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Behind "AIDS Breakthrough" Headlines, December 2004: Important Research, Not So New

By John S. James

December 31, 2004

Press stories in mid December 2004 about an AIDS breakthrough from Rutgers University and elsewhere were exaggerated in the media, but the treatment development is real and important. It concerns a family of experimental antiretrovirals called DAPYs, now in early human trials. These drugs are in the same class as efavirenz (Sustiva) and nevirapine (Viramune), but they appear to be much more effective against HIV, in large part because they have been rationally designed to make it very difficult for the virus to develop resistance against them. They are active against HIV that has become resistant to efavirenz and nevirapine.

Almost three years ago at the Retroviruses conference in early 2002 the public learned that one of these drugs, TMC125 (an experimental antiretroviral made by Tibotec) produced an almost 2-log (100 fold) drop in HIV viral load in only 1 week, in a human study in 12 volunteers. TMC125 is now in large phase II trials at many different sites. For more information about the early human report, see AIDS Treatment News, April 12, 2002, Twelve-week results from the phase II studies of TMC125 are expected in 2005, possibly at the Retroviruses conference in February.

A key element in the design of these drugs is the use of flexible molecules, so that they can fit into different shapes of the "active pocket" of the reverse transcriptase enzyme, even after that shape changes due to resistance mutations that could make non-flexible molecules ineffective. The two different kinds of flexibility used are sometimes called "wiggling" and "jiggling." This approach may be useful for treatment of many diseases, not just HIV.

The occasion for the December 2004 media was an upcoming publication in the Journal of Medicinal Chemistry about a new compound (called R278474, or rilpivirine), that works like TMC125 but might be more effective;1 it is much earlier in testing, however. R278474 was 10 to 20 times more active than efavirenz in laboratory tests -- and no resistance breakthrough was observed at 30 days, while it was seen at six days with efavirenz. This paper describes the drug, and also the technical history of the development of DAPY drugs including TMC125 and R278474, emphasizing the work of multidisciplinary teams of scientists in Belgium and the U.S.

Longer versions of the recent news reports are at

Technical Reference

  1. Janssen PAJ, Lewi PJ, Arnold E, and others. In search of a novel anti-HIV drug: Multidisciplinary coordination in the discovery of 4-[[4-[[4-[(1E)-2-Cyanoethenyl]-2,6-dimethylphenyl] amino]-2pyrimidinyl]amino]benzonitrile (R278474, rilpivirine). Journal of Medicinal Chemistry. This article was released early online and will be published soon, but the exact reference is not yet available.

ISSN # 1052-4207

Copyright 2004 by John S. James. Permission granted for noncommercial reproduction, provided that our address and phone number are included if more than short quotations are used.

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