Next-Generation Integrase Inhibitors: Where to After Raltegravir?

• Published in: Drugs (New York, N.Y.) N.Y.), 2013-03, Vol.73 (3), p.213-228
• Main Authors: Karmon, Sharon L., Markowitz, Martin
• Format: Article
• Language: English
• Subjects: Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Binding sites; Biological and medical sciences; Clinical Trials as Topic; Drug Discovery; Drug dosages; Enzymes; FDA approval; Genomes; Growth factors; Heterocyclic Compounds, 3-Ring - pharmacokinetics; Heterocyclic Compounds, 3-Ring - pharmacology; HIV; HIV Infections - drug therapy; HIV Integrase Inhibitors - pharmacokinetics; HIV Integrase Inhibitors - pharmacology; Human immunodeficiency virus; Humans; Infections; Internal Medicine; Leading Article; Medical sciences; Medicine; Medicine & Public Health; Pharmacology. Drug treatments; Pharmacology/Toxicology; Pharmacotherapy; Pyrrolidinones - pharmacokinetics; Pyrrolidinones - pharmacology; Quinolones - pharmacokinetics; Quinolones - pharmacology; Raltegravir Potassium
• ISSN: 0012-6667; 1179-1950
• DOI: 10.1007/s40265-013-0015-5

The integrase enzyme facilitates the incorporation of HIV-1 proviral DNA into the host cell genome and catalyses a function vital to viral replication. Inhibitors of this enzyme represent the newest class of antiretroviral drugs in our armamentarium to treat HIV-1 infection. Raltegravir, an integrase strand transfer inhibitor, was the first drug of this class approved by the US FDA; it is a potent and well tolerated antiviral agent. However, it has the limitations of twice-daily dosing and a relatively modest genetic barrier to the development of resistance. These qualities have prompted the search for agents with once-daily dosing, a more robust barrier to resistance, and a resistance profile of limited overlap with that of raltegravir. We review a series of integrase inhibitors that are in clinical or advanced pre-clinical studies. Elvitegravir, recently approved by the FDA as part of the elvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine fixed-dose combination pill has the benefit of being part of a one-pill, once-daily regimen, but suffers from extensive cross-resistance with raltegravir. Dolutegravir is the most advanced second-generation integrase inhibitor, and it boasts good tolerability, once-daily dosing with no need for a pharmacological enhancer, and relatively little cross-resistance with raltegravir. S/GSK1265744 has been developed into a long-acting parenteral agent that shows a high barrier to resistance in vitro and the potential for an infrequent dosing schedule. BI 224436 is in early clinical trials, but is unlikely to demonstrate cross-resistance with other integrase inhibitors. The inhibitors of the lens epithelium-derived growth factor (LEDGF)/p75 binding site of integrase (LEDGINs) are extremely early in development. Each of these contributes a new benefit to the class and will extend the treatment options for patients with HIV-1 infection.