The following information offers an in-depth discussion of one type of drug resistance testing: phenotypic testing. You will learn what phenotypic testing is, how it differs from other resistance testing methods, and how it can help physicians design more effective treatment regimens.

• What is phenotypic testing?
• How does phenotypic testing compare to genotypic testing?
• How is phenotypic resistance testing performed?
• What do the results of phenotypic testing mean?
• Why is phenotypic resistance testing important?
• Is phenotypic testing approved by the FDA?
• How can someone get a phenotypic resistance test?
• How is phenotypic testing impacting HIV therapy?

Phenotypic testing directly exposes a person's virus to each of the currently available antiviral drugs. The virus is exposed to a specific drug, and then evaluated to determine how much of the drug is required to block viral activity. An individual's virus is considered to be less susceptible to a particular drug when more of the drug is required to block the virus.

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Phenotypic testing is a direct measure of drug resistance that does not require the same level of interpretation that genotypic testing requires. That means that a person's virus is directly exposed to antiviral medications and evaluated to determine whether or not the drugs adequately slow the growth of the virus. In genotypic analysis, genetic mutations are evaluated to predict the possibility of drug resistance and the virus never comes in contact with the drug. Although phenotypic testing can take longer to be performed and tends to be more expensive, the quality and reliability of the result is beyond what is attainable with genotypic testing.

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Recent advances in technology have made phenotypic testing faster and therefore more feasible for frequent use. What used to slow down phenotypic assays was the time that it took to grow copies of an individual's virus for testing with all of the different drugs. The following is a detailed description of how phenotypic testing is performed using what is known as recombinant technology:

How a copy of HIV is made:
Step 1- A sample of blood is taken from the patient.

Step 2- From the sample, key portions of the genes within the patient's virus are copied. This process is called amplification.

Step 3- Once step 2 is complete, the amplified genes are inserted into a laboratory sample of HIV. Genes similar to those copied in step 2 are missing from the laboratory sample, so the laboratory sample of HIV is only a "shell" that cannot grow.

Step 4- When step 3 is complete, the laboratory HIV becomes a complete genetic copy of the patient's HIV.

Measuring phenotypic drug resistance
Step 1- The copies of the patient's virus made in the previous steps are exposed to antiretroviral drugs. Depending on the type of phenotypic test being used, the virus may be exposed to all of the approved antiviral drugs or only a select few drugs.

Step 2- The ability of the virus to grow (or not grow) in the presence of each antiviral drug is evaluated. The virus is exposed to varying strengths, or concentrations, of each antiviral drug.

Step 3- The ability of the patient's virus to grow in the presence of the drugs is compared to a reference virus that is known to be 100% susceptible to all antiviral drugs. The comparison between the patient's virus and the reference virus provide the phenotyping results. These results tell doctors how much of a particular drug is needed to stop the growth of HIV by 50% (compared to how much is needed to stop the reference virus by 50%).

Results- The patient's virus is considered to be resistant to a particular drug if more of the drug is required to block viral activity than is required to block the reference virus.

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The results of phenotypic testing mean that if a person's virus is less susceptible (resistant) to a particular drug, that drug is less likely to work for him or her. However, even if an individual shows resistance to a particular drug, that drug may still be effective, as long the person's level of resistance is not too high. The maximum level of resistance that someone can have before a drug is no longer considered to be effective is called a cutoff value.

Because phenotypic testing measures the amount of drug required to inhibit viral activity, a person's level of resistance can be defined-as the amount of drug increases, so does the level of resistance. With this information, rather than immediately eliminating a drug because resistance is detected, physicians can evaluate a person's level of resistance to determine whether or not the drug is a still a viable treatment option.

Once a physician has a complete understanding of a person's resistance status and therapy options, he or she can develop a treatment plan that avoids the use of ineffective drugs. This results in a therapy regimen that is more likely to be effective for a longer period of time. In addition to helping physicians select more effective therapies, there are long-term benefits that arise from using resistance testing to direct treatment decisions. These include avoiding the use of potentially ineffective drugs, and in turn, reducing the health risks associated with medication side effects. By optimizing therapy regimens, phenotypic resistance testing can also reduce the amount of money wasted on purchasing unnecessary medications.

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Phenotypic drug resistance testing is an important tool in HIV therapy that gives physicians a more complete picture of a person's health and therapy options. The results of phenotypic testing can help physicians determine which drugs may not work in a patient's therapy, allowing them to create treatment plans that are more likely to suppress the virus for a longer period of time.

In addition to helping physicians select more effective therapies, there are long-term benefits that arise from using resistance testing to direct treatment decisions. These include avoiding the use of potentially ineffective drugs, and in turn, reducing the health risks associated with medication side effects. By optimizing therapy regimens, phenotypic resistance testing can also reduce the amount of money wasted on purchasing unnecessary medications.

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Drug resistance testing does not require FDA approval. In fact, the FDA has stated that it does not want to regulate this type of test at this time. Laboratories that perform drug resistance tests are regulated by the Health Care Finance Administration (HCFA), according to the requirements of the Clinical Laboratory Improvement Act (CLIA).

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People who are interested in having phenotypic resistance testing need to request the procedure from their doctor. Once the patient requests a test, a member of his or her medical team will draw a sample of blood and send it to a laboratory where the test is performed. Once the laboratory receives the sample, results will be delivered to the physician in a minimum of 14 days or a maximum of eight weeks, depending on the brand of phenotypic resistance test that is used.

Phenotypic testing can cost anywhere from $700 to $1,000. Most third-party payors, including Medicare, currently cover phenotypic analysis; however, individual insurance carriers make their own determinations regarding coverage. Physicians may need to check with a patient's insurance carrier before ordering a test.

There are several companies that perform HIV drug resistance testing. Some of these companies offer help lines, staffed with insurance specialists who can assist people with insurance preapproval or reimbursement. Because these companies understand the important role drug resistance testing can play in HIV therapy, many also offer special programs for individuals with low incomes and no health insurance.

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Because drug resistance has become a significant factor in antiviral therapy, the way HIV is treated is evolving to include a more widespread use of phenotypic resistance testing. By using phenotypic resistance tests, physicians can gain greater insight into a patient's health and therapy options, giving them the information they need to optimize treatment regimens and improve treatment outcomes.

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