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how can I read it?
Jun 25, 2008

Hi doc, You have not answered my last four questions, I guess they are FAQ so I have to look deeper in forums. My boyfriend is now ready for treatment, his viral load drpped to 250 in less than one month, to me it was astonishing, 150 in less than one moth. well you must know doc that in El Tigre, Venezuela there is no specialist for HIV all we have is an Intern Doctor who attended some conference and is familiar with HIV treatment. If we want a specialist we have to travel all the way to CAracas. This is not a problem at the moment but what if we get sicker. This doctor is a lovely the greatest woman ever but I dont really trust her methods, because I keep reading your forums and i realise there is lack of knowledge in her answers. Well Bob, my question is: I took my boyfriend to Caracas for Resistance Test (I dont know its name in english) I dont know how to read it and my doctor seems not to know either. Can you explain a little bit about this test, I know as a matter of fact that i wont survive without medical help and I dont intend to become a doctor, I just want to make sure that the answer she gives me is based on real knowledge. I have one more question, based on that test what is the best treatment for my boyfriend, who by the way dumped me, after two years together when he knew that he needed meds, I want to help him anyways, we also have a foundation here and it is my job to assist them somehow. Take care doc, By the way I just found out who your steve is, lucky you. Take care and I hope you keep succeeding and your CD4 count reaches 1500, take care bob, hugs from Venezuela

Response from Dr. Frascino

Hello Venezuela Guy,

Please note I get gazillions of questions on a continuous basis from throughout the cyber universe. Consequently, that you even had one of your questions answered is rather remarkable and quite lucky, statistically speaking. Although I try to read all the questions that come into my "inbox," I can only personally respond to a very small percentage of them and yes, I do encourage everyone to search the archives for the information or reassurance they are seeking.

Regarding resistance tests, there are two basic types, a genotype and a phenotype. I'll post some information (from the archives!) that explains these two tests. (Please note this information is now several years old and we've made significant progress in identifying new mutations since this article was published. I'm reposting this particular article because it gives a good summary of the differences between the two main types of resistance tests). As for a specific up-to-date interpretation of your boyfriend's drug resistance test results, this may well require an HIV specialist intervention. I would recommend he have a genotype test. Perhaps you could establish care with an HIV specialist in Caracas who could interpret the resistance test and recommend a treatment regimen for your boyfriend. And then your local doctor could consult with the Caracas specialist intermittently as needed, as she monitors your boyfriend's progress, reviews lab work results, evaluates problems, etc. You could then just make trips to Caracas once a year or so to check in with the specialist for "fine tuning." Of course, now that your boyfriend dumped you, well, this may not be a workable option for him, but it might work for you, if and when you are ready to begin an anti-HIV medication regimen.

Good luck.

Dr. Bob

HIV Drug Resistance Tests

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 Drug Position of Drug in the Gene, Protease 20 30 36 46 48 50 54 63 71 82 84 88 90 101 Amprenavir Indinavir Nelfinavir Ritonavir Saquinavir Major mutations: clearly associated with drug resistance. Minor mutations: add to the resistance caused by major mutations. Natural variants: natural variants of the virus that can add to drug resistance.

Table 2: Reverse Transcriptase Mutations Drug Position of Drug in the Gene, Reverse Transcriptase 41 65 67 70 74 75 103 115 116 151 181 184 188 210 215 219 333 3TC Abacavir AZT AZT + ddI/ddC AZT + 3TC d4T ddI / ddC Delavirdine Efavirenz Nevirapine Adefovir Major mutations: clearly associated with drug resistance. Minor mutations: add to the resistance caused by major mutations.

Genotypic Testing: The Pros and Cons

Table 3 lists advantages and disadvantages of genotypic tests. This test is cheaper and much faster than a phenotypic test but still costs $300600. 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 Pros Cons Less complex test May be less useful for resistance to protease inhibitors Less expensive May need expert interpretation More widely available Most cannot detect minor species Works at a lower viral load Links between genes and resistance not fully understood More rapid results Lab quality varies Must be on anti-HIV therapy

Genotypic Tests: How They're Done

The most common way that genotypic testing is done uses a machine that reads the gene sequence of the protease and RT genes. The results are compared to an original, or not mutated, HIV gene sequence. Any mutations are checked against a list of changes known to cause drug resistance.

Most drugs follow a set pattern of resistance mutations. However, this test is less good at predicting resistance to protease inhibitors (PI) which have more varied mutations. It also only detects mutations that make up 20-50% of the total viral population, so it will not pick up very low levels of resistant virus.

A second technique, called line probe assay or LiPA, uses a specific probe (something that looks for specific mutations) to detect resistant mutations. There is a probe for each of the mutations known to lead to drug resistance. It can detect mutations that make up as little as 2-5% of the total virus population.

A third method, called GeneChip, uses a chip that has many markers built onto it. A blood sample is put onto the chip and it is passed through a scanner. The results are compiled by a computer which shows any mutations in the genes.

The accuracy of the results does not seem to differ among the different types of tests. It is more important that the lab has good quality control and skilled staff.

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:

Low-level: 2- to 4-fold increase in the amount of drug needed to stop HIV reproduction. Moderate-level : 4- to 10-fold increase. High-level: 10-fold or greater increase. 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 Cons

Table 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 Pros Cons Directly measures drug effect More expensive Easier to interpret Results may take a while Information on cross-resistance Complex test Limited availability Cannot detect minor species Must be on HIV therapy

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.

Company Name of Test Cost Phone Genotypic Tests Applied Sciences/Visible Genetics HIV-1 TruGene Assay $380 800-254-9868 LabCorp/Virco VircoGen $450 800-533-0567 ViroLogic GeneSeq $450 800-777-0177 Specialty Labs GenotypR PLUS $600 800-421-7110 Stanford HIV Genotyping $300 650-723-5706 Phenotypic Tests LabCorp/Virco Antivirogram $880 800-533-0567 ViroLogic PhenoSense $775/995 800-777-0177

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.

Commentary

It 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

Genotypic tests look for known resistance mutations in the RT and protease genes. Phenotypic tests assess whether a drug can stop the growth of HIV in a test tube. The tests are expensive and may not be reimbursed by health coverage. The person must be on therapy and have a detectable viral load when the test is conducted. Quality of testing varies between labs. Treatment decisions should not be based on a single test. They should include factors such as a person's personal preferences about therapy, considerations of potential short- and long-term side effects associated with therapy, and considerations around keeping future options open.



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