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Questions about resistance testing
Jul 1, 2004

Do you think that genotypic tests are particularly useful when looking for (ruling out) a single mutation that confers resistance? (i.e. when deciding about taking 3TC, Sustiva, Viramune, Rescriptor, Viracept)--because if you've got one of those, you should not take the drug? And it's much harder to interpret, say, TAMS or the six protease mutations?

If so then would it be accurate to say that pheontypic tests are particularly useful where clinical cutoffs have been established in relation to fold-resistance (and less useful where such cutoffs have not been established)? If so, what should we make of IAS-USA (Hirsch, M., et al CID 2003: 37:117): "For example, data from the NARVAL trial show a continuous inverse relationship between fold-resistance and response rate for saquinavir and efavirenz (i.e. the higher the fold-resistance, the lower the rate of viral suppression); thresholds above which no response was observed were noted for stavudine, didanosine, abacavir, and amprenavir [cite Obry, Castigliola, Race 2001]. No correlation between fold-resistance and treatment response was observed, however, for zidovudine, lamivudine, nelfinavir, and nevirapine."

Thus could we say that phenotypic testing IS particularly useful for assessing whether to stop Invirase/Fortovase, Sustiva, Zerit, Videx, Ziagen, and Agenerase?

By the way did the NARVAL trial use certain genotypic tests and were their results indicative of these specific tests? Do genotypic tests manufactured by different companies vary dramatically in their results? If so, what would you recommend an informed patient do? Also if most docs have trouble interpreting resistance tests, what is an informed patient to do? How can a patient tell if their doc is informed or not? Is their some sort of second party the test can be sent to for interpretation?

And could we say that phenotypic testing is NOT useful for deciding whether to stop (or not initiate) AZT, 3TC, Viracept, or Viramune? The same source says clinical cutoffs have been established for "relatively few drugs (e.g. abacavir, tenofovir and lopinavir-ritonavir) [cite Lanier 2001 for abacavir/phenosense; Kempf 2000 for lopinavir (unsure if ritonavir was included); Miller 2001 for tenofovir] Thus could we add to the list where phenotypic testing IS particularly useful the following: Ziagen, Viread, Kaletra? And are there more recent studies that establish or rule out fold-resistance cutoffs for other drugs?

Finally, does the virtual phenotype get you the "best of both worlds"? First you look for mutations--so you get clear answers where a single mutation confers resistance. (Thus, for example, you would spot a mutation that rules out 3TC, where phenotypic testing could not tell you to stop 3TC.) Then, the database does the phenotyping and it can tell you to rule out certain other drugs for which phenotypic tests can establish cutoffs though genotypic tests are harder to interpret (say, Ziagen, Agenerase or Kaletra)? So would it be appropriate to say that virtual phenotyping is good BOTH for all the drugs about which genotypic tests are especially dispostivie, AND for all the drugs about which phenotypic tests are especially dispositive????

Also how much say does a patient actually have in determining which test their doc uses? Can a patient try to tell their doctor which resistance test they should use?

Response from Dr. Conway

You seem to be well informed on all the issues surrounding resistance. Good for you!!!

In general terms, genotypic resistance tests are easiest to interpret if fewer mutations are present, and the easiest is for lamivudine, NNRTIs and perhaps nelfinavir and atazanavir. In these cases, a single mutation confers high-grade resistance to the drug. If it's there, the virus is resistant, and if not...the virus is sensitive.

For most NRTIs and PIs, the relationship between genotype and clinical response to therapy gets complicated if many mutations are present, and this is where having a phenotypic test is most helpful. Ideally, you would be reassured in interpreting phenotyic resistance test results in light of clinical cut-offs, but this is not always available. If it is, though, it should be used. Other than for NNRTIs or 3TC (where the genotype gives you almost all the information you need), I would think of phenotypic resistance testing as equally valuable for all the drugs. NARVAL may not have shown benefit for specific drugs due to the fact that most patients were already resistant to NNRTIs and lamivudine and that little zidovudine was used (most patients were put on stavudine). Thus, the lack of correlations was a particularity of the trial rather than a reflection on the concept of resistance and its usefulness.

All of the genotypic tests seem equally good, and I do not favor one over the other. I really dislike Virtual Phenotype (unless you are a Virtual Patient!!!). If you need a phenotype, get a real one...For me, the rule of thumb is that if I expect the genotype to be complicated, I will possibly ask for a phenotype.

As for your doc being informed or not and what test to use...ask him/her!!!! Most docs working in this field are used to a partnership with their patients and are also used to asking for help from an expert when they need it.

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