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Project Inform
HIV Drug Resistance Tests
April 2001 Table of Contents
A number of drugs are now available for treating HIV disease. With more drugs to choose from, treatment decisions may be more difficult. In some people, HIV becomes resistant to one or more of the anti-HIV drugs they are taking. Their viral load increases and they have to change to a new drug combination. HIV resistance testing may help guide making decisions about the best new drug combinations to try.
What Is Drug Resistance?HIV can change itself so that anti-HIV drugs do not work as well. This is called drug resistance, and it's one of the most common reasons why HIV therapy fails. Drug-resistant HIV then needs higher levels of the same drugs to stop it from reproducing. In general, when four or more times as much drug is needed to suppress the virus in a test tube, the virus is considered resistant to that drug.Increasing doses of drugs to overcome resistance is not possible because higher doses lead to increased risk of side effects. So when resistance occurs, people often need to change to a new anti-HIV drug combination.
How Does HIV Become Resistant?Resistance is usually due to changes in viral genes, called mutations. Because HIV mutates easily and reproduces very rapidly, a person may have many different HIV strains in his or her body.Today's drugs are not completely able to stop HIV from reproducing. If a resistant virus develops, it can grow in the presence of the drug and viral load subsequently starts to rise. Drug-resistant virus will grow more quickly and become the most prominent virus in a person's blood.
What Is Resistance Testing?Lab tests can show whether a person's virus is likely to be suppressed by each anti-HIV drug. There are two different types of resistance tests. Genotypic tests look for genetic mutations that have been linked to drug resistance. Phenotypic tests assess which drugs can stop HIV growing in a lab setting. To accurately measure drug resistance, people should be on anti-HIV drugs and have a viral load of over 1,000 copies. Otherwise, the results may not be accurate or the test cannot be performed.
How Do Genotypic Tests Work?Current anti-HIV drugs target one of two vital HIV genes or proteins. They are reverse transcriptase (RT) and protease. Genotypic tests look for mutations in the genes for these drug targets. Mutations at certain positions in the genes have been linked to drug resistance. For example, a mutation at position 30 of the protease gene results in resistance to nelfinavir (see Table 1).
Genotypic Testing: What Do the Results Mean?Genotypic test results list the mutations found in the protease and RT genes of a person's HIV. They will usually tell you what this means in terms of drug resistance. Tables 1 and 2 show the known mutations that give resistance to current HIV drugs. The genotypic test report can be hard to understand. You and your doctor may need to consult a specialist who knows how to read and interpret the results.Table 1: Protease Mutations
Table 2: Reverse Transcriptase Mutations
Genotypic Testing: The Pros and ConsTable 3 lists advantages and disadvantages of genotypic tests. This test is cheaper and much faster than a phenotypic test but still costs $300–600. Results usually return within a week.A major problem with genotypic testing is that it will miss unknown gene mutations. Also, while the effects of some mutations are clear-cut, this is not always true. A mutation that does not cause resistance by itself could lead to resistance when combined with other mutations. Also, resistance to one drug sometimes results in increased sensitivity to another. One example is that resistance to 3TC reduces resistance to AZT. Genotypic Testing: Advantages and Disadvantages
How Do Phenotypic Tests Work?Phenotypic testing measures the amount of drug needed to suppress the growth of HIV in a laboratory setting. Known levels of drug stop reproduction of non-resistant HIV. Resistant HIV, though, requires higher levels of the same drug to stop reproduction. In the test, the amount of drug is increased until it is enough to stop virus reproduction.Genotypic and phenotypic tests usually give the same results, but not always. Phenotypic tests may pick up resistance not seen in genotypic tests if there are only low levels of resistant virus. Also, the mutations that lead to resistance are not yet well understood, particularly for newer drugs, and thus may not be included in genotypic tests.
