In vitro resistance selections using elvitegravir, raltegravir, and two metabolites of elvitegravir M1 and M4

• Published in: Antiviral research 2012-02, Vol.93 (2), p.288-296
• Main Authors: Margot, Nicolas A., Hluhanich, Rebecca M., Jones, Gregg S., Andreatta, Kristen N., Tsiang, Manuel, McColl, Damian J., White, Kirsten L., Miller, Michael D.
• Format: Article
• Language: English
• Subjects: Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Cell Line; Drug Resistance, Viral; HIV; HIV Infections - drug therapy; HIV Infections - virology; HIV Integrase - genetics; HIV Integrase - metabolism; HIV Integrase Inhibitors - pharmacology; HIV-1 - drug effects; HIV-1 - enzymology; HIV-1 - genetics; Human viral diseases; Humans; Immunodeficiencies; Immunodeficiencies. Immunoglobulinopathies; Immunopathology; Infectious diseases; Integrase inhibitor; Medical sciences; Mutation; Pharmacology. Drug treatments; Pyrrolidinones - pharmacology; Quinolones - metabolism; Quinolones - pharmacology; Raltegravir Potassium; Resistance selection; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids
• ISSN: 0166-3542; 1872-9096
• DOI: 10.1016/j.antiviral.2011.12.008

► Elvitegravir is an HIV-1 integrase strand transfer inhibitor in phase 3 clinical testing. ► Two metabolites (M1 and M4) of EVG are found at low level in EVG-treated subjects. ► We conducted resistance selection and cross-resistance analyses of M1 and M4 in vitro. ► We found that the resistance profiles of M1 and M4 overlap with that of EVG. ► Therefore, M1 and M4 are unlikely to alter the resistance profile of EVG in the clinic. Elvitegravir is a strand transfer inhibitor of HIV-1 integrase that is currently undergoing phase 3 clinical testing. The two predominant metabolites of elvitegravir, M1 and M4 (elvitegravir hydroxide and elvitegravir glucuronide), have been shown to inhibit HIV-1 integrase in vitro. While they are markedly less potent than elvitegravir and present only at low levels in plasma clinically, we investigated their potential to select for elvitegravir resistance in vitro. Resistance selection experiments using metabolites M1 and M4 led to the development of the previously reported elvitegravir integrase resistance mutations H51Y, T66A, E92G, and S147G, as well as a novel S153F substitution. Additional resistance selection experiments using elvitegravir led to the development of previously reported integrase inhibitor resistance mutations (T66I, F121Y, and S153Y) as well as a novel R263K integrase mutation. Phenotypic analyses of site-directed mutants with these mutations demonstrated broad cross-resistance between elvitegravir and its M1 and M4 metabolites with more limited cross-resistance to the integrase inhibitor raltegravir. Overall, our in vitro studies demonstrate that the resistance profile of the M1 and M4 metabolites of elvitegravir overlaps with that of the parent molecule elvitegravir; as such, their presence at low levels is not considered clinically relevant.