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Resistance Again - If you're bored tell me to go away!

Jan 28, 2010

Hello, T'is I once more with a further question re: 'potential resistance.' Thanks very much for your patience and understanding and sorry if I am hogging your time.

I have just read this article

It says that genotype results are delivered as 'high' 'possible' or 'none.' Is this a reference to the US? My results included 'low level' and 'potential' (the latter i guess correlates with 'possible')

According to this study: "Of the 267 "possible" resistant genotypic results, 47 were resistant by virtual phenotype (17.6%)."

This was the conclusion "Although this study did not include data for the actual phenotype, several studies have demonstrated excellent correlation between the test interpretations derived from the virtual phenotype and the actual phenotype[3,4] suggesting that the virtual phenotype is a viable alternative for the actual phenotype. Even so, most clinical laboratories perform genotyping assays for determining HIV drug resistance. The findings presented in this manuscript indicate that overall in our patient population, a "possible" result by rules-based testing generally resulted in a sensitive result by virtual phenotype. However, analysis by specific drug class revealed that a "possible" result for PI was more closely correlated to resistance."

This seems to say a possible/potential result doesn't 100% imply the presence of any level of resistance.

Last of all (and I promise this is my last question on this topic) Do you think I should request phenotype or virtual phenotype tests if available (this seems logical if the above report means what i think it means) I don't want to start treatment on a PI regimen if i might be susceptible to another NRTI as well as 3tc/ftc.

Many , many, many thanks

Response from Dr. McGowan

Thanks for your questions. It is very important to understand some of the tools that we use to plan therapy. The study you were referring to compared 2 types of resistance tests. The genotype, which takes the viral genes for reverse transcriptase (the target of NRTIs and NNRTIs) and the protease (the target of protease inhibitors- PIs)and determines their genetic codes. Then they compare the changes in the patient's viral genes (called mutations) as compared to a "standard" or what we call "wild type" virus that lacks mutations. The pattern of these mutations is then analyzed to see which ones are known to cause drug resistance. Based on the pattern of these mutations, the level of resistance can be predicted. Some mutatiions are easy to call...if they are there then we know that certain drugs will not work. Other mutations are less strong and may not totally negate the action of the drug or may need to be combined with other mutations in order to block the action of the drug, those patterns are harder to call and may be interpreted as "possible" resistance. The virtual phenotype uses a computer database to essentially help interpret the genotype results. The lab has collected virus from thousands of samples, calculated the genotype and then run a phenotype test on them. The phenotype takes the patients RT and protease genes and inserts then into a test virus to see how it grows when exposed to each of the drugs. If it is killed, the virus is susceptible, if it isn't killed it is resistant, if it can be killed but takes more drug to do the killing than would be expected for a non-mutant (wild-type) virus, then that is partially resistant. So to run the virtual phenotype you take the results of your patient's genotype and see if it matches any of the sequences in the database. The more matches the better the results. Then they take the phenotype results for the matches and report the average out as the likely phenotype for that virus. The results of the virtual phenotype are only as good as the number of matches to the test genotype that they have in the database. The virtual phenotype is used sometimes because it is less expnesive than running a separate phenotype, can save money and is more easily available. Only special labs can run phenotypes, many more labs can run genotypes near to home. So, if the pattern of mutations is relatively straight forward (as is often the case for NRTIs and NNRTIs) there is not much added benefit for getting a phenotype in addition to a genotype. When the mutatiuonal patterns can be more complex (as is often seen with PIs) or if someone has been on more than 1 or 2 failing treatments, a phenotype can add additional information to the interpretation. Usually we would start off with a genotype and only do a phenotype if a mix of mutations were found.

Best, Joe

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