Non-nucleoside RT inhibitors

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) interfere with reverse transcriptase by binding directly to the enzyme. They are not competitive with nucleoside reverse transcriptase inhibitors as they work at a different site on the reverse transcriptase enzyme and are not incorporated into the viral DNA.

The licensed NNRTIs are:

• EFV   efavirenz (Sustiva/Stocrin)
• ETR   etravirine (Intelence)
• NVP   nevirapine (Viramune)
• DLV   delavirdine (Rescriptor, only licensed for use in the US)*

Etravirine, from Tibotec, was licensed in the US and Europe in 2008 and is the first new NNRTI in a decade. It is called a second-generation NNRTI, as its mechanism of action is different from the older NNRTIs. It is a diarylpyrimidine (DAPY), designed to fit into different shaped binding pockets in the reverse transcriptase enzyme. Etravirine is approved for use in treatment-experienced patients when it is added to a highly active antiretroviral therapy (HAART) regimen. Its European licence specifies that it must be used in a protease inhibitor (PI)-boosted HAART regimen.^{1 2 3}

Rilpivirine (TMC278), also from Tibotec, has shown potency similar to that of efavirenz in two 48-week randomised phase III studies for treatment-naive participants. Pooled analysis of the ECHO and THRIVE studies showed that after 48 weeks of treatment the proportions with viral load below 50 copies/ml were almost identical (84.3% in the rilpivirine arm, 82.3% in the efavirenz arm), a non –inferior outcome. A higher virological failure rate was seen in the rilpivirine group, and a higher rate of discontinuation due to adverse events was seen in the efavirenz group. Gilead is now seeking a license for a fixed dose combination of rilpivirine, tenofovir and 3TC.⁴

RDEA806 is an NNRTI, developed by Ardea Biosciences, with a high barrier to resistance against the common mutations that develop with efavirenz and nevirapine. A phase II, multicentre dose-ranging study of this drug is currently enrolling treatment-naive patients in Europe. The proof-of-concept monotherapy study of this drug in treatment-naive patients showed a minimum one log decline in viral load with no evidence of rash or central nervous system side-effects such as those found in efavirenz.⁵

2248761 (formerly IDX899, GSK 2248761) is in development by ViiV Healthcare, a specialist HIV company established by GlaxoSmithKline (GSK) and Pfizer. In vitro studies showed a long half-life and ability to inhibit both wild-type and NNRTI-resistant HIV. A  proof-of-concept study in treatment-naive patients took place that showed efficacy and tolerability. Phase II studies will be dose-ranging and will attempt to characterise the dose-response and concentration-response curves.[ref] The company also plans to test 761 in combination with the integrase inhibitor GSK-572 as a fixed dose, NRTI-sparing combination.

UK-453,061 (lersivirine), a Pfizer drug now being developed by ViiV Healthcare, is another second-generation NNRTI. Similar to the other investigational drugs mentioned above, it does not seem to have a significant effect on CYP3A4 metabolic activity and also appears to be active against the common NNRTI mutations. Patients are being enrolled into a phase II two-arm study comparing UK-453,061 to efavirenz, both taken with Truvada.⁶

* Delavirdine (Rescriptor), was licensed in the US, but not in Europe. It is rarely used because of its reduced efficacy, cross-resistance patterns, drug interactions, and inconvenient dosing requirements as compared to the other NNRTIs. 

For further information on specific NNRTIs, see A to Z of antiretroviral drugs.