchedule
TreatmentTreatmentFailureFailure
Viral FactorsViral FactorsDiseaseDiseaseCharacteristicsCharacteristics
HostHostFactorsFactors
TreatmentTreatmentScheduleSchedule
TreatmentTreatmentFailureFailure
Viral Resistance
• Intrinsic properties of viral strains that counteract the antiviral action of antiviral drugs
Incidence of Peg-IFN-RibavirinTreatment Failures
2%2%
00
1515
3030
4545
606054%54%
48%48%
58%58%
24%24%
16%16% 18%18%
Genotype 1 Genotypes 2/3Genotype 1 Genotypes 2/3
PEG-IFN-PEG-IFN-αα2a+ribavirin 2a+ribavirin (Fried et al)(Fried et al)
PEG-IFN-PEG-IFN-αα2a+ribavirin 2a+ribavirin (Hadziyannis et al)(Hadziyannis et al)
PEG-IFN-PEG-IFN-αα2b+ribavirin 2b+ribavirin (Manns et al)(Manns et al)
(Manns et al, Lancet 2001 ; Fried et al, N Engl J Med 2002 ; Hadziyannis et al, Ann Intern Med 2004) (Manns et al, Lancet 2001 ; Fried et al, N Engl J Med 2002 ; Hadziyannis et al, Ann Intern Med 2004)
HCV Kinetics by GenotypeEC-sponsored DITTO-Trial
(Pawlotsky et al., manuscript in preparation)
00
11
22
33
44
55
66
77 HCV RNA (log IU/ml)HCV RNA (log IU/ml)
00 44 77 88 1515 2222 292911-7-7-28-28
Genotype 4Genotype 4
Genotype 1Genotype 1
Genotype 3Genotype 3
** = significant difference, 4 and 1 = significant difference, 4 and 1 vsvs 3 3
**
**
****
** ****
Quantitative assay cutoffQuantitative assay cutoff
Qualitative assay cutoffQualitative assay cutoff
HCV Kinetics by GenotypeEC-sponsored DITTO-Trial
00
11
22
33
44
55
66
77 HCV RNA (log IU/ml)HCV RNA (log IU/ml)
00 44 77 88 1515 2222 292911-7-7-28-28
Genotype 4Genotype 4
Genotype 1Genotype 1
Genotype 3Genotype 3
** = significant difference, 4 and 1 = significant difference, 4 and 1 vsvs 3 3
**
**
****
** ****
Quantitative assay cutoffQuantitative assay cutoff
Qualitative assay cutoffQualitative assay cutoff
(Pawlotsky et al., manuscript in preparation)
HCV Kinetics by GenotypeEC-sponsored DITTO-Trial
00
11
22
33
44
55
66
77 HCV RNA (log IU/ml)HCV RNA (log IU/ml)
00 44 77 88 1515 2222 292911-7-7-28-28
Genotype 4Genotype 4
Genotype 1Genotype 1
Genotype 3Genotype 3
** = significant difference, 4 and 1 = significant difference, 4 and 1 vsvs 3 3
**
**
****
** ****
Quantitative assay cutoffQuantitative assay cutoff
Qualitative assay cutoffQualitative assay cutoff
(Pawlotsky et al., manuscript in preparation)
HCV Kinetics by GenotypeEC-sponsored DITTO-Trial
00
11
22
33
44
55
66
77 HCV RNA (log IU/ml)HCV RNA (log IU/ml)
00 44 77 88 1515 2222 292911-7-7-28-28
Genotype 4Genotype 4
Genotype 1Genotype 1
Genotype 3Genotype 3
** = significant difference, 4 and 1 = significant difference, 4 and 1 vsvs 3 3
**
**
****
** ****
Quantitative assay cutoffQuantitative assay cutoff
Qualitative assay cutoffQualitative assay cutoff
(Pawlotsky et al., manuscript in preparation)
Viral FactorsViral Factors
Antiviral Antiviral resistanceresistance
DelayedDelayedclearanceclearance
LongerLongerhalf-life ofhalf-life of
infected cellsinfected cells
Summary
• HCV resistance to IFN- antiviral effect exists
• Its molecular mechanisms are unknown and probably complex
• It accounts for only a small part of IFN--based treatment failures
SNP and SVR in the IDEAL Trial1 3 5 7 9 11 13 15 17 19 21 X M
2 4 6 8 10 12 14 16 18 20 22 Y
-log10
(P)
0.0
15.0
30.0
-log10(P)
0.0
15.0
