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NS3 GT1a

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Asunaprevir

MutationEC50 (nM)Fold-shiftPhenotypeClinical RASReferenceComments
WT (1a_H77)0.761xlikely susceptible 24 nM in product label
A5V
Q9R
V36A2.33xlikely susceptible 2
V36F
V36Gresistance possibleYesClincal TE RAV (4)
V36I
V36L1.82xresistance possibleYes2,1Clnical VF RAV (1)
V36M1.52xresistance possibleYes2,1Clnical TE RAV (1,4)
V36T
V38G
A39V
T40A0.51xlikely susceptible 2
Q41H
Q41K
Q41L
Q41R
F43I
F43L2.74xlikely susceptible 2
F43S
F43V
I48V
T54A0.330.4xlikely susceptible 2
T54C
T54G
T54I
T54S0.741xresistance possibleYes2,4Clincal TE RAV (4)
V55Aresistance possibleYes1Clnical VF RAV (1)
V55I2.23xlikely susceptible 2
Y56F
Y56H
R62K0.741xlikely susceptible 2
P67S
V71A
D79E0.361xlikely susceptible 2
N77S
Q80G
Q80H
Q80I
Q80K2.5January 14, 1900resistance possibleYes2,4Clinical VF RAV (3,4)
Q80L0.91xresistance possibleYes2,4Clinical VF RAV (3,4)
Q80M
Q80N
Q80Rresistance possibleYes4Clincal TE RAV (4)
Q80S
Q89R
V107I
R109K
V113L
R109K
G120S
S122A
S122C
S122G0.651xresistance possibleYes2,4Clincal TE RAV (4)
S122Iresistance possibleYes4Clincal TE RAV (4)
S122N0.691xresistance possibleYes2,4Clincal TE RAV (4)
S122P
S122R2.63xlikely susceptible 2
S122Tresistance possibleYes4Clincal TE RAV (4)
S122V
R123M
I132V
I132L
I132T
V132I
S138T
P146S
S147A [Conflicting WT, not used in algorithm]
A150V
R155A
R155Gresistance possibleYes4Clincal VE RAV (4)
R155I
R155K1621xresistance likelyYes2,1,4Clinical TE RAV (1,4)
R155M
R155Qresistance possibleYes4Clincal VE RAV (4)
R155S
R155T
R155V
R155W
A156G
A156I
A156L
A156M
A156P
A156S
A156T
A156V
V158A
V158I
A166S
D168A1723xresistance likelyYes2,1,4Clinical TE RAV (1,4)
D168C
D168E4458xresistance likelyYes2,1,4Clinical TE RAV (1,4)
D168Fresistance possibleYes4Clincal VF RAV (4)
D168G1114xresistance likely
D168Hresistance possibleYes4Clincal VF RAV (4)
D168I
D168K
D168L
D168Nresistance possibleYes4Clincal VF RAV (4)
D168R
D168S
D168Tresistance possibleYes1,4Clinical TE RAV (1,4)
D168V283373xresistance likelyYes2,1Clinical TE RAV (1)
D168Y473622xresistance likelyYes2,1,4Clinical TE RAV (1,4)
I 170F
I 170T3.65xresistance possible 2
I170V0.671xlikely susceptible 2
N174S
N174Y11xlikely susceptible 2
N174R
L175M
T178I
T185S
I248V [Conflicting WT, not used in algorithm]
P264S
P334S
S342P
T343N
T344I
L356F
E357G
E357K
V358T
V406A
V406I
I407V
T449I
P470S
A477T
V511I
G534S
E555D
I586N
V629I
I660V
Q9Any+A156T
V36A+R155K4458xresistance likely2
V36L+Q80K45xresistance possible2
V36L+R155K
V36L+T54S
V36M+A156T
V36M+D168G
V36M+Q41R
V36M+Q80K
V36M+R155K55xresistance likely1
V36M+S122N
V36M+V55A
Q41K+Q80K
Q41R+Q89R
Q41R+A156T
Q41R+D168A
Q41R+D168E
Q41R+D168G
Q41R+D168H
Q41R+D168V
Q41R+I170V
Q41R+Q80K
F43L+Q80K
F43L+R155K
F43L+D168V
T54A+R155K
T54A+Q80K
T54S+Y56H
T54S+R155K
T54S+V55I
T54S+Q80L
V55A+D168E
V55A+Q80K
V55A+R155K
V55A+Q80R
V55I+A156P
V55I+Q80K
V55I+R155K
Y56F+Q80K
Y56H+A156G
Y56H+D168A
Y56H+D168E
Y56H+D168N
Y56H+D168V
Y56H+D168Y
V71A+I170V
Q80KR+D168E
Q80K+A156T
Q80K+D168A
Q80K+D168E184242xresistance likely2
Q80K+D168V542713xresistance likely2
Q80K+D168Y
Q80K+I170T
Q80K+R155K4660xresistance likely2,1
Q80K+R155G
Q80K+R155T
Q80K+S122N
Q80K+ I 170T
Q80L+D168E
Q80L+R155K
Q80L+S122N
Q80N+I170V
Q80R+A156T
Q80R+R155K
Q89R+A156T
Q89R+A156V
S122A+R155K
S122G+R155K
S122R+R155K
S122N+R155K
S122N+D168Y
S122T+R155K
A150V+A156T
R155K+D168A
R155K+D168E
R155K+D168V
R155K+D168N
R155K+ I 170T
R155K+I170T
R155K+I170V
R155K+N178G
R155K+P334S
R155K+S342P
R155K+T449I
R155K+V406A
R155N+D168E
R155T+D168N
R155W+A156G
A156G+D168A
A156T+D168N
A156V+D168E
D168A+I170T
D168V+P334S
D168V+S342P
D168V+E357K
D168V+V406A
D168V+V406I
D168V+L470S
D168V+T449I
D168Y+P334S
D168Y+S342P
D168Y+E357K
D168Y+V406A
D168Y+T449I
I170T+D168E
I170T+D168N
I170V+D168E
I170V+D168N
E357K+D168V
E357K+D168Y
E357K+R155K
E357K+D168Any
V 36L+Q80K+R155S
V36L+V55A+Q80K
V36L+Q80K+R155K
V36M+Q41R+D168G
V36M+Y56H+D168A
V36M+Y56H+D168E
V36M+Q80K+R155K
V36M+Q80K+S122N
V36M+R155K+I170V
V36M+T54S+R155K
V36M+T54S+V55I
V36M+V55A+Q80K
V36M+V107I+R155K
V36M+Y56H+D168A
V36M+Y56H+D168E
Q41H+Q80K+S122N
Q41H+Q80K+S122G
F43L+Q80R+R155K
T54A+Q80K+R155K
T54S+Q80K+R155K
T54S+R155T+D168N
T54S+V55I+Q80K
T54S+V55I+Q80L
T54S+V55I+R155K
T54S+Y56H+I170V
V55A+D168E+I170V
V55A+Q80K+R155K
V55A+R155K+D168E
Y56H+A156G+D168A
Q80K+D168E+I170V
Q80K+R155K+D168E
Q80K+R155K+D168G
Q80K+R155K+I170T
Q80K+R155T+D168N
Q80R+R155K+D168E
S122G+R155K+I170V
S122R+R155N+D168E
R155W+A156G+D168N
R155K+A156V+D168A
R155Q+A156S+D168G
F43L+Q80L+A156G+S342P
Q41K+F43L+Q80K+D168Y
T54S+S122G+R155K+I170V
T54S+V55A+Q80R+I170V
T54S+V55I+S122G+R155K
T54S+V55I+S122G+R155K+I170V
V55A+Q80R+D168E+I170V
V36A+V36M+F43L+D168H+E357K
V23A(NS4A)
V23V(NS4A)+D168V
V23V(NS4A)+D168Y
1. Lontok et al. (2015) HEPATOLOGY 62:1623-1632)
2. McPhee et al (2012) AAC 56(7):3670-3681  http://aac.asm.org/content/early/2012/04/12/AAC.00308-12.short
3. Manns M, et al. 2014. The Lancet 384: 1597-605
4. Sunvepra Canadian Product Monograph 2016