Phenotypic Testing: What Do the Results Mean?Resistance is usually reported as the level of drug needed to reduce viral replication by 50% (called inhibitory concentration 50 or IC50) or 90% (IC90). The level of resistance is graded by comparing this value for an individual's HIV with the levels for non-resistant (commonly called wild-type) virus:
With most drugs, high-level resistance is likely to mean that they are no longer able to block viral growth in the body. Moderate resistance might be overcome by achieving higher drug levels in the blood. This may be accomplished by using novel combinations of some drugs. However, simply increasing the dose of drugs can be dangerous, as this can increase the risk of side effects. The protease inhibitor ritonavir, for example, can increase the blood levels of many other drugs, including other PIs. Using ritonavir wisely, in strategic combinations, may be helpful in some cases to increase the potency of other anti-HIV drugs without resulting in increased side effects. It can also alter the levels of other drugs in the body, so it must be used with caution (and consultation with a very knowledgeable pharmacist) when used together with other therapies (including over-the-counter therapies). Drugs that have low-level or moderate resistance may still work as a part of combination therapy. As with genotypic testing, the results can be difficult to interpret. You and your doctor may need to consult an experienced specialist to interpret the results and devise a course of action for treatment changes, if needed.
Phenotypic Testing: Pros and ConsTable 4 shows some advantages and disadvantages of phenotypic testing. Phenotypic tests are considered the gold standard of resistance testing. They show directly whether a drug is active against a person's HIV. Similar tests are used to test for bacterial resistance before treatment with antibiotics.A phenotypic test usually requires a blood sample from someone with a viral load over 1,000. It can detect mutations that make up 10-20% of the total viral load. However, a big drawback with is its cost at $800-1,000 per test. Also, the results take 4-6 weeks to come through. Drugs are not usually tested in combinations. Since there are so many possible combinations of drugs, this would be very expensive and time-consuming. Phenotypic Testing: Advantages and Disadvantages
How Do I Access Resistance Testing?Many labs offer genotypic testing. Phenotypic testing is less widely available. The table below shows labs offering resistance tests. They may not all be as reliable in their ability to provide good results. They differ in quality control, test sensitivity and the accuracy and interpretation of results.
None of these tests have yet been approved by the Food and Drug Administration (FDA). However, with growing evidence of their value, more insurance companies and other third-party payers are willing to pay for them. The FDA has paved the way for makers of genotypic tests to apply for approval, although there are no plans to do the same for phenotypic tests.
What Does the Research Show?Treatment decisions based on the results of resistance testing are more likely to have better anti-HIV responses. In the GART and Viradapt studies, people who used genotypic tests and used the results to guide their treatment choices had greater reductions in HIV levels than people who did not have the test when making treatment changes. Phenotypic testing results also improved HIV treatment decision-making. In a study of 274 volunteers, viral load was decreased more in the group who made treatment decisions based on phenotypic testing.
CommentaryIt is still not clear when and how often to use these tests and how to make decisions based on their results. Resistance testing may be useful for treatment success. However, neither type of test can tell for sure which drugs people will get the most benefit from. Also, lack of resistant virus in the blood does not mean that it's not elsewhere in the body, such as in semen or spinal fluid.Two groups who could benefit from resistance testing are those who are newly infected (including newborn babies) and those who are changing drugs due to treatment failure. Because of concerns of mother-to-child transmission of resistant HIV, resistance tests are recommended for pregnant women. Resistance tests are not helpful for predicting failure in those who are currently succeeding on therapy. It is thought that 5% of newly infected people have drug-resistant HIV. However, this varies in different populations. So testing may be useful for making treatment decisions where resistant HIV is more prevalent. If a person experiences viral breakthrough (increasing viral load) while on anti-HIV therapy, resistance testing must be done before he or she stops treatment in order ensure accurate test results. In the absence of drugs, normal virus can quickly outgrow resistant virus, so the resistant virus will not be spotted by the test. If the wrong treatment is chosen, the resistant virus can quickly become dominant again. While resistance testing may give helpful information, a treatment decision should not be made on a single test. It's important to think about other factors such as a person's choice, potential side effects of various anti-HIV drugs and keeping future options open.
The Bottom Line
This article was provided by Project Inform. |
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