GS-9131 Exhibits Potential as ART for Individuals Harboring Some NRTI Resistance

GS-9131, a novel nucleoside reverse transcriptase inhibitor (NRTI) in development by Gilead Sciences, Inc., is a promising antiretroviral candidate for individuals displaying resistance to other NRTIs.

Investigators employed cell culture models to examine how viruses act when under increasing drug pressure. Their findings were presented in a poster session at the Annual Conference on Retroviruses and Opportunistic Infections (CROI 2019) on March 7, 2019.

The research team infected cord blood mononuclear cells (CBMC) and MT-2 cells with clinical isolates and subjected them to increasing levels of GS-9131 and tenofovir (TFV) in order to evaluate virus growth. Weekly measures of reverse transcriptase (RT) activity were noted, and viral RNA was extracted from tissue culture supernatants and sequenced in order to identify alterations in the RT region.

No major resistance mutations were observed in the CBMC viral cultures after 40 weeks of sustained treatment, and most of the isolates successfully endured moderate to very high drug concentrations—500-20,000-fold increase for GS-9131 and 100-20,000-fold for TDF.

“Using 3TC as a control, the M184I or V mutations rapidly arose in most viruses. Previous studies with GS-9148, for which GS-9131 is a prodrug, were done in MT-2 cells, and some resistance patterns were identified,” investigators reported. “In our experiment using MT-2 cells, no major resistance pathways emerged. One isolate did select for the L187M mutation, which was also identified in the previous study.”

Because of the lack of emergent variants, investigators believe that GS-9131 shows promise as an antiretroviral for HIV treatment, specifically in individuals who have displayed NRTI mutations. GS-9131’s versatility to be used in tandem with other therapies also make it a good option for patients harboring NRTI resistance.

Bluma Brenner, PhD, project director at the Lady Davis Institute at the McGill AIDS Centre and the lead inveastigator on the study, spoke with Contagion® to explain GS-9131's potential as a salvage therapy (see video above).

"It has a very unique resistance profile," Dr Brenner said. "It is active against K65R-resistant viruses so, given the fact that people are failing drugs, especially in Africa now, we still need salvage drug therapies and alternative drugs."

The poster, “Favourable Outcome of In Vitro Selections With Novel NRTI Prodrug GS-9131,” was presented on Thursday, March 7, 2019, at CROI 2019 in Seattle, Washington.