HIV-1 Resistance to the Nonnucleoside Reverse Transcriptase Inhibitors

Abstract

Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are widely used to treat and prevent HIV-1 infection. Most first-line antiretroviral therapies typically include two nucleoside reverse transcriptase inhibitors with one NNRTI (nevirapine (NVP), efavirenz or rilpivirine (RPV)). Etravrine has been approved for the treatment of HIV-infected antiretroviral therapy-experienced individuals, including those with prior NNRTI exposure. In the HIV-1 prevention arena, single-dose NVP is used to prevent mother-to-child transmission ((MTCT)); the ASPIRE and Ring studies are evaluating whether a vaginal ring containing dapivirine can prevent HIV-1 infection in women; a microbicide gel formulation containing the urea-PETT derivative MIV-150 is in a phase I study to evaluate safety, pharmacokinetics, pharmacodynamics, and acceptability; and a long-acting RPV formulation is under development for preexposure prophylaxis (PrEP). Given their widespread use, particularly in resource-limited settings, there is concern in regard to overlapping resistance between the different NNRTIs. In this chapter we comprehensively review the mechanisms of action and resistance to the NNRTIs that are used clinically. A better understanding of NNRTI resistance—including the mechanisms involved—is important for (1) predicting response to treatment; (2) surveillance of transmitted drug resistance; and (3) development of new classes of NNRTIs with higher genetic barriers to resistance.