AEGiS-13IAC: Progressive emergence of protease inhibitor resistance: clinical relevance of resistance assays in patients with HAART failure.

13th International AIDS Conference

Durban, South Africa - July 9-July 14, 2000

Progressive emergence of protease inhibitor resistance: clinical relevance of resistance assays in patients with HAART failure.

Int Conf AIDS 2000 Jul 9-14; 13:44 (abstract no.. LbPeB7047)

Servais J, Lambert C, Plesseria JM, Fontaine E, Robert I, Arendt V, Staub T, Schneider F, Hemmer R, Burtonboy G, Schmit JC;;; Centre de Recherche Public Sante Luxembourg, Laboratoire de Retrovirologie, Luxembourg. Fax: +352.4411.6113, E-mail: retrovirology@chl.lu.

OBJECTIVES: To study the significance of PI resistance assays in HAART failure.

METHODS: For 26 patients in virological failure despite two NRTI and one PI (indinavir, ritonavir, saquinavir), resistance testing was retrospectively carried out sequentially 2 years using direct sequencing, a tine probe assay (INNO-LiPA, Innogenetics) for RT and protease (experimental kit), and an in-house recombinant virus assay for approved Pls.

RESULTS: Genotypic assays on 148 isolates yielded rare major discrepancies (<1%). INNO-LiPA detected more mixtures than sequencing but displayed codon hybridization failures for RT. Combinations of key protease mutations predicted phenotypic resistance to the drug used and cross-resistance to nelfinavir, in 90% (sequencing), respectively 80% (INNOLiPA) of cases. In regression analysis, for both assays, the total number of key mutations was associated with phenotypic resistance to the four PI. L10I, A71 V/T, K20R added to predictive value. 84% of tested isolates remained sensitive to amprenavir. Susceptibility levels for the 5 PI were well associated (r2>0.36). For genotypic and phenotypic assays, results were significantly associated with both virological and clinical outcome in multivariate analyses. Relevant thresholds were 4 and 8-fold for indinavir/ritonavir, 2.5 and 8-fold for saquinavir. LIPA detected a transient mixed population 184V appearing before V82A. Mutations M461, G48V, and L90M were often transient and drug pressure related.

CONCLUSIONS: All PI resistance assays are predictive of virological and clinical outcome. Algorithms for predicting PI resistance phenotype may be enhanced by including so-called secondary mutations. Cross-resistance is largely encountered for first generation PI and nelfinavir, but not for amprenavir. Certain key mutations appear in the earlier steps of the resistance pathway or are related to a specific drug history, highlighting the importance of the detection limit of resistance assay.

Keywords: AEGIS, Antiretroviral Therapy, Highly Active, HIV Protease Inhibitors, Saquinavir, Ritonavir, Protease Inhibitors, Indinavir, Phenotype, Nelfinavir, Mutation, Sulfonamides, VX 478, Human, genetics, AIDS
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