Boceprevir

MutationEC50 (nM)Fold-shiftClinical RASPhenotypeClinical RASReferenceComments
WT (1a_H77)1x likely susceptible1
A5V
Q9R
V36AYesresistance likelyYes1Clinical TE RAV (1)
V36F
V36G
V36I
V36L
V36MYesresistance likelyYes1Clinical TE RAV (1)
V36T
V38G
A39V
T40A
Q41H
Q41K
Q41L
Q41R
F43I
F43L
F43S
F43V
I48V
T54AYesresistance likelyYes1Clinical TE RAV (1)
T54C
T54G
T54I
T54SYesresistance likelyYes1Clinical TE RAV (1)
V55AYesresistance likelyYes1Clinical TE RAV (1)
V55IYesresistance likelyYes1Clinical TE RAV (1)
Y56F
Y56H
R62K
P67S
V71A
D79E
N77S
Q80G
Q80H
Q80I
Q80KJanuary 1, 1970
Q80L
Q80M
Q80N
Q80R
Q80S
Q89R
V107IYesresistance likelyYes1Clinical TE RAV (1)
R109K
V113L
R109K
G120S
S122A
S122C
S122G
S122I
S122N
S122P
S122R
S122T
S122V
R123M
I132V
I132L
I132T
V132I
S138T
P146S
S147A [Conflicting WT, not used in algorithm]
A150V
R155A
R155G
R155I
R155KYesresistance likelyYes1Clinical TE RAV (1)
R155M
R155Q
R155S
R155T
R155V
R155W
A156G
A156I
A156L
A156M
A156P
A156SYesresistance likelyYes1Clinical TE RAV (1)
A156TYesresistance likelyYes1Clinical TE RAV (1)
A156V
V158A
V158IYesresistance likelyYes1Clinical TE RAV (1)
A166S
D168A
D168C
D168E
D168F
D168G
D168H
D168I
D168K
D168L
D168NYesresistance likelyYes1Clinical TE RAV (1)
D168R
D168S
D168T
D168V
D168Y
I 170FYesresistance likelyYes1Clinical TE RAV (1)
I 170TYesresistance likelyYes1Clinical TE RAV (1)
I170VYesresistance likelyYes1Clinical TE RAV (1)
N174S
N174Y
N174R
L175M
T178I
T185S
I248V [Conflicting WT, not used in algorithm]
P264S
P334S
S342P
T343N
T344I
L356F
E357G
E357K
V358T
V406A
V406I
I407V
T449I
P470S
A477T
V511I
G534S
E555D
I586N
V629I
I660V
Q9Any+A156T
V36A+R155K
V36L+Q80K
V36L+R155K
V36L+T54S
V36M+A156T
V36M+D168G
V36M+Q41R
V36M+Q80K
V36M+R155K
V36M+S122N
V36M+V55A
Q41K+Q80K
Q41R+Q89R
Q41R+A156T
Q41R+D168A
Q41R+D168E
Q41R+D168G
Q41R+D168H
Q41R+D168V
Q41R+I170V
Q41R+Q80K
F43L+Q80K
F43L+R155K
F43L+D168V
T54A+R155K
T54A+Q80K
T54S+Y56H
T54S+R155K
T54S+V55I
T54S+Q80L
V55A+D168E
V55A+Q80K
V55A+R155K
V55A+Q80R
V55I+A156P
V55I+Q80K
V55I+R155K
Y56F+Q80K
Y56H+A156G
Y56H+D168A
Y56H+D168E
Y56H+D168N
Y56H+D168V
Y56H+D168Y
V71A+I170V
Q80KR+D168E
Q80K+A156T
Q80K+D168A
Q80K+D168E
Q80K+D168V
Q80K+D168Y
Q80K+I170T
Q80K+R155K
Q80K+R155G
Q80K+R155T
Q80K+S122N
Q80K+ I 170T
Q80L+D168E
Q80L+R155K
Q80L+S122N
Q80N+I170V
Q80R+A156T
Q80R+R155K
Q89R+A156T
Q89R+A156V
S122A+R155K
S122G+R155K
S122R+R155K
S122N+R155K
S122N+D168Y
S122T+R155K
A150V+A156T
R155K+D168A
R155K+D168E
R155K+D168V
R155K+D168N
R155K+ I 170T
R155K+I170T
R155K+I170V
R155K+N178G
R155K+P334S
R155K+S342P
R155K+T449I
R155K+V406A
R155N+D168E
R155T+D168N
R155W+A156G
A156G+D168A
A156T+D168N
A156V+D168E
D168A+I170T
D168V+P334S
D168V+S342P
D168V+E357K
D168V+V406A
D168V+V406I
D168V+L470S
D168V+T449I
D168Y+P334S
D168Y+S342P
D168Y+E357K
D168Y+V406A
D168Y+T449I
I170T+D168E
I170T+D168N
I170V+D168E
I170V+D168N
E357K+D168V
E357K+D168Y
E357K+R155K
E357K+D168Any
V 36L+Q80K+R155S
V36L+V55A+Q80K
V36L+Q80K+R155K
V36M+Q41R+D168G
V36M+Y56H+D168A
V36M+Y56H+D168E
V36M+Q80K+R155K
V36M+Q80K+S122N
V36M+R155K+I170V
V36M+T54S+R155K
V36M+T54S+V55I
V36M+V55A+Q80K
V36M+V107I+R155K
V36M+Y56H+D168A
V36M+Y56H+D168E
Q41H+Q80K+S122N
Q41H+Q80K+S122G
F43L+Q80R+R155K
T54A+Q80K+R155K
T54S+Q80K+R155K
T54S+R155T+D168N
T54S+V55I+Q80K
T54S+V55I+Q80L
T54S+V55I+R155K
T54S+Y56H+I170V
V55A+D168E+I170V
V55A+Q80K+R155K
V55A+R155K+D168E
Y56H+A156G+D168A
Q80K+D168E+I170V
Q80K+R155K+D168E
Q80K+R155K+D168G
Q80K+R155K+I170T
Q80K+R155T+D168N
Q80R+R155K+D168E
S122G+R155K+I170V
S122R+R155N+D168E
R155W+A156G+D168N
R155K+A156V+D168A
R155Q+A156S+D168G
F43L+Q80L+A156G+S342P
Q41K+F43L+Q80K+D168Y
T54S+S122G+R155K+I170V
T54S+V55A+Q80R+I170V
T54S+V55I+S122G+R155K
T54S+V55I+S122G+R155K+I170V
V55A+Q80R+D168E+I170V
V36A+V36M+F43L+D168H+E357K
V23A(NS4A)
V23V(NS4A)+D168V
V23V(NS4A)+D168Y
1. Lontok et al. (2015) HEPATOLOGY 62:1623-1632)

