Mutation Test for Anti-HIV Drugs
Mar 4, 1997
I recently read (in The Washington Blade) a brief piece about a mutation test that "a few" doctors are using to determine what mutations that HIV already has in patients. I asymptomatic HIV + man who does a great deal of reading (including your web site), so I understand the importance of this information for treatment purposes. What do you know about it? Should I ask my doctor here in Washington, D.C.? Will he have access to it? According to the acticle (quoting the Journal of the International Association of Physicians in AIDS Care), the test costs between $300 and $600, which I could pay for if necessary. If my doctor can't offer it, could I have the test done at Johns Hopkins or another leading HIV research center? What say you, Doc?
Response from Dr. Cohen
You are referring to genotype analysis, which tells you which mutations are present (either in the reverse transcriptase enzyme or the protease enzyme-- they are usually two separate tests). The idea is that by knowing which mutations are present, you can determine which drugs you're still sensitive to and which drugs you're resistant to, and can then make a more informed decision about which drugs to include in your therapy. The idea is very attractive to us infectious disease physicians, who use sensitivity tests routinely to help guide our therapy against bacterial infections.
There are a few problems with these tests, however, that make me think that it's a technology whose time has not come (yet). First, for many antiretroviral agents, resistance is not an all-or-none phenomenon. While you can safely say that if you have a mutation at codon 184 you are resistant to 3TC, you can't say the same thing for protease inhibitors. With protease inhibitors, resistance is a matter of degree. You rarely have high-level resistance without at least three mutations, but some mutations are more likely to lead to resistance than others. That leads to problems with the interpretation of these tests, especially when you're trying to use them to figure out protease inhibitor resistance. Unlike bacterial sensitivity tests, where you can demonstrate that the bug won't grow in the presence of certain antibiotics but will grow in the presence of others, these genotype assays just tell you about the presence of mutations without giving functional or "phenotypic" information.
There's another problem that I think is even more important. Let's say you took AZT monotherapy for a couple years back when that was in vogue. It stopped working due to resistance, and you switched to other therapy. You haven't taken AZT in three or four years. If you send your blood to the lab and get a genotype analysis, the report will probably tell you that your virus does not contain the 215 mutation or other AZT mutations and is therefore sensitive to AZT. That is because after you stopped taking AZT, the so called "wild type" (AZT sensitive) strain of HIV returned and became the predominate strain in your body.
However, if you were to believe that report and take AZT again, you would probably become resistant in a matter of weeks, because enough AZT resistant virus would be hanging around waiting for just such an opportunity. It wouldn't be there in quantities large enough to register on the genotype analysis, but it would be there. So in relying on the genotype analysis, you would have been seriously mislead. The genotype analysis, therefore, may be useful for telling you about resistance to drugs you're currently taking, but may give misleading information about resistance to drugs you've taken in the past.
That's a long explanation of why we are not yet using those tests at Johns Hopkins. I think that these tests will have a role in our management before too long, but we need to learn more about their limitations and their applicability to real-life clinical situations before we can make them as routine as viral load tests and CD4 counts.
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