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HIV Drug ResistanceHIV Drug Resistance
          
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Resensitization of HIV to different medications
Jan 19, 2005

Is there any official or unofficial protocol for resensitizing the virus to previously resistant medications. I have heard that a drug holiday can sometimes cause the wild type virus to proliferate and the resistant virus to die off. I have also heard that the virus through numerous mutations can become so dysfunctional that it can actually mutate to a form that is again resistant to previously resistant medications. Would you please comment?

Response from Dr. Sherer

No, there is no such protocol. Remember that a person is infected with a 'swarm' of virus, not a single species, and there is an ongoing shift in the dominant species from the first moment of infection. Antiretroviral therapy (ART) interferes with this shift by suppressing all viral replication in the bloodstream, and most, but not all, replication in tissue reservoirs such as the central nervous system and the gonads. When resistance occurs, and there is a rising viral load in the blood indicating ongoing viral replication, this means that a new mutant has become the dominant strain.

You may be referring to the observed phenomenon in patients who were infected with virus with no mutations at baseline (i.e. 'wild type' virus), who now have a resistant strain with ongoing viral replication and a rising viral load, and who then stop all drugs and experience the overgrowth of the original 'wild type' virus. If you then do a resistance test in this situation, no mutations are found. However, that doesn't mean that the mutations are gone, or that the virus is 're-sensitized'; rather, the mutations are 'archived' in a sub-population of virus, and will re-emerge promptly if the virus is re-exposed to the same drugs that the patient was taking when the resistance first developed.

This is one reason why its so important for your doctor to have a complete record of the drugs you have taken in the past when he or she interprets a resistance test and determines your next drug regimen.

To sum up: You should regard resistance as always undesirable, and a permanent state. Once you acquire a resistance mutation, you always have it, either in the dominant viral population, or, as I explained above, in an archived state in a minor viral population. The mutation can and will re-emerge at a later time under the right circumstances, i.e. re-exposure to the same drug regimen.

To the second question, it is true that some ART regimens decrease the virus' ability to replicate, i.e. decrease its 'fitness.' Phenotypes measure this in the laboratory as the 'replication capacity', i.e. the ability of the virus to undergo one replication cycle in the laboratory. (Fitness is more complex that this single measure, and many other factors contribute to fitness.) The NNRTIs, like Sustiva, seem to have little effect on fitness. The NRTIs like lamivudine have a large effect. And the PIs are variable. The clinical impact of all of this remains unclear. There is some evidence that lowered replication capacity may be associated with less condquences of ongoing viremia, but the data are still quite limited.

None of these observations should distract anyone with HIV+ who is on ART from the major business at hand, i.e. to adhere to medications as well as possible, missing no or as few doses as possible, in order to get the best possible outcome of therapy.

The virus is unforgiving, and doesn't forget our mistakes. All resistance is bad news, and the best way to deal with it is to prevent it.


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