Background:  UK-453,061 is a NNRTI with potent antiviral activity against HIV-1 wild type and clinically relevant NNRTI-resistant viruses in vitro. Studies in healthy volunteers indicated that UK-453,061 has good bioavailability, is safe and well tolerated, and is efficacious when used as short-term monotherapy in HIV-1-infected patients.  

Methods:  The antiviral activity of UK-453,061 was tested against clinically derived viruses from treatment naïve patients representing different HIV-1 subtypes or carrying transmitted NNRTI-resistant mutations in the PhenoSense assay. Drug combination was assessed using a cytopathic effect cell based assay. Each combination was titrated against HIV-1 NL4-3 acutely infected SupT1 cells and virus growth determined indirectly after 5 days culture. Data were analyzed using the MacSynergy II 3-dimensional model of Pritchard and Shipman.
Results:  UK-453,061 inhibited a panel of 45 pseudotyped subtype B and non-subtype B viruses (representing subtypes A, BF, C, D, F, and G). All viruses were susceptible to UK-453,061 with IC₅₀ fold-change to the reference virus ≤10 (43 viruses within 2-fold). UK-453,061 was active against 61 of 62 viruses with transmitted NNRTI resistance (IC₅₀ fold-change reference virus ≤10). The remaining virus gave an IC₅₀ fold-change reference virus >10 and carried a triple NNRTI mutation K101E+V106I/M+Y188F/L. NNRTI-resistance mutations at K103 (48%) were the most prevalent in this virus panel, followed by Y181 (11%), K101 (11%), and Y188 (11%). Additive antiviral interactions were observed when UK-453,061 was tested in combination with protease inhibitor, and the fusion inhibitor enfuvirtide, while synergistic interactions were frequently obtained with examples of the NRTI and integrase drug classes.
Conclusions:  The in vitro data indicates UK-453,061 to be active against viruses from different origins and with transmitted NNRTI drug resistance and supports the continued development of UK-453,061 in combination with clinically approved HIV therapies.