Community Forum Summary April 1999
Switching Therapies: Treatment Failure & Resistance Testing
Moderator: Ann Northrup
Speakers: Roy Gulick, M.D., Director, Cornell Clinical Trials Unit
Michael Barr, Treatment Action Group
There is no clear consensus on how to proceed with antiviral therapy after virologic "failure." Failure (a term used for lack of a better word) occurs when an individual whose viral load is maximally suppressed experiences an increase in the amount of HIV virus in his or her blood. After failure, it is common to attempt "salvage" therapy, that is, to initiate a regimen containing drugs that an individual has not taken before. The success of salvage regimens is often limited, however, because the virus has mutated and is not controlled by antiretroviral medications.
At the Community Forum on April 14, 1999, Dr. Roy Gulick, Director of the Cornell Clinical Trials Unit, and Mr. Michael Barr, Editor of TAG Line, discussed the implications of viral resistance in salvage therapy and provided vital information for patients to discuss with their doctors.
Initial Therapy for HIV Infection
Dr. Gulick reviewed the Department of Health and Human Services' recommendations for initial therapy of HIV infection. The current standard-of-care in the United States is to begin antiviral treatment with two nucleoside reverse transcriptase inhibitors (NRTIs), and either one protease inhibitor (PI), or a combination of two protease inhibitors, or a specific non-nucleoside reverse transcriptase inhibitor (NNRTI). [See chart] Initial antiviral therapy can be very successful in reducing the amount of HIV virus in an individual's blood to below detectable levels. Over time, however, resistance to initial treatment can develop.
Reasons for Treatment Failure
Viral resistance, as explained by Dr. Gulick, occurs when the HIV virus mutates (changes), forming a strain of the virus that is not controlled by antiretroviral medications. Eventually, this strain becomes the most prominent strain in an individual's body, and his or her viral load increases because the medications are rendered ineffective and the virus multiplies rapidly. Factors that contribute to the development of viral resistance include:
- Baseline resistance: An individual is initially infected with a strain of HIV that is already resistant to drug treatment.
- Use of less potent therapy: An individual begins HIV therapy with a regimen that is less powerful than the recommended initial therapy and the virus mutates quickly.
- Sequential monotherapy: Therapy is started with one drug, then another is added later, and then another is added even later; this gives the virus a chance to grow resistant to the drugs one at a time.
- Poor adherence to treatment regimen: Inability (for any reason) to take antiviral drugs as prescribed for maximum effectiveness.
- Low levels of drug in the body or unfavorable reactions with other drugs.
- Lack of tissue reservoir penetration: The drug does not control virus that is in body tissues such as the brain.
Additionally, individuals who fail their treatment regimens are more likely to have had:
- a high viral load when they began treatment,
- a longer time with a detectable viral load,
- a lower CD4 count,
- a lower potency regimen, and
- a viral load that never dropped below 50 copies/mL than individuals who remain maximally suppressed.
Strategies for Effective Salvage Regimens
No strategies tried thus far for salvage therapy have been particularly effective. One approach is to switch all current drugs to new drugs. For example, an individual taking AZT, 3TC, and Crixivan could switch to two new NRTIs and a new PI. Resistance to one drug in a class of drugs, however, may result in resistance to all drugs in that class. This "cross resistance" is a major problem in salvage regimens. In clinical trials, the success rate of new regimens (measured by the number of participants who have reduced their viral loads below the limit of detection) has been low. [See below] Other salvage strategies include:
- "Mega" Drug regimens: switching a patient to a new regimen that contains 4-7 drugs;
- "Recycling" drugs: going back to old treatments that the patient has taken before; and
- Using newer drugs that are still in development, such as protease inhibitors that are more powerful than their predecessors, or drugs in new classes.
What's New in Salvage Therapy Research?
