Starting in the early 1990s, a number of structurally unrelated non-nucleoside compounds were discovered to be potent non-competitive inhibitors of HIV reverse transcriptase. These compounds share the property of having highly specific activity against HIV-1 but not against HIV-2 or other retroviruses. These compounds bind to a deep pocket in reverse transcriptase and disrupt the catalytic site of the enzyme. Three NNRTIs, nevirapine, delavirdine, and efavirenz, are presently approved, and several others are in various stages of development.

The biggest drawback to this class of drugs is that high-level resistance can emerge within 2 to 4 weeks in patients receiving these compounds as single drugs. This resistance is associated with one or more mutations in reverse transcriptase. There is some evidence that the development of this resistance is slowed somewhat and that more sustained activity of these compounds can be obtained if they are used in potent combination drug regimens in which the viral load is suppressed to undetectable levels. This finding has increased the interest somewhat in this class of drugs, and several others are now in clinical development, including HBY097, MKC-442, and calanolide A. However, there is a substantial degree of cross-resistance among the NNRTI, and patients who become resistant to one may not respond to others in the future. This point underscores the importance of using anti-HIV drugs in a manner that reduces the development of resistance.

Nevirapine, delavirdine, and efavirenz are all metabolized by the cytochrome P-450 system. However, whereas nevirapine induces the P-450 system, delavirdine acts as an inhibitor of P-450 CYP3A and can thus suppress the metabolism of PIs such as saquinavir. This may make delavirdine attractive to use in combination with PIs. Efavirenz is a mixed inducer/inhibitor of cytochrome P-450 and can have mixed effects on these drugs. The principal toxicity of these drugs is a rash, which can on occasion progress to Stevens-Johnson syndrome. Other toxicities include headache, fatigue, and elevated hepatic transaminase levels. Efavirenz can also cause central nervous system symptoms.