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epivir and drug resistance tests unreliable for naive docs
Mar 4, 2004

yrs. ago i had a doctor who gave me a pheno-geno type test to see what drugs i was resistant to. Epivir, my favorite HIV drug came out showing i was resistant to it. My doc at that time said Pay no attention to that. It's like being a false negative. Another doc i had to see said not to worry about resistance to epivir since almost everyone is -- at least according to the tests. I have since learned that there is only a certain mutation of epivir that tests resistant and that most of the drug is NOT resistant or i'm not resistant to it. Can you clarify all this epivir/resistance talk. My new doctor wanted to take me off epivir as soon as resistance came back in his test. i told him not to and that it was a mistake, but he goes by the book. Fortunately, however, he must have asked someone because since then he has never brought the subject up again nor did he take me off epivir. It makes me think that even though some doctors treat a lot of HIV patients, they do not know something as simple as that. And that irritates me.

Response from Dr. Sherer

Your confusion, and your doctor's uncertainty, are understandable. The most common cause of 3TC resistance is the M184V mutation. There are some other NRTI mutations that reduce the efficacy of 3TC, like the K65r. However, the M184V is usually the first to appear. In single drug studies from the past, even with the M184V mutation, 3TC retained an anti-viral effect of about one-half log, so some physicians choose to leave it in second line and later regimens.

Added to that, the presence of the M184V offers modest benefit to the activity of AZT, with which it is most often paired, and appears to delay the emergence of other resistance mutations to AZT. This also has led some physicians to leave it in second line and later regimens in combination with AZT.

So that's the data and the theory. I know of only one study, recently conducted, of patients on a failing regimen containing 3TC, in which half of the patients were left on 3TC and the other half were taken off of it, at the same time that the regimens were entirely changed, and after 48 weeks there was no difference in viral load or CD4 outcomes between the two groups. So the 'benefits' of leaving 3TC in a failing regimen with known 3TC resistance is not proven. This one study does not answer the question, since the study design and the patients study may not be representative of all patients, including you.

In my own practice, my first concern with a second line regimen after a first regimen failure is to find a regimen of three or more drugs which the patient can take and to which his/her virus is sensitive. In the presence of genotypic or phenotypic evidence of resistance to 3TC, I am less concerned with its possible small contribution to the next regimen, and I prefer to have three or more fully active drugs in the second regimen.

Finally, some of the confusion may have arisen from your resistance test, which you called a "pheno-geno type test." Was it a genotype, which measures the actual gene sequence of the majority species (>20%) in your blood, and gives information about the mutations at each location, as in "M184V"...or was it a phenotype, which measures the response of your virus to each drug and gives information about the 'fold-change' in the response of your virus to each drug in comparison to wild-type virus.. or was it both?

In most cases, these tests agree with each other, i.e. if you show the M184V on a genotype, your phenotype might show a 50-fold reduction in the response of your virus to 3TC. Occassionally a genotype will show a characteristic mutation, such as the M184V, before it has become part of the dominant population of circulating virus, and the phenotype will show that your virus is susceptible to the drug. Experience has shown that most often this type of genotype test will be followed by a phenotype test showing resistance.

And then, fortunately less commonly, the results are discordant in other ways, and an expert opinion is needed, along with a repeat of the tests.

The complexity of the virus is a source of irritation to us all.


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