Abstract Body

There remains a need for an NRTI with potent activity against HIV-1 virus with NRTI resistance. GS-9131 is a monoamidate prodrug of the nucleotide analog GS-9148 (phosphonomethoxy-2′-fluoro-2′,3′-dideoxydidehydroadenosine). GS-9131 undergoes conversion in lymphocytes to GS-9148 diphosphate, a potent inhibitor of HIV-1 RT. GS-9148 has a low potential for mitochondrial toxicity and renal accumulation. Here we report on the antiviral activity and resistance profile of GS-9131.

GS-9131 was subjected to extensive in vitro evaluation of antiviral activity and resistance profile. The PhenoSense HIV assay was used to compare the activity of GS-9131 and the NRTIs (ZDV, ddI, d4T, FTC, ABC, and TFV) against HIV-1 variants with all major types of NRTI resistance mutations. GS-9131 activity was also determined against 14 HIV-1 clinical isolates and 1 HIV-2 isolate in peripheral blood mononuclear cells.

GS-9131 had potent activity against laboratory strains of HIV-1 both in primary cells and T-cell lines (EC50 = 25-200 nM) and exhibited potent antiretroviral activity against HIV-1 isolates of subtypes A, B, C, D, E, F, group O and N (EC50 0.29-113 nM). GS-9131 also had potent activity against HIV-2 (EC50 = 21 nM) and showed low cytotoxicity in multiple cell types including renal cells (CC50 > 100 µM). The activity of GS-9131 was not affected by the presence of RT mutations K65R, L74V, M184V or their combinations (EC50 fold change < 1). Viruses with 4 or more thymidine analog mutations (TAMs), including one with the T69-insertion, showed minimal changes (0.68 to 1.5-fold) in susceptibility to GS-9131, a change smaller than any other tested NRTI. Passaging of HIV-1 in the presence of the parent drug GS-9148 selected for a primary K70E mutation in combination with D123N and T165I, or the poorly fit Q151L mutation in combination with K70E, L74I, and L187F/M in RT; these variants conferred <3-fold and 50-fold reduced susceptibility to GS-9131, respectively. GS-9131 (GS-9148) was synergistic in combination studies with AZT, FTC, ABC, efavirenz, the integrase inhibitors bictegravir and dolutegravir, and the PI lopinavir, and additive with TFV and TAF.

GS-9131 exhibits potent in vitro antiretroviral activity and a favorable resistance profile including lower levels of resistance than approved NRTIs. GS-9131 is an attractive candidate for further clinical development with a potential for once daily dosing and efficacy in patients with NRTI resistance.