Table 1. Open in new tab Integrase...

Wild Type (Consensus Subtype B)*	Position*	Mutation*	*Naive (%; n= 4,435)**	*RAL Rx (%; n= 105)**	RAL Fold^†	EVG Fold^†	572 Fold^†	In vitro and In vivo Selection Data^§
Primary RAL and/or EVG INI Resistance Mutations Observed In vivo
T	66	I	0	0	1	15	1	In vitro and in vivo by EVG [2, 7–8].
		A	.1	1.8	1	10	1	In vitro and in vivo by EVG [2, 9] and rarely by RAL [2, 35].
		K	0	0	10	80	2	In vitro and in vivo by EVG [2, 9].
E	92	Q	0	8.5	5	30	2	In vitro and in vivo by RAL and EVG [2, 12–14].
Y	143	C	0	4.8	4	1	1	In vitro and in vivo by RAL [12, 14–16, 19]. Y143H usually occurs as part of a mixture with Y143RC.
		R	0	12	20	1	1
		H	.1	2.4	2	1	1
S	147	G	.1	0	1	8	NA	In vitro and in vivo by EVG [2, 7].
Q	148	H	0	35	20	6	1^¶	In vitro and in vivo by RAL and EVG [2, 9, 12, 14–16, 19]
		R	0	14	30	100	1^¶
		K	0	3.8	40	70	1^¶
N	155	H	0	46	20	40	1	In vitro and in vivo by RAL and EVG [2, 12–16, 19].
Primary RAL and/or EVG INI Resistance Mutations Observed Solely In vitro
E	92	V	0	0	3	20	4	In vitro by EVG and GS-9160 [9, 22].
F	121	Y	0	0	5	10	1	In vitro by RAL and EVG [7, 9].
P	145	S	0	0	1	>150	1	In vitro by EVG [9].
Q	146	P	0	0	1	10	NA	In vitro by EVG [7].
V	151	A	0	0	5	5	NA	In vitro by GS-9160 [22].
		L	.1	.9	8	30	4	In vitro by L870,812 [9]. Reported in one patient receiving RAL [16]
N	155	S	0	0	10	40	1	In vitro by S-1360 [9]
Accessory RAL/EVG Resistance Mutations
H	51	Y	0	2.9	3	4	NA	In vitro and in vivo by EVG [2, 7] and in vivo by RAL [18].
V	54	I	.5	1.0	1	1	NA	In vitro by RAL [10]
L	68	V	.8	0	1	1	NA	In vivo by EVG [2].
L	74	M	2.5	10	1	1	1	In vivo by RAL usually with N155H [12, 14–15].
Q	95	K	.1	1.9	1	1	NA	In vitro by EVG and RAL [2, 7].
T	97	A	2.2	17	1	1	NA	In vivo by RAL usually with Y143 mutations [13, 16, 18, 21].
H	114	Y	0	0	1	4	NA	In vitro by EVG [8].
T	125	K	0	0	1	1	NA	In vitro by L-870,812 [9].
A	128	T	.5	1.0	1	1	NA	In vitro by RAL and EVG [8, 10].
E	138	K	0.1	1.9	1	1	1	In vitro and in vivo by RAL and EVG usually with Q148 mutations [2, 35]
		A	0	3.8	1	1	1
G	140	S	.1	36	1	1	1	In vitro and in vivo with Q148HR in patients receiving RAL [12, 14–16, 19, 35] and EVG [2]. G140AC is a less well-studied variant in this position [9, 22].
		A	0	2.9	1	1	1
		C	0	0	1	1	1
V	151	I	2.9	16	1	1	1	In vitro and in vivo by RAL [9, 14, 19, 48]. In vitro by EVG [9].
S	153	Y	0	0	1	3	2.5	In vitro by EVG [2].
E	157	Q	2.0	2.9	2.5	2.5	NA	In vitro by EVG [7] and rarely in vivo by RAL [13].
G	163	R	.5	8.6	1	1	NA	In vivo by RAL [12, 35].
		K	.4	3.8	NA	NA	NA
S	230	R	.1	3.8	1	1	NA	In vitro by RAL and EVG [8].
R	263	K	.1	1.9	1	5	NA	In vitro by EVG [2]

Wild Type (Consensus Subtype B)*

Position*

Mutation*

Naive* (%; n= 4,435)

RAL Rx* (%; n= 105)

RAL Fold^†

EVG Fold^†

572 Fold^†

In vitro and In vivo Selection Data^§

Primary RAL and/or EVG INI Resistance Mutations Observed In vivo

In vitro and in vivo by EVG [2, 7–8].