(Abstracts from the 6th Conference on Retroviruses an Opportunistic Infections, January 31-February 4, 1999, Chicago, IL)
After 16 weeks of therapy, 32% of subjects had an undetectable viral load (68% had failed salvage therapy). Subjects with an initial viral load of less than 15,000 copies did better than subjects with an initial viral load of greater than 15,000 copies (43% failed as compared to 81%), and subjects who received nelfinavir were less likely to fail the new regimen (55% failed as compared to 76%). (S. Hammer et al.)
37 patients who were failing a combination regimen were assigned to receive a "Mega" regimen containing 6 or more antiretroviral drugs. Of the 37 patients, after a median follow-up period of 8 months, 10 patients had an undetectable viral load. (V. Miller et al.)
Dr. Gulick's Recommendations
- Don't start antiviral medication until you are ready: you should understand the implications of being on treatment and be able to commit to adhering to your regimen.
- Discuss the goals of antiviral therapy and the possible side effects of all antiviral medications with your doctor before beginning any regimen.
- Tell your doctor about all medications that you are taking; drug interactions can make your medicines less effective.
- Take your medications on schedule as much as possible and pay attention to food and water requirements.
- If you must stop your medications, stop them all at the same time.
- Don't start or add one drug at a time.
- Keep up with new information and research study options.
Q&A
Q: When is a person ready to start antiviral treatment?
A: Some guidelines:
- T-cell count below 500
- Viral load above 10-20,000 copies of HIV/mL of blood
- Mentally prepared to accept responsibility of taking medications properly
- Has support from friends and family
Q: What effect could low plasma concentration of antiretroviral medications have on resistance?
A: In some cases, treatment failure may be the result of low levels of drug in an individual's blood stream. The concentration of drug in the body can vary up to 10 times between different people taking the same doses of certain antiviral medications. Clinical studies of new medications examine the level of medication in the body after dosing in an attempt to ensure maximum effectiveness.
Q: Should you stop therapy if you are failing?
A: If an individual has end-stage AIDS, and the medications are significantly decreasing his or her quality of life, therapy can be stopped in order to make the individual more comfortable. Anyone who is not at that stage of illness and wants to go off medication could test his or her viral load, go off drug, and be retested in 2 weeks. If the viral load jumps up after treatment is stopped, it is advisable to restart. If the individual decides to remain off therapy, he or she should be monitored carefully.
The Details of Resistance
Michael Barr provided insight into some of the more intricate details of resistance. HIV drug resistance is a reduction in the ability of antiretroviral drugs to block the reproduction (replication) of HIV. Drug resistance can render antiretroviral drugs less effective, or even ineffective, and can significantly reduce treatment options.
Resistance typically occurs as a result of small mutations (changes) in HIV's genetic material (RNA). Mutations occur frequently in HIV, as the virus reproduces at an extraordinarily fast rate (1 to 10 billion new copies per day), and the copying of HIV's genetic material is not very accurate. These mutations lead to changes in certain proteins called enzymes that regulate the production of HIV. Many enzymes, including reverse transcriptase, integrase, and protease, are necessary for HIV to replicate inside a cell. If a mutation of a single site in the reverse transcriptase gene occurs, the change will remain a part of the virus as it replicates or until another copying error occurs. Some mutations cause the virus to become so weak that it cannot replicate effectively; other mutations may cause the virus to become even more infectious.
Antiretroviral drugs work by inhibiting HIV's ability to replicate or infect new cells. In a person taking antiretroviral drugs that are effective, most of the HIV is destroyed or prevented from replicating. As a result of random mutations, however, some strains of HIV are not affected by the presence of such drugs, and can replicate. Viral load rises rapidly, and treatment failure occurs.