30.0
-log10
(P)
0.0
15.0
30.0
Chromosome 19 ideogram
0 M 10 M 20 M 30 M 40 M 50 M 60 M
39,623 K 39,666 K 39,708 K 39,750 K 39,793 K 39,835K
PAK4 SYCN IL28B IL29 LRFN1NCCRP1 AC011445.6IL28A GMFG
IL28B IL28AAC011445.6
39,711 K 39,721 K 39,732 K 39,743 K 39,753 K 39,764K
rs12979860P=1.37 _10-28
1 3 5 7 9 11 13 15 17 19 21 X M2 4 6 8 10 12 14 16 18 20 22 Y
-log10
(P)
0.0
15.0
30.0
-log10(P)
0.0
15.0
30.0
-log10
(P)
0.0
15.0
30.0
Chromosome 19 ideogram
0 M 10 M 20 M 30 M 40 M 50 M 60 M
39,623 K 39,666 K 39,708 K 39,750 K 39,793 K 39,835K
PAK4 SYCN IL28B IL29 LRFN1NCCRP1 AC011445.6IL28A GMFG
IL28B IL28AAC011445.6
39,711 K 39,721 K 39,732 K 39,743 K 39,753 K 39,764K
rs12979860P=1.37 _10-28
IL28B
(Ge et al, Nature, 2009;461:399-401)(Ge et al, Nature, 2009;461:399-401)
rs12979860 Allele and SVR
(Ge et al, Nature, 2009;461:399-401)(Ge et al, Nature, 2009;461:399-401)
rs12979860 Allele Frequency
12%12%
39%39%
49%49%
37%37%
16%16%
47%47%
C/CC/C C/TC/T T/TT/T
CaucasianCaucasianancestryancestry
n=871n=871
African AmericanAfrican Americanancestryancestry
n=191n=191
(Ge et al, Nature, 2009;461:399-401)(Ge et al, Nature, 2009;461:399-401)
Geographic Distribution
(Thomas et al, Nature, 2009;461:798-801)(Thomas et al, Nature, 2009;461:798-801)
Effect on HCV Kinetics (Caucasians)
ΔΔ H
CV
RN
A (
Lo
gH
CV
RN
A (
Lo
g101
0
IU/m
L)
IU/m
L)
CT
TT-3.0
-2.0
-1.0
0
Weeks
-4.0
-5.0
2 4 120
-6.0 CC
(Thompson et al, AASLD 2009) (Thompson et al, AASLD 2009)
ΔΔ H
CV
RN
A (
Lo
gH
CV
RN
A (
Lo
g101
0
IU/m
L)
IU/m
L) CT
TT
-3.0
-2.0
-1.0
0
Weeks
-4.0
-5.0
2 4 120
-6.0
CC
Effect on HCV Kinetics(African Americans)
(Thompson et al, AASLD 2009) (Thompson et al, AASLD 2009)
-5-5
-4-4
-3-3
-2-2
-1-1
00
00 44 88 1212 1616 2020 2424Weeks of therapyWeeks of therapy
HC
V R
NA
red
uct
ion
(L
og
HC
V R
NA
red
uct
ion
(L
og
1010 I
U/m
L)
IU
/mL
)
TT
CT
NSNS
P=0.045P=0.045
P=0.021P=0.021
P=0.004P=0.004
P=0.0005P=0.0005
VK on High-Dose Peg IFNAccording to IL28B
Genotype
(Chevaliez et al, AASLD 2010) (Chevaliez et al, AASLD 2010)
SVR Predictors
Odds RatioOdds Ratio 95% CI95% CI p-valuep-value
rs12979860 CC vs non-CCrs12979860 CC vs non-CC 5.25.2 4.14.1 6.76.7 <0.0001<0.0001
HCV RNA ≤ 600,000 IU/mLHCV RNA ≤ 600,000 IU/mL 3.13.1 2.32.3 4.14.1 <0.0001<0.0001
Caucasian vs African AmericanCaucasian vs African American 2.82.8 2.02.0 4.04.0 <0.0001<0.0001
Hispanic vs African AmericanHispanic vs African American 2.12.1 1.31.3 3.63.6 0.0040.004
METAVIR score ≤F2 METAVIR score ≤F2 2.72.7 1.81.8 4.04.0 <0.0001<0.0001
Fasting blood sugar < 5.6 mmol/LFasting blood sugar < 5.6 mmol/L 1.71.7 1.31.3 2.22.2 <0.0001<0.0001
(Thompson et al, AASLD 2009) (Thompson et al, AASLD 2009)
Summary
• In patients infected with HCV genotype 1, the rs12979860 genotype:
• Is strongly associated with the SVR
• Explains 60% of the ethnic influence on SVR
• Influences HCV kinetics on therapy
• Is probably a marker of patient cell “resistance“ to the effect of IFN- through mechanisms that remain to be elucidated
II
HCV Resistance to Ribavirin ?
• Direct inhibition of HCV RNA-dependent RNA polymerase ?
• Depletion of intracellular GTP pools via IMPDH inhibition ?
• RNA mutagenesis leading to "error catastrophe" ?
• Enhancement of IFN-induced responses in the liver ?
