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A question of Resistance
Nov 15, 2001

Dr. Little great to see that you are still here and thank you for all the valuable information which you have put forth on this site. Its insiteful,sensitive,and always informitive! My questions are directed at getting your opinons on some up coming drugs in the pipeline. First with regaurd to T-20 do you think its unique ristanace profile will make it more difficult for the virus to devolope ristance to it verses the currently available drugs? I have been doing a lot of research and it appears for my findings that the biggest problem of resistance is the fact that while the currently available drugs do a wonderful job when taken and taken correctly to suppress viral replication and thus mutation; they still all fall short of completly shutting off the virus from replicating. This is particualarly difficult since much of the replication that is going on in a patient who is at <50 is going on in the viral reservors which the currently available drugs cant seem to reach. While I understand that even if we could some how shut off completly the virus ablity to reproduce itself we still would not have a cure it would at least put an end to the problem of resistance and render the virus in a perminate state of remission as long as the person took there medication. My question is can we ever get to a point where we can shut down viral replication completly?? What about Drugs that inhibit CCR5 and CRCX4(it would I think be neccesary to use both to avoid giving selective advantage to virus using CRCX4 which when this occurs seems to create a "supervirus" and we can do without that) What is the status of intergase inhibitors and HGTV43(antisense drug) Thank you for your assistance and as always my best to you.

Response from Dr. Little

Regarding T-20, I think that the unique mechanism of action of this drug will make it (or the drugs that are developed in this class) useful for patients who already have some drug resistance to available agents, but still have treatment options left and need an additional agent to give their treatment regimen more potency. With regard to T-20, resistance to this drug has already been observed in patients taking this drug as monotherapy and as such, I do not think that there are any unique properties which make it more special other than a another different option for people who have limited options and are willing to consider a drug which needs to be taken by daily injection.

You are correct that the best way to avoid the development of drug resistance is to take a therapeutic regimen which COMPLETLEY suppresses the viral load below the limit of detection. If T-20 is part of this regimen then it is great, but I do not think that it's new mechanism of action compared to the other drugs means it will take the virus longer to develop resistance if used in an incompletely suppressive regimen.

Part of the difficulty with treatments which might suppress viral replication more than currently available drugs is that we have no way to measure suppression which is below 50 copies (some research assays go lower, but these are not widely available). Right now, you are correct, that the best we are able to do is keep the viral load less than 50 and work hard to keep it there as long as possible. Other drugs such as the CXCR4 and CCR5, and integrase inhibitors are still in very early stages of development (antisense compounds even more preliminary) - too early really to say how great a promise they may or may not hold for treatment.

HIV+ to HIV-
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