Convergent Combination Therapy


Convergent Combination Therapy

Seattle Treatment Education Project (STEP) Perspective, Vol. 5, No. 2 - July 1993 * 127 Broadway E. Ste 200 Seattle, WA 98102
Joel Gibson, MS

As mentioned in the article above, the combined use of Nevirapine (NVP) with AZT and ddI in in vitro studies done at Harvard Medical School and recently published in the journal Nature, deserves some special attention. Chow et. al. have discovered in their laboratory that they are able to keep the virus from replicating when therapeutic amounts of the three reverse transcriptase inhibitors mentioned above were added together in culture. This article has stimulated much interest and speculation among people with HIV, health care providers, and researchers. The idea behind Chow's discovery is that the virus mutates in order to overcome the addition of AZT to culture. When ddI is added to this culture, it mutates again in a slightly different region of the reverse transcriptase (RT) enzyme. When a third drug is added to this same culture, either Nevirapine or pyridinones, the virus mutates again in yet another region in order to "get around" the inhibitory effects of this third drug. It is the combination of these three viral mutations that causes it to mutate itself out of being able to replicate. Essentially, the RT enzyme which is needed for the virus to successfully infect new cells, was rendered inoperable. The resulting implications of these studies are very exciting.

However, some precautionary notes on this article should be addressed. First and foremost, the studies were done in vitro. Whether this effect will be seen in people is still very much up in the air. Second, since we are talking about RT inhibitors whether they are nucleosides or non- nucleosides, they are only effective in cells which have not been infected. Already infected cells will not be affected by this combination of drugs. Thirdly, since multiple sites of mutation are usually necessary for resistance to occur, couldn't other combinations of mutation sites still render the virus resistant to the drugs but not cause the RT enzyme to be knocked out? And fourth, if a mechanism is present such as stated in Larder's article about the reversal of AZT resistance by the development of resistance to some non-nucleoside RT inhibitors, wouldn't this eliminate this "convergent" effect which so effectively inactivated the RT enzyme in Chow's experiments? The answers to these questions will hopefully be answered in ACTG 241 and other like trials. The results of which are eagerly awaited.

For more complete information on convergent combination therapy, non- nucleoside RT inhibitors, ACTG 241, and associated planned trials, see one or both of the following well written articles:

* Loftus, R. Convergent Combination Therapy. March/April 1993. Treatment Issues 7(3):1-5.

* James, J.S. Convergent Combination Therapy. March 5, 1993. AIDS Treatment News 170:1-5.
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Always watch for outdated information. This article first appeard in 1993. This material is designed to support, not replace, the relationship that exists between you and your doctor.

Copyright © 1993 - Seattle Treatment Education Project (STEP) - All rights reserved. Noncommercial reproduction is encouraged. STEP is published four times a year by the Seattle Treatment Education Project, 127 Broadway East, 3rd Floor, Seattle, WA 98102.    Email: step100@aol.com  STEP web page

This information is designed to support, not replace, the relationship that exists between you and your doctor.
©1993. AEGIS.