TABLE 2.
APV genotypic and phenotypic resistance profiles before initiation, Cmins, and inhibitory quotients after initiation of APV-containing salvage therapy in patients previously treated with a protease inhibitor
| Patient group and no.a | Previous protease inhibitor experienceb (total duration [mo]) | Previous treatment before APV initiation | Amino acid differences from clade B consensus c
|
APV
|
APV-containing salvage therapy | APV
|
||||
|---|---|---|---|---|---|---|---|---|---|---|
| Reverse transcriptase sequence (NNRTI resistance and S69S insertion) | Protease sequence | Fold IC90c resistance d | IC90c (ng/ml)e | Mean Cmin (ng/ml) f | Inhibitory quotientg | |||||
| Group A | ||||||||||
| With detectable viral load at week 24
|
||||||||||
| 1 | DV,RTV,SQV,NFV (28) | d4T-3TC-NFV | None | L10I, M46I, A71V, N88D, L90M | 1.5 | 175 | ddI-EFV-APV | 65 | 0.4 | |
| 2 | IDV,NFV (24) | AZT-3TC-NFV | None | L10I, M36I, I54V, A71I, G73S, V82A, L90M | 2.9 | 350 | ddI-HU-EFV-APV | 55 | 0.2 | |
| 3 | IDV,RTV,SQV (37) | 3TC-ABC-ddI-HU | A98G, K101E, V108I, Y181C, G190A, S69S | L10I, K20M, M36I, I54V, L63P, A71V, G73S, V82A, L90M | 2.9 | 350 | AZT-3TC-ADF-EFV-APV | 60 | 0.2 | |
| 4 | SQV,IDV (33) | d4T-3TC-IDV | None | L10I, M46I, A71V, I84V, L90M | 4.7 | 560 | ABC-EFV-APV | 260 | 0.5 | |
| 5 | IDV,NFV,RTV,SQV (33) | d4T-ddI-RTV-SQV | None | L10I, I54V, A71V, V77I, V82F, L90M | 10.6 | 1260 | ddI-HU-EFV-APV | 70 | 0.06 | |
| 8 | RTV (22) | AZT-3TC-RTV | None | K20I, M36I, L63P, V82I, L90M | 1.5 | 175 | d4T-ddI-EFV-APV | 5 | 0.03 | |
| With undetectable viral load at week 24
|
||||||||||
| 6 | SQV, NFV (32) | AZT-3TC-NFV | None | I54V, A71V, V77I, V82F | 3.8 | 455 | d4T-ddI-EFV-APV | 35 | 0.08 | |
| 7 | NFV (10) | AZT-3TC-NFV | None | D30N, M36V/I, A71T, V77V/I | 0.6 | 70 | ddC-3TC-EFV-APV | 50 | 0.7 | |
| Group B | ||||||||||
| With detectable viral load at week 24
|
||||||||||
| 9 | IDV (36) | d4T-ddI-IDV | A98G, S69S | L10I, M46M, M46I, I54V, L63P, V82A, V82S, L90M | 4.1 | 490 | AZT-3TC-ABC-EFV-RTV-APV | 1,550 | 3.2 | |
| With undetectable viral load at week 24
|
||||||||||
| 10 | RTV,IDV (39) | AZT-3TC-IDV | None | L10I, K20R, M36I, I54A, L63P, A71V, V82T, V82A, V82S, L90M | 4.1 | 490 | d4T-ddI-EFV-RTV-APV | 1,010 | 2.1 | |
| 11 | SQV,RTV,NFV (40) | AZT-3TC-NFV | A98G | L10I, M46I, L63P, A71A/T/V/I, G73S, V77I, L90M | 4.1 | 490 | ddI-3TC-EFV-RTV-APV | 1,285 | 2.6 | |
| 12 | IDV,SQV,NFV (39) | d4T-3TC-NFV | None | L10I, M36I, L63P, V77I, L90F | 0.2 | 21 | AZT-ddI-EFV-RTV-APV | 3,015 | 145 | |
| 13 | IDV,RTV,SQV (35) | d4T-3TC-RTV-SQV | None | L10I, M46L, I54V, L63P, A71I, V82A, I84V, L90M | 9.8 | 1,162 | AZT-3TC-EFV-RTV-APV | 1,590 | 1.4 | |
| 14 | IDV,RTV,NFV (36) | ddI-3TC-NFV-EFV | K103N, P225H | L63P, V82A | 1.2 | 140 | ddI-3TC-EFV-RTV-APV | 1,460 | 10.4 | |
| 15 | RTV,NFV,SQV (42) | ddI-SQV-NFV-EFV | S69S | M36I, I54V, L63A, V82A | 1.5 | 175 | AZT-ddI-NVP-RTV-APV | 1,000 | 5.7 | |
| 16 | IDV,RTV,SQV (42) | ddI-ABC-RTV-SQV | None | L10V, K20R, M36I, M46V, G48V, I54T, I54V, L63P, V82A | 2.8 | 329 | AZT-ABC-EFV-RTV-APV | 1,190 | 3.6 | |
| 17 | RTV,IDV,NFV (41) | AZT-3TC-IDV | None | L63P, V77I | 0.6 | 70 | ddI-NVP-RTV-APV | 1,685 | 24 | |
| 18 | IDV,NFV (46) | d4T-3TC-NFV | None | D30N | 0.3 | 35 | ddI-EFV-RTV-APV | 1,365 | 39 | |
| 19 | IDV,RTV (48) | d4T-3TC-RTV | None | L10I, K20R, M36I, I54V, L63P, A71V, V82A | 1.4 | 175 | ddI-3TC-EFV-RTV-APV | 1,355 | 7.7 | |
| 20 | NFV (26) | d4T-ddI-NFV | None | L10V/I, K20K/R, M36V, I54L, L63P, L90M | 4.9 | 595 | 3TC-EFV-RTV-APV | 910 | 1.5 | |
| 21 | IDV,RTV,NFV (41) | AZT-3TC-NFV | None | L10V, L63P, A71T, N88D | 0.9 | 105 | d4T-ddI-EFV-RTV-APV | 985 | 9.3 | |
| 22 | IDV,RTV (36) | d4T-ABC-EFV | A98S, L100I, G190S,K101E, Y181C, S69S | L63P | 1.2 | 140 | 3TC-EFV-RTV-APV | 1,160 | 8.3 | |
Group A patients received APV without ritonavir, whereas group B patients received ritonavir at 100 mg b.i.d.
IDV, indinavir; NFV, nelfinavir; RTV, ritonavir; SQV, saquinavir; APV, amprenavir; AZT, zidovudine; ddI, didanosine; ddC, zalcitabine, 3TC, lamivudine; d4T, stavudine; ABC, abacavir; HU, hydroxyurea; EFV, efavirenz; NVP, nevirapine.
For protease, all amino acid differences relative to the HIV-1 clade B consensus sequence are listed. Major genotypic APV resistance mutations are M46I, M46L, I54L, I54M, I54V, V82A, V82F, V82I, V82T, I84V, and L90M and are shown in boldface. Viruses with more than three major mutations at different codons were considered resistant to APV. For reverse transcriptase, only those differences associated with resistance to NNRTI and S69S insertions are listed.
Fold resistance compared to that for reference strain NL4-3. An IC90c greater than four times that for NL4-3 (480 ng/ml) was considered resistance and is shown in boldface.
The IC90c was determined by recombinant virus assay and is the IC90 corrected for protein binding by multiplication by 7.
The mean Cmin was calculated by using the values at steady state (those on days 14, 21, 30) over the first month of treatment.
The inhibitory quotient was calculated as the mean Cmin divided by the IC90c.