XI International HIV Drug Resistance Workshop: Basic Principles and Clinical Implications Seville, Spain, 2–5 July 2002

BACKGROUND: Current genotypic algorithms for predicting phenotypic resistance to the protease inhibitors (PIs) lopinavir and amprenavir lack sensitivity relative to algorithms for most other PIs. Reduced susceptibility to lopinavir is associated with 23 mutations in protease (PR): L10F/I/R/V, K20M/R, L24I, M46I/L, F53L, I54L/T/V, L63P, A71I/L/V/T, V82A/F/T, I84V and L90M (lopinavir mutations). Resistance to amprenavir is associated with eight mutations: five primary (V32I, I50V, I54L/M, and I84V) and three secondary (M46I/L and I47V). By these criteria, only two positions (46 and 84) are shared between the two PIs.

METHODS: Protease genotype (GT) and phenotype (PT) for 1418 patient samples with at least one primary PR mutation or one PI with reduced susceptibility (fold change [FC] >2) were analysed. Samples were classified as lopinavir resistant by GT (GT-R) if six or more lopinavir mutations were present, and by PT (PTR) if the FC was over 10. Amprenavir GT-R was defined as presence of any of primary amprenavir mutation, and PT-R was defined as FC >2.5. The relative prevalence of mutations in groups of samples was compared using Fisher’s exact test (P <0.001 considered significant).

RESULTS: Using the published lopinavir algorithm, 182 samples classified as GT-S (13%) actually tested PT-R. A comparison of the prevalence of PR mutations in the discordant GT-S/PT-R samples and the concordant GT-S/PT-S samples (n=489) identified several additional mutations that are significantly associated with lopinavir PT-R. These mutations fell into one of three categories: 1) known lopinavir mutations that have a stronger effect on phenotype than others: L10I/F, K20M, M46I/L, I54V/T, V82A; 2) new amino acid substitutions at known positions: K20I, I54M/A/S, L63T, V82S; and 3) mutations at positions not included in the current lopinavir rules: G16E, V32I, L33F, E34Q, K43T, I47V, G48V, I50V, Q58E, T74S, L76V, L89I/M. Notably, six of eight amprenavir resistance mutations (underlined) are represented in one of these three categories. G16E, V32I and I47V are also known to be selected by lopinavir in vitro. From a list of 26 mutations associated with amprenavir FC >2.5 based on univariate analysis, 23 are also associated with lopinavir FC >2.5. Using regression analysis, the correlation between FC (log-transformed) for the two PIs was better for amprenavir GT-R samples compared to amprenavir GT-S samples (R²=0.52 vs 0.39). However, the presence of amprenavir mutations was not sufficient for lopinavir FC >10, requiring accumulation of eight or more mutations from an expanded list.

CONCLUSIONS: Cross-resistance between lopinavir and amprenavir is under appreciated. Existing genotypic interpretation algorithms are not sensitive enough for identification of viruses with reduced lopinavir and/or amprenavir susceptibility. This finding has implications for the use of lopinavir-based salvage therapy after failure of amprenavir-based regimens, or vice versa.

PRESENTING AUTHOR: NT Parkin

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2002-07-02
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