1.8

In vitro and in vivo by EVG [2, 9] and rarely by RAL [2, 35].

In vitro and in vivo by EVG [2, 9].

8.5

In vitro and in vivo by RAL and EVG [2, 12–14].

143

4.8

In vitro and in vivo by RAL [12, 14–16, 19]. Y143H usually occurs as part of a mixture with Y143RC.

2.4

147

In vitro and in vivo by EVG [2, 7].

148

1^¶

In vitro and in vivo by RAL and EVG [2, 9, 12, 14–16, 19]

100

1^¶

3.8

1^¶

155

In vitro and in vivo by RAL and EVG [2, 12–16, 19].

Primary RAL and/or EVG INI Resistance Mutations Observed Solely In vitro

In vitro by EVG and GS-9160 [9, 22].

121

In vitro by RAL and EVG [7, 9].

145

>150

In vitro by EVG [9].

146

In vitro by EVG [7].

151

In vitro by GS-9160 [22].

In vitro by L870,812 [9]. Reported in one patient receiving RAL [16]

155

In vitro by S-1360 [9]

Accessory RAL/EVG Resistance Mutations

2.9

In vitro and in vivo by EVG [2, 7] and in vivo by RAL [18].

1.0

In vitro by RAL [10]

In vivo by EVG [2].

2.5

In vivo by RAL usually with N155H [12, 14–15].

1.9

In vitro by EVG and RAL [2, 7].

2.2

In vivo by RAL usually with Y143 mutations [13, 16, 18, 21].

114

In vitro by EVG [8].

125

In vitro by L-870,812 [9].

128

1.0

In vitro by RAL and EVG [8, 10].

138

0.1

1.9

In vitro and in vivo by RAL and EVG usually with Q148 mutations [2, 35]

3.8

140

In vitro and in vivo with Q148HR in patients receiving RAL [12, 14–16, 19, 35] and EVG [2]. G140AC is a less well-studied variant in this position [9, 22].

2.9

151

2.9

In vitro and in vivo by RAL [9, 14, 19, 48]. In vitro by EVG [9].

153

2.5

In vitro by EVG [2].

157

2.0

2.9

2.5

In vitro by EVG [7] and rarely in vivo by RAL [13].

163

8.6

In vivo by RAL [12, 35].

3.8

230

3.8

In vitro by RAL and EVG [8].

263

1.9

In vitro by EVG [2]

