[28] ANALYSES OF SUSCEPTIBILITY AND CROSS-RESISTANCE BETWEEN TMC114 AND OTHER PROTEASE INHIBITORS AMONG >56,000 ROUTINE SAMPLES, USING LINEAR REGRESSION MODEL-BASED FOLD CHANGE PREDICTIONS

15th International HIV Drug Resistance Workshop

13-17 June 2006, Sitges, Spain

ANALYSES OF SUSCEPTIBILITY AND CROSS-RESISTANCE BETWEEN TMC114 AND OTHER PROTEASE INHIBITORS AMONG >56,000 ROUTINE SAMPLES, USING LINEAR REGRESSION MODEL-BASED FOLD CHANGE PREDICTIONS

Antivir Ther. 2006, 11:S33 (abstract no. 28)

M Staes¹, E Van Craenenbroeck¹, H Vermeiren¹, J Villacian¹, L Bacheler², M-P de Béthune³, S De Meyer³, G Picchio⁴
¹Virco BVBA, Mechelen, Belgium; ²VircoLab, Inc., Durham, NC, USA; ³Tibotec BVBA, Mechelen, Belgium; ⁴VircoLab, Inc., Bridgewater, NJ, USA

BACKGROUND: Previous studies have shown that TMC114 (darunavir) exhibits potent in-vitro and in-vivo activity against protease inhibitor (PI)-resistant HIV-1 isolates. This study evaluates the predicted phenotypic susceptibility of HIV-1 to TMC114 in recent routine clinical samples with different levels of PI resistance.

METHODS: Fold changes in EC₅₀ (FC) for TMC-114 and other PIs were predicted using multiple linear regression models (Virtual Phenotype-LM) on 56,018 sequences submitted to Virco for routine resistance analysis in 2004-2005. FC values were interpreted using virco®TYPE HIV-1 v4.0.00-specific clinical cutoffs (CCOs) for seven PIs; a biological cut-off (BCO) was used for atazanavir. For TMC-114, CCO₁=3.4 and CCO₂=96.9 were used. Two categories (susceptible [S], FC≤BCO and resistant [R], FC> BCO), or three categories (maximal response [MaxR], FC≤CCO₁; reduced response [RR], CCO₁ <FC ≤CCO₂; minimal response [MinR], FC> CCO₂) of PI susceptibility were defined by applying one BCO or two CCOs, respectively.

RESULTS: Of 56,018 samples, 34% showed decreased susceptibility (RR+MinR) to at least one PI. When compared with other PIs, TMC-114 exhibited the lowest (0.2%) and second lowest (5.0%) proportion of samples with MinR and RR, respectively, followed by tipranavir in the MinR category (1.5%). The lowest (4.9%) proportion of samples in the RR category was observed for saquinavir. Furthermore, susceptibility to TMC-114 scored as MaxR in 50.8%, 53.5%, 25.3%, 41.9%, 27.7%, 73.9%, and 72.5% of samples with MinR or RR to indinavir (n=2,064), saquinavir (n=2,471), amprenavir (n=3,645), lopinavir (n=2,947), tipranavir (n=836), nelfinavir (n=10,401) and atazanavir (n=10,076), respectively. In total, 3.8% of samples had RR+MinR to both TMC-114 and tipranavir; 6.4% had RR+MinR to tipranavir but MaxR to TMC-114; and 1.4% had RR+MinR to TMC-114 but MaxR to tipranavir. In a sample subset (1.3%, n=731) with MinR/R to all PIs except TMC-114 and tipranavir, 69.6% had RR+MinR to both PIs; 18.6% had RR+MinR only to tipranavir, with MaxR to TMC-114; and 7.8% had RR+MinR only to TMC-114, with MaxR to tipranavir.

CONCLUSIONS: These results confirm and extend the suggestion that TMC-114 has a high genetic barrier to the development of resistance, and that HIV-1 isolates with high levels of resistance to individual or multiple PIs remain susceptible to TMC-114.

2006-06-13
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