Antiviral characteristics of GSK1265744, an HIV integrase inhibitor dosed orally or by long-acting injection

• Published in: Antimicrobial agents and chemotherapy 2015-01, Vol.59 (1), p.397-406
• Main Authors: Yoshinaga, Tomokazu, Kobayashi, Masanori, Seki, Takahiro, Miki, Shigeru, Wakasa-Morimoto, Chiaki, Suyama-Kagitani, Akemi, Kawauchi-Miki, Shinobu, Taishi, Teruhiko, Kawasuji, Takashi, Johns, Brian A, Underwood, Mark R, Garvey, Edward P, Sato, Akihiko, Fujiwara, Tamio
• Format: Article
• Language: English
• Subjects: Anti-HIV Agents; Anti-HIV Agents - therapeutic use; Antiviral Agents; Cell Line; Drug Resistance, Viral - genetics; Heterocyclic Compounds, 3-Ring - therapeutic use; HIV Infections; HIV Infections - drug therapy; HIV Infections - virology; HIV Integrase - drug effects; HIV Integrase Inhibitors; HIV Integrase Inhibitors - therapeutic use; HIV-1; HIV-1 - drug effects; HIV-1 - genetics; Human immunodeficiency virus; Humans; Microbial Sensitivity Tests; Pyridones; Pyridones - therapeutic use; Quinolones - therapeutic use; Raltegravir Potassium - therapeutic use; Virus Replication - drug effects
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/aac.03909-14

GSK1265744 is a new HIV integrase strand transfer inhibitor (INSTI) engineered to deliver efficient antiviral activity with a once-daily, low-milligram dose that does not require a pharmacokinetic booster. The in vitro antiviral profile and mechanism of action of GSK1265744 were established through integrase enzyme assays, resistance passage experiments, and cellular assays with site-directed molecular (SDM) HIV clones resistant to other classes of anti-HIV-1 agents and earlier INSTIs. GSK1265744 inhibited HIV replication with low or subnanomolar efficacy and with a selectivity index of at least 22,000 under the same culture conditions. The protein-adjusted half-maximal inhibitory concentration (PA-EC50) extrapolated to 100% human serum was 102 nM. When the virus was passaged in the presence of GSK1265744, highly resistant mutants with more than a 10-fold change (FC) in EC50 relative to that of the wild-type were not observed for up to 112 days of culture. GSK1265744 demonstrated activity against SDM clones containing the raltegravir (RAL)-resistant Y143R, Q148K, N155H, and G140S/Q148H signature variants (FC less than 6.1), while these mutants had a high FC in the EC50 for RAL (11 to >130). Either additive or synergistic effects were observed when GSK1265744 was tested in combination with representative anti-HIV agents, and no antagonistic effects were seen. These findings demonstrate that, similar to dolutegravir, GSK1265744 is differentiated as a new INSTI, having a markedly distinct resistance profile compared with earlier INSTIs, RAL, and elvitegravir (EVG). The collective data set supports further clinical development of GSK1265744.