The Virtual Phenotype

A third approach to resistance testing is the "virtual" phenotype. This assay, developed by Virco, is really a genotype resistance that is interpreted with the aid of a large database of samples with paired genotypic and phenotypic data. Viruses with genotypes that are similar to the patient's virus are identified by searching the database, and the average IC50 of these matching viruses is calculated. This information is then used to estimate the likely phenotype of the patient's virus. Since the database currently has >18,000 paired genotypes and phenotypes, there is a high likelihood that a large number of matches can be found for most genotypes encountered in practice. The actual and virtual phenotype show excellent correlation (r2>0.8) for most drugs (15). Moreover, retrospective analysis of samples from the VIRA 3001 study (see below) showed that the VirualPhenotype performed as well as the actual phenotype in predicting response to treatment (16). Several studies are underway to test the performance of the VirtualPhenotype in patient management.

The VirtualPhenotype has important strengths and weaknesses. The main strength of this approach is that it reduces complex genotypic data to simple phenotypic categories based on a rational, data-driven analysis of similar genotypes. Reports indicate the number of matches, and the proportion of sensitive and resistant viruses among the matches. It is important to remember, however, that the virtual phenotype only provides an estimate of the probable phenotype of the patient's virus-the actual phenotype could be more or less sensitive than the average value obtained from the database. The main weakness of this approach is that the confidence placed in the result depends on the number of matches, and on picking the right codons to incorporate into the database search. Correlation between actual and virtual phenotype will be weaker for newer drugs or in cases where there are fewer matches due to unusual genotypes. Also, the virtual phenotype may place undue emphasis on using genotypes to predict phenotype, rather than treatment outcome.

4/15/01

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