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Antiretroviral Drug Resistance Testing: The Time is Now! A Consensus Statement of the HIVresistanceWeb Editorial Board: Charles Boucher, Michael Kozal and Douglas Mayers
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written by The HIVresistanceWeb Advisory Board
published on HIVresistanceWeb: September 25, 1998
In the June 24th issue of the Journal of the American Medical Association, an expert panel concluded that "Plasma HIV RNA level and CD4+ cell count are the primary values that should be used to guide the initiation of antiretroviral therapy and subsequent changes in therapy." They suggested that "Genotypic and phenotypic testing for HIV resistance to antiretroviral drugs may prove useful for individual patient management. Assays under development need validation, standardization, and a clearer definition of their clinical roles." In an accompanying editorial by Douglas Mayers, a member of this site's editorial Board, it is suggested that while expensive, these tests are less than the cost of 1 month of combination therapy. The ability of these assays to detect wild type virus and cross resistance among other antiretroviral agents makes them useful today in selecting drugs that may provide reasonably good antiviral activity.
Just three days later, in Lake Maggiore, Italy, and later in Geneva, Switzerland, researchers presented data that linked phenotypic data to genotypic data, showed the predictive value of both phenotypic and genotypic data, and demonstrated that these tools are useful in research and community settings. Rudi Pauwels (Virco, Mechelen, Belgium) reviewed a new, rapid assay that is 1000-fold more sensitive than the previous generation of assays. Using a new version of software, Pauwel's and colleagues' algorithm correctly predicted 16 of 19 samples as sensitive to protease inhibitors. It also correctly identified 33 of 34 "resistant" isolates. Nicholas Hellmann, using a competing commercial assay (ViroLogic, San Francisco, USA), similarly showed that baseline phenotype was the strongest predictor of virological outcome in 18 study participants who had all failed indinavir therapy.
Amy Patick (Agouron Pharmaceuticals, San Diego, USA; collaborating with Virco) found that 12 of 14 (86%) of patients who lacked mutations at positions 48, 82, 84 and 90 responded to nelfinavir as a salvage regimen after experiencing virological failure on at least one PI. Randall Lanier (Glaxo Wellcome, USA; in association with Virco) studied baseline genotype and phenotype of abacavir-treated patients from a pool of five trial populations. He correlated them with viral load response at week 16. He found that individuals who had only a 74V or 184V mutation at baseline responded as well to abacavir as those with a wild-type virus population. Only those individuals with three or more AZT mutations at baseline, with or without 184V, had an attenuated response to therapy.
Andrew Zolopa (Stanford, USA) showed that individuals who had none of the seven major PI resistance mutations had a greater virologic response to saquinavir+ritonavir+RTI salvage therapy than those with a D30N mutation or those with 3 or more mutations (median 2.4 log10 decline vs. median 2.0 log10 vs. no median decline in HIV RNA). Baseline genotype was a strong and independent predictor of clinical response. Similar utility of genotypic results was identified by Richard Harrigan (BC Center for Excellence in HIV/AIDS, Vancouver, Canada) in a community setting.
So what does all this mean for the practicing clinician? We obviously have a bias as evidenced by our participation in this web site. We believe that the time to learn how to use and interpret resistance assays is now. We also believe that there is ample evidence now available to document the utility of these assays in predicting both responses and failures to antiretroviral therapy.
Given the high degree of correlation between phenotypic and genotypic assays and the ease of genotypic assays, we believe that these assays will ultimately be as readily used to manage HV patients as determinations of CD4 counts and HIV RNA levels. Technical improvements in DNA sequencing and software will lower the cost and improve the accuracy of these assays just as widespread use of DNA PCR led to greater efficiencies for those tests. In the mean time, HIV physicians need to rapidly increase their knowledge base in this area. We hope that HIVresistanceWeb will help in providing a basis for such a new educational effort.
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