Glecaprevir

MutationEC50 (nM)Fold-shiftPhenotypeClinical RASReplicative Fitness (7)ReferenceComments
WT (1a_H77)0.211xlikely susceptible 1002,1,70.21-0.85, clinical isolate=0.3 (0.05-3.8)
A5V
Q9R
V36A0.180.8xresistance possibleYes1307Clinical TE RAV (7)
V36Fresistance possibleYes7Clincial VF RAS, 3% (7)
V36G
V36I
V36L0.160.8xlikely susceptible 827
V36M0.281.4xresistance possibleYes815,7Clinical BT RAS (5,7)
V36T
V38G
A39V
T40A
Q41H
Q41K
Q41L
Q41R0.331.6xlikely susceptible 367
F43I
F43L0.050.3xlikely susceptible 177
F43S
F43V
I48V
T54A
T54C
T54G
T54I
T54S0.21xlikely susceptible 6.27,6
V55Aresistance possibleYes7Clinical VF RAV (7)
V55I0.050.2xresistance possibleYes817Clinical VF RAV (7)
Y56F
Y56H0.210.1xresistance possibleYes3.55,7Clinical VF RAS, 13% NGS (5,7)
R62K
P67S
V71A0.090.4xlikely susceptible 1.47
D79E
N77S
Q80G
Q80H
Q80I
Q80K0.190.9xresistance possibleYes916,7Clincial VF RAV (7)
Q80L0.442.1xresistance possibleYes387Clinical VF RAV, 99% NGS (7)
Q80M
Q80N
Q80R0.271.3xlikely susceptible 447
Q80S
Q89R0.341.6xlikely susceptible 1057
V107I
R109K
V113L
R109K
G120S
S122A
S122C
S122G1xresistance possibleYes8Clinical TE RAS (8)
S122I
S122N
S122P
S122R
S122T
S122V
R123M
I132Vresistance possibleYes7Clinical TE RAS (7)
I132L
I132T
V132I7Clinical TE RAV (7). wrong ref aa
S138T
P146S
S147A [Conflicting WT, not used in algorithm]
A150V0.10.5xlikely susceptible 667
R155A
R155G2
R155I
R155K0.110.5xresistance possibleYes317,2,8Clinical TE RAV (7,8)
R155M0.180.9xlikely susceptible 5.67
R155Q
R155S0.341.6xlikely susceptible 2.17
R155T0.391.9xresistance possibleYes5.17Clinical TE RAV (7)
R155V0.211xlikely susceptible 207
R155Wresistance possible8Clinical BT RAS (8)
A156G0.130.6xresistance possibleYes457,8Clinical TE RAV (7,8)
A156I
A156L
A156M
A156P
A156S
A156T2901400xresistance likelyYes5.22,6,7,8Clinical TE RAV (7,8)
A156Vunfit resistance possibleYes<0.52,3,5,7,8Clinical TE&BT RAV (3,5,7,8)
V158A
V158I
A166S
D168A0.844xresistance likelyYes357,2,5Clinical BT RAS (5,7)
D168C
D168E0.271.3xresistance possibleYes347,8Clinical BT RAV (7,8)
D168F11.555xresistance likely 47
D168G
D168H0.914.3xresistance possible 247
D168I
D168K
D168L
D168N0.080.4xlikely susceptible 287
D168R
D168S
D168Tresistance possibleYes5,7Clinical BT RAS (5,7)
D168V0.934.4xresistance possible 1.57
D168Y8.641xresistance likelyYes3.57Clincial VF RAS,2% (7)
I 170F
I 170T0.10.5xlikely susceptible 9.97
I170V0.21xlikely susceptible 777,6
N174S
N174Y
N174R
L175M
T178I
T185S
I248V [Conflicting WT, not used in algorithm]
P264S
P334S0.120.6xlikely susceptible 977
S342P0.10.5xlikely susceptible 927
T343N
T344I
L356F
E357G
E357K0.341.6xlikely susceptible 1317
V358T
V406A0.170.8xlikely susceptible 977
V406I0.140.7xlikely susceptible 927
I407V
T449I0.160.8xlikely susceptible 857
P470Sunfit<0.57
A477T
V511I
G534S
E555D
I586N
V629I
I660V
Q9Any+A156T
V36A+R155K
V36L+Q80K
V36L+R155K
V36L+T54S
V36M+A156T
V36M+D168G
V36M+Q41R
V36M+Q80K
V36M+R155K0.140.7xlikely susceptible297
V36M+S122N
V36M+V55A
Q41K+Q80K
Q41R+Q89R0.311.5xlikely susceptible227
Q41R+A156T
Q41R+D168A
Q41R+D168E1.78xresistance possible1547
Q41R+D168G
Q41R+D168H
Q41R+D168V
Q41R+I170Vunfit <0.57
Q41R+Q80K
F43L+Q80K
F43L+R155K0.160.8xlikely susceptible7.27
F43L+D168V2.713xresistance likely237
T54A+R155K
T54A+Q80K
T54S+Y56H
T54S+R155K
T54S+V55I
T54S+Q80L
V55A+D168E
V55A+Q80K
V55A+R155K
V55A+Q80R
V55I+A156P
V55I+Q80K
V55I+R155K
Y56F+Q80K
Y56H+A156G<0.57
Y56H+D168A8.239xresistance likely467
Y56H+D168E9.847xresistance likely4.77
Y56H+D168N
Y56H+D168V8.942xresistance likely157
Y56H+D168Y9.445xresistance likely1.17
V71A+I170V0.73.3xresistance possible17
Q80KR+D168E
Q80K+A156T
Q80K+D168A0.783.7xresistance possible287
Q80K+D168E
Q80K+D168V1.46.9xresistance possible57
Q80K+D168Y1048xresistance likely27
Q80K+I170T
Q80K+R155K0.090.4xlikely susceptible0.47
Q80K+R155G1.27.4xresistance possible5.87
Q80K+R155T
Q80K+S122N
Q80K+ I 170T
Q80L+D168E
Q80L+R155K
Q80L+S122N
Q80N+I170V
Q80R+A156T7503700xresistance likely7,2
Q80R+R155K
Q89R+A156T7533583xresistance likely17,2
Q89R+A156V229410922xresistance likely27
S122A+R155K
S122G+R155K
S122R+R155K
S122N+R155K
S122N+D168Y
S122T+R155K
A150V+A156Tunfit<0.57
R155K+D168A
R155K+D168E
R155K+D168V
R155K+D168N
R155K+ I 170T
R155K+I170T
R155K+I170V
R155K+N178G
R155K+P334S0.060.3xlikely susceptible687
R155K+S342P0.060.3xlikely susceptible207
R155K+T449I0.080.4xlikely susceptible867
R155K+V406A0.080.4xlikely susceptible7
R155N+D168E
R155T+D168N5.928xresistance likely527
R155W+A156Gresistance likely8Clinical BT RAS (8)
A156G+D168A6.732xresistance likely9.17
A156T+D168N
A156V+D168Eresistance likely8Clinical BT RAS (8)
D168A+I170T
D168V+P334S1.15.1xresistance possible127
D168V+S342P0.683.2xresistance possible287
D168V+E357K6.430xresistance likely247
D168V+V406A1.46.7xresistance possible8.17
D168V+V406I0.492.3xlikely susceptible137
D168V+L470Sunfit<0.5
D168V+T449I10.650xresistance likely187
D168Y+P334S9.947xresistance likely1.47
D168Y+S342P5.426xresistance likely117
D168Y+E357K15.172xresistance likely8.27
D168Y+V406A10.952xresistance likely1.57
D168Y+T449I10.650resistance likely3.37
I170T+D168E0.251.2xlikely susceptible217
I170T+D168N0.212.5xlikely susceptible5.37
I170V+D168E0.180.9xlikely susceptible227
I170V+D168N0.090.4xlikely susceptible267
E357K+D168V
E357K+D168Y
E357K+R155K
E357K+D168Any
V 36L+Q80K+R155S
V36L+V55A+Q80K
V36L+Q80K+R155K
V36M+Q41R+D168G
V36M+Y56H+D168A33.9162xresistance likely357
V36M+Y56H+D168E26.7127xresistance likely1.67
V36M+Q80K+R155K
V36M+Q80K+S122N
V36M+R155K+I170V
V36M+T54S+R155K
V36M+T54S+V55I
V36M+V55A+Q80K
V36M+V107I+R155K
V36M+Y56H+D168A33.9162xresistance likely7
V36M+Y56H+D168E26.7127xresistance likely7
Q41H+Q80K+S122N
Q41H+Q80K+S122G
F43L+Q80R+R155K
T54A+Q80K+R155K
T54S+Q80K+R155K
T54S+R155T+D168N
T54S+V55I+Q80K
T54S+V55I+Q80L
T54S+V55I+R155K
T54S+Y56H+I170V
V55A+D168E+I170V
V55A+Q80K+R155K
V55A+R155K+D168E
Y56H+A156G+D168Aunfit <0.57
Q80K+D168E+I170V
Q80K+R155K+D168E
Q80K+R155K+D168G
Q80K+R155K+I170T
Q80K+R155T+D168N
Q80R+R155K+D168E
S122G+R155K+I170V
S122R+R155N+D168E
R155W+A156G+D168N
R155K+A156V+D168Aunfit <0.57
R155Q+A156S+D168G
F43L+Q80L+A156G+S342P
Q41K+F43L+Q80K+D168Y
T54S+S122G+R155K+I170V
T54S+V55A+Q80R+I170V
T54S+V55I+S122G+R155K
T54S+V55I+S122G+R155K+I170V
V55A+Q80R+D168E+I170V
V36A+V36M+F43L+D168H+E357K
V23A(NS4A)0.361.7xlikely susceptible7
V23V(NS4A)+D168Vunfit<0.57
V23V(NS4A)+D168Y7.134xresistance likely187
1. Poordad F, et al. 2016. In vitro 1: 3
2. Ng et al.   [Abstract 636]. -CROI. Boston, 2014 http://www.croiconference.org/sites/all/abstracts/636.pdf
3. Krishnan et al.  EASL 2017.. http://natap.org/2017/EASL/EASL_18.htm
4. Kwo PY, et al. 2017. Journal of Hepatology 67: 263-71
5.  Poordad et al. (2017) Hepatology 66:389-397  https://www.ncbi.nlm.nih.gov/pubmed/28128852
6 Ng et al AASLD 2015 http://www.natap.org/2015/AASLD/AASLD_25.htm
7. FDA Microbiology Review https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209394Orig1s000MicroR.pdf
8. M. S. Sulkowski et al., in 2018 AASLD. http://www.natap.org/2018/AASLD/AASLD_20.htm