Ribavirin’s Antiviral Mechanisms
Ribavirin’s Antiviral Effect
(Pawlotsky et al., Gastroenterology 2004;126:703-14)
-1.0-1.0
-0.5-0.5
0.00.0
0.50.5
00 22 44 66 88 1010 1212 1414 1616 1818 2020 2222 2424 2626 2828
Mean HCV RNA decrease (log IU/ml)Mean HCV RNA decrease (log IU/ml)
Time (days)Time (days)
ControlsControls
RibavirinRibavirinmonotherapymonotherapy
-1.5-1.5
-1.0-1.0
-0.5-0.5
0.00.0
+0.5+0.5
00 22 44 66 88 1010 1212 1414
DaysDays
HCV RNA changes (log IU/ml)HCV RNA changes (log IU/ml)
-1.5-1.5
-1.0-1.0
-0.5-0.5
0.00.0
+0.5+0.5
00 22 44 66 88 1010 1212 1414
DaysDays
HCV RNA changes (log IU/ml)HCV RNA changes (log IU/ml)
-1.5-1.5
-1.0-1.0
-0.5-0.5
0.00.0
+0.5+0.5
00 22 44 66 88 1010 1212 1414
DaysDays
HCV RNA changes (log IU/ml)HCV RNA changes (log IU/ml)
-1.5-1.5
-1.0-1.0
-0.5-0.5
0.00.0
+0.5+0.5
00 22 44 66 88 1010 1212 1414
DaysDays
HCV RNA changes (log IU/ml)HCV RNA changes (log IU/ml)
(Pawlotsky et al., Gastroenterology 2004;126:703-14)
Ribavirin’s Antiviral Effect
Summary
• Ribavirin mechanisms of action in chronic hepatitis C remain unknown
• Ribavirin direct antiviral effect is modest and transient
• Long-term ribavirin administration does not select for specific resistance substitutions
III
HCV Resistance to Direct Acting Antivirals
HCV ResistanceHCV Resistance
• Definition Selection of viral variants bearing amino acid
substitutions that alter the drug target and thereby confer reduced susceptibility to the drug
• Resistant variants are pre-existing at baseline as minor viral populations All single mutants ~10% of double mutants
(Pawlotsky JM, Ther Adv Gastroenterol 2009;2:205-219; Perelson AS, unpublished data) (Pawlotsky JM, Ther Adv Gastroenterol 2009;2:205-219; Perelson AS, unpublished data)
sensitivesensitive
resistantresistant
Mechanisms of Resistance
sensitivesensitive
resistantresistant
DrugDrug
Mechanisms of Resistance
sensitivesensitive
resistantresistant
DrugDrug
resistantresistant
Mechanisms of Resistance
sensitivesensitive
sensitivesensitive
resistantresistant
DrugDrug Stop drugStop drug
resistantresistant
Mechanisms of Resistance
sensitivesensitive
sensitivesensitive
resistantresistant
sensitivesensitive
resistantresistant
DrugDrug Stop drugStop drug
resistantresistant
Mechanisms of Resistance
sensitivesensitive
sensitivesensitive
resistantresistant
sensitivesensitive
resistant + fitresistant + fit
DrugDrug Stop drugStop drug
resistantresistant
Mechanisms of Resistance
sensitivesensitive
sensitivesensitive
resistantresistant
DrugDrug Stop drugStop drug
resistantresistant
Mechanisms of Resistance
sensitivesensitive
resistant + very fitresistant + very fit
sensitivesensitive
Chronic HCV infection is curable
by therapy
sensitivesensitive
resistantresistant
Mechanisms of Resistance
sensitivesensitive
resistantresistant
DrugDrug
resistantresistant
Mechanisms of Resistance
sensitivesensitive
resistantresistant
DrugDrug Stop drugStop drug
resistantresistant
Mechanisms of Resistance
resistantresistant
HCV Life Cycle
(Popescu & Dubuisson, Biol Cell 2009;102:63-74)
DAAs in Development
• NS3/4A protease inhibitors
• Inhibitors of HCV replication• Nucleoside/nucleotide analogue inhibitors
of RdRp• Non-nucleoside inhibitors of RdRp (NNIs)• NS5A inhibitors• Cyclophylin inhibitors
