Pharmacokinetics of HIV non-nucleoside reverse-transcriptase inhibitors

Abstract

In most parts of the world, first-line antiretroviral therapy typically contains a non-nucleoside reverse-transcriptase inhibitor (NNRTI). This class of drugs includes efavirenz, nevirapine and new generation agents including etravirine (ETR). NNRTI-containing regimens are widely preferred as first-line therapy in treatment guidelines. There is the potential for significant drug interactions when NNRTIs are coadministered with other drugs, for example those used in the treatment of TB and other antiretroviral therapy drugs, such as protease inhibitors. Pharmacokinetic profiles of these NNRTIs, together with immunological and virological factors, would influence the choice of agents used in the various regimens for the treatment of HIV infection. Despite being disparate agents with different chemical structures, NNRTIs share similar modes of action on HIV reverse-transcriptase. They are principally metabolized by the various cytochrome P450 isoforms, including CYP3A4 and CYP2B6. They themselves may be inducers (efavirenz, nevirapine and ETR) or inhibitors (delavidine) of these enzymes. First-generation NNRTIs have a relatively low genetic barrier to the acquisition of drug resistance, whereas ETR has a higher genetic barrier to drug resistances and requires the accumulation of more than one key mutation in HIV reverse transcriptase. Other second-generation agents, including rilpivirine (TMC 278), are currently undergoing clinical trials, with initial data suggesting higher potency, longer duration of action and a low genetic barrier to resistance in common with other diarylpyrimidines, including ETR.