icon- folder.gif   Conference Reports for NATAP  
  AIDS 2010
18th International AIDS Conference (IAC)
July 18-23 2010
Vienna, Austria
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Activity of the Next Generation Integrase Inhibitor S/GSK1349572
and Two First Generation Inhibitors Across a Broad Panel of HIV Subtype Isolates in PBMCs and MDMs

  Reported by Jules Levin
18th Intl AIDS Conference, July 18-23 2010, Vienna (home of gelato and high sugar in blood!)
Mark R. Underwood1, Cindy L. Vavro1, Roger G. Ptak2, Brian A. Johns1, Akihiko Sato,3Tomokazu Yoshinaga1, Masanori Kobayashi1, Tamio Fujiwara1 1GlaxoSmithKline, Research Triangle Park, NC, US; 2Southern Research Institute, Frederick, MD, USA; 3Shionogi & Co., Ltd, Osaka, Japan

Background: S/GSK13495721is a next generation once daily unboosted integrase inhibitor (INI) that is currently in Phase2b clinical studies. S/GSK1349572 and two first generation INIs were tested against a broad panel of HIV isolates in PBMCs and monocyte-derived-macrophages (MDMs). In addition, S/GSK1349572 and one first generation INI were separately tested against 13 subtype B isolates.
Methods: Twenty-five HIV-1 isolates including at least three from each group M subtype (A-G) and from group O and three HIV-2 isolates were assayed in PBMCs. Four HIV-1 isolates were also evaluated in MDMs. PBMC assays were run with Ficoll fractionated cells and used an RT endpoint. MDM assays were run with cells purified from Ficoll fractionated PBMCs via plate adherence and used a P24 endpoint. The susceptibility of 13 subtype B isolates was determined with Monogram Biosciences RHIN PhenoSense assay.
Results: S/GSK1349572 had sub nM IC50s against Group M subtypes A-G (means from 0.22-0.62nM), Group O (mean 0.87nM), and HIV-2 (mean 0.29nM) isolates in PBMCs. Similar IC50s were observed in MDMs (mean 0.76nM). The first generation INIs RSC-18382and S/GSK3647353had low nM IC50s against subtypes A-G (means from 1.2-3.65 and 1.31-1.97), group O (means of 3.04 and 2.31), HIV-2 (means of 2.36 and 2.03), and in MDMs (means of 2.8 and 7.39). No differences between subtype susceptibility were apparent. In the Phenosense assay, mean (range) nM IC50s were 0.52 (0.41-0.6) for S/GSK1349572 and 3.05 (1.6-3.8) for S/GSK364735.
Conclusions: S/GSK1349572 was highly potent, with sub nM mean IC50s against HIV in all assays. First generation INIs RSC-1838 and S/GSK364735 were less potent, with low nM IC50s. The antiviral activity of all three INIs was independent of HIV subtype, and was T cell and MDM independent. These observations support further clinical development of S/GSK1349572 across all HIV-1 subtypes