NS3/4A Protease Active Site
Antiviral Efficacy of NS3/4A PIs
Drug Phase Dose DurationMedian/mean log
HCV RNA reduction
Telaprevir III 750 mg q8h 14 days -4.4
Boceprevir III 400 mg tid 7 days -1.6
TMC435 II 200 mg qd 7 days -4.1
Danoprevir (RG7227) II 200 mg q8h 14 days -3.8
Vaniprevir (MK-7009) II 700 mg bid 8 days -4.7
BI201335 II 240 mg qd 14 days -4.0
Narlaprevir II 400 mg bid 7 days -4.2
BMS-650032 Ib 300 mg bid 3 days -3.3
ACH-1625 Ib 600 mg bid 4.5 days -3.9
GS-9256 Ib 200 mg bid 3 days -2.8
Asp168
Ala156
Arg155
Thr54
Val36
(Pawlotsky J-M, Ther Adv Gastroenterol 2009;2: 205-219) (Pawlotsky J-M, Ther Adv Gastroenterol 2009;2: 205-219)
Amino Acid Substitutions Amino Acid Substitutions Associated with PI ResistanceAssociated with PI Resistance
Amino Acid Substitutions Amino Acid Substitutions Associated with PI ResistanceAssociated with PI Resistance
Resistance and Fitness
In vivoIn vivo
fitnessfitness
ResistanceResistance
(Kieffer T, et al. Hepatology 2007;46:631-9)(Kieffer T, et al. Hepatology 2007;46:631-9)
(Reesink HW, et al. Gastroenterology 2006;131:997-1002)(Reesink HW, et al. Gastroenterology 2006;131:997-1002)
Telaprevir Resistance
-5-5
-4-4
-3-3
-2-2
-1-1
00
11
00 11 22 33 44 55 66 77 88 99 1010 1111 1212 1313 1414
Study Time (Days)Study Time (Days)
Med
ian
HC
V R
NA
Ch
ang
eM
edia
n H
CV
RN
A C
han
ge
fro
m B
asel
ine
(Lo
gfr
om
Bas
elin
e (L
og
1010
IU/m
L)
IU/m
L)
Placebo VX-950 450 mg q8h VX-950 1250 mg q12h
0
1
2
3
4
5
6
7
0 10 20 30 40 50 60 70 80 90
HC
V R
NA
(L
og
HC
V R
NA
(L
og
1 010
I U/ m
L)
IU/m
L)
WeeksWeeks
WTWT
AABB CC DD
EE FF
AA BB CC
DD EER155K/NR155K/NV36L/MV36L/MWTWT
A40TA40TV36L/M + A40TV36L/M + A40TR155K/N + A40TR155K/N + A40TV36L/M + R155K/NV36L/M + R155K/NV36L/M + R155K/N + A40TV36L/M + R155K/N + A40T
TVR-Peg-IFNTVR-Peg-IFN
Telaprevir Resistance (PROVE2)
(Chevaliez S, et al., EASL 2009)(Chevaliez S, et al., EASL 2009)
Telaprevir Resistance (PROVE2)H
CV
RN
A (
Lo
gH
CV
RN
A (
Lo
g1 01
0 I U
/ mL
) IU
/mL
)
WeeksWeeks
WTWT
AABB
CC
DD
EE
R155K/E + T42SR155K/E + T42SWTWT
AA BBWTWT
CC DD EE
TVR-Peg-IFNTVR-Peg-IFN
SOCSOC
00
11
22
33
44
55
66
77
00 88 1616 2424 3232 4040 4848 5656 6464 7272
(Chevaliez S, et al., EASL 2009)(Chevaliez S, et al., EASL 2009)
Antiviral Efficacy of NUCs
Drug Phase Dose DurationMedian/mean log
HCV RNA reduction
R7128 II 1500 mg bid 14 days -2.7
IDX184 II 100 mg qd 3 days -0.7
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
Antiviral Efficacy of NNIs
Drug Phase Dose DurationMedian/mean log
HCV RNA reduction
GS-9190 II 40 mg bid 8 days -1.4
Filibuvir II 300 mg bid 8 days -2.1
ANA598 II 800 mg bid 3 days -2.9
BI207127 II 800 mg q8h 3 days -3.1
VCH-759 II 400 mg tid 10 days -1.7
ABT-333 II 600 mg bid 2 days -1.5
VX-222 Ib 750 mg bid 3 days -3.2
MK-3281 Ib 800 mg bid 7 days -1.3 (1a), -3.8 (1b)
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
AA
BB
CC
DD
polpol
Filibuvir (Pfizer) Resistance in IFN Null-Responders
(Mori et al., EASL 2010)
Thumb 2 domainM423
Filibuvir
Antiviral Efficacy of NS5A Inhibitors
Drug Phase Dose DurationMedian/mean log
HCV RNA reduction
BMS790052 II 10 mg qd 1 day -3.2
AZD7295 Ib 233 mg q8h 5 days -2.1 (only 1b)
BMS-790052 Resistance in vitro
