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  20th Conference on Retroviruses and
Opportunistic Infections
Atlanta, GA March 3 - 6, 2013
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Long-Acting Integrase Inhibitor Shields Macaques From Anal Simian HIV
  20th Conference on Retroviruses and Opportunistic Infections, March 3-6, 2013, Atlanta
Mark Mascolini
Two doses of GSK1265744-LAP protected eight macaques from rectal challenge with simian HIV (SHIV), a simian immunodeficiency virus with an HIV coat [1]. The investigational integrase inhibitor is already being studied in humans.
Preexposure prophylaxis (PrEP) with oral tenofovir/emtricitabine, oral tenofovir, or tenofovir gel has protected some women and men from HIV in placebo-controlled trials. But all three strategies failed in two other trials involving African women, mainly because of poor adherence. A long-acting injected PrEP agent would obviate the need for daily adherence and could be a useful prophylactic for women and men who could get such a shot without fear of stigma.
GSK744, the drug itself is the nanoparticle as the write-up implies - the drug itself is the nanoparticle. The injectable formulation is a dispersion of pure drug particles of sub-micron size. I suggest the following to describe GSK744 nanosuspension: The long-acting formulation is a nanosuspension of crystalline GSK1265744 drug, milled to submicron size, along with surfactants, mannitol and water for injection. This approach is similar to that used for TMC278-LA and allows for high drug loading into the injectable formulation and therefore a lower dose volume. Both GSK744 and TMC278 can be made as nanosuspensions because the drug molecules have specific attributes that permit such an approach - not the case for many other ARVs. This approach is different from others, for example the Howard Gendelman/U Nebraska group, who are investigating antiretrovirals that are polymer-encased with folic acid attached to the polymer to encourage macrophage uptake of the nanoparticle.
GSK1265744 half-life in the nanoparticle suspension ranged from 21 to 50 days after a single injection of various test doses in 56 HIV-negative volunteers [2].
US researchers collaborating with GlaxoSmithKline, developer of GSK1265744, tested the protective potential of GSK744LAP in 16 macaques, 8 of them given an intramuscular injection of GSK744LAP at a dose of 50 mg/kg at two points 4 weeks apart and 1 week before SHIV exposure. Eight control macaques received no GSK744LAP. All macaques were rectally challenged once a week for up to 8 weeks with SHIV162p3 at a TCID50 of 50. The researchers monitored macaques for SHIV infection with real-time polymerase chain reaction amplification of viral gag sequences in plasma samples collected weekly.
All animals tolerated GSK744LAP. The macaques not injected with the integrase inhibitor all became infected after a median of two rectal SHIV exposures (range 1 to 7 weeks). None of the 8 macaques treated with GSK744LAP a week before SHIV challenge became infected during the 8 SHIV challenges or 3 weeks after the last challenge (P < 0.0001 versus control).
No proviral DNA could be detected in peripheral blood mononuclear cells and no anti-SHIV antibodies could be detected in plasma of treated macaques. Both signals of infection could be detected in untreated animals.
Plasma concentrations of GSK1265744 throughout the study period remained comparable to exposures achieved in humans with an 800-mg loading dose and another 400 mg 4 weeks later. GSK1265744 trough concentrations were also similar in macaques and humans.
The researchers plan to monitor all macaques for at least 10 weeks after the last SHIV challenge. The animals will then be sacrificed to permit extensive tissue analysis for SHIV. The investigators also plan to study GSK744LAP in female macaques.
They conclude that "GSK744LAP appears to be a promising next-generation PrEP agent suitable for monthly to quarterly injections."
1. Andrews C, Gettie A, Russell--Lodrigue K, et al. Long-acting parenteral formulation of GSK1265744 protects macaques against repeated intrarectal challenges with SHIV. 20th Conference on Retroviruses and Opportunistic Infections. March 3-6, 2013. Atlanta. Abstract 24LB.
2. Spreen W, Ford SL, Chen S, et al. Pharmacokinetics, safety and tolerability of the HIV integrase inhibitor S/GSK1265744 long acting parenteral nanosuspension following single dose administration to healthy adults. XIX International AIDS Conference. July 22-27, 2012. Washington, DC. Poster TUPE040.