HIV-1 Resistance to First- and Second-Generation Non-nucleoside Reverse Transcriptase Inhibitors

Resistance to the first-generation non-nucleoside reverse transcriptase inhibitors nevirapine andefavirenz is characterized by rapid selection of viruses carrying one or several mutations in the reversetranscriptase gene, which immediately confer high-level resistance as well as cross-resistance to thetwo drugs. Such mutations have been detected close to the non-nucleoside reverse transcriptaseinhibitor binding site and also in the connection domain of HIV reverse transcriptase. They lead to aloss of drug affinity without affecting viral fitness. As a single mutation is enough to confer high-levelresistance, transmission of non-nucleoside reverse transcriptase inhibitor-resistant viruses (currently2-7% of cases) is strongly associated with virologic failure of non-nucleoside reverse transcriptaseinhibitor-based first-line regimens. The development of second-generation non-nucleoside reversetranscriptase inhibitors is a major challenge. The most promising compounds, etravirine and rilpivirine,are active on mutant viruses and possess a relatively high genetic barrier for resistance. Data on etravirineresistance in patients already exposed to first-generation non-nucleoside reverse transcriptase inhibitorsshow that, among 17 mutations in the reverse transcriptase gene, at least three must be presentsimultaneously in order to diminish etravirine activity. Recent studies of the prevalence of resistance inlarge databases of patients already exposed to nevirapine and efavirenz show that more than threequartersof strains will still be sensitive to etravirine in both the southern and northern hemispheres. Thefirst data on rilpivirine resistance are encouraging, but still too preliminary.