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Resistance Problems
Sep 6, 2001

Dr Little I was wondering if you could answer a question or two concerning the magnitude and the causes of HIV mutations associated with resistance to current treatments. My first question is what do you belive or what do find the research to show as the primary cause of resistance? Is it that people who are infected with the virus are incorrectly or not taking at all thier medications? Or is that the virus is mutating around the current thearpy? If its both could you give a estimate on the proportions of both? Finnally how do you feel that we will best be able to get a handel on the problem of resistance? Through new and better drugs?(could you suggest drugs that you see in the future down the pipeline as real success at dealing with this issue? ) Finnally could you perhaps tell if it would be possible cause to the virus to mutate to such an exstint that it would be rendered far less harmful possibly more vonerable to our treatment or eradication? By the way excellent job you are doing here at this web site have read several of your postings and you seem exceptionally knowlagable on this subject.

Response from Dr. Little

Your first question - it is both. The most common pattern is that people are not able to stick with the rigorous treatment schedule required for potency by currently available therapies and then the virus is given the opportunity to replicate or reproduce again and the viral load becomes detectable. Then, and in fact at any time that the virus is actively replicating, there are natural replication "mistakes" that the virus makes (not in response to the therapy, but as part of the normal viral lifecycle) which cause mutations to arise. These mutations can arise anywhere and may be of little consequence, except when they occur in the area of the virus which interacts with the antiretroviral drugs. If one of the mutations means that this virus interacts less well with the drug, then it has a replication advantage over the other circulating viruses and over time, may become the predominant strain in the ciruculation (at which point drug resistance will be detectable with testing). It is assumed that the virus will always behave like this, which means that only drugs which do not EVER permit viral replication are likely to prevent the selection for drug resistant virus - and we do not have a drug that meets these standards yet. Our best hope for drugs in the pipeline is that they will be associated with fewer side effects and can be taken less frequently so that the chances that patients will skip doses to avoid unpleasant side effects or forget doses becomes less likely - thus drug resistance becomes less common because more people have complete viral suppression (viral loads less than 50).

The idea that the virus could become so "mutated" that it was less capable of causing harm is a very reasonable idea when carried to the extreme. These highly mutated strains often do replicate less well that drug susceptible strains, but still at a level sufficient to infect T cells and cause disease progression. There is the possibility that this strategy could be used in the future in the drug development field, but we are not there yet.


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