Genetic mechanisms of resistance to NRTI and NNRTI.

Resistance to nucleoside reverse transcriptase inhibitors (NRTIs) seems to develop following three different pathways. Discriminatory mutations favor the binding of physiologic nucleosides over that of drugs. The newly so-called nucleoside-associated mutations (NAMs) enhance the removal of chain terminators (pyrophosphorolysis) from the cDNA in formation. Finally, some inserts at the p6 region within the gag gene (i.e., PTAP duplications) may favor virus escape from NRTI through a greater accumulation of RT molecules per virion. In respect to nonnucleoside reverse transcriptase inhibitors (NNRTIs), resistance often results from single mutations (K103N is the most frequently found) located at or near the drug pocket binding.