Simon Collins, HIV i-Base
A poster presented in vitro results of an NRTI compound from Gilead that appears has been in preclinical development for at least a decade. 
GS-9131 is a prodrug of GS-9148 – and early animal and in vitro drug resistance studies on GS-9148 were presented at CROI in 2006. 
Other previously published studies have highlighted the potential for low risk of toxicity in animal studies. The compound retains in vitro phenotypic sensitivity to broad NRTI resistance including mutations at K65R, L74V and M184V and multiple TAMS.
The poster at CROI 2017, confirms results from previously published studies (from 2007) into the activity against common NRTI mutations. The compound has good potency (EC50: 25 to 200 nM) with activity against HIV-1 subtypes A, B, C, D, E, F, group O and N (EC50: 0.29 to 113 nM), and also against HIV-2. 
Serial passaging of HIV-1 in the presence of GS-9148 selected two resistance pathways: (i) a primary K70E mutation plus D123N and T165I; or (ii) Q151L with K70E, L74I, and L187F/M. These variants conferred reduced susceptibility to GS-9131 of <3-fold and 50-fold, respectively.
Of note, synergistic activity was reported for GS-9131 in combination with AZT, FTC, abacavir, efavirenz, bictegravir, dolutegravir and lopinavir, and additive activity with TFV and TAF.
The poster concludes: “GS-9131 is an attractive candidate for further clinical development with a potential for once daily dosing and efficacy in patients with NRTI resistance” which seems slightly incongruous given how long this compound has been with the company.
This early data is interesting. The potency and resistance profile of this compound would help a larger number of people now than ten years ago. Coformulation with other drugs that overcome drug resistance is important for both high- and low-income countries.
- White KL et al. GS-9131 is a novel NRTI with activity against NRTI-resistant HIV-1. CROI 2017, 13-16 February 2017, Seattle. Poster abstract 436.
http://www.croiconference.org/sessions/gs-9131-novel-nrti-activity-against-nrti-resistant-hiv-1 (abstract and poster)
- Cihlar T et al. GS9148: A Novel Nucleotide Active against HIV-1 Variants with Drug-resistance Mutations in Reverse Transcriptase. 1 13th Conference on Retroviruses and Opportunistic Infections, 5-8 February 2006, Denver. Late breaker oral abstract 45LB.
- Cihlar T et al. Design and Profiling of GS-9148, a Novel Nucleotide Analog Active against Nucleoside-Resistant Variants of Human Immunodeficiency Virus Type 1, and Its Orally Bioavailable Phosphonoamidate Prodrug, GS-9131. Antimicrob Agents Chemother. 2008 Feb; 52(2): 655–665. Published online 2007 Dec 3. doi: 10.1128/AAC.01215-07.