Grazoprevir

MutationEC50 (nM)Fold-shiftPhenotypeClinical RAS ReferenceCommentsSVR with BL RAS in a 12-wk Rx
WT (1a_H77)0.31xlikely susceptible 10.95
A5V
Q9R0.9xlikely susceptible 10
V36A0.51.7xresistance possibleYes2,6Clinical TE RAV (2)1
V36F
V36G
V36I1xlikely susceptible 9
V36L0.51.7xresistance possibleYes2,4,1,5,9Clinical TE RAV (4,1,9)
V36M0.31xresistance possibleYes2,3,4,1,5,9Clinical TE RAV (4,1,2,3,9) 1
V36T
V38G
A39V0.3xlikely susceptible 9
T40A
Q41H
Q41K
Q41L
Q41R9.2xresistance possible 10,9stable replicon=2.2x (9)
F43I
F43L1.9xlikely susceptible 9
F43S
F43V
I48Vresistance possibleYes9Clinical TE RAV (9)
T54A0.7xlikely susceptible 9
T54C
T54G
T54I
T54S0.31.1xlikely susceptible 6,5,9
V55A0.51.7xresistance possibleYes2,5,9Clincial VF RAV (9)0
V55I0.20.6xlikely susceptible 5,9
Y56F1.1xresistance possibleYes1,6Clinical TE RAV (1,6)
Y56H31xresistance likelyYes1,3,4,6,5,9Clinical TE RAV (4,9)
R62K
P67S0.4xlikely susceptible 10
V71A
D79E
N77S
Q80G
Q80H
Q80I
Q80K0.58.1xresistance likelyYes9,2,3,6,5,10Clincial TE RAV (9), stable replicon=1.1x
Q80L17xresistance likely 9
Q80M
Q80N
Q80R0.41.3xlikely susceptible 2,9
Q80Sresistance possibleYes9Clinical VF RAV (9)
Q89R0.7xlikely susceptible 10
V107I0.7xresistance possibleYes3,4,1,9Clinical TE RAV (4,1,9)
R109K2xlikely susceptible 9
V113L0.5xlikely susceptible 10
R109K2.0xlikely susceptible 9
G120S
S122A0.7xlikely susceptible 9
S122C
S122G0.30.4xresistance possibleYes5,2,9Clinical TE RAV (5,2)
S122I
S122N
S122P
S122R3xlikely susceptible 3,6,5,9
S122T2.2xresistance possibleYes5Clinical TE RAV (1)
S122V
R123M
I132V0.8xresistance possibleYes9Clincial VF RAV (9)
I132L
I132T0.8xlikely susceptible 9
V132I
S138T
P146S2.4xlikely susceptible 9
S147A [Conflicting WT, not used in algorithm]
A150V
R155A
R155Gresistance possibleYes2Clinical TE RAV (2)
R155Iresistance possibleYes4,1,9Clinical TE RAV (4,9)
R155K1.39.3xresistance likelyYes2,4,1,6,10,9Clinical TE RAV (4,9), stable replicon=4.3x0.87
R155M
R155Q35xresistance likely 8
R155Sresistance possibleYes2Clinical TE RAV (2)
R155T9.7xresistance likelyYes9Clinical VF RAV (9)
R155V
R155W21.9xresistance likelyYes9Clinical TE RAS (5)
A156G45xresistance likelyYes1,4,9Clinical TE RAV (4,1,7,3,9)
A156I
A156L9182295xresistance likelyYes5,9Clinical TE RAV (5,7)
A156M
A156P
A156S3xlikely susceptible 6,91
A156Tunfit197xresistance likelyYes10,4,1,2,3,5,9,7Clinical TE RAV (4,1,2,3,5,9,7)1
A156Vunfit>100xresistance likelyYes4,1,3,9Clinical TE RAV (4,1,3,9). SEAP
V158Aresistance possibleYes4,1,9Clinical TE RAV (4,1,9)
V158I0.3xLikely susceptible 9
A166S
D168A7695-228xresistance likelyYes1,2,3,4,6,5,10,9Clinical TE RAV (4,1,2,3,5,9)
D168Cresistance possibleYes1,9Clinical TE RAV (1), D168x(9)
D168E12.841xresistance likelyYes9,1,2,4,5,10,9Clinical TE RAV (5,1,2,4,9), stable replicon=16x0
D168F16.821xresistance likely 1
D168G25.632xresistance likelyYes1,2,4,9Clinical TE RAV (4,9)
D168H9.612xresistance likely 1,9
D168I3240xresistance likely 1,9
D168K169.6212xresistance likelyYes1,9Clinical TE RAV (2)
D168L8.811xresistance likely 1,9
D168N6.437xresistance likelyYes9,1,3,4,5Clinical TE RAV (4,1,3,5,9), stable replicon=3x0
D168R
D168S2.3xLikely susceptible 4,9
D168T78.498xresistance likelyYes1,5,9Clinical TE RAV (5)
D168V44.856-122xresistance likelyYes1,3,4,5,10,9Clinical TE RAV (4,1,3,5,9)0
D168Y83.2104xresistance likelyYes1,3,4,6,5,9Clinical TE RAV (4,1,3,5,9)
I 170F
I 170T0.72.3xLikely susceptible 2,6.7,5
I170V0.112.3xresistance possibleYes5Clinical TE RAV (5), stable replicon=0.3x
N174S
N174Y
N174R
L175M
T178I
T185Sresistance possibleYes9Clinical TE RAV (9)
I248V [Conflicting WT, not used in algorithm]
P264S
P334S
S342P
T343N
T344I
L356F
E357Gresistance possibleYes9Clinical TE RAV (9)
E357Kresistance possibleYes9Clinical TE RAV (9)
V358T
V406A
V406I
I407V
T449I
P470S
A477T
V511I
G534S
E555D
I586N
V629I
I660V
Q9Any+A156T155xresistance likely10
V36A+R155K
V36L+Q80K1.4xlikely susceptible9,2
V36L+R155K
V36L+T54S
V36M+A156T481xresistance likely3
V36M+D168G
V36M+Q41R
V36M+Q80K
V36M+R155K9.9xresistance possible91
V36M+S122N
V36M+V55A
Q41K+Q80K
Q41R+Q89R
Q41R+A156T
Q41R+D168A167xresistance likely10
Q41R+D168E
Q41R+D168G
Q41R+D168H
Q41R+D168V100xresistance likely10
Q41R+I170V
Q41R+Q80K
F43L+Q80K
F43L+R155K
F43L+D168V
T54A+R155K
T54A+Q80K
T54S+Y56H
T54S+R155K5.7xresistance possible9
T54S+V55I
T54S+Q80L
V55A+D168E
V55A+Q80K
V55A+R155K
V55A+Q80R13xresistance likely9
V55I+A156P
V55I+Q80K
V55I+R155K
Y56F+Q80K
Y56H+A156G
Y56H+D168A974xresistance likely9,3
Y56H+D168E
Y56H+D168N61xresistance likely3,9
Y56H+D168V
Y56H+D168Y
V71A+I170V
Q80KR+D168E
Q80K+A156T
Q80K+D168A
Q80K+D168E
Q80K+D168V
Q80K+D168Y
Q80K+I170T
Q80K+R155K41.5xresistance likely9
Q80K+R155G
Q80K+R155T
Q80K+S122N
Q80K+ I 170T
Q80L+D168E
Q80L+R155K
Q80L+S122N
Q80N+I170V
Q80R+A156T
Q80R+R155K
Q89R+A156T538xresistance likely10
Q89R+A156V
S122A+R155K7.4xresistance possible9
S122G+R155K10.7xresistance likely9
S122R+R155K7xresistance possible9
S122N+R155K5.6xresistance possible9
S122N+D168Y
S122T+R155K6.7xresistance possible9
A150V+A156T
R155K+D168A7.0xresistance possible9
R155K+D168E3.7xlikely susceptible9
R155K+D168V7.4xresistance possible9
R155K+D168N7.6xresistance possible9
R155K+ I 170T
R155K+I170T
R155K+I170V
R155K+N178G
R155K+P334S
R155K+S342P
R155K+T449I
R155K+V406A
R155N+D168E
R155T+D168N11.7xresistance likely9
R155W+A156G32.6xresistance likely9
A156G+D168A
A156T+D168N8929xresistance likely9transient replicon=3978x
A156V+D168E
D168A+I170T
D168V+P334S
D168V+S342P
D168V+E357K
D168V+V406A
D168V+V406I
D168V+L470S
D168V+T449I
D168Y+P334S
D168Y+S342P
D168Y+E357K
D168Y+V406A
D168Y+T449I
I170T+D168E
I170T+D168N
I170V+D168E
I170V+D168N
E357K+D168V
E357K+D168Y
E357K+R155K
E357K+D168Any
V 36L+Q80K+R155S1451xresistance likely2,9
V36L+V55A+Q80K
V36L+Q80K+R155K
V36M+Q41R+D168G
V36M+Y56H+D168A
V36M+Y56H+D168E
V36M+Q80K+R155K
V36M+Q80K+S122N
V36M+R155K+I170V
V36M+T54S+R155K
V36M+T54S+V55I
V36M+V55A+Q80K
V36M+V107I+R155K10.6xresistance likely9
V36M+Y56H+D168A
V36M+Y56H+D168E
Q41H+Q80K+S122N
Q41H+Q80K+S122G
F43L+Q80R+R155K
T54A+Q80K+R155K
T54S+Q80K+R155K
T54S+R155T+D168N
T54S+V55I+Q80K
T54S+V55I+Q80L
T54S+V55I+R155K
T54S+Y56H+I170V
V55A+D168E+I170V
V55A+Q80K+R155K
V55A+R155K+D168E
Y56H+A156G+D168A17000xresistance likely9
Q80K+D168E+I170V
Q80K+R155K+D168E
Q80K+R155K+D168G
Q80K+R155K+I170T
Q80K+R155T+D168N
Q80R+R155K+D168E
S122G+R155K+I170V
S122R+R155N+D168E
R155W+A156G+D168N4763xresistance likely9
R155K+A156V+D168A
R155Q+A156S+D168G111.1xresistance likely9
F43L+Q80L+A156G+S342P
Q41K+F43L+Q80K+D168Y
T54S+S122G+R155K+I170V
T54S+V55A+Q80R+I170V
T54S+V55I+S122G+R155K
T54S+V55I+S122G+R155K+I170V
V55A+Q80R+D168E+I170V
V36A+V36M+F43L+D168H+E357K
V23A(NS4A)
V23V(NS4A)+D168V
V23V(NS4A)+D168Y
1. Zapatier Product Label (Canada)
2. Howe et al. (2014) CID 59(12): 1657-1665.
3. Black et al (2015) EASL PO0891
4. Zepatier US Product Label
5. Bonsall et al. (2018) Infection and Drug Resistance (in press)
6. Lahser et al (2016) Antimicrob Agents Chemother. 60: 2954-2964
7.  Lahser et al . AASLD 2016  http://www.natap.org/2016/AASLD/AASLD_61.htm (EN)
8. Jenssen et al Antimicrobial agents and chemotherapy 2015; 59(12): 7426-36.
9. FDA Zepatier Microbiology/Virology Review_208261Orig1s000MicroR
10. FDA Microbiology/Virology Reviews VoseviMicrobiology Reviews_2091950Orig1a000MicroR

