Resistance testing grows in treatment importance
HIV pioneer researcher shares some insights
(Editor’s note: David D. Ho, MD, is the scientific director and chief executive officer of the Aaron Diamond AIDS Research Center and a professor at The Rockefeller University, both in New York City. Ho received his medical doctorate from Harvard Medical School and is renowned internationally for his pioneering studies on the dynamics of HIV infection and its effects upon the human immune system. Ho also is an expert on antiretroviral drug therapy and resistance testing for HIV and is a member of the ViroLogic Scientific Advisory Board. AIDS Alert asked Ho to explain how HIV resistance testing has evolved and how important a role it will play in future treatment planning.)
AIDS Alert: When the first research was published about HIV resistance testing, and even up until a year ago, there was some doubt that such a tool could ever become practical for regular use in HIV treatment planning. Now the International AIDS Society USA Panel has published recommendations for using antiretroviral drug resistance testing, and the panel says such testing should be incorporated into some patients’ HIV management.
What has changed with regard to resistance testing technology and availability within the past year, and will resistance testing ever become a routine part of HIV treatment?
David Ho: The shift toward resistance testing is due to three reasons. First, the tests have become easier and better, and several are now readily available commercially. Second, as AIDS physicians confront cases with complicated treatment histories, there is a growing sense of realization that having knowledge about the resistance profile of the viral population would be helpful. Third, there are preliminary studies suggesting that the use of resistance testing could improve patient outcome.
AIDS Alert: At the 4th International Workshop on HIV Drug Resistance and Treatment Strategies held in Sitges, Spain, in June, ViroLogic Inc. of San Francisco presented research showing that its phenotypic resistance testing assay, called PhenoSense HIV, could determine resistance profiles of AIDS drugs that are still in development, including drugs in the new class of integrase inhibitors.
How difficult do you believe it will be in coming years for resistance tests to keep up with all of the new antiretroviral medications? And do you predict there will be a time when drug manufacturers will no longer have any new drugs to add to the AIDS arsenal and so resistance testing and juggling the available antiretroviral treatments will be the only means for clinicians to keep patients a step ahead of disease progression?
David Ho: It will take some work to develop commercial assays to test for resistance to new classes of antiretroviral agents. However, it is certainly within our capabilities. For example, we already have HIV entry inhibitors that are in clinical development. Assays to measure for resistance against such entry inhibitors will be needed in the near future. As for the second part of this question, I truly believe that drug development effort will continue. However, it is difficult to predict the pace of their development. There will always be a need to optimally use the drugs in our current arsenal, and resistance testing will add to that.
AIDS Alert: When should physicians consider using a phenotypic resistance test instead of a genotypic resistance test, and vice versa?
David Ho: Our knowledge level is insufficient to be able to translate every genotype into a phenotype. Phenotyping is much more direct. It is also consistent with many years of clinical practice in managing bacterial infections, where resistance to antibiotics had traditionally been determined using simple phenotyping techniques.
AIDS Alert: The International AIDS Society’s recommendations state that HIV drug resistance testing should not be used as the principal criterion for decisions on changing antiretroviral therapy, that such decisions still should be based on plasma viral load. So how should a clinician handle a patient’s treatment when a resistance report predicts the failure of certain antiretrovirals, even though the patient’s viral load remains low?
David Ho: If the viral load remains low in the presence of some drug-resistant viruses, there is no rush to change the regimen. However, given HIV’s propensity to change, it is likely that increasing drug resistance, followed by increasing viral load, would be an expected outcome in the future. Thus, more careful monitoring of the patient would be warranted. On the other hand, some physicians/ patients may use the phenotyping data to modify the regimen in order to achieve better viral suppression. These choices are generally made on a case-by-case basis.
AIDS Alert: The resistance testing recommendations also speak of unresolved technical issues, including a need for adequate standardization and clinical validation. Can those issues be resolved and, if it’s likely, how long do you predict it will take to do so?
David Ho: As for any commercial test, there are many quality assurance and quality control issues to address. I have no doubt that such technical matters will be resolved within the coming year. However, more definitive clinical studies are required to prove that the use of resistance testing can indeed improve prognosis of a patient. Several such studies are already under way, but they may need a year or two to complete.
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