HIV-1 integrase inhibitor resistance and its clinical implications

Abstract

With the approval in 2007 of the first integrase inhibitor (INI), raltegravir, clinicians became better able to suppress virus replication in patients infected with human immunodeficiency virus type 1 (HIV-1) who were harboring many of the most highly drug-resistant viruses. Raltegravir also provided clinicians with additional options for first-line therapy and for the simplification of regimens in patients with stable virological suppression. Two additional INIs in advanced clinical development-elvitegravir and S/GSK1349572-may prove equally versatile. However, the INIs have a relatively low genetic barrier to resistance in that 1 or 2 mutations are capable of causing marked reductions in susceptibility to raltegravir and elvitegravir, the most well-studied INIs. This perspective reviews the genetic mechanisms of INI resistance and their implications for initial INI therapy, the treatment of antiretroviral-experienced patients, and regimen simplification.

Figure 1.

HIV-1 integrase (IN) inhibitor resistance mutations superimposed on a crystal structure of the IN central core domain bound to a prototype diketo acid inhibitor (5CITEP; PDB 1QS4) [54]. IN residues 56 to 165 are displayed in gray cartoon mode to represent secondary structural properties. 5CITEP is represented using cyan spheres. Active site residues D64, D116, and D152 are in white. Sites associated with the most commonly occurring primary mutations are in red (T66, E92, G140, S147, Q148, and N155). Sites associated with the most common accessory mutations (L74, T97, E138, V151, S153, and S163) and with primary mutations that have been observed solely in vitro (F121, Q145, and P146) are in yellow. Mg⁺⁺ is a blue sphere. Residues 141 to 144, which form part of the highly mobile loop extending between G140 and G149, were not resolved in this crystal structure.