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When to Jump to New Virus Entry Inhibitors
Feb 13, 2001

It appears some of the forthcoming virus entry inhibitors such as the "fusion inhibitors" (T-20 or T-1249) may be available in a year or two. Others, such as a "zinc finger inhibitor" (ADA) may also be on their way. I read in the news that "zinc finger inhibitors represent potentially an important contribution to combination therapy in AIDS because they are not likely to produce escape mutants. ADA could potentiate the effects of fusion inhibitors." However, I also listened to an interesting lecture from the the 8th Conference on Retrovirus on "Closing the Door to HIV entry" (http://www.retroconference.org/2001/ - great site to check out!) today. It seems to suggest that multiple virus entry inhibitors may be better than one, ultimately. I have also read that HIV can develop resistance to T-20. In your opinion, could this mean that just like classes preceding them, that some of us who have run the course with the existing 15 available drugs could also lose the benefits of this new class of anti-HIV drugs if we start using them sequentially rather than together? Or is it just simply too soon to tell?

Response from Dr. Pavia

Great question, and I am glad you had a chance to hear the talk on viral entry by Robert Doms. It was a phenomenal talk in person, and I am glad it is available on the net.

It is a safe bet that HIV will develop escape mutants to almost any approach if one drug is used alone and if it does not completely suppress replication. We keep hoping we have found a target that cannot mutate, but that is certainly not true for the fusion domain, the target of T20 and T1249. It looks as if using CD4 or CCR5 inhibitors with T20 type drugs will be a very potent combination.

The capsid zinc finger is a very small molecule that may not be able to mutate much, but we are still a ways from having a zinc finger inhibitor that is looking like a successful drug. And, we have heard the "the virus can't escape" story before, only to learn we had underestimated the virus. Don't underestimate this opponent.

In general, it is important to pair any new agent with other drugs that will be effective and NOT TO USE THEM SEQUENTIALLY. This may be re using old drugs based on resistance testing and pharmacologic boosting, or it may mean waiting for other new drugs. Tenofovir, DAPD, T20 and tipranavir are all coming along well, and should be available over the next 12 months or so. Good luck, and as they said in revolutionary times, keep your powder dry...

ATP



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