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.


  1. Sungkanuparph S et al. Evaluating the role of etravirine in the second-line antiretroviral therapy after failing an initial non-nucleoside reverse transcriptase inhibitor-based regimen in a resource-limited setting. Curr HIV Res 6(5): 474-476, 2008
  2. Madruga JV et al. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1 infected patients in DUET-1: 24-week results from a randomised, double-blind, placebo-controlled trial. The Lancet 370: 29-38, 2007
  3. Lazzarin A et al. Efficacy and safety of TMC125 (etravirine) in treatment-experienced HIV-1 infected patients in DUET-2: 24-week results from a randomised, double-blind, placebo-controlled trial. The Lancet 370: 39-48, 2007
  4. Cohen C Pooled week 48 efficacy and safety results from ECHO and THRIVE, two double-blind, randomised phase III trials comparing TMC278 versus efavirenz in treatment-naïve HIV-1-infected patients. Eighteenth International AIDS Conference, Vienna, abstract THLBB206, 2010
  5. Moyle G et al. RDEA806, a novel HIV non-nucleoside reverse transcriptase inhibitor, shows positive outcome in treatment of naive HIV patients. 48th International Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2008). Washington, DC. October 25-28, 2008. Abstract H-893. 48th International Conference on Antimicrobial Agents and Chemotherapy, Washington, DC, abstract H-893, 2008
  6. Fatkenheuer G et al. Short-term monotherapy with UK-453,061, a novel NNRTI, reduces viral load in HIV-infected patients. Fourth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Sydney, abstract WESS202, 2007
Community Consensus Statement on Access to HIV Treatment and its Use for Prevention

Together, we can make it happen

We can end HIV soon if people have equal access to HIV drugs as treatment and as PrEP, and have free choice over whether to take them.

Launched today, the Community Consensus Statement is a basic set of principles aimed at making sure that happens.

The Community Consensus Statement is a joint initiative of AVAC, EATG, MSMGF, GNP+, HIV i-Base, the International HIV/AIDS Alliance, ITPC and NAM/aidsmap

This content was checked for accuracy at the time it was written. It may have been superseded by more recent developments. NAM recommends checking whether this is the most current information when making decisions that may affect your health.

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