SubtypeSubtype SustitutionSustitution EC50EC50 Fold-changeFold-change Replication Replication level (% wt)level (% wt)
1b replicon1b replicon
wtwt 2.6±0.32.6±0.3 11 100100
L31VL31V 61±1561±15 2424 144±47144±47
Y93HY93H 49±1349±13 1919 20±720±7
wtwt 5.9±3.75.9±3.7 11 100100
1a replicon1a replicon
M28TM28T 4,100±3604,100±360 360360 31±2331±23
Q30HQ30H 8,700±1,9008,700±1,900 1,9001,900 75±3175±31
Q30RQ30R 7,300±1,1007,300±1,100 1,1001,100 41±1641±16
L31ML31M 2,100±6102,100±610 610610 55±1555±15
L31VL31V 20,000±6,00020,000±6,000 6,0006,000 117±29117±29
Y93CY93C 11,000±4,00011,000±4,000 4,0004,000 11±711±7
(Gao et al., Nature 2010;465:96-100)
Antiviral Efficacy of Cyclophylin Inhibitors
Drug Phase Dose DurationMedian/mean log
HCV RNA reduction
Alisporivir(DEBIO-025)
II 1200 mg bid 14 days -3.6
SCY-465 Ib 900 mg qd 15 days -2.2
NIM 811 II 600 mg bid 14 days None
Alisporivir Resistance in vitro
3’UTRNS3 NS4
A BNS5A
ANS5B5’UTR neo
HCV
IRES
EMCV
IRES
Domain IDomain I Domain IIDomain II Domain IIIDomain III
3636 213213 250250 342342 356356 447447
R262QR262Q R318WR318WA241PA241P D320ED320E
A241P + A241P + R262QR262Q
A241P + A241P + R318WR318W
R262Q + R262Q + R318WR318W
R318W + R318W + D320ED320E
A241P + A241P + R262Q + R262Q + R318WR318W
A241P + A241P + R262Q + R262Q + R318W + R318W +
D320ED320E
Fold-Fold-changechangevs vs wtwt
1.021.02 1.581.58 1.371.37 3.673.67 1.721.72 3.893.89
(Coelmont et al., EASL 2009)
IV
Triple Combination Treatment Failure
DAADAA
Prevention of DAA Resistance
DAADAA
RibavirinRibavirinPegylated Pegylated IFN-IFN-
++
Prevention of DAA Resistance
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
• Growth of uncontrolled DAA-resistant HCV variants
7171 76767070
27273333
1717
00 00
00
2020
4040
6060
8080
100100
<0.5<0.5
LogLog1010 HCV RNA level at week 4 (Lead-in phase) HCV RNA level at week 4 (Lead-in phase)
0.5 0.5 –– <1.0
<1.0
1.0 1.0 –– <1.5
<1.5
1.5 1.5 –– <2.0
<2.0
2.0 2.0 –– <3.0
<3.0
3.0 3.0 –– <4.0
<4.0≥≥4.04.0
Undetectable
Undetectable
N=7N=7 N=21N=21 N=10N=10 N=11N=11 N=21N=21 N=12N=12 N=11N=11 N=3N=3
Tre
atm
ent
failu
res
(%)
Tre
atm
ent
failu
res
(%)
(Kwo et al., AASLD 2009) (Kwo et al., AASLD 2009)
Treatment Failures in SPRINT-1Treatment Failures in SPRINT-1Failures according to lead-in, 28wkFailures according to lead-in, 28wk
00
2020
4040
6060
8080
100100
<0.5<0.5
LogLog1010 HCV RNA level at week 4 (Lead-in phase) HCV RNA level at week 4 (Lead-in phase)
0.5 0.5 –– <1.0
<1.0
1.0 1.0 –– <1.5
<1.5
1.5 1.5 –– <2.0
<2.0
2.0 2.0 –– <3.0
<3.0
3.0 3.0 –– <4.0
<4.0≥≥4.04.0
Undetectable
Undetectable
N=9N=9 N=13N=13 N=17N=17 N=10N=10 N=14N=14 N=17N=17 N=12N=12 N=9N=9
(Kwo et al., AASLD 2009) (Kwo et al., AASLD 2009)
5656
3838 3535
2020 21211818
88 00
Treatment Failures in SPRINT-1Treatment Failures in SPRINT-1Failures according to lead-in, 48wkFailures according to lead-in, 48wk
Tre
atm
ent
failu
res
(%)
Tre
atm
ent
failu
res
(%)
SVR According to Lead-in (SPRINT-2, non-black)
29%29%29%29%
39%39%39%39%
82%82%82%82%
% o
f p
atie
nts
w
ith
SV
R%
of
pat
ien
ts
wit
h S
VR
% o
f p
atie
nts
w
ith
SV
R%
of
pat
ien
ts
wit
h S
VR
00
1010
2020
3030
4040
5050
6060
7070
8080
9090
100100
BOC/RGTBOC/RGT BOC/PR48BOC/PR48