Wild Type (Consensus Subtype B)*	Position*	Mutation*	*Naive (%; n= 4,435)**	*RAL Rx (%; n= 105)**	RAL Fold^†	EVG Fold^†	572 Fold^†	In vitro and In vivo Selection Data^§
Primary RAL and/or EVG INI Resistance Mutations Observed In vivo
T	66	I	0	0	1	15	1	In vitro and in vivo by EVG [2, 7–8].
		A	.1	1.8	1	10	1	In vitro and in vivo by EVG [2, 9] and rarely by RAL [2, 35].
		K	0	0	10	80	2	In vitro and in vivo by EVG [2, 9].
E	92	Q	0	8.5	5	30	2	In vitro and in vivo by RAL and EVG [2, 12–14].
Y	143	C	0	4.8	4	1	1	In vitro and in vivo by RAL [12, 14–16, 19]. Y143H usually occurs as part of a mixture with Y143RC.
		R	0	12	20	1	1
		H	.1	2.4	2	1	1
S	147	G	.1	0	1	8	NA	In vitro and in vivo by EVG [2, 7].
Q	148	H	0	35	20	6	1^¶	In vitro and in vivo by RAL and EVG [2, 9, 12, 14–16, 19]
		R	0	14	30	100	1^¶
		K	0	3.8	40	70	1^¶
N	155	H	0	46	20	40	1	In vitro and in vivo by RAL and EVG [2, 12–16, 19].
Primary RAL and/or EVG INI Resistance Mutations Observed Solely In vitro
E	92	V	0	0	3	20	4	In vitro by EVG and GS-9160 [9, 22].
F	121	Y	0	0	5	10	1	In vitro by RAL and EVG [7, 9].
P	145	S	0	0	1	>150	1	In vitro by EVG [9].
Q	146	P	0	0	1	10	NA	In vitro by EVG [7].
V	151	A	0	0	5	5	NA	In vitro by GS-9160 [22].
		L	.1	.9	8	30	4	In vitro by L870,812 [9]. Reported in one patient receiving RAL [16]
N	155	S	0	0	10	40	1	In vitro by S-1360 [9]
Accessory RAL/EVG Resistance Mutations
H	51	Y	0	2.9	3	4	NA	In vitro and in vivo by EVG [2, 7] and in vivo by RAL [18].
V	54	I	.5	1.0	1	1	NA	In vitro by RAL [10]
L	68	V	.8	0	1	1	NA	In vivo by EVG [2].
L	74	M	2.5	10	1	1	1	In vivo by RAL usually with N155H [12, 14–15].
Q	95	K	.1	1.9	1	1	NA	In vitro by EVG and RAL [2, 7].
T	97	A	2.2	17	1	1	NA	In vivo by RAL usually with Y143 mutations [13, 16, 18, 21].
H	114	Y	0	0	1	4	NA	In vitro by EVG [8].
T	125	K	0	0	1	1	NA	In vitro by L-870,812 [9].
A	128	T	.5	1.0	1	1	NA	In vitro by RAL and EVG [8, 10].
E	138	K	0.1	1.9	1	1	1	In vitro and in vivo by RAL and EVG usually with Q148 mutations [2, 35]
		A	0	3.8	1	1	1
G	140	S	.1	36	1	1	1	In vitro and in vivo with Q148HR in patients receiving RAL [12, 14–16, 19, 35] and EVG [2]. G140AC is a less well-studied variant in this position [9, 22].
		A	0	2.9	1	1	1
		C	0	0	1	1	1
V	151	I	2.9	16	1	1	1	In vitro and in vivo by RAL [9, 14, 19, 48]. In vitro by EVG [9].
S	153	Y	0	0	1	3	2.5	In vitro by EVG [2].
E	157	Q	2.0	2.9	2.5	2.5	NA	In vitro by EVG [7] and rarely in vivo by RAL [13].
G	163	R	.5	8.6	1	1	NA	In vivo by RAL [12, 35].
		K	.4	3.8	NA	NA	NA
S	230	R	.1	3.8	1	1	NA	In vitro by RAL and EVG [8].
R	263	K	.1	1.9	1	5	NA	In vitro by EVG [2]

Table 1.

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Integrase Inhibitor (INI) Resistance Mutations: Prevalence in INI-Naive and Raltegravir-Treated Individuals and Estimated Effect on Susceptibility to Raltegravir (RAL), Elvitegravir (EVG), and S/GSK1349572 (572)

