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Genotypic vs. phenotypic tests
May 24, 2004

Big question, but I was wondering your opinion. What are the advantages and disadvantages to phenotypic resistance testing and genotypic and what's a virtual phenotype? What do you use and why? THanks!

Response from Dr. Sherer

There are advantages and disadvantages to both types of resistance tests. Often, as in my case, a clinician's experience is dictated by which test is available due to costs or hospital/clinic policy.

Genotypes detect mutations in the RNA molecule of a patient's HIV. These are referred to by a standard nomenclature that shows the amino acid in wild type, the locus of the mutation, and the mutant amino acid. Thus the common resistance mutation for Epivir (3TC or lamivudine) is the M184V, with the wild type methionine ("M") being replaced by a valine ("V") mutation at the 184 position.

In contrast, a phenotype measures the ability of each drug to inhibit an individual patient's virus in a standard assay, and it is reported out as the 'fold-change' in the amount of drug needed to inhibit viral growth, as compared to the amount of drug needed to inhibit wild type virus. So a virus that is susceptible to abacavir might have a fold change of 1.4, and a virus that is resistant to abacavir might have a fold change of 10. Note that a reliable cut-off above which the virus is considered to be resistant is need for phenotype testing, and this has proven to be a problem. In general, progress has been made defining these cut-offs for most available HIV drugs at this point.

One limitation in both assays is the inability to detect minority variants, i.e. mutant virus that is prevalent at < 10-20% of the total viral population. Resistance tests thus provide information on the dominant species in an individual's viral 'swarm', but that information is incomplete.

Another important principle of resistance testing in people who are taking ART is the need to perform the resistance test while the individual is still taking their current regimen, in order to assess whether the virus is still susceptible to it. Often HIV will 'revert to wild type' when drugs are withdrawn within weeks to months, i.e. wild type virus will overgrow mutant variants, and thus misleading results may be seen in a genotype or phenotype. This is one reason why a resistance test can only be interpreted properly with a complete history of past treatments, treatment responses, interruptions, etc.

There are advantages and disadvantages to both methods. Genotypes tend to be faster and less expensive. Genotypes often change in advance of a real reduction in susceptibility. And while there are many familiar patterns of resistance with common agents and regimems, novel mutations are still being identified.

In general, genotypes tend to be used first, and in the assessment of earlier treatment failure, though this varies somewhat by region and by individual clinician's choice. Phenotypes have the advantage of showing the behavior of a patient's virus when there are multiple past regimens and resistance mutations, so they are often preferred in patients who are heavily treatment experienced.

And finally, while there is evidence of benefit in the use of resistance tests when changing therapy due to virologic failure, there have been trials showing no difference between the educated guesses of experienced clinicians based on the treatment history and the use of resistance tests. Also, the long term benefit of decisions made with resistance tests have not been established. And resistance tests may not lead to patient benefit in settings where the remaining treatment benefits are limited.

Nonetheless, the current standard of care includes resistance testing in chronically infected patients prior to treatment, when changing a regimen to due virologic failure, and in the choice of regimens for pregnant women and the prevention of pernatal transmission.

The virtual phenotype is actually a standard genotype with an extensive data base of matched genotypes and phenotypes, with some 75,000+ matched pairs, from which is reported the likelihood of susceptiblity to drugs based on this large data base. Thus the reported outcome resembles a phenotype, but in fact the test performed is a genotype. The advantage of virtual phenotypes in comparison to a standard phenotype is the speed, relatively lower cost, and vast data base from which the information is obtained. However, a limitation is the situation in which a certain combination of mutations has a 40% likelihood of susceptibility and a 60% likelihood of resistance. Such a report does not provide a clinician with sufficient information on which to make a clear decision, and a phenotype would still be needed.

My own clinical experience was driven initially by limited access to phenotype testing. Thus I prefer a genotype for all patients before therapy, as well as in the setting of virologic failure in the consideration of the next ART regimen. I tend to reserve phenotypes for complex patients with multiple resistance mutations.

For more information, consult the IAS-USA resistance guidelines at the website below.

I am unphenotypable. Why and how common is this?
Risk of blooming with a resistant strain?

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