Paritaprevir

MutationEC50 (nM)Fold-shiftPhenotypeClinical RASReferenceComments
WT (1a_H77)0.861xlikely susceptible 2, 1
A5V
Q9R
V36A3xresistance possibleYes1,5,6 ,3 ,8Clinical TE RAV (5,2,6,8); clinical VF RAV (3,8)
V36F
V36G
V36I
V36L2xlikely susceptible 1,8
V36M2xresistance possibleYes1,5,6,2 ,3 ,8Clinical TE RAV (5,2,6,8); clinical VF RAV (3,8)
V36Tresistance possibleYes2,8Clinical TE RAV (2,8)
V38G
A39V
T40A
Q41H
Q41K
Q41L
Q41R
F43I
F43L20xresistance likelyYes1,2,6,7,8Clinical TE RAV ( 2, 6,8)
F43S
F43V
I48V
T54A
T54C
T54G
T54I
T54S0.4xlikely susceptible 1
V55A
V55I1xresistance possibleYes2,6 ,3 ,8Clinical TE RAV (2,6,8); clinical VF RAV (3)
Y56F
Y56H3xresistance possibleYes5,2, 6,8Clinical TE RAV (5, 3, 2, 6,7,8)
R62K
P67S
V71A
D79E
N77S
Q80G
Q80H
Q80I
Q80K3xresistance possibleYes1,2, 6,7,8Clinical RAV(8). 89% (BLQ80K) vs. 97% (WT)
Q80L2xresistance possibleYes1,2,8Clinical TE RAV (2,8)
Q80M
Q80N
Q80R2xlikely susceptible 1
Q80S
Q89R
V107I
R109K
V113L
R109K
G120S
S122A
S122C
S122G
S122I
S122N
S122P
S122R
S122T
S122V
R123M
I132Vresistance possibleYes2,6,8Clinical TE RAV (2,6,8)
I132L
I132T
V132I
S138T
P146S
S147A [Conflicting WT, not used in algorithm]
A150V
R155A
R155G14xresistance likelyYes1,7,2,8Clinical VF RAV (7)
R155I
R155K4.440xresistance likelyYes8,5,3,2,6,7,1Clinical TE RAV (5,2 ,6,8 ); clinical VF RAV (3,7)
R155M1xlikely susceptible 8
R155Q
R155S7xresistance possible 1,7,2,8
R155T7xresistance likelyYes1,7,8Clinical VF RAV (7)
R155V5xresistance possible 8
R155W11xresistance likely 1,7,8
A156Gresistance possibleYes2,8Clinical TE RAV (2,8)
A156I
A156L
A156M
A156P
A156S
A156T17xresistance likely 1,6,2,7,8replicon RAV
A156Vunfit7,8
V158A
V158I
A166S
D168A50xresistance likelyYes1,5,3,2,6,7,8Clinical TE RAV (2,6,8); clinical VF RAV (3,5)
D168C
D168E14xresistance likelyYes1, 3, 6,7,8clinical VF RAV (3,7)
D168F206xresistance likelyYes6, 2,7,8Clinical TE RAV (2,8)
D168G
D168H62xresistance likelyYes1,2, 6,7,8Clinical TE RAV (2,6,8)
D168I50 - 219xresistance likelyYes6, 2,8Clinical TE RAV (2,8)
D168K96873xresistance likely 8
D168L50 - 219xresistance likelyYes6, 2,8Clinical TE RAV (2,8)
D168N13xresistance likelyYes1,2, 6,7,8Clinical TE RAV (2,8)
D168R
D168S
D168T50 - 219xresistance likelyYes6, 2,8Clinical TE RAV (2,8)
D168V13596xresistance likelyYes1,3,4, 5, 2, 6,7,8Clinical TE RAV (5,2,6,8); clinical VF RAV (3,4)
D168Y307219xresistance likelyYes1, 5, 3, 2, 6,7,8Clinical TE RAV (5,2,6); clinical VF RAV (3)
I 170F
I 170T
I170V
N174S
N174Y
N174R
L175M
T178I
T185S
I248V [Conflicting WT, not used in algorithm]
P264S
P334Sresistance possibleYes2,8Clinical TE RAV (2,8), helicase domain
S342Presistance possibleYes2,8Clinical TE RAV (2,8), helicase domain
T343N
T344I
L356F
E357G
E357K2.42xresistance possibleYes2,6,8Clinical TE RAV (2,6,8), helicase domain
V358T
V406Aresistance possibleYes2,8Clinical TE RAV (2,8), helicase domain
V406Iresistance possibleYes2,8Clinical TE RAV (2,8), helicase domain
I407V
T449Iresistance possibleYes2,8Clinical TE RAV (2,8), helicase domain
P470Sresistance possibleYes2,8Clinical TE RAV (2,8), helicase domain
A477T
V511I
G534S
E555D
I586N
V629I
I660V
Q9Any+A156T
V36A+R155K9669xresistance likely8
V36L+Q80K
V36L+R155K
V36L+T54S
V36M+A156T
V36M+D168G
V36M+Q41R
V36M+Q80K
V36M+R155K11179xresistance likely1, 5, 3, 6,8+2-7x vs. single R155K or D168any (2)
V36M+S122N
V36M+V55A
Q41K+Q80K
Q41R+Q89R
Q41R+A156T
Q41R+D168A
Q41R+D168E
Q41R+D168G
Q41R+D168H
Q41R+D168V
Q41R+I170V
Q41R+Q80K
F43L+Q80K
F43L+R155K13999xresistance likely8
F43L+D168V246176xresistance likely8
T54A+R155K
T54A+Q80K
T54S+Y56H
T54S+R155K
T54S+V55I
T54S+Q80L
V55A+D168E
V55A+Q80K
V55A+R155K
V55A+Q80R
V55I+A156P
V55I+Q80K
V55I+R155K
Y56F+Q80K
Y56H+A156G
Y56H+D168A483352xresistance likely6,1,8+2-7x vs. single R155K or D168any (2)
Y56H+D168E
Y56H+D168N>26xresistance likely6,1+2-7x vs. single R155K or D168any (2)
Y56H+D168V785561xresistance likely3,8clinical VF RAV (5)
Y56H+D168Y632451xresistance likely5,8
V71A+I170V
Q80KR+D168E
Q80K+A156T
Q80K+D168A10877xresistance likely8
Q80K+D168E
Q80K+D168V340243xresistance likely8
Q80K+D168Y468334xresistance likely8
Q80K+I170T
Q80K+R155K2719xresistance likely1,8
Q80K+R155G
Q80K+R155T
Q80K+S122N
Q80K+ I 170T
Q80L+D168E
Q80L+R155K
Q80L+S122N
Q80N+I170V
Q80R+A156T
Q80R+R155K
Q89R+A156T
Q89R+A156V
S122A+R155K
S122G+R155K
S122R+R155K
S122N+R155K
S122N+D168Y
S122T+R155K
A150V+A156T
R155K+D168A
R155K+D168E
R155K+D168V
R155K+D168N
R155K+ I 170T
R155K+I170T
R155K+I170V
R155K+N178G
R155K+P334S
R155K+S342P
R155K+T449I
R155K+V406A
R155N+D168E
R155T+D168N8863xresistance likely8
R155W+A156G
A156G+D168A
A156T+D168N
A156V+D168E
D168A+I170T
D168V+P334S
D168V+S342P
D168V+E357K
D168V+V406A
D168V+V406I
D168V+L470S
D168V+T449I
D168Y+P334S
D168Y+S342P
D168Y+E357K
D168Y+V406A
D168Y+T449I
I170T+D168E
I170T+D168N
I170V+D168E
I170V+D168N
E357K+D168V574410xresistance likely8
E357K+D168Y487348xresistance likely8
E357K+R155K >74xresistance likely2,6,1+2-7x vs. single R155K or D168any (2)
E357K+D168Any>26xresistance likely2,6,1+2-7x vs. single R155K or D168any (2)
V 36L+Q80K+R155S
V36L+V55A+Q80K
V36L+Q80K+R155K
V36M+Q41R+D168G
V36M+Y56H+D168A
V36M+Y56H+D168E
V36M+Q80K+R155K
V36M+Q80K+S122N
V36M+R155K+I170V
V36M+T54S+R155K
V36M+T54S+V55I
V36M+V55A+Q80K
V36M+V107I+R155K
V36M+Y56H+D168A
V36M+Y56H+D168E
Q41H+Q80K+S122N
Q41H+Q80K+S122G
F43L+Q80R+R155K
T54A+Q80K+R155K
T54S+Q80K+R155K
T54S+R155T+D168N
T54S+V55I+Q80K
T54S+V55I+Q80L
T54S+V55I+R155K
T54S+Y56H+I170V
V55A+D168E+I170V
V55A+Q80K+R155K
V55A+R155K+D168E
Y56H+A156G+D168A
Q80K+D168E+I170V
Q80K+R155K+D168E
Q80K+R155K+D168G
Q80K+R155K+I170T
Q80K+R155T+D168N
Q80R+R155K+D168E
S122G+R155K+I170V
S122R+R155N+D168E
R155W+A156G+D168N
R155K+A156V+D168A
R155Q+A156S+D168G
F43L+Q80L+A156G+S342P2Clinical TE RAV (2), helicase domain
Q41K+F43L+Q80K+D168Y
T54S+S122G+R155K+I170V
T54S+V55A+Q80R+I170V
T54S+V55I+S122G+R155K
T54S+V55I+S122G+R155K+I170V
V55A+Q80R+D168E+I170V
V36A+V36M+F43L+D168H+E357K6
V23A(NS4A)
V23V(NS4A)+D168V
V23V(NS4A)+D168Y
1. Pilot-Matias et al. (2015) AAC 59(2):988-997
2. Viekira Pak US Product Label Jan 28, 2016
3. Lontok et al. (2015) HEPATOLOGY 62:1623-1632)
4. Poordad et al (2014) NEJM 370 (21):1973 – 1982
5. Krishnan et al (2015) AAC 59(9): 5445 – 5453
6. Holkira Canadian Product Monograph Oct 14, 2015
7. Sulkowski et al (2016) CROI poster 16LB-3113
8.  FDA NDA Microbiology/Virology Review Veikira Pak_ 206619Orig1s000

