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12th International HIV Drug Resistance Workshop10–14 June 2003, Cabo del Sol, Los Cabos, Mexico |
BACKGROUND: GW433908 (908) is an investigational protease inhibitor (PI) with demonstrated antiviral efficacy, durability and tolerability in antiretroviral (ART)-naïve and -experienced subjects. Although no protease resistance-associated mutations were selected during 48 weeks of treatment with ritonavir-boosted 908 QD (SOLO trial, n=322) protease mutations were detected infrequently with unboosted 908 twice-daily (NEAT trial, n=166). In the NEAT trial, the predominant protease mutations selected were the V32I+I47V (n=4) and I54L or M (n=4) mutations, consistent with an amprenavir-like resistance profile for unboosted 908. In one subject, the I54L was replaced with the L33F+I50V mutations at a later time-point, after continued treatment with unboosted 908 in the presence of detectable viral load. To understand the potential cross resistance to other PIs, clinical isolates containing the V32I+I47V, I54L/M or I50V mutations were selected from a database of patient samples and susceptibility to all marketed PIs was assessed.
METHODS: Approximately 16000 HIV clinical samples from the ViroLogic database, with matching genotypes and phenotypes, were examined to identify samples with the following primary mutational pathways : V32I+I47V, I54L/M or I50V. Samples with mixtures at these specific amino acids were excluded, as were samples that also contained certain primary protease mutations (D30N, G48V, V82A/T/S/F, I84V or L90M) that would indicate prior exposure to PIs. The presence of the primary protease mutation M46I/L was included because this mutation had been observed with the V32I+I47V (n=1) or I54L/M (n=1) mutations in NEAT. The median fold-change in susceptibility was calculated for samples with the specified mutation(s).
RESULTS: Fifty clinical isolates were identified: V32I+I47V (n=12), I54L/M (n=13/n=6) and I50V (n=19). The primary mutation M46I/L had a high frequency for all mutational pathways (67% with V32I+I47V, 37% with I54L/M and 74% with I50V). Certain secondary mutations were also present at an elevated incidence of >25%, including L63P for the V32+I47V mutations; L10V, M36I, L63P and V77I for the I54L/M mutations; and L33F, L63P, A71V, V77I and V82I for the I50V mutation. For the viruses identified, and in the presence of these additional protease mutations, viruses with V32I+I47V, I54L/M and I50V, had median fold-changes to amprenavir of 3.4-, 3.6- and 20-fold, respectively. For V32I+I47V, I54L/M and I50V, the median fold-change for saquinavir (0.5, 1.0 and 1.2, respectively) and indinavir (2.5, 1.3 and 1.0, respectively) were below the assay cut-off. The median fold-changes were also below the clinical cut-off for lopinavir (2.9, 1.5 and 8.2, respectively). With respect to nelfinavir, samples were sensitive or had low-level resistance, with fold-changes of 3.0, 3.6 and 2.2. Low-level cross resistance was also seen for ritonavir, with fold-changes of 3.4, 2.9 and 6.8.
CONCLUSION: Clinical isolates with mutational patterns similar to those selected by unboosted 908 remain sensitive to most other PIs, suggesting that viruses present after treatment failure of an unboosted 908 regimen will respond to second-line PI-containing therapy.
PRESENTING AUTHOR: L Ross
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2003-07-08
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