Background: GSK1265744 (GSK744), an InSTI and analogue of dolutegravir, exhibits potent antiviral activity following short-term monotherapy in infected patients. The physicochemical properties of GSK744 permit a long-acting parenteral (LAP) formulation in a nanoparticle suspension (200 mg/mL). Following a single injection of GSK744LAP in healthy volunteers, a plasma half-life of 21 to 50 days was observed, supporting monthly or even quarterly dosing in humans. While oral and topical pre-exposure prophylaxis (PrEP) modalities have demonstrated protection against HIV-1 transmission, the modest and variable efficacy results have been largely attributed to lack of adherence to the prescribed regimen. GSK744LAP may offer an opportunity to address this deficiency in current approaches to PrEP. Our study used rhesus macaques repeatedly challenged with low doses of SHIV intrarectally to assess the protective efficacy of GSK744LAP.

Methods: 8 male macaques were injected intramuscularly with GSK744LAP (50 mg/kg) at 2 time points 4 weeks apart starting 1 week prior to the first virus exposure. An additional 8 male macaques were untreated and served as placebo controls. All animals were challenged intrarectally each week with SHIV162p3 (50 TCID₅₀) for up to 8 exposures. Infection status was monitored by real-time polymerase chain reaction (PCR) amplification of viral gag sequences from plasma obtained weekly.

Results: GSK744LAP was well tolerated by all animals. The infection status of each monkey was evaluated throughout. All 8 placebo macaques became infected after a median of 2 rectal exposures (range 1 to 7). Of the 8 GSK744LAP-treated macaques, none had detectable systemic viremia 3 weeks after the last virus challenge (see Figure). In these protected animals, the plasma concentrations of GSK744 throughout the period of virus challenges were comparable to the clinically relevant exposure in humans. All protected macaques will be monitored for a minimum of 10 weeks following the last challenge before sacrifice to extensively investigate for evidence of SHIV infection.

Conclusions: Our results show GSK744LAP, at clinically relevant plasma concentrations, can protect macaques against repeated intrarectal challenges with SHIV. Preclinical evaluations to determine the minimum protective plasma level of GSK744LAP and virus-challenge experiments in female macaques are planned. GSK744LAP appears to be a promising next-generation PrEP agent suitable for monthly to quarterly injections.