The rise of second-generation non-nucleoside reverse transcriptase inhibitors: etravirine, rilpivirine, UK-453061 and RDEA-806

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are a crucial component of current highly active antiretroviral therapy (HAART) treatments for HIV-1 infection. One of the major limitations of the two most widely used NNRTIs, efavirenz and nevirapine, is their low genetic barrier to resistance, in addition to their undesirable side effects. The goal of current investigational NNRTI development is to create a safe, well-tolerated drug with a high genetic barrier to resistance that is active against known NNRTI-associated resistance mutations. This review discusses three investigational NNRTIs, rilpivirine (TMC-278), UK-453061 and RDEA-806, which are at different stages of development, as well as etravirine (TMC-125), a second-gene ration NNRTI that was recently granted accelerated approval by the FDA.