Simeprevir

MutationEC50 (nM)Fold-shiftPhenotypeClinical RASReferenceVF in SMV+P/R (#pts) (4)Comments
WT (1a_H77)221xlikely susceptible5,2
A5Vresistance possibleYes2Clinical TE RAS (4)
Q9R0.8xlikely susceptible 5
V36A
V36F
V36G
V36I
V36L8xresistance possible 3
V36M
V36T
V38G
A39V
T40A
Q41H
Q41K
Q41L
Q41R5.4xresistance possible 5,4
F43I2no specific Clincial RAS indicated (2)
F43L2no specific Clincial RAS indicated (2)
F43S
F43V2no specific Clincial RAS indicated (2)
I48V
T54A
T54C
T54G
T54I
T54S8xresistance possible 3
V55A
V55I
Y56F
Y56H
R62K
P67S1.2xlikely susceptible 5
V71Aresistance possibleYes41Clinical TE RAS, 98% NGS (4)
D79E
N77S
Q80G2no specific Clincial RAS indicated (2)
Q80H2no specific Clincial RAS indicated (2)
Q80I2no specific Clincial RAS indicated (2)
Q80KMarch 2, 1900resistance likelyYes1,2,3,4<11Clinical TE RAV (1,2)..'9-11x FS
Q80Lresistance possibleYes23Clinical TE RAV, 50% NGS (2)
Q80M2no specific Clincial RAS indicated (2)
Q80N
Q80R13xresistance likelyYes1,2,3,47Clinical TE RAV (1,2,4). 8x - 13x FS
Q80S
Q89R1.5xlikely susceptible 5
V107I
R109K
V113L1.5xlikely susceptible 5
R109K
G120Sresistance possibleYes2Clinical TE RAS (4)
S122Aresistance possibleYes2<11Clinical TE RAV (2)
S122Cresistance possibleYes3Clinical TE RAS (4)
S122Gresistance possibleYes1,2<11Clinical TE RAV (1,2), >10% VF
S122Iresistance possibleYes2<11Clinical TE RAV (2)
S122N8xresistance likelyYes3Clinical TE RAV (2)
S122P
S122R20xresistance likelyYes1,2,311Clinical TE RAV (1,2)
S122Tresistance possibleYes2<11Clinical TE RAV (2)
S122V
R123Mresistance possibleYes42Clinical TE RAS (4)
I132V
I132Lresistance possibleYes46Clinical TE RAS (4)
I132T
V132I
S138T
P146S
S147A [Conflicting WT, not used in algorithm]resistance possibleYes41Clincial TE RAS, 99% NGS (4)
A150V
R155A
R155Gresistance possibleYes2,42Clinical TE RAV (2,4)
R155I2no specific Clincial RAS indicated (2)
R155K34-95xresistance likelyYes1,2,3,4,6,7100Clinical TE RAV (1,2,4,6,7)
R155M2no specific Clincial RAS indicated (2)
R155Q3xresistance possibleYes3<11Clinical TE RAV (2)
R155S2no specific Clincial RAS indicated (2)
R155T20-100xresistance likelyYes2,3,42Clinical TE RAV (2,4)
R155V
R155W2no specific Clincial RAS indicated (2)
A156G27xresistance likelyYes3,2Clinical TE RAV (2)
A156I
A156L2no specific Clincial RAS indicated (2)
A156M2no specific Clincial RAS indicated (2)
A156P
A156S2no specific Clincial RAS indicated (2)
A156T33-100xresistance likely 3,5
A156V20-100xresistance likely 3
V158A
V158I
A166S
D168A79x-335xresistance likelyYes1,2,3,4,513Clinical TE RAV (1,4)
D168C2no specific Clincial RAS indicated (2)
D168E26-49xresistance likelyYes1,2,3,4,5,6,724Clinical TE RAV (1,4,6,7)
D168Fresistance possibleYes2<11Clinical TE RAV (2)
D168G2no specific Clincial RAS indicated (2)
D168H801xresistance likelyYes1,2,3<11Clinical TE RAV (1)
D168I2no specific Clincial RAS indicated (2)
D168K2no specific Clincial RAS indicated (2)
D168L2no specific Clincial RAS indicated (2)
D168N2no specific Clincial RAS indicated (2)
D168R
D168S2no specific Clincial RAS indicated (2)
D168Tresistance possibleYes2<11Clinical TE RAV (2)
D168V780-1610xresistance likelyYes1,2,3,4,515Clinical TE RAV (1,4)
D168Y2no specific Clincial RAS indicated (2)
I 170F
I 170T13-15xresistance likelyYes1,2,3,4,6,710Clinical TE RAV (1,4,6,7)
I170V8xresistance possible 3
N174Sresistance possibleYes6Clinical SMV+SOF TE RAS (6)
N174Y
N174Rresistance possibleYes42Clinical TE RAV (4)
L175M
T178Iresistance possibleYes48Clinical TE RAV (4)
T185S
I248V [Conflicting WT, not used in algorithm]resistance possibleYes41Clinical TE RAS, 99% NGS (4)
P264S 42
P334S
S342P
T343Nresistance possibleYes43Clincla VF RAS, 62%NGS (4)
T344Iresistance possibleYes42Clincla VF RAS, 76%NGS (4)
L356Fresistance possibleYes46Clinical TE RAV (4)
E357G
E357K
V358T41
V406A
V406I41
I407V41
T449I
P470S
A477Tresistance possibleYes42Clincial VF RAS (4)
V511Iresistance possibleYes42Clinical TE RAV (4)
G534Sresistance possibleYes45Clinical VF RAS
E555Dresistance possibleYes42Clincal TE RAS, 50% NGS (4)
I586N41
V629Iresistance possibleYes41Clinical TE RAS, 51% NGS (4)
I660Vresistance possibleYes41Clinical TE RAS, 27% NGS (4)
Q9Any+A156T36xresistance likely5
V36A+R155K
V36L+Q80K
V36L+R155K
V36L+T54S
V36M+A156T
V36M+D168G
V36M+Q41R
V36M+Q80K
V36M+R155K55-72xresistance likely3
V36M+S122N
V36M+V55A
Q41K+Q80K
Q41R+Q89R
Q41R+A156T
Q41R+D168A364xresistance likely5
Q41R+D168E
Q41R+D168G
Q41R+D168H
Q41R+D168V790xresistance likely5
Q41R+I170V
Q41R+Q80K
F43L+Q80K
F43L+R155K
F43L+D168V
T54A+R155K
T54A+Q80K
T54S+Y56H
T54S+R155K
T54S+V55I
T54S+Q80L
V55A+D168E
V55A+Q80K
V55A+R155K
V55A+Q80R
V55I+A156P
V55I+Q80K
V55I+R155K
Y56F+Q80K
Y56H+A156G
Y56H+D168A
Y56H+D168E
Y56H+D168N
Y56H+D168V
Y56H+D168Y
V71A+I170V
Q80KR+D168E589xresistance likelyYes3Clinical TE RAV (2)
Q80K+A156T
Q80K+D168A
Q80K+D168E
Q80K+D168V
Q80K+D168Y
Q80K+I170T
Q80K+R155K1859-2000xresistance likely3,4
Q80K+R155G
Q80K+R155T
Q80K+S122N
Q80K+ I 170T120xresistance likely3
Q80L+D168E>1320xresistance likely4
Q80L+R155K
Q80L+S122N
Q80N+I170V
Q80R+A156T
Q80R+R155K
Q89R+A156T75xresistance likely5
Q89R+A156V
S122A+R155K
S122G+R155K16xresistance likely3
S122R+R155K26-750xresistance likely3
S122N+R155K
S122N+D168Y
S122T+R155K
A150V+A156T
R155K+D168A
R155K+D168E439xresistance likelyYes3Clinical TE RAS (4, 6, 7)
R155K+D168V
R155K+D168N
R155K+ I 170T92xresistance likelyYes3Clincial TE RAV (8)
R155K+I170T
R155K+I170V
R155K+N178G>34xresistance likelyYes8Clincial SMV+SOF TE RAV (8)
R155K+P334S
R155K+S342P
R155K+T449I
R155K+V406A
R155N+D168E
R155T+D168N
R155W+A156G
A156G+D168A
A156T+D168N
A156V+D168E
D168A+I170T
D168V+P334S
D168V+S342P
D168V+E357K
D168V+V406A
D168V+V406I
D168V+L470S
D168V+T449I
D168Y+P334S
D168Y+S342P
D168Y+E357K
D168Y+V406A
D168Y+T449I
I170T+D168E
I170T+D168N
I170V+D168E
I170V+D168N
E357K+D168V
E357K+D168Y
E357K+R155K
E357K+D168Any
V 36L+Q80K+R155S
V36L+V55A+Q80K
V36L+Q80K+R155K
V36M+Q41R+D168G
V36M+Y56H+D168A
V36M+Y56H+D168E
V36M+Q80K+R155K
V36M+Q80K+S122N
V36M+R155K+I170V
V36M+T54S+R155K
V36M+T54S+V55I
V36M+V55A+Q80K
V36M+V107I+R155K
V36M+Y56H+D168A
V36M+Y56H+D168E
Q41H+Q80K+S122N
Q41H+Q80K+S122G
F43L+Q80R+R155K
T54A+Q80K+R155K
T54S+Q80K+R155K
T54S+R155T+D168N
T54S+V55I+Q80K
T54S+V55I+Q80L
T54S+V55I+R155K
T54S+Y56H+I170V
V55A+D168E+I170V
V55A+Q80K+R155K
V55A+R155K+D168E
Y56H+A156G+D168A
Q80K+D168E+I170V
Q80K+R155K+D168E768xresistance likely3
Q80K+R155K+D168G
Q80K+R155K+I170T
Q80K+R155T+D168N
Q80R+R155K+D168E575xresistance likely3
S122G+R155K+I170V
S122R+R155N+D168E
R155W+A156G+D168N
R155K+A156V+D168A
R155Q+A156S+D168G
F43L+Q80L+A156G+S342P
Q41K+F43L+Q80K+D168Y
T54S+S122G+R155K+I170V
T54S+V55A+Q80R+I170V
T54S+V55I+S122G+R155K
T54S+V55I+S122G+R155K+I170V
V55A+Q80R+D168E+I170V
V36A+V36M+F43L+D168H+E357K
V23A(NS4A)
V23V(NS4A)+D168V
V23V(NS4A)+D168Y
1. Lontok et al. (2015) HEPATOLOGY 62:1623-1632)
2. Olysio US Product Label
3. Sorbo et al. (2018) Drug Resistance Update (in press)  https://doi.org/10.1016/j.drup.2018.01.004
4. FDA Microbiology/Virology Reviews simeprevir_205123Orig1s000MicroR
5. FDA Microbiology/Virology Reviews VoseviMicrobiology Reviews_2091950Orig1a000MicroR
6. Lawitz et al.The Lancet 2014;384:1756-65.
7. Kwo et al. Hepatology 2016;64:370-80.
8. Lawitz et al., Hepatology 2016;64:360-9.

