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  52nd ICAAC Interscience Conference on
Antimicrobial Agents and Chemotherapy
September 9-12, 2012, San Francisco
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Resistance Findings on Experimental S/GSK Long-Acting Integrase Inhibitor
  52nd ICAAC, September 9-12, 2012, San Francisco

ICAAC: Antiviral Characteristics Of S/GSK1265744, An HIV Integrase Inhibitor (INI) Dosed By Oral Or Long-acting Parenteral Injection....once monthly or 3 months dosing/PrEP/HAART - (09/10/12)

Mark Mascolini

Cell studies showed generally low-level resistance with S/GSK1265744, a long-acting integrase inhibitor that may control HIV with a single shot administered once a month [1]. The findings suggest a high barrier to resistance, limited or low potential for cross-resistance to raltegravir and elvitegravir. However, a site-directed mutant bearing a key double mutation selected by raltegravir selected additional mutations in tests with the new S/GSK compound.

S/GSK1265744, called 744 for short, is being developed in a long-acting parenteral formulation for chronic HIV infection and also possibly for preexposure prophylaxis (PrEP). In an earlier study, 744 showed strong antiviral activity at an oral dose of 30 mg once daily, suppressing viral load by a median 2.6 log10 copies/mL at treatment day 11 [2]. A nanosuspension formulation of 744 had a half-life of 21 to 50 days after a single intramuscular or subcutaneous injection, a result indicating that once-monthly dosing may be possible [3].

The new study assessed resistance to 744 in experiments that passaged an HIV-1 lab strain in MT-2 cells under increasing concentrations of 744. The researchers calculated fold change in resistance to 744 as a ratio of 50% inhibitory concentration (IC50) against wild-type (nonmutant) virus.

The IC50 of 744 in human peripheral blood mononuclear cells was 0.22 nM. IC50s for raltegravir, elvitegravir, and dolutegravir in PMBCs were 2 nM, 2 nM, and 0.51 nM. The 744 compound had a 408-fold potency shift in 100% human serum, compared with shifts of 4.7-fold for raltegravir, 22-fold for elvitegravir, and 75-fold for dolutegravir.

Exposure of HIV-infected MT-2 cells to 744 for up to 112 days did not produce highly resistant mutant virus. Maximum resistance to S/GSK744 in these assays was 8.4-fold.

Ten site-directed molecular clones containing a single raltegravir- or elvitegravir-associated mutation had less than a 2-fold change in susceptibility to 744. The mutations Q148K and K148R, which make HIV resistant to raltegravir, yielded only 5.6-fold and 5.1-fold changes in susceptibility to 744. Fifteen site-directed molecular clones containing 14 double mutations had less than a 12-fold change in susceptibility to 744.

In response to a question after the presentation, Shionogi's T. Yoshinaga said they had tested 744 against virus containing the double mutant with substitutions at positions 140 and 148 (often selected by raltegravir [4]), as in a previous study with dolutegravir. Like dolutegravir, 744 selected additional mutations in virus already harboring those critical changes.


1. Yoshinaga T, Kobayashi M, Seki T, et al. Antiviral characteristics of S/GSK1265744, an HIV integrase inhibitor (INI) dosed by oral or long-acting parenteral injection. 52nd Interscience Conference on Antimicrobials and Chemotherapy (ICAAC). September 9-12, 2012. San Francisco. Abstract H-550.

2. Min S, et al. Pharmacokinetics (PK) and safety in healthy and HIV-infected subjects and short-term antiviral efficacy of S/GSK1265744, a next generation once daily HIV integrase inhibitor. 49th Interscience Conference on Antimicrobial Agents and Chemotherapy. September 2009. San Francisco. Abstract H-1228. NATAP Report: Pharmacokinetics (PK) and Safety in Healthy and HIV-Infected Subjects and Short-Term Antiviral Efficacy of S/GSK1265744, a Next Generation Once Daily HIV Integrase Inhibitor - (09/17/09)

3. 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. NATAP Report: Pharmacokinetics, Safety and Tolerability of the HIV Integrase Inhibitor S/GSK1265744 Long Acting Parenteral Nanosuspension Following Single Dose Administration to Healthy Adults - (07/25/12)

4. Saladini F, Meini G, Bianco C, et al. Prevalence of HIV-1 integrase mutations related to resistance to dolutegravir in raltegravir na´ve and pretreated patients. Clin Microbiol Infect. 2012;18:E428-E430.