Table 1.
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] |
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].