Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

When HIV infects a CD4 cell in a person's body, it copies its own genetic code into the cell's DNA. In this way, the cell is then "programmed" to create new copies of HIV. HIV's genetic material is in the form of RNA. In order for it to infect CD4 cells, it must first convert its RNA into DNA. HIV's reverse transcriptase enzyme is needed to perform this process.

NNRTIs, also known as "non-nucleosides" or "non-nukes" for short, attach themselves to reverse transcriptase and prevent the enzyme from converting RNA to DNA. In turn, HIV's genetic material cannot be incorporated into the healthy genetic material of the cell, and prevents the cell from producing new virus.

The non-nucleoside reverse transcriptase inhibitors (NNRTIs) directly inhibit the HIV-1 reverse transcriptase (RT) by binding in a reversible and non-competitive manner to the enzyme. The currently available NNRTIs are nevirapine, delavirdine, and efavirenz; other compounds are under evaluation. NNRTIs are extensively metabolized in the liver through cytochrome P450, leading to pharmacokinetic interactions with compounds utilizing the same metabolic pathway, particularly PIs, whose plasma levels are altered in the presence of NNRTIs. NNRTIs are drugs with a low genetic barrier, i.e. a single mutation in RT genoma induces a high-level of phenotypic resistance, preventing the use of NNRTIs as monotherapy. In naive patients, several trials have shown the value of NNRTIs in combination with nucleosides and/or protease inhibitors. Small pilot studies have shown that NNRTIs may be useful as second-line therapy.

However, due to the rapid emergence of resistant virus to these compounds in case of incomplete viral suppression, NNRTIs should not be added to current failing antiretroviral regimen. The most common side-effect reported with nevirapine and delavirdine is rash. The incidence of rash is rather similar under these two compounds, but severe rash is less frequent with delavirdine. The most common adverse reactions reported with efavirenz are central nervous system complaints such as dizziness. Rash is reported less frequently than with nevirapine or delavirdine, and is usually mild. NNRTIs resistance mutations are located in the amino acid residues aligning the NNRTI-binding "pocket" site. High-level resistance is often associated with a single point mutation which develops within this site (especially codon groups 100 - 108 and 181 - 190). Patients failing on one NNRTI are very likely to possess multiple NNRTI resistance mutations. NNRTIs should always be used as part of a potent antiretroviral therapy to insure suppression of viral replication, thus circumventing the rapid selection of cross-resistant variants.

NNRTI drugs list :

Brand Name Generic Name Manufacturer Name

Intelence etravirine Tibotec Therapeutics

Rescriptor delavirdine, DLV Pfizer

Sustiva efavirenz, EFV Bristol Myers-Squibb

Viramune nevirapine, NVP Boehringer Ingelheim

Atripla efavirenz, emtricitabine and tenofovir disoproxil fumarate Bristol-Myers Squibb and Gilead Sciences