NNRTI constitute an essential part of our antiretroviral therapy arsenal. Increasingly, first HAART regimens administered to drug-naive individuals include approved drugs of this class. There is growing concern that the fact that a single mutation confers high-grade phenotypic resistance to these agents will limit their usefulness, especially if they are prescribed in a suboptimal manner.

Little et al (abstract 25) reported that primary NNRTI resistance (defined as >10-fold reduction in susceptibility) may be present in up to 7% of viruses isolated in a broad range of North American patients with acute HIV infection during 1999-2000 [1]. This compares to a rate of 2% in similar isolates during 1995-1998. Zaidi et al (abstract 155) reported a rate of 1.7% in 603 recent U.S isolates, but this included a number of chronically-infected individuals who could have had primary resistance, but in whom it is no longer detectable in the absence of drug pressure [2].

As preliminary evidence suggests that the time to complete virologic response to therapy may be longer in patients with drug resistance who are receiving NNRTIs (to date, a non-significant trend), there may be a cause for concern. This supports current IAS-USA guidelines that support the use of resistance testing in patients with acute/early infection and those who do not respond to initial therapy in an appropriate way. An additional concern has been that NNRTI resistance may also emerge in the setting of treatment interruptions when all drugs are stopped simultaneously. This would be due to the longer half-life of the NNRTI, which could lead, effectively, to exposure to NNRTI monotherapy for 24 hours or longer. Ruiz et al (abstract 122) evaluated 7 patients on NNRTI who underwent a treatment interruption, 4 of whom experienced a near immediate virologic rebound without NNRTI resistance [3]. Further evidence of the relative "difficulty" for NNRTI resistance mutations to emerge was presented by Prasad et al (abstract 121). In patients on 3TC and delavirdine (as part of first HAART regimen) who developed a resistance mutation in the setting of virologic breakthrough, the M184V mutation was always identified, rather than any NNRTI-associated change [4]. This being said, in the setting of salvage therapy in 69 NNRTI-naive individuals, 40 of 69 failed at 12 weeks, 33 of whom showed at least one NNRTI resistance mutation (K103N, Y181C, and/or G190A). The rate of breakthrough was associated with the ability to add new potent drugs to the regimen. Thus, if we do not "protect" the NNRTI, resistance WILL emerge. An interesting strategy may be to monitor drug levels to reduce the likelihood of resistance. Indeed, Gonzalez de Requena et al (abstract 115) evaluated the strategy of increasing nevirapine doses to 600 mg/day in 18 patients with low level virologic breakthrough [5]. This increased mean nevirapine plasma levels from 3.5 to 7.5 g/mL, and led to virologic suppression in 10 of 18 cases. This approach may be worth exploring in a controlled fashion.

The concept of NNRTI hypersusceptibility was evaluated in a small study comparing the response of 11 individuals carrying isolates showing hypersusceptibility to efavirenz with 14 wild-type controls (abstract 107) [6]. Interestingly, the controls exhibited a BETTER virologic response, making it less and less clear that hypersusceptibility will be of any clinical significance in the case of NNRTI.

What we really need are new agents in this class. This in particularly true in light of the fact that in a systematic search of the Virco database (>20,000 isolates), a new mutation (Y318F) was identified that may confer NNRTI resistance (Kemp et al; abstract 44) [7]. Its presence, irrespective of other mutations, predicts a 10-fold increase in resistance to all currently marketed NNRTI. In site-directed mutants, it is associated with 40-fold reduced susceptibility to delavirdine, and potentiates the effect of K103N and Y181C on efavirenz and nevirapine resistance. Whether or not this mutation proves to be of clinical significance, it is clear that the development of NNRTI resistance is certain to be an increasing problem in years to come.

Of the new drugs, the second generation NNRTI TMC120 and TMC125 may offer the most promise (De Bethune et al, abstract 7) [8]. In vitro resistance takes longer to emerge and usually requires two mutations (Y181C/Y188L or Y181C/L100I). The drugs retain activity against K103N mutants. The clinical development of one or both agents is eagerly awaited. Capravirine (Alexander et al, abstract 10) was also shown to retain activity against 18/28 clinical K103 isolates, including those carrying it in combination with V108I or P225H [9]. Unfortunately, the development of this molecule is now being delayed by reports of toxicity in animal models. Finally, the SJ-3366 drug exhibits the same resistance pattern as current NNRTI, but may also act as an inhibitor of envelope-mediated infection events (Buckheit et al, abstract 13) [10]. This alone, however, may not warrant its further clinical development.

In summary, NNRTI remain important, effective molecules in our fight to control HIV/AIDS. More insightful knowledge of issues surrounding the development of resistance to available and developmental drugs of this class in the clinic will certainly help us use them to maximum benefit as we make individual treatment decisions with our patients.

References
Abstracts can be accessed by hyperlink after registering for the 5th International Workshop on HIV Drug Resistance & Treatment Strategies Webcast at Mediscover.net