Non-nucleosidic reverse transcriptase inhibitors

The non-nucleoside reverse transcriptase inhibitors (NNRTIs) directly inhib it the HIV-1 reverse transcriptase (RT) by binding in a reversible and non- competitive manner to the enzyme. The currently available NNRTIs are nevira pine, delavirdine, and efavirenz; other compounds are under evaluation. NNR TIs are extensively metabolized in the liver through cytochrome P450, leadi ng to pharmacokinetic interactions with compounds utilizing the same metabo lic pathway, particularly Pls, whose plasma levels are altered in the prese nce of NNRTIs, NNRTIs are drugs with a low genetic barrier, i.e. a single m utation in RT genoma induces a high-level of phenotypic resistance, prevent ing the use of NNRTIs as monotherapy. In naive patients, several trials har e shown the value of NNRTIs in combination with nucleosides and/or protease inhibitors. Small pilot studies have shown that NNRTIs may be useful as se cond-line therapy. However, due to the rapid emergence of resistant virus t o these compounds in case of uncomplete viral suppression, NNRTIs should no t be added to current failing antiretroviral regimen. The most common side- effect reported with nevirapine and delavirdine is rash. The incidence of r ash is rather similar under these two compounds, but severe rash is less fr equent with delavirdine. The most common adverse reactions reported with ef avirenz are central nervous system complaints such as dizziness. Rash is re ported less frequently than with nevirapine or delavirdine, and is usually mild, NNRTIs resistance mutations are located in the aminoacid residues ali gning the NNRTI-binding "pocket" site. nigh-level resistance is often assoc iated with a single point mutation which develops within this site (especia lly codon groups 100-108 and 181-190). Patients failing on one NNRTI are ve ry likely to possess multiple NNRTI resistance mutations. NNRTIs should alw ays be used as part of a potent antiretroviral therapy to insure suppressio n of viral replication, thus circumventing the rapid selection of cross-res istant variants.