(Poordad et al., AASLD 2010)(Poordad et al., AASLD 2010)
82%82%82%82%
<1 log HCV RNA <1 log HCV RNA decreasedecrease<1 log HCV RNA <1 log HCV RNA decreasedecrease
≥≥1 log HCV RNA1 log HCV RNAdecreasedecrease≥≥1 log HCV RNA1 log HCV RNAdecreasedecrease
SVR According to Lead-in (RESPOND-2, non-black)
33%33%33%33% 34%34%34%34%
79%79%79%79%
% o
f p
atie
nts
w
ith
SV
R%
of
pat
ien
ts
wit
h S
VR
% o
f p
atie
nts
w
ith
SV
R%
of
pat
ien
ts
wit
h S
VR
00
1010
2020
3030
4040
5050
6060
7070
8080
9090
100100
BOC/RGTBOC/RGT BOC/PR48BOC/PR48
(Bacon et al., AASLD 2010)(Bacon et al., AASLD 2010)
73%73%73%73%
<1 log HCV RNA <1 log HCV RNA decreasedecrease<1 log HCV RNA <1 log HCV RNA decreasedecrease
≥≥1 log HCV RNA1 log HCV RNAdecreasedecrease≥≥1 log HCV RNA1 log HCV RNAdecreasedecrease
Telaprevir Rollover Study 107
0
20
40
60
80
100
37%
55%
75%
97%
59%
Pat
ien
ts W
ith
Un
det
ecta
ble
H
CV
RN
A (
%)
TOTALN=117
Priornull-response
N=51
Prior partialresponse
N=29
Priorbreakthrough
N=8
PriorrelapseN=29
(Berg et al., EASL 2010) (Berg et al., EASL 2010)
REALIZE Trial-Telaprevir Arms
0
20
40
60
80
100
31%
57%
86%
65%
Pat
ien
ts W
ith
Un
det
ecta
ble
H
CV
RN
A (
%)
TOTAL Priornull-response
Prior partialresponse
Priorrelapse
(Vertex press release, Sept 7, 2010) (Vertex press release, Sept 7, 2010)
Treatment Failures on Triple Combination with a DAA
• Insufficient response to Peg-IFN and ribavirin
• Growth of uncontrolled DAA-resistant HCV variants
Incidence of HCV resistanceIncidence of HCV resistance
(Hézode et al., N Engl J Med 2009;360:1839-50) (Hézode et al., N Engl J Med 2009;360:1839-50)
ArmArm EventEvent NN VL <LODVL <LOD Wild-typeWild-type Low-levelLow-levelresistanceresistance
High-levelHigh-levelresistanceresistance
T12PR24T12PR24BreakthroughBreakthrough 44 -- -- -- 44
RelapseRelapse 88 -- 11 44 33
T12PR12T12PR12BreakthroughBreakthrough 11 -- 11 -- --
RelapseRelapse 1919 33 11 1313 22
T12P12T12P12BreakthroughBreakthrough 1919 22 -- 99 88
RelapseRelapse 2222 44 -- 1616 22
-5-5
-4-4
-3-3
-2-2
-1-1
00
11
Study TimeStudy Time
Med
ian
HC
V R
NA
Ch
ang
eM
edia
n H
CV
RN
A C
han
ge
fro
m B
asel
ine
(Lo
gfr
om
Bas
elin
e (L
og
1010
IU/m
L)
IU/m
L)
DAA Resistance
-5-5
-4-4
-3-3
-2-2
-1-1
00
11
Wild-type, sensitive HCVWild-type, sensitive HCV
Study TimeStudy Time
Med
ian
HC
V R
NA
Ch
ang
eM
edia
n H
CV
RN
A C
han
ge
fro
m B
asel
ine
(Lo
gfr
om
Bas
elin
e (L
og
1010
IU/m
L)
IU/m
L)
DAA Resistance
-5-5
-4-4
-3-3
-2-2
-1-1
00
11
Wild-type, sensitive HCVWild-type, sensitive HCV
Resistant HCVResistant HCV
Study TimeStudy Time
Med
ian
HC
V R
NA
Ch
ang
eM
edia
n H
CV
RN
A C
han
ge
fro
m B
asel
ine
(Lo
gfr
om
Bas
elin
e (L
og
1010
IU/m
L)
IU/m
L)
DAA Resistance
-5-5
-4-4
-3-3
-2-2
-1-1
00
11
Study TimeStudy Time
Med
ian
HC
V R
NA
Ch
ang
eM
edia
n H
CV
RN
A C
han
ge
fro
m B
asel
ine
(Lo
gfr
om
Bas
elin
e (L
og
1010
IU/m
L)
IU/m
L)
Triple Combo Failure
-5-5
-4-4
-3-3
-2-2
-1-1
00
11
Study TimeStudy Time
Med
ian
HC
V R
NA
Ch
ang
eM
edia
n H
CV
RN
A C
han
ge
fro
m B
asel
ine
(Lo
gfr
om
Bas
elin
e (L
og
1010
IU/m
L)
IU/m
L)
Triple Combo FailurePotent IFNPotent IFN-ribavirin effect-ribavirin effect
-5-5
-4-4
-3-3
-2-2
-1-1
00
11
Wild-type, sensitive HCVWild-type, sensitive HCV
Study TimeStudy Time
Med
ian
HC
V R
NA
Ch