Telaprevir

MutationEC50 (nM)Fold-shiftClinical RASPhenotypeClinical RASReferenceComments
WT (1a_H77)1x likely susceptible1
A5V
Q9R
V36A>10% VFresistance likely1
V36F
V36G>10% VFresistance likely1
V36I>10% VFYesresistance likelyYes1Clinical TE RAV (1)
V36L>10% VFYesresistance likelyYes1Clinical TE RAV (1)
V36M>10% VFYesresistance likelyYes1Clinical TE RAV (1)
V36T
V38G
A39V
T40A
Q41H
Q41K
Q41L
Q41R
F43I
F43L
F43S
F43V
I48V
T54A>10% VFYesresistance likelyYes1Clinical TE RAV (1)
T54C
T54G
T54I
T54S>10% VFYesresistance likelyYes1Clinical TE RAV (1)
V55A
V55I
Y56F
Y56H
R62K
P67S
V71A
D79E
N77S
Q80G
Q80H
Q80I
Q80KJanuary 1, 1970
Q80L
Q80M
Q80N
Q80R
Q80S
Q89R
V107I
R109K
V113L
R109K
G120S
S122A
S122C
S122G
S122I
S122N
S122P
S122R
S122T
S122V
R123M
I132V<10% VFYesresistance possibleYes1Clinical TE RAV (1)
I132L
I132T
V132I
S138T
P146S
S147A [Conflicting WT, not used in algorithm]
A150V
R155A
R155G>10% VFYesresistance likelyYes1Clinical TE RAV (1)
R155I
R155K>10% VFYesresistance likelyYes1Clinical TE RAV (1)
R155M>10% VFYesresistance likelyYes1Clinical TE RAV (1)
R155Q
R155S
R155T>10% VFYesresistance likelyYes1Clinical TE RAV (1)
R155V
R155W
A156G
A156I
A156L
A156M
A156P
A156S>10% VFYesresistance likelyYes1Clinical TE RAV (1)
A156T>10% VFYesresistance likelyYes1Clinical TE RAV (1)
A156V>10% VFYesresistance likelyYes1Clinical TE RAV (1)
V158A
V158I
A166S
D168A
D168C
D168E
D168F
D168G
D168H
D168I
D168K
D168L
D168N<10% VFYesresistance possibleYes1Clinical TE RAV (1)
D168R
D168S
D168T
D168V
D168Y
I 170F
I 170T
I170V
N174S
N174Y
N174R
L175M
T178I
T185S
I248V [Conflicting WT, not used in algorithm]
P264S
P334S
S342P
T343N
T344I
L356F
E357G
E357K
V358T
V406A
V406I
I407V
T449I
P470S
A477T
V511I
G534S
E555D
I586N
V629I
I660V
Q9Any+A156T
V36A+R155K
V36L+Q80K
V36L+R155K
V36L+T54S
V36M+A156T
V36M+D168G
V36M+Q41R
V36M+Q80K
V36M+R155K
V36M+S122N
V36M+V55A
Q41K+Q80K
Q41R+Q89R
Q41R+A156T
Q41R+D168A
Q41R+D168E
Q41R+D168G
Q41R+D168H
Q41R+D168V
Q41R+I170V
Q41R+Q80K
F43L+Q80K
F43L+R155K
F43L+D168V
T54A+R155K
T54A+Q80K
T54S+Y56H
T54S+R155K
T54S+V55I
T54S+Q80L
V55A+D168E
V55A+Q80K
V55A+R155K
V55A+Q80R
V55I+A156P
V55I+Q80K
V55I+R155K
Y56F+Q80K
Y56H+A156G
Y56H+D168A
Y56H+D168E
Y56H+D168N
Y56H+D168V
Y56H+D168Y
V71A+I170V
Q80KR+D168E
Q80K+A156T
Q80K+D168A
Q80K+D168E
Q80K+D168V
Q80K+D168Y
Q80K+I170T
Q80K+R155K
Q80K+R155G
Q80K+R155T
Q80K+S122N
Q80K+ I 170T
Q80L+D168E
Q80L+R155K
Q80L+S122N
Q80N+I170V
Q80R+A156T
Q80R+R155K
Q89R+A156T
Q89R+A156V
S122A+R155K
S122G+R155K
S122R+R155K
S122N+R155K
S122N+D168Y
S122T+R155K
A150V+A156T
R155K+D168A
R155K+D168E
R155K+D168V
R155K+D168N
R155K+ I 170T
R155K+I170T
R155K+I170V
R155K+N178G
R155K+P334S
R155K+S342P
R155K+T449I
R155K+V406A
R155N+D168E
R155T+D168N
R155W+A156G
A156G+D168A
A156T+D168N
A156V+D168E
D168A+I170T
D168V+P334S
D168V+S342P
D168V+E357K
D168V+V406A
D168V+V406I
D168V+L470S
D168V+T449I
D168Y+P334S
D168Y+S342P
D168Y+E357K
D168Y+V406A
D168Y+T449I
I170T+D168E
I170T+D168N
I170V+D168E
I170V+D168N
E357K+D168V
E357K+D168Y
E357K+R155K
E357K+D168Any
V 36L+Q80K+R155S
V36L+V55A+Q80K
V36L+Q80K+R155K
V36M+Q41R+D168G
V36M+Y56H+D168A
V36M+Y56H+D168E
V36M+Q80K+R155K
V36M+Q80K+S122N
V36M+R155K+I170V
V36M+T54S+R155K
V36M+T54S+V55I
V36M+V55A+Q80K
V36M+V107I+R155K
V36M+Y56H+D168A
V36M+Y56H+D168E
Q41H+Q80K+S122N
Q41H+Q80K+S122G
F43L+Q80R+R155K
T54A+Q80K+R155K
T54S+Q80K+R155K
T54S+R155T+D168N
T54S+V55I+Q80K
T54S+V55I+Q80L
T54S+V55I+R155K
T54S+Y56H+I170V
V55A+D168E+I170V
V55A+Q80K+R155K
V55A+R155K+D168E
Y56H+A156G+D168A
Q80K+D168E+I170V
Q80K+R155K+D168E
Q80K+R155K+D168G
Q80K+R155K+I170T
Q80K+R155T+D168N
Q80R+R155K+D168E
S122G+R155K+I170V
S122R+R155N+D168E
R155W+A156G+D168N
R155K+A156V+D168A
R155Q+A156S+D168G
F43L+Q80L+A156G+S342P
Q41K+F43L+Q80K+D168Y
T54S+S122G+R155K+I170V
T54S+V55A+Q80R+I170V
T54S+V55I+S122G+R155K
T54S+V55I+S122G+R155K+I170V
V55A+Q80R+D168E+I170V
V36A+V36M+F43L+D168H+E357K
V23A(NS4A)
V23V(NS4A)+D168V
V23V(NS4A)+D168Y
1. Lontok et al. (2015) HEPATOLOGY 62:1623-1632)

