In the HIV life cycle, the HIV-1 integrase enzyme plays a vital role to insert the HIV-1 proviral DNA into the host chromosome. It is a rational target to design inhibitors for HIV treatment and prevention. This chapter focuses on three FDA approved HIV-1 integrase strand transfer inhibitors (INSTIs); raltegravir, elvitegravir and dolutegravir. Raltegravir is the first approved HIV-1 integrase inhibitor. It blocks HIV-1 replication by inhibiting the strand-transfer activities of integrase with a rapid absorption (Tmax ~ 4 h). With twice daily dosing, approximately 83% of raltegravir is bound to human plasma proteins and its terminal elimination half-life is approximately 9 hours. For raltegravir, no adjustment of dosing is necessary for food, gender, age, body mass index, or hepatic and renal function. It has significant anti-HIV potency in both antiretroviral treatment-naïve and treatment-experienced patients. As the second approved HIV-1 integrase inhibitor, elvitegravir is absorbed rapidly with the Tmax being 3-4 h. The absorption of elvitegravir increased up to three folds when it was administered with food. It was approved to be used once daily as part of a fixed-dose combination, known as stribild, which is a complete regimen for the treatment of adults with antiretroviral treatment-naïve HIV-1 infection. Dolutegravir is a second-generation integrase inhibitor that has more rapid and sustained virologic suppression than raltegravir and elvitegravir. It is time to the maximum plasma concentration (Tmax) is 1 h. The terminal elimination half-life of dolutegravir is 13 ~ 14 h. Clinically, dolutegravir is a commonly used antiretroviral regiment for both treatmentnaïve and treatment-experienced patients. In summary, HIV-1 integrase inhibitors are a novel class of antiretroviral drug, which provide a tremendous advancement in AIDS treatment options.
Keywords: Administration, adverse effects, catalytic mechanism, clinical trials, DNA, dolutegravir, drug interactions, elvitegravir, function, HIV-1 integrase, inhibitors, pharmacodynamics, pharmacokinetics, raltegravir, resistance, structure.