Antiviral Activity of Bictegravir, a Potent Next Generation HIV-1 Integrase Strand Transfer Inhibitor
by M Tsiang, E Kan, L Tsai, G Jones, R Bam, G Stepan, N Novikov, S Eng, G Lee, R Gong, E Aguayo, S Ahmadyar, Y Xu, A Niedziela-Majka, S Yant, H Yu, C Voitenleitner, G Birkus, M Perron, J Feng, S Lazerwith, H Jin, T Cihlar
Background: GS-9883 is a potent once-daily unboosted integrase strand transfer inhibitor currently in clinical development in combination with tenofovir alafenamide (TAF) and emtricitabine (FTC) for the treatment of HIV-1 infection. Methods: The inhibitory activity of GS-9883 was tested against wild-type HIV-1 integrase enzyme. Antiviral potency and cytotoxicity were assessed in MT-2 and MT-4 T-cell lines and primary human CD4+ T-cells and macrophages. Inhibition of integration was assessed by qPCR of 2-LTR circles and integration junctions. A panel of 14 HIV-1 and one HIV-2 clinical isolates was used for antiviral profiling. Antiviral activity of GS-9883 was also tested against several non-HIV viruses. Cytotoxicity of GS-9883 was also tested in four non-target cell lines (Huh-7, HepG2, PC-3, MRC-5) and human primary hepatocytes. Antiviral activity of GS-9883 in pairwise combination with antiretrovirals was also assessed.
Results: GS-9883 inhibited HIV-1 integrase enzyme strand transfer activity (IC50 = 7.5 ± 0.3 nM). Treatment with GS-9883 increased abortive 2-LTR circles and decreased viral-host DNA integration junctions in infected cells. GS-9883 exhibited high potency and selectivity in HIV-1 assays using lymphoblastoid T-cell lines, primary human CD4+T cells, and macrophages with EC50 range of 1.5 to 6.6 nM and selectivity indices of 1500 to 8700. GS-9883 was highly potent against all tested HIV-1 subtypes and HIV-2 in human PBMCs (mean EC50 = 0.81 nM range of <0.05 to 1.71 nM), and showed no activity against HBV, HCV, Influenza, HRV or RSV. GS-9883 had low cytotoxicity in multiple human cell lines (CC50 range from 35 to >44 μM) and in primary human hepatocytes (CC50 >100 μM). Highly synergistic in vitro antiviral effect was observed for combinations of GS-9883 with TAF, FTC or darunavir.
Conclusions: GS-9883 is a novel, potent and selective HIV integrase strand transfer inhibitor. GS-9883 was highly synergistic in combinations with TAF, FTC or darunavir. These data support the clinical investigation of GS-9883 for the treatment of HIV-1 infection.