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Author Topic: Article Resistance testing - which test and drugs  (Read 1066 times)

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Offline John2038

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Article Resistance testing - which test and drugs
« on: November 28, 2007, 11:46:14 AM »
Interesting article about resistance testing and choosing a drug accordingly.

November 2007

SAN DIEGO — All treatment-naive patients with HIV should get tested for drug resistance to help select the best initial regimen; treatment-experienced patients with treatment failure should also undergo resistance testing. Although this can be costly, it leads to improved treatment outcomes, ultimately making use of the tests a cost-effective strategy.

Cost and turnaround time factor into what test to order and when both genotype and phenotype provide us with vital information in selecting antiviral regimens, you should factor that in with the cost of treating a patient overall said Paul E. Sax, MD, clinical director of the HIV program and division of infectious disease at Brigham and Women’s Hospital and associate professor of medicine at Harvard Medical School. Then you realize the most expensive test can be a real value.

Sax presented the latest in resistance testing indications, cost, and a look at current and potential future drug resistance tests at the 45th Annual Meeting of the Infectious Diseases Society of America, held here recently.
 
Resistance testing options

A basic genotype test to determine mutations correlating with drug resistance is ordered most often, and is useful for treatment-naive patients and those patients who fail early lines of therapy. It has the advantages of a faster turnaround time and lower cost.

A phenotype test, which provides the fold change (the difference in virus susceptibility vs. wild type), can also give an estimated likelihood of a full response, partial response or no response to an HIV drug. A phenotype test may also provide replication capacity, which is a surrogate for viral fitness.
Phenotype tests cost more and take longer for results than genotype tests, and should be reserved for treatment-experienced patients with potentially complicated resistance patterns.

So-called virtual phenotype tests are also available. They provide genotypes and then an estimated phenotype based on linear regression analysis from a large database of phenotypes. Hence, they are a sophisticated way to help interpret genotypes.
Virtual phenotypes are very useful for complex resistance cases when phenotype testing is unavailable; they are less expensive and offer a more rapid turnaround time than phenotype Sax said.
The most comprehensive assessment of resistance is to order both a phenotype and a genotype test. Such testing provides a net assessment of whether the virus is sensitive or resistant to a given drug.

The combined genotype-phenotype is a very powerful tool, and I believe that in patients for whom you are ordering a phenotype — those with extensive drug resistance, especially to protease inhibitors and NRTIs — this test is justified, Sax said. It’s not that much more expensive and you get much more information.
 
Tropism assays provide information on whether the patient’s virus enters the cell via the CCR5 receptor (R5 tropic), the CXCR4 receptor (X4 tropic), or can use both receptors (dual mixed tropic).
Only patients with R5 tropic virus should be treated with the CCR4-antagonist maraviroc, hence tropism testing should precede use of this drug Sax said.
The presence of dual-mixed tropic virus is also associated with more rapid disease progression, but use of the tropism assay for assessing this risk is not currently standard of care.

Test costs may vary widely from approximately $300 to $400 for a genotype to $1,960 for a tropism assay. Negotiated prices vary also depending on the setting.


 
Resistance mutations

If patients develop resistance on their first-line regimen, most of the time it is with single nucleoside or non-nucleoside reverse transcriptase inhibitor mutations. The most common would be M184V and K103N, respectively.
M184V leads to high level resistance to lanivudine and emtricitabine, but fortunately all the remaining nucleosides retain some activity. As a result, there are many options for subsequent therapy Sax said.

If a nonnucleoside reverse transcriptase inhibitor (NNRTI) regimen is failing, and resistance is documented, the NNRTI should be stopped promptly.

Stop the NNRTI immediately because it is no longer providing clinically meaningful antiviral activity; you are only going to accumulate more resistance mutations which could potentially impair future response to investigational NNRTIs, such as etravirine Sax said.

Protease inhibitor resistance can be extraordinarily complex, as there are often dozens of potential substitutions involving multiple amino acids with varying effects on resistance.
You have better things to do with your time than memorize the specific resistance mutations associated with all of the drugs available Sax said.

Sax offered a simplified way to choose protease inhibitors.

•   If there is no protease inhibitor resistance, then all the boosted PIs provide excellent options for therapy. These include lopinavir/r (Kaletra, Abbot), atazanavir/r (Reyataz, Bristol Myers Squibb), fosamprenavir (Lexiva, GlaxoSmithKline) and darunavir/r (Prezista, Tibotec)].

•   If there is low-level PI resistance, then it appears that darunavir/r is the best option based on the results of the TITAN study.

•   For viruses that are highly resistant to PIs, the choice is generally among darunavir/r or tipranavir/r (Aptivus, Boehringer Ingelheim), with selection optimally based on results of phenotype testing.


More rapid and less costly ways to assess viral tropism should be available in the next few years, as should genotype testing for integrase inhibitor resistance, Sax said.

For more information

•   Sax PE. New issues in HIV resistance testing. #593. Presented at: the 45th Annual Meeting of the Infectious Diseases Society of America; Oct. 4-7, 2007; San Diego.
•   For the latest drug resistance figures online, visit http://hivdb.stanford.edu.

« Last Edit: November 28, 2007, 12:24:50 PM by John2038 »

 


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