Voxilaprevir

MutationEC50 (nM)Fold-shiftPhenotypeClinical RASReferenceComments
WT (1a_H77)0.5 (0.53)1xlikely susceptible 3mean of 26 GT1 clinical isolates , 2 nM in transient replicon
A5V
Q9R0.6xlikely susceptible transient replicon
V36A2.0xresistance possibleYes3,4clinical VF RAS 2.3%(2,4)
V36F
V36G2.5-20xresistance possible 3,1
V36Ilikely susceptible 3
V36L2.1xlikely susceptible 3
V36M0.9xlikely susceptible 3
V36T
V38G
A39V
T40A
Q41Hlikely susceptible 3
Q41Klikely susceptible 3,4clinical VF RAV (1% NGS) (4)
Q41Llikely susceptible 3
Q41R4resistance possible 4,3,1transient replicon
F43I
F43Llikely susceptible3
F43S5.1xresistance possible 3,1
F43V
I48V
T54A0.6xlikely susceptible 3
T54Clikely susceptible 3
T54Glikely susceptible 3
T54Iunfit
T54S0.5xlikely susceptible 3
V55A1.1xlikely susceptible 3
V55I1.0xlikely susceptible3
Y56Flikely susceptible 3
Y56Hlikely susceptible3
R62K
P67S0.3xlikely susceptible 4transient replicon
V71A
D79E
N77S
Q80Gunfit
Q80H
Q80I
Q80K0.8xresistance possibleYes3Clinical VF RAV, 99.7% NGS (4)
Q80L1.8xlikely susceptible 3
Q80Mlikely susceptible 3
Q80N0.7xlikely susceptible 3
Q80R0.9xlikely susceptible 3
Q80S
Q89R
V107Ilikely susceptible 3
R109K
V113L1xlikely susceptible 4transitent replicon
R109K
G120S
S122Alikely susceptible 3
S122C0.8xlikely susceptible 3
S122G0.8xlikely susceptible 3
S122I
S122N1.9xlikely susceptible 3
S122Plikely susceptible 3
S122R1.0xlikely susceptible 3
S122T0.7xlikely susceptible 3
S122Vlikely susceptible 3
R123M
I132Vlikely susceptible 3
I132L
I132T
V132I
S138T
P146S
S147A [Conflicting WT, not used in algorithm]
A150V
R155Alikely susceptible 3
R155G4.6xresistance possible 3,1
R155I
R155K0.7xlikely susceptible 3
R155M
R155Q
R155S
R155Tlikely susceptible 3
R155V
R155W56xresistance likely 3,1
A156Gresistance possible3,1, Cl;iA156Any >2.5x (1),
A156I>2.5xresistance possible1.3A156Any but not indicate clincial VF(1)
A156L>100xresistance likely 3,2,4,1
A156M>2.5xresistance possibleYes1A156Any but not indicate clincial VF(1)
A156Punfit>2.5xresistance possibleYes1A156Any but not indicate clincial VF(1)
A156S>2.5xresistance possibleYes3,1A156Any but not indicate clincial VF(1)
A156T283resistance likely 3,2,4
A156Vunfit>2.5xresistance possible1A156Any but not indicate clincial VF(1)
V158Alikely susceptible 3
V158Ilikely susceptible 3
A166Slikely susceptible 3
D168A8.4xresistance possible 3,4
D168C
D168E0.7xlikely susceptible 3
D168F2.5-20xresistance possible 3
D168G1.1xlikely susceptible 3
D168H1.6xlikely susceptible 3
D168I2.5-20xresistance possible 3
D168K20-100xresistance likely 3
D168L20-100xresistance likely 1
D168N0.2xlikely susceptible 3
D168R20-100xresistance likely 3
D168Slikely susceptible 3
D168T2.5-20xresistance possible 3
D168V4.2xresistance possible 3,4
D168Y1.6xlikely susceptible 3
I 170Flikely susceptible 3
I 170Tlikely susceptible 3
I170Vlikely susceptible 3
N174S
N174Y
N174R
L175Mlikely susceptible 3
T178I
T185S
I248V [Conflicting WT, not used in algorithm]
P264S
P334S
S342P
T343N
T344I
L356F
E357G
E357K
V358T
V406A
V406I
I407V
T449I
P470S
A477T
V511I
G534S
E555D
I586N
V629I
I660V
Q9Any+A156T678xresistance likely 4
V36A+R155K
V36L+Q80K2.5-20xresistance possible3
V36L+R155Klikely susceptible3
V36L+T54S2.5-20xresistance possible3
V36M+A156T
V36M+D168Glikely susceptible3
V36M+Q41R2.5-20xresistance possible3
V36M+Q80K2.5-20xresistance possible3
V36M+R155Klikely susceptible3
V36M+S122N2.5-20xresistance possible3
V36M+V55Alikely susceptible3
Q41K+Q80K2.8resistance possible3
Q41R+Q89R
Q41R+A156T>100xresistance likely3
Q41R+D168A22xresistance likely4,3
Q41R+D168E
Q41R+D168G2.5-20xresistance possible3
Q41R+D168H2.5-20xresistance possible3
Q41R+D168V12xresistance likely4
Q41R+I170V
Q41R+Q80K2.8resistance possible3
F43L+Q80K3.4resistance possible3
F43L+R155Klikely susceptible3
F43L+D168V
T54A+R155Klikely susceptible3
T54A+Q80Klikely susceptible3
T54S+Y56H2.5-20xresistance possible3
T54S+R155Klikely susceptible3
T54S+V55Ilikely susceptible3
T54S+Q80Llikely susceptible3
V55A+D168Elikely susceptible3
V55A+Q80Klikely susceptible3
V55A+R155Klikely susceptible3
V55A+Q80R
V55I+A156Punfit
V55I+Q80Klikely susceptible3
V55I+R155Klikely susceptible3
Y56F+Q80Klikely susceptible3
Y56H+A156G
Y56H+D168A
Y56H+D168E
Y56H+D168N
Y56H+D168V
Y56H+D168Y
V71A+I170V
Q80KR+D168E
Q80K+A156Tunfit3
Q80K+D168A
Q80K+D168E2.5-20xresistance possible3
Q80K+D168V
Q80K+D168Y116.5resistance likely3
Q80K+I170Tlikely susceptible3
Q80K+R155Klikely susceptible3
Q80K+R155G
Q80K+R155Tlikely susceptible3
Q80K+S122Nlikely susceptible3
Q80K+ I 170T
Q80L+D168E10.8xresistance likely3
Q80L+R155Klikely susceptible3
Q80L+S122Nlikely susceptible3
Q80N+I170Vlikely susceptible3
Q80R+A156T
Q80R+R155Klikely susceptible3
Q89R+A156T1088xresistance likely4
Q89R+A156V
S122A+R155K
S122G+R155K6.2xresistance possible3
S122R+R155K
S122N+R155K
S122N+D168Y2.5-20xresistance possible3
S122T+R155K
A150V+A156T
R155K+D168A
R155K+D168Elikely susceptible3
R155K+D168V
R155K+D168Nlikely susceptible3
R155K+ I 170T
R155K+I170Tlikely susceptible3
R155K+I170V1.2xlikely susceptible3
R155K+N178G
R155K+P334S
R155K+S342P
R155K+T449I
R155K+V406A
R155N+D168Elikely susceptible3
R155T+D168N20-100xresistance likely3
R155W+A156G
A156G+D168A
A156T+D168N
A156V+D168E
D168A+I170T2.5-20xresistance possible3
D168V+P334S
D168V+S342P
D168V+E357K
D168V+V406A
D168V+V406I
D168V+L470S
D168V+T449I
D168Y+P334S
D168Y+S342P
D168Y+E357K
D168Y+V406A
D168Y+T449I
I170T+D168E
I170T+D168N
I170V+D168E
I170V+D168N
E357K+D168V
E357K+D168Y
E357K+R155K
E357K+D168Any
V 36L+Q80K+R155S
V36L+V55A+Q80Klikely susceptible3
V36L+Q80K+R155Klikely susceptible3
V36M+Q41R+D168G2.5-20xresistance possible3
V36M+Y56H+D168A
V36M+Y56H+D168E
V36M+Q80K+R155Klikely susceptible3
V36M+Q80K+S122Nunfit3
V36M+R155K+I170V3.6xresistance possible3
V36M+T54S+R155Klikely susceptible3
V36M+T54S+V55Ilikely susceptible3
V36M+V55A+Q80Klikely susceptible3
V36M+V107I+R155K
V36M+Y56H+D168A
V36M+Y56H+D168E
Q41H+Q80K+S122N1.9xlikely susceptible3
Q41H+Q80K+S122G2xlikely susceptible3
F43L+Q80R+R155Kunfit3
T54A+Q80K+R155Klikely susceptible3
T54S+Q80K+R155Klikely susceptible3
T54S+R155T+D168N2.5-20xresistance possible3
T54S+V55I+Q80Klikely susceptible3
T54S+V55I+Q80L7xresistance possible3
T54S+V55I+R155Klikely susceptible3
T54S+Y56H+I170V11.1xresistance likely3
V55A+D168E+I170V1.5xlikely susceptible3
V55A+Q80K+R155Klikely susceptible3
V55A+R155K+D168Elikely susceptible3
Y56H+A156G+D168A
Q80K+D168E+I170V8xresistance possible3
Q80K+R155K+D168Elikely susceptible3
Q80K+R155K+D168Glikely susceptible3
Q80K+R155K+I170Tlikely susceptible3
Q80K+R155T+D168N2.5-20xresistance possible3
Q80R+R155K+D168E
S122G+R155K+I170V5.2xresistance possible3
S122R+R155N+D168E10.7xresistance likely3
R155W+A156G+D168N
R155K+A156V+D168A
R155Q+A156S+D168G
F43L+Q80L+A156G+S342P
Q41K+F43L+Q80K+D168Y232.7xresistance likely3
T54S+S122G+R155K+I170V9.2xresistance possible3
T54S+V55A+Q80R+I170V1.3xlikely susceptible3
T54S+V55I+S122G+R155K5.9xresistance possible3
T54S+V55I+S122G+R155K+I170V4.1xresistance possible3
V55A+Q80R+D168E+I170V4.9xresistance possible3
V36A+V36M+F43L+D168H+E357K
V23A(NS4A)
V23V(NS4A)+D168V
V23V(NS4A)+D168Y
1. Sarrazin C, et al. 2017. Gastroenterology 152: S1062  http://www.natap.org/2017/EASL/EASL_57.htm
2. Vosevi US Porduct Label
3. Dvory-Sobol H et al 2017 AASLD.  http://www.natap.org/2017/AASLD/AASLD_29.htm
4. FDA Microbiology/Virology Reviews VoseviMicrobiology Reviews_2091950Orig1a000MicroR