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HIV Drug ResistanceHIV Drug Resistance
          
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What causes resistance?
Apr 17, 2001

I tested positive in November of 2000. My initial viral load was around 170,000 and my T-Cell count was around 200. My physician prescribed a drug therapy that includes Kaletra (3 capsules twice a day), Ziagen (300MG - One Capsule Twice a day) and Videx EC (400MG One Capsule every day on an empty stomach). My latest tests (12March2001) are: Viral Load - 128; T-Cell - 525. I have been very carefull never to miss a dosage.

What causes drug resistance? Can my viral load reach zero and the bounce upward even if I follow the drug therapy perfectly? Is the combination of drugs that I am on now so pwerful that if I develop a resistance will I then have no other remaining options.

Thanks for your time.

Response from Dr. Little

The combination you are on (I assume your first regimen ever) is very potent. It sounds like you have responded well, though I would hope to see your viral load drop below 50 within the next month or two. Regarding resistance, in general, resistance is permitted to develop any time there is ongoing viral replication in the presence of antiretroviral drug therapy. That is, during viral replication, the virus is very error-prone. We have actually determined fairly good estimates of how many mistakes the virus makes per cycle of replication. Now if this mistake results in some change to the virus that makes it incapable of surviving, then the virus dies and you will not know any difference (ie. a "defective" virus). On the other hand, if one of these random mistakes occurs which by chance results in a genetic change in the area of the virus which interacts with a drug(s), then the change may influence the nature of this interaction. That is, the change (or mutation) may result in an improved ability to replicate in the presence of antiretroviral drug concentrations in the blood that would normally kill the virus. If this happens, then this new "mutant" virus has a survival advantage over the other viruses present in this individual. In other words, this new "mutant" virus will carry on making new copies of itself while other non-mutant viruses are killed by the drugs in the blood stream. Since the division (or replication) of each HIV particle gives rise to more than one new "daughter" virus, gradually, the offspring of the resistant virus will take over or become the predominant form in the blood. When this happens and a drug resistance test is done, it will detect the predominant form of the virus present, in this case the mutant form, and the person will be told that they have evidence of drug resistance.

The reason this all becomes more complicated is that the rate at which this happens varies for the different drugs and the time necessary to develop resistance may be as short as two weeks or as long as several months. Once resistance develops, it is generally related to the drugs that were taken during the time that the resistant mutant emerged, thus, one may have resistance detected to one or two drugs in the regimen that the person is taking and no resistance to other drugs. Another problem though - all of our currently available antiretroviral drugs fall into three different classes of drugs. When drug resistance occurs to one drug in a class of drugs (for instance the protease inhibitors), there may be partial cross-resistance to the other drugs in this class, since all of the drugs in each class are sort of related to each other. So the bad news is that even when someone develops resistance to one drug, they may also have partial (or occasionally complete) resistance to one or more of the related drugs in that class. Drug resistance testing has become quite sophisticated and the results can often be interpreted to know what the next best regimen may be for someone who has developed drug resistance.

Last but not least, the most common way to develop drug resistance is to have incomplete viral suppression for a period of time while antiretroviral therapy is still being taken. However, a person can also get infected with a drug resistant virus if the person who exposed them to HIV also had drug resistance (from prior therapy) and then passed this virus on to the newly infected person. In this case, the newly infected person has never taken any therapy, yet may harbor drug resistant virus. Testing shortly after infection may identify drug resistance in these individuals. I hope this is not too confusing. While I hope it is premature to think that you should be worrying about drug resistance - never missing a dose is the single most important thing that you can do to prevent this from happening - you are likely to have several options if you should ever develop drug resistance to one or more drugs in your current regimen (you do not necessarily fail all drugs at once in a regimen, since as I said the time necessary to develop drug resistance varies significantly from drug to drug), you should have other options. There is another whole class of drugs, the non-nucleoside reverse transcriptase inhibitors (NNRTIs) which you have not tried and are very potent. One of these could be used with other drugs which you have had no exposure to in the future.

Your physician will follow your viral load during the first 6 months on therapy and if the rate of viral load decline does not meet standard expectations, then often a drug resistance test will be done to rule out this possibility. I hope this helps.


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