Background:  TMC114 is a potent, next-generation protease inhibitor (PI), active against wild type (EC₅₀ = 3.5 nM) and PI-resistant HIV-1. The in vivo antiviral efficacy of TMC114 was shown in a 2-week phase 2a trial in multiple PI-experienced patients. In the current study, the in vitro antiviral activity of TMC114 was measured against >4360 recent clinical HIV isolates and compared to the currently approved PI:  indinavir, ritonavir, nelfinavir, saquinavir, amprenavir, lopinavir (LPV), and atazanavir.

Methods:  Phenotypic and genotypic analyses were performed by the Antivirogram and VirtualPhenotype assays, respectively, on samples submitted for routine resistance testing.

Results:  Of all isolates, 37% (n = 1632) showed a decreased susceptibility to at least one of the currently approved PI (fold change in EC₅₀ >4, as compared to wild type). TMC114 was more potent than the current PI against this subset of PI-resistant isolates: EC₅₀ values were <10 nM for 79% of samples and >100 nM for only 1% of samples. In the same subset of PI-resistant isolates (fold change >4 to 1 or more PI), the activity of TMC114 and the current PI was compared in samples resistant to 1 to 7 PI. Nearly 46% of these isolates showed a decreased susceptibility to 6 or 7 PI, emphasizing the high degree of cross-resistance amongst the current PI. For LPV, a median fold change above the clinical cut-off (>10) was observed in isolates with decreased susceptibility to more than 4 PI. In contrast, for TMC114, a median fold change of 3.3 was observed in samples with decreased susceptibility to all 7 PI. The influence of the number of primary PI mutations (D30N, M46I/L, G48V, I50V/L, V82A/F/T/S, I84V, or L90M) on the activity of TMC114 and the current PI was studied in samples with an available genotype (n = 887). For all current PI, a median fold change ³4 (range 4 to 30) was seen in samples with only 2 primary PI mutations, whereas for TMC114, the median fold change was <4 for the samples with 3 or more mutations.

Conclusions:  TMC114 is a potent, next-generation PI active against a broad range of PI-resistant clinical isolates. A median fold change <4 was found for isolates resistant to all 7 currently approved PI and for isolates carrying 3 or more primary PI mutations. The influence of the number of primary PI mutations on the in vivo activity of TMC114, will be further investigated in the current phase IIb trials, where the number of primary PI mutations (1, 2, ³3) will be used as a stratification factor.

Keywords: protease inhibitor; TMC114; resistance