Table 3. Protease inhibitor resistance mutations*.
| 23 | 24 | 30 | 32 | 33 | 46 | 47 | 48 | 50† | 53 | 54 | 73 | 76† | 82 | 84 | 88† | 90 | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| L | L | D | V | L | M | I | G | I | F | I | G | L | V | I | N | L | |
| ATVr | I | F | IL | V | VM | L | L | VTALM | ST | ATFS | VAC | DS | M | ||||
| DRVr‡ | I | F | VA | V | LM | ST | V | VAC | M | ||||||||
| FPVr | I | F | IL | VA | V | VTALM | ST | V | ATFS | VAC | M | ||||||
| IDVr | I | V | IL | V | L | VTALM | ST | V | AFTS | VAC | S | M | |||||
| LPVr | I | I | F | IL | VA | VM | V | VTALM | V | AFTS | VAC | M | |||||
| NFV | I | I | N | F | IL | V | VM | L | VTALM | ST | AFTS | VAC | DS | M | |||
| SQVr | I | VM | L | VTALM | ST | AT | VAC | S | M | ||||||||
| TPVr§ | I | F | IL | V | VAM | ATFSL | VAC | M | |||||||||
The first row of letters contains the consensus amino acid at the position indicated by the number in the preceding row. All amino acids are indicated by their one letter code. Mutations in bold have been shown to reduce in vitro susceptibility or in vivo virologic response. Mutations in bold underline are relative contraindications to the use of specific PI. Several additional uncommon mutations at the 17 positions in this table are also selected by PI, but have not been evaluated phenotypically including L24F, L33I, M46V, F53Y, I54S, G73C/A, V82M/C, and N88T/G. In contrast, V82I and L33V are polymorphisms that are not associated with PI therapy. Accessory protease mutations that are not in the table include the polymorphic mutations L10I/V, I13V, K20R/M/I, M36I, D60E, I62V, L63P, A71V/T, V77I, and I93L and the non-polymorphic mutations L10F/R, V11I, E34Q, E35G, K43T, K45I, K55R, Q58E, A71I/L, T74P/A/S, V75I, N83D, P79A/S, I85V, L89V, T91S, Q92K and C95F.
I50L increases susceptibility to all PI except ATV; I50V and I54L increase TPV susceptibility; N88S increases FPV susceptibility; L76V increases ATV, SQV and TPV susceptibility.
A genotypic susceptibility score (GSS) for DRV based on the POWER clinical trials includes the number of the following 11 mutations: V11I, V32I, L33F, I47V, I50V, I54L/M, G73S, L76V, I84V, and L89V201. In a subsequent update the substitution of T74P for G73S led to an improved model202.
A GSS for TPV/r based on the RESIST studies identified 21 mutations at 11 positions: L10V, I13V, K20M/R/V, L33F, E35G, M36I, K43T, M46L, I47V, I54A/M/V, Q58E, H69K, T74P, V82L/T, N83D, and I84V184. An updated TPV/r GSS excluded I13V, K20M/R/V, E35G, and H69K; reclassified I47V, I54A/M/V, Q58E, T74P, V82L/T, and N83D as major mutations; reclassified L10V, M36I, K43T, M46L, and I84V as minor mutations; and included L24I, I50L/V, I54L, and L76V as mutations likely to improve TPV susceptibility and virological response200. A complete listing of studies of genotypic PI response predictors can be found at: http://hivdb.stanford.edu/pages/geno_clinical_review/PI.html ATVr: atazanavir/ritonavir(r); DRVr: darunavir/r; FPVr: fosamprenavir/r; IDVr: indinavir/r; LPVr: lopinavir/r; NFV: nelfinavir; SQVr: saquinavir/r; TPVr: tipranavir/r.