Useful Terms
Mutation
an accidental change in the genetic structure of a virus that occurs when the virus is copying itself
Viral Resistance
changes in the structure of the reverse transcriptase gene or the protease gene that permit the virus to reproduce in the presence of antiviral drugs
Cellular Resistance
changes in the way the cell absorbs drugs and incorporates the drugs into cellular processes; in essence, antiviral medications poison the cell, and the cell adapts by absorbing less drug (the mechanism and the full implications of cellular resistance are not well understood)
Cross Resistance
resistance to all members of a class of antiviral drugs resulting from resistance to one member of that family (for example, an individual who is resistant to Sustiva is usually resistant to the other NNRTIs)
Genotypic and Phenotypic Testing
There are two different tests that measure viral resistance, and there are advantages and disadvantages to each type of test. Genotype testing identifies specific mutations in the genetic structure of the virus. Since specific mutations are associated with one or more antiviral drugs, the test can help determine which antiviral drugs will not be effective. For example, one of the mutation sites on the reverse transcriptase gene that is associated with the use of NNRTIs is at position 103 of the gene. If an individual's genotypic test identifies a mutation known as K103N at that site, it is unlikely that the individual will benefit from treatment with any of NNRTIs (because of cross-resistance).
Advantages of genotypic testing are that it is:
- readily available;
- easy to perform; and
- rapidly performed.
Disadvantages of genotypic testing are that it is:
- expensive ($300 - 500 per test); unable to detect mutations in minority species of the virus which can multiply rapidly and become dominant;
- not a direct measure of resistance;
- results may be difficult to interpret; and
- patients must have a viral load of greater than 1,000 copies/mL in order to yield an accurate result.
Phenotypic testing measures the concentration of a drug required to inhibit viral replication in a test tube by an amount such as 50% or 95%. The defined amount is called IC (inhibitory concentration) 50 or IC95. Interestingly, this is the method used by researchers to determine whether a drug might be effective against HIV before using it in human clinical trials.
Unlike genotypic tests, phenotypic resistance testing generally does not require a high viral load. Like genotypic testing, however, it is recommended that patients still be taking antiretroviral therapies at the time of the test.
Advantages of phenotypic testing are that:
- results are easier to interpret.
Disadvantages of phenotypic testing are that it is:
- relatively difficult to obtain;
- extremely labor intensive and can take several weeks to perform; and
- very expensive ($800 and up per test).
Why are These Tests Useful?
Genotypic testing can be useful in devising salvage therapy regimens, as it helps physicians rule out drugs that will not be beneficial to treatment-experienced patients. At the 6th Conference on Retroviruses and Opportunistic Infections (February, 1999, in Chicago, Illinois), J.D. Baxter and colleagues presented data showing that after 8 weeks of salvage therapy, 50% of individuals whose physicians used genotypic test results when determining a salvage regimen had an undetectable viral load. Only 23% of individuals whose physicians did not have access to genotypic testing had an undetectable viral load.
Results from another study, presented at the 4th International Congress on Drug Therapy in HIV Infection (November, 1998 in Glasgow, Scotland), showed that people who made treatment changes based on the results of genotypic testing were almost twice as likely to have undetectable viral loads than people who made treatment changes based on viral load only (30% vs. 17%, respectively). According to the team of researchers conducting the study, the results suggest that drug resistance testing was of significant help in determining which drugs should be used in a salvage regimen to yield more effective results. The results are from a relatively small, short-term study; more information is needed from additional clinical trials.
Another important use of resistance testing is in devising initial treatment regimens. There are individuals who are initially infected with treatment-resistant strains of HIV. If resistance testing is performed, medications to which the individual is already resistant can be eliminated from his or her initial treatment regimen.
Q&A
Q: Is there any beneficial resistance?
A: There is some evidence that resistance to 3TC may be beneficial, as it can result in fewer new mutations to the virus. For an unknown reason, resistance to 3TC seems to result in a more "faithful" virus, i.e., a virus that copies itself with fewer mistakes. The field of viral resistance is constantly changing, and observations such as this one are not backed by concrete explanations.
Q: Are there any independent benefits of protease inhibitors?
A: In people whose viral loads rebound, resistance to protease inhibitors may not always be the cause of the rebound. The predominant strain of virus may not exhibit mutations associated with protease inhibitor resistance, and sometimes it may be best to continue the current protease inhibitor and switch other drugs.
Q: Can genotypic/phenotypic tests be run on frozen blood samples?
A: Yes, as long as they are stored properly, it should be possible.
Summary writer - Anne Monroe with contributions from Timothy Horn.