Wild Type (Consensus Subtype B)*	Position*	Mutation*	*Naive (%; n= 4,435)**	*RAL Rx (%; n= 105)**	RAL Fold^†	EVG Fold^†	572 Fold^†	In vitro and In vivo Selection Data^§
Primary RAL and/or EVG INI Resistance Mutations Observed In vivo
T	66	I	0	0	1	15	1	In vitro and in vivo by EVG [2, 7–8].
		A	.1	1.8	1	10	1	In vitro and in vivo by EVG [2, 9] and rarely by RAL [2, 35].
		K	0	0	10	80	2	In vitro and in vivo by EVG [2, 9].
E	92	Q	0	8.5	5	30	2	In vitro and in vivo by RAL and EVG [2, 12–14].
Y	143	C	0	4.8	4	1	1	In vitro and in vivo by RAL [12, 14–16, 19]. Y143H usually occurs as part of a mixture with Y143RC.
		R	0	12	20	1	1
		H	.1	2.4	2	1	1
S	147	G	.1	0	1	8	NA	In vitro and in vivo by EVG [2, 7].
Q	148	H	0	35	20	6	1^¶	In vitro and in vivo by RAL and EVG [2, 9, 12, 14–16, 19]
		R	0	14	30	100	1^¶
		K	0	3.8	40	70	1^¶
N	155	H	0	46	20	40	1	In vitro and in vivo by RAL and EVG [2, 12–16, 19].
Primary RAL and/or EVG INI Resistance Mutations Observed Solely In vitro
E	92	V	0	0	3	20	4	In vitro by EVG and GS-9160 [9, 22].
F	121	Y	0	0	5	10	1	In vitro by RAL and EVG [7, 9].
P	145	S	0	0	1	>150	1	In vitro by EVG [9].
Q	146	P	0	0	1	10	NA	In vitro by EVG [7].
V	151	A	0	0	5	5	NA	In vitro by GS-9160 [22].
		L	.1	.9	8	30	4	In vitro by L870,812 [9]. Reported in one patient receiving RAL [16]
N	155	S	0	0	10	40	1	In vitro by S-1360 [9]
Accessory RAL/EVG Resistance Mutations
H	51	Y	0	2.9	3	4	NA	In vitro and in vivo by EVG [2, 7] and in vivo by RAL [18].
V	54	I	.5	1.0	1	1	NA	In vitro by RAL [10]
L	68	V	.8	0	1	1	NA	In vivo by EVG [2].
L	74	M	2.5	10	1	1	1	In vivo by RAL usually with N155H [12, 14–15].
Q	95	K	.1	1.9	1	1	NA	In vitro by EVG and RAL [2, 7].
T	97	A	2.2	17	1	1	NA	In vivo by RAL usually with Y143 mutations [13, 16, 18, 21].
H	114	Y	0	0	1	4	NA	In vitro by EVG [8].
T	125	K	0	0	1	1	NA	In vitro by L-870,812 [9].
A	128	T	.5	1.0	1	1	NA	In vitro by RAL and EVG [8, 10].
E	138	K	0.1	1.9	1	1	1	In vitro and in vivo by RAL and EVG usually with Q148 mutations [2, 35]
		A	0	3.8	1	1	1
G	140	S	.1	36	1	1	1	In vitro and in vivo with Q148HR in patients receiving RAL [12, 14–16, 19, 35] and EVG [2]. G140AC is a less well-studied variant in this position [9, 22].
		A	0	2.9	1	1	1
		C	0	0	1	1	1
V	151	I	2.9	16	1	1	1	In vitro and in vivo by RAL [9, 14, 19, 48]. In vitro by EVG [9].
S	153	Y	0	0	1	3	2.5	In vitro by EVG [2].
E	157	Q	2.0	2.9	2.5	2.5	NA	In vitro by EVG [7] and rarely in vivo by RAL [13].
G	163	R	.5	8.6	1	1	NA	In vivo by RAL [12, 35].
		K	.4	3.8	NA	NA	NA
S	230	R	.1	3.8	1	1	NA	In vitro by RAL and EVG [8].
R	263	K	.1	1.9	1	5	NA	In vitro by EVG [2]

