The availability of effective combination antiretroviral therapy (ART) has transformed HIV infection from an almost uniformly fatal diagnosis to a manageable chronic disease for persons living in areas of the world with widespread access to treatment [1-3]. Sustaining treatment success requires antiretroviral drugs that are potent, well tolerated, and convenient. Introduction of the first HIV-1 integrase inhibitor, raltegravir, followed by a second integrase inhibitor, elvitegravir, has expanded the range of efficacious options.
This topic will address the pharmacology of HIV integrase inhibitors. Clinical trial data concerning the use of these agents is found elsewhere. (See "Clinical trials of HIV antiretroviral therapy: Integrase inhibitors".)
In 2009, raltegravir was approved for use in treatment-naive and treatment-experienced HIV-infected patients. Elvitegravir was subsequently approved for use in treatment-naive HIV-infected patients in August 2012 as part of a fixed-dose antiretroviral combination regimen that incorporates tenofovir, emtricitabine, elvitegravir, and cobicistat into a single tablet. Cobicistat is an inhibitor of the cytochrome P450 enzyme CYP3A4, which is the primary metabolic pathway for elimination of many drugs, including elvitegravir. As such, it works as a pharmacologic enhancer of elvitegravir; it does not have any intrinsic anti-HIV activity of its own. Tenofovir and emtricitabine are approved antiretroviral drugs that are nucleoside analogs and work by inhibiting HIV reverse transcriptase. (See "Clinical trials of HIV antiretroviral therapy: Integrase inhibitors" and "Pharmacology of nucleoside reverse transcriptase inhibitors".)
MECHANISM OF ACTION
HIV integrase is one of three enzymes (reverse transcriptase, protease, and integrase) encoded by the virus, which are essential for HIV replication. After entry into CD4+ T cells, viral RNA is transcribed into DNA by HIV reverse transcriptase. Following this step, the integrase enzyme combines with viral DNA and other cellular cofactors to form the preintegration complex (PIC) [4-9]. Subsequently, the integrase enzyme removes a nucleotide from each 3’ DNA terminus, thereby exposing reactive hydroxyl groups. The PIC then enters the host cell nucleus where it binds to host cell DNA. Integrase nicks each strand of the host cell DNA and exposes the 5’ phosphate groups, enabling covalent bonding of host and viral DNA. After this strand transfer is complete, host cell enzymes repair gaps between the viral and host DNA.
Raltegravir and elvitegravir both target the strand transfer step of viral DNA integration and are sometimes referred to as “INSTI” (integrase strand transfer inhibitor) drugs. These drugs prevent or inhibit the binding of the pre-integration complex to host cell DNA, thus terminating the integration step of HIV replication.