GSK1265744 demonstrates robust in vitro activity against various clades of HIV-1.

Abstract

Antiretroviral agents have been approved by the U.S. Food and Drug Administration for use as pre-exposure prophylaxis (PrEP) against acquisition of HIV-1 in high-risk populations.1 Studies of daily oral emtricitabine and tenofovir disoproxil (FTC/TDF) have demonstrated variable efficacy in preventing incident infections.2 This variability is thought due in large part to issues surrounding adherence to the prescribed daily oral medication regimen.3 Disappointingly, two trials, FEM-PrEP and VOICE, were stopped prematurely due to futility, and measurements of plasma drug concentrations revealed that fewer than 30 percent of participants were taking the drug appropriately.4,5 It has been hypothesized that the use of long acting antiretroviral agents given by intramuscular injection in the clinic may overcome some obstacles to adherence. GSK1265744 (GSK744), an analog of the integrase inhibitor dolutegravir, is formulated as a long-acting (LA) injectable nanosuspension.6 When given intramuscularly, it has demonstrated a prolonged half-life in plasma of 21 to 50 days. When dosed at 800 mg, levels of drug have remained greater than 4 times the 90% protein-adjusted inhibitory concentration (PAIC90) for up to three months, supporting dosing every 12 weeks.7 GSK744 LA has shown 90 to 100% efficacy in preventing SHIV162P3 transmission intrarectally and intravaginally in animal models. 8,9. Given this pharmacokinetic profile and its activity in the macaque/SHIV model, this compound has entered the clinic for testing as a next generation PrEP agent. It is critical that a next generation global PrEP agent be active against a variety of HIV-1 clades. To this end, we determined the relative effective concentrations of GSK744 against a panel of recombinant viruses containing integrase coding regions derived from various clades of HIV-1