Wild Type (Consensus Subtype B)*	Position*	Mutation*	*Naive (%; n= 4,435)**	*RAL Rx (%; n= 105)**	RAL Fold^†	EVG Fold^†	572 Fold^†	In vitro and In vivo Selection Data^§
Primary RAL and/or EVG INI Resistance Mutations Observed In vivo
T	66	I	0	0	1	15	1	In vitro and in vivo by EVG [2, 7–8].
		A	.1	1.8	1	10	1	In vitro and in vivo by EVG [2, 9] and rarely by RAL [2, 35].
		K	0	0	10	80	2	In vitro and in vivo by EVG [2, 9].
E	92	Q	0	8.5	5	30	2	In vitro and in vivo by RAL and EVG [2, 12–14].
Y	143	C	0	4.8	4	1	1	In vitro and in vivo by RAL [12, 14–16, 19]. Y143H usually occurs as part of a mixture with Y143RC.
		R	0	12	20	1	1
		H	.1	2.4	2	1	1
S	147	G	.1	0	1	8	NA	In vitro and in vivo by EVG [2, 7].
Q	148	H	0	35	20	6	1^¶	In vitro and in vivo by RAL and EVG [2, 9, 12, 14–16, 19]
		R	0	14	30	100	1^¶
		K	0	3.8	40	70	1^¶
N	155	H	0	46	20	40	1	In vitro and in vivo by RAL and EVG [2, 12–16, 19].
Primary RAL and/or EVG INI Resistance Mutations Observed Solely In vitro
E	92	V	0	0	3	20	4	In vitro by EVG and GS-9160 [9, 22].
F	121	Y	0	0	5	10	1	In vitro by RAL and EVG [7, 9].
P	145	S	0	0	1	>150	1	In vitro by EVG [9].
Q	146	P	0	0	1	10	NA	In vitro by EVG [7].
V	151	A	0	0	5	5	NA	In vitro by GS-9160 [22].
		L	.1	.9	8	30	4	In vitro by L870,812 [9]. Reported in one patient receiving RAL [16]
N	155	S	0	0	10	40	1	In vitro by S-1360 [9]
Accessory RAL/EVG Resistance Mutations
H	51	Y	0	2.9	3	4	NA	In vitro and in vivo by EVG [2, 7] and in vivo by RAL [18].
V	54	I	.5	1.0	1	1	NA	In vitro by RAL [10]
L	68	V	.8	0	1	1	NA	In vivo by EVG [2].
L	74	M	2.5	10	1	1	1	In vivo by RAL usually with N155H [12, 14–15].
Q	95	K	.1	1.9	1	1	NA	In vitro by EVG and RAL [2, 7].
T	97	A	2.2	17	1	1	NA	In vivo by RAL usually with Y143 mutations [13, 16, 18, 21].
H	114	Y	0	0	1	4	NA	In vitro by EVG [8].
T	125	K	0	0	1	1	NA	In vitro by L-870,812 [9].
A	128	T	.5	1.0	1	1	NA	In vitro by RAL and EVG [8, 10].
E	138	K	0.1	1.9	1	1	1	In vitro and in vivo by RAL and EVG usually with Q148 mutations [2, 35]
		A	0	3.8	1	1	1
G	140	S	.1	36	1	1	1	In vitro and in vivo with Q148HR in patients receiving RAL [12, 14–16, 19, 35] and EVG [2]. G140AC is a less well-studied variant in this position [9, 22].
		A	0	2.9	1	1	1
		C	0	0	1	1	1
V	151	I	2.9	16	1	1	1	In vitro and in vivo by RAL [9, 14, 19, 48]. In vitro by EVG [9].
S	153	Y	0	0	1	3	2.5	In vitro by EVG [2].
E	157	Q	2.0	2.9	2.5	2.5	NA	In vitro by EVG [7] and rarely in vivo by RAL [13].
G	163	R	.5	8.6	1	1	NA	In vivo by RAL [12, 35].
		K	.4	3.8	NA	NA	NA
S	230	R	.1	3.8	1	1	NA	In vitro by RAL and EVG [8].
R	263	K	.1	1.9	1	5	NA	In vitro by EVG [2]

NOTE. *Direct PCR sequences of HIV-1 group M plasma viruses from 4,435 INI-naive individuals [29]. The RAL-Rx % is the no. of patients with a virus sequence containing a mutation divided by the number of RAL-treated patients (n = 105) obtained from 12 published references in the Stanford HIV Drug Resistance Database [32]. Although several RAL-treated individuals had multiple sequences, no mutation was counted more than once per individual. ^†In vitro susceptibility in the absence of other INI resistance mutations. Most data were derived from site-directed mutants. When data were available from multiple studies or determined using multiple assays the fold resistance approximates the median of the multiple results. ^§S-1360, L-870,812, and GS-9160 are investigational INIs. ^¶Site-directed mutants with Q148H, Q148R, or Q148K do not decrease 572 susceptibility. However, viruses having one of these mutations in combination with E138K and/or G140S may have up to 10- to 20-fold decreased 572 susceptibility [11, 33].

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