The "first generation" of non-nucleoside reverse transcriptase inhibitors (NNRTIs) comprises efavirenz [link?] (Sustiva), nevirapine (Viramune), and delavirdine (Rescriptor). Unlike protease inhibitors and most NRTIs, which require several mutations to develop a high degree of resistance, a high level of resistance to all three of these NNRTIs results from either one of two single mutations (K103N or Y181C). Therefore, resistance to these drugs can emerge very readily if HIV viral load is not quickly and fully suppressed to very low levels.

After treatment is stopped, NNRTI resistance mutations disappear at highly variable rates between patients, and can persist for over six years ^[1]. Furthermore, all three of these NNRTIs are highly cross-resistant; studies have demonstrated high rates of failure in patients treated with an NNRTI after the failure of a previous NNRTI-based regimen ^{[2] [3] [4] [5]}.

A "second generation" of NNRTIs, specifically designed to avoid this earlier pattern of NNRTI resistance, has now been developed.