The Body Covers: The 7th European Conference on Clinical Aspects and Treatment of HIV-Infection
Satellite Symposium: Clinical Advances in the Treatment of HIV Disease
Convergent versus Divergent Treatment Strategies: Is One Better Than the Other?
October 24, 1999
1999: The Science of Resistance Comes of AgeAuthored by Dr. Andrew Zolopa
Assistant Professor of Medicine
Stanford University, CA
A number of studies have confirmed the increasingly acknowledged utility of resistance testing in a number of settings. There are tests which report the genetic changes that HIV makes that help it grow despite antiviral medications -- this is called genotyping. There are other tests that directly measure how well HIV grows in the presence of antivirals -- this is known as phenotyping. There are ongoing challenges in the development of these tests, including the need to standardize the testing itself. The use of these tests has been focussed on two circumstances -- deciding on the first regimen based on pre-existing resistance, and selecting a subsequent regimen based on what resistance patterns have developed as a result of drug therapy.
There are mutations which tend to arise first on antivirals known as the primary mutations, and these tend to decrease the sensitivity of HIV to the drug. However, sometimes these mutations cause HIV to pay a "price" in how well it can continue to grow, and under the continued pressure of this same medication secondary mutations often arise. These mutations appear to further increase the resistance of HIV against the drug, and also improve the fitness of HIV's ability to grow. These secondary mutations may also increase the likelihood of cross resistance within a class of medications, as medications may differ in their primary mutation site, but may overlap in their secondary mutations.
There are several studies all of which demonstrate the connection of resistance mutations and response to a medication. For example, studies of using either nelfinavir or ritonavir/saquinavir based combinations confirm that resistance testing can predict who will be successful in these situations. Similarly, data on the use of the nucleoside abacavir demonstrate that there is a direct link with other medication resistance patterns, in that the presence of multiple mutations to either AZT and/or 3TC impair the response to abacavir as well. Dr. Zolopa also demonstrated the contribution of resistance testing over the medication history in one study. He explored the predictive value of both history taking and resistance testing in a study that followed patients who were given ritonavir/saquinavir combinations after having viral rebound on a prior PI. He demonstrated that while history can be of value, most of the prediction was captured in the results of resistance testing, and little additional predictive accuracy was seen when adding history to the resistance assay results.
Two studies have demonstrated that, when switching from regimen to another, the results of resistance testing can contribute information that increases the likelihood of viral suppression. One done in the US (the GART study) and another in Europe (Viradapt) used a genotype for patients having viral rebound on a PI containing regimen. In both studies, the test doubled the success of achieving viral suppression on the next regimen. This benefit appeared to be true regardless of the number of antivirals used, as well as whether a new class of antivirals (nonnucleosides) was given in the next regimen. The role of phenotyping in this circumstance in currently in active study, and results are expected early next year to better define how that test can assist in defining treatment options.
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