ang
eM
edia
n H
CV
RN
A C
han
ge
fro
m B
asel
ine
(Lo
gfr
om
Bas
elin
e (L
og
1010
IU/m
L)
IU/m
L)
Triple Combo FailurePotent IFNPotent IFN-ribavirin effect-ribavirin effect
-5-5
-4-4
-3-3
-2-2
-1-1
00
11
Wild-type, sensitive HCVWild-type, sensitive HCV
Resistant HCVResistant HCV
Study TimeStudy Time
Med
ian
HC
V R
NA
Ch
ang
eM
edia
n H
CV
RN
A C
han
ge
fro
m B
asel
ine
(Lo
gfr
om
Bas
elin
e (L
og
1010
IU/m
L)
IU/m
L)
Triple Combo FailurePotent IFNPotent IFN-ribavirin effect-ribavirin effect
-5-5
-4-4
-3-3
-2-2
-1-1
00
11
Wild-type, sensitive HCVWild-type, sensitive HCV
Resistant HCVResistant HCV
Study TimeStudy Time
Med
ian
HC
V R
NA
Ch
ang
eM
edia
n H
CV
RN
A C
han
ge
fro
m B
asel
ine
(Lo
gfr
om
Bas
elin
e (L
og
1010
IU/m
L)
IU/m
L)
Triple Combo FailurePotent IFNPotent IFN-ribavirin effect-ribavirin effect
CUREDCURED
-5-5
-4-4
-3-3
-2-2
-1-1
00
11
Study TimeStudy Time
Med
ian
HC
V R
NA
Ch
ang
eM
edia
n H
CV
RN
A C
han
ge
fro
m B
asel
ine
(Lo
gfr
om
Bas
elin
e (L
og
1010
IU/m
L)
IU/m
L)
Triple Combo FailureModerate IFNModerate IFN-ribavirin effect-ribavirin effect
-5-5
-4-4
-3-3
-2-2
-1-1
00
11
Study TimeStudy Time
Med
ian
HC
V R
NA
Ch
ang
eM
edia
n H
CV
RN
A C
han
ge
fro
m B
asel
ine
(Lo
gfr
om
Bas
elin
e (L
og
1010
IU/m
L)
IU/m
L)
Triple Combo FailureModerate IFNModerate IFN-ribavirin effect-ribavirin effect
Wild-type, sensitive HCVWild-type, sensitive HCV
-5-5
-4-4
-3-3
-2-2
-1-1
00
11
Study TimeStudy Time
Med
ian
HC
V R
NA
Ch
ang
eM
edia
n H
CV
RN
A C
han
ge
fro
m B
asel
ine
(Lo
gfr
om
Bas
elin
e (L
og
1010
IU/m
L)
IU/m
L)
Triple Combo FailureModerate IFNModerate IFN-ribavirin effect-ribavirin effect
Wild-type, sensitive HCVWild-type, sensitive HCV
Resistant HCVResistant HCV
-5-5
-4-4
-3-3
-2-2
-1-1
00
11
Study TimeStudy Time
Med
ian
HC
V R
NA
Ch
ang
eM
edia
n H
CV
RN
A C
han
ge
fro
m B
asel
ine
(Lo
gfr
om
Bas
elin
e (L
og
1010
IU/m
L)
IU/m
L)
Triple Combo FailureModerate IFNModerate IFN-ribavirin effect-ribavirin effect
Wild-type, sensitive HCVWild-type, sensitive HCV
Resistant HCVResistant HCV
CUREDCUREDoror
RELAPSE with RESISTANT VIRUSRELAPSE with RESISTANT VIRUS
-5-5
-4-4
-3-3
-2-2
-1-1
00
11
Study TimeStudy Time
Med
ian
HC
V R
NA
Ch
ang
eM
edia
n H
CV
RN
A C
han
ge
fro
m B
asel
ine
(Lo
gfr
om
Bas
elin
e (L
og
1010
IU/m
L)
IU/m
L)
Triple Combo FailureModest or null IFNModest or null IFN-ribavirin effect-ribavirin effect
-5-5
-4-4
-3-3
-2-2
-1-1
00
11
Study TimeStudy Time
Med
ian
HC
V R
NA
Ch
ang
eM
edia
n H
CV
RN
A C
han
ge
fro
m B
asel
ine
(Lo
gfr
om
Bas
elin
e (L
og
1010
IU/m
L)
IU/m
L)
Triple Combo FailureModest or null IFNModest or null IFN-ribavirin effect-ribavirin effect
Wild-type, sensitive HCVWild-type, sensitive HCV
-5-5
-4-4
-3-3
-2-2
-1-1
00
11
Study TimeStudy Time
Med
ian
HC
V R
NA
Ch
ang
eM
edia
n H
CV
RN
A C
han
ge
fro
m B
asel
ine
(Lo
gfr
om
Bas
elin
e (L
og
1010
IU/m
L)
IU/m
L)
Triple Combo FailureModest or null IFNModest or null IFN-ribavirin effect-ribavirin effect
Wild-type, sensitive HCVWild-type, sensitive HCV
Resistant HCVResistant HCV
-5-5
-4-4
-3-3
-2-2
-1-1
00
11
Study TimeStudy Time
Med
ian
HC
V R
NA
Ch
ang
eM
edia
n H
CV
RN
A C
han
ge
fro
m B
asel
ine
(Lo
gfr
om
Bas
elin
e (L
og
1010
IU/m
L)
IU/m
L)
