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Understanding HIV/AIDS Drug Resistance Assays*

By Andrea Ho-Kean, Pharm.D.

January/February 2001

HIV/AIDS drug resistance is a frequent cause of HIV/AIDS medication failure and presents a major challenge for physicians as they try to effectively suppress viral load to an undetectable level. In the past, physicians have had limited guidance in selecting the most effective combination of medications for a patient with HIV. Research studies suggest that new technologies such as phenotypic and genotypic HIV drug-resistance assays (lab tests) may assist physicians in making better treatment decisions. It is likely that these assays may become routine laboratory tests in the near future. The following information may help you better understand these resistance assays and their future roles in treatment decisions. (Note: It is important to understand the concepts of viral resistance and resistance mutations in order to fully appreciate how the resistance assays work. The recommended readings at the end of this article provide background information on viral resistance.)

What Are Antiretroviral Drug-Resistance Assays and Why Are They Important?

Drug-resistance assays are unique laboratory tests used by HIV/AIDS specialists to determine whether the virus infecting a patient is likely to respond to specific antiretroviral medications.

What Types of Resistance Assays Are Available and Is One Better than the Other?

Currently, there are two types of resistance assays used in clinical practice and in research: phenotypic and genotypic assays. Genotypic resistance testing detects the presence of specific genetic mutations that are thought to cause drug-resistance, such as the M184V mutation associated with lamivudine (Epivir) therapy. Phenotypic resistance testing directly measures the ability of a patient's virus to grow in the presence of known blood concentrations of antiretroviral drugs. There are distinct advantages and disadvantages associated with each test and there has been no consensus among experts as to whether one is better than the other (see table).

In the past, phenotypic assays were criticized for a lack of sensitivity in detecting drug-resistant minor species (viruses that exist as a smaller sub-population of the wild type viruses) and the fact that it took a longer time (four to six weeks) to get results. However, PhenoSense(TM) HIV, a new test by ViroLogic offers significant improvements in the ability to detect minor species that comprise as little as 10 percent of the total viral population. In addition, the results from this test are now available within two weeks.

From a practical sense, the ideal test should be accurate, easy to use, readily available, sensitive to minor viral species, without restrictions on viral load requirement for test accuracy, and reasonably priced. There are some physicians who prefer the phenotypic assay because it is a direct measure of drug sensitivity against the virus, and it is easy to use and interpret. Others may select the genotypic assay for its ability to predict the likelihood of drug resistance. Still others believe that both tests may actually complement each other in treating and monitoring HIV/AIDS patients. Hopefully, further research will address the appropriate use of these two tests together in enhancing patient care.

How Are These Assays Currently Used?

The resistance assays are beginning to be used routinely in patient care. This may increase, since an International AIDS Society (IAS-USA) Panel has recently published Drug Resistance Testing Guidelines to assist clinicians in better use of the resistance tests (for additional info see: www.IASUSA.org). The ISA-USA panel recommends the following criteria for the use of the HIV-resistance assays:

The panel suggests that resistance testing be considered in the following situations:

The ISA-USA panel points out that the resistance assays should not be used as the sole criterion for deciding when to initiate or change therapy. Physicians are urged to consider other important factors such as: patient's drug history, viral load, tolerance, adherence, concomitant medications and diseases prior to adding or eliminating a drug.

What Are the Potential Future Implications of These Assays?

The resistance assays offer scientifically sophisticated tools for physicians. Early studies suggest they are useful in improving short-term patient outcomes by allowing better selection of the most effective antiretroviral medications. In addition, earlier switching to a more sensitive medication guided by these tests may have an invaluable impact on preserving a patient's immune system, minimizing unnecessary side effects and costs, and most importantly, the development of drug resistant mutations. Despite this optimism, physicians and patients are still presented with complex questions such as: Which test is best suited for a given clinical condition? What are the long-term health benefits for patients? What are the long-term economic benefits associated with these assays? Which insurance companies are covering the assays? Future studies should address these concerns. In the meantime, most physicians agree that proper use of the resistance assays may actually reduce long-term costs associated with treating and monitoring HIV/AIDS patients.

* Reprinted with permission of LIFETIMES2 Magazine, Issue 1, 2000, a publication of Stadtlander's Pharmacy.


AssaysAdvantagesDisadvantages

Phenotypic Assays:

1. PhenoSense(TM) HIV, ViroLogic (South San Francisco, CA) (800) 777-0177

2. Antivirogram(TM) Virco (Mechelen, Belgium) (800) 533-0567

  • Direct measure of susceptibility of patients' HIV to antiretroviral drugs

  • Physician-friendly -- easier to interpret than genotypic assays

  • Turn-around time for results is better

  • Reproducible results

  • Reliable results with repeated tests

  • Evaluates susceptibility to all available antiretroviral drugs

  • Can be modified to evaluate new class(es) of HIV drug
  • Not available at all labs

  • May not detect all minor and subspecies of virus

  • Potential exists for false negative results, because patient's sample may contain a mixture of drug-sensitive and resistant viruses

  • Results from the assays made by different manufactures may not be comparable

  • Cost per test: $700-1,000

Genotypic Assays:

1. VircoGen(TM), Virco (Mechelen, Belgium) (800) 533-0567

2. TRUGENE(TM) HIV-1 Applied Sciences/Visible Genetics (Toronto, ONT) (770) 734-9872

3. Genotypic resistance testing (ABI/PE Biosystem, Foster City, CA) Stanford Hospital and Clinic, Microbio/Virology Lab (650) 723-6671

  • Available at many commercial and academic labs

  • Technically less demanding; therefore, results are available in days

  • Results from assays made by different manufacturers are easier to compare
  • Indirect measure of drug sensitivity

  • May not detect all minor and subspecies of virus

  • Potential for false positive or false negative results (i.e., may over-estimate and under-estimate drug resistance)

  • Difficult to interpret the results because of complex interactions between types of mutations (e.g., M184V mutation associated with lamivudine reverses the resistance to zidovudine)

  • Cost per test: $400-600

Glossary

Gene or gene mutation: a change in the genetic code. Think of genetic code like letters in a word. If you change the order of the letters, the word doesn't make sense anymore. These changes in the code happen randomly as HIV reproduces. Sometimes, antiviral medications can't make sense of the changes; therefore, they can't work against the virus. In an attempt to survive and fight back, the virus will continue using the mutation against the drug and drug resistance occurs.

Genotype: genetic information or the genetic code that determines a specific genetic trait (e.g., the color of your eyes or hair). In HIV, if the virus has normal genetic information, it will most likely be sensitive to antiviral medications. If the virus has mutated genetic information, it may be resistant to an antiviral medication.

Phenotype: an observable characteristic or behavior (e.g., the personality of an individual). In HIV, phenotype normally refers to drug resistance or susceptibility.

Resistance: reduction in an organism's sensitivity to a particular drug. In other words, the virus is no longer vulnerable to a particular antiviral medication. Viral resistance is thought to be the result of genetic mutations.

Resistance assay: a laboratory test used to see if a drug would work against a virus or bacteria. In the case of HIV, the current resistance tests need the patient to have a particular viral load in order to work. They also need a resistant minor species to make up a particular amount of the virus in order to find it.

Wild type virus: naturally occurring virus that is circulating before drug resistance develops.

Recommended Readings:

  1. Horn, Tim; Cox, Spencer and Richman, Douglas. A No-Nonsense Guide to HIV Drug Resistance Testing. University of California, San Diego.

  2. Resistance Testing Comes of Age. Project Inform, April 2000.

  3. Geno- and Phenotypic-Resistance Tests. Project Inform, March 2000.




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