Triple Combo FailureModest or null IFNModest or null IFN-ribavirin effect-ribavirin effect
Wild-type, sensitive HCVWild-type, sensitive HCV
Resistant HCVResistant HCVRELAPSE or BREAKTHROUGHRELAPSE or BREAKTHROUGH
with RESISTANT VIRUSwith RESISTANT VIRUS
V
Prevention of Treatment Failures
Prevention of Treatment Failure
• Prediction of treatment failure (assessment of IFN-ribavirin responsiveness)
• Prevention of treatment failure in poor IFN responders
Weeks on therapyWeeks on therapy
363600 24241212 4848
SPRINT-2 TrialBoceprevir, Naïve, Genotype 1
6060 7272
*RVR = undetectable HCV RNA at week 4 of boceprevir treatment (i.e. at week 8)*RVR = undetectable HCV RNA at week 4 of boceprevir treatment (i.e. at week 8)
Boceprevir Boceprevir 800 mg tid 800 mg tid
+ + Peg-IFNPeg-IFN2b 2b + RBV+ RBV
Follow-upFollow-upPeg-IFNPeg-IFN2b 2b + RBV+ RBV
Peg-Peg-IFNIFN2b 2b + RBV+ RBV
Follow-upFollow-up
44
Peg-IFNPeg-IFN2b 2b + RBV+ RBV
Follow-upFollow-up
Peg-IFNPeg-IFN2b2b+ RBV+ RBV Follow-upFollow-up
no
RV
Rn
o R
VR
Boceprevir Boceprevir 800 mg tid 800 mg tid
+ + Peg-IFNPeg-IFN2b 2b + RBV+ RBV
Peg-Peg-IFNIFN2b 2b + RBV+ RBV
RV
RR
VR
2828
N >
100
0N
> 1
000
Weeks on therapyWeeks on therapy
363600 24241212 4848
REALIZE TrialTelaprevir, Nonresponders, Genotype 1
6060 7272
*eRVR = undetectable HCV RNA at week 4 and week 12*eRVR = undetectable HCV RNA at week 4 and week 12
Telaprevir Telaprevir 750 mg q8h 750 mg q8h
+ + Peg-IFNPeg-IFN2a 2a + RBV+ RBV
Follow-upFollow-upPeg-IFNPeg-IFN2a 2a + RBV+ RBV
Peg-Peg-IFNIFN2a 2a + RBV+ RBV
Peg-IFNPeg-IFN2a 2a + RBV+ RBV
Follow-upFollow-up
282844
Peg-IFNPeg-IFN2a 2a + RBV+ RBV Follow-upFollow-up
Telaprevir Telaprevir 750 mg q8h 750 mg q8h
+ + Peg-IFNPeg-IFN2a 2a + RBV+ RBV
N = 260N = 260
N = 260N = 260
N = 130N = 130
Prevention of Treatment Failure
• High-dose pegylated IFN and/or ribavirin in combination with protease inhibitors
• Quadruple therapy in order to increase the barrier to resistance of DAAs in combination with pegylated IFN and ribavirin
• IFN-free regimens with multiple DAAs
55%
26%
34%39%
21%
11%6%
53% 55%
0%
10%
20%
30%
40%
50%
60%
70%
W4 W12 W24
< 1 log10 HCV-RNA decrease
1 to 2 log10 HCV-RNA decrease
≥≥ 2 log10 HCV-RNA decrease
Undetectable HCV-RNA (<15 IU/mL)
1% 8%
22%
(Hézode et al., AASLD 2010)
High-Dose Pegylated IFN- and Ribavirin in Non-Responders
GS-9256 (PI) + Tegobuvir (NNI)
0 7 14 21 280
1
2
3
4
5
6
7
8
((<<2255 IIUU//mmLL))HC
V R
NA
IU
/mL
(L
og
)
Days
(Zeuzem et al., AASLD 2010)
GS-9256 + tegobuvir
GS-9256 (PI) + Tegobuvir (NNI)
0 7 14 21 280
1
2
3
4
5
6
7
8
((<<2255 IIUU//mmLL))
Days
(Zeuzem et al., AASLD 2010)
HC
V R
NA
IU
/mL
(L
og
)
GS-9256 + tegobuvir
GS-9256 + tegobuvir + ribavirin
BMS-650032 (PI) + BMS-790052 (NS5A)
0 1 2 3 4 6 8 10 121
2
3
4
5
6
7
0 1 2 3 4 6 8 10 12
1
2
3
4
5
6
7
Weeks
HC
V R
NA
(lo
g10
)H
CV
RN
A (
log
10)
No Peg/ribavirin
+Peg/ribavirin
Weeks
(Lok et al., AASLD 2010)
Danoprevir + RG7128 ComboINFORM-1 Trial
(Gane et al., Lancet 2010; published online)
Days DaysDays
Danoprevir, 900 mg bid + RG7128Danoprevir, 900 mg bid + pegIFNand ribavirin Increasing doses of danoprevir and RG7128
Conclusions
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 growth 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