July 14, 2003
Dr. Kuritzkes gave an excellent and comprehensive review on a variety of aspects of HIV drug resistance. Drug resistance, he noted, is the major factor in HIV treatment failure. Factors associated with the development of HIV drug resistance include: adherence, pharmacologic interactions, host factors (such as genetics that predispose one to disease progression, or the pretreatment viral load and CD4 count), limited potency of some HIV drugs, pre-existing resistance and acquired resistance (either through drug treatment or transmission).
Dr. Kuritzkes discussed the changing epidemiology of HIV drug resistance, noting that several recent reports had found the number of acutely infected people with drug resistant HIV to be around 10 percent. In addition, over 50 percent of people treated in the U.S. have some evidence of resistance. This is primarily a consequence of earlier suboptimal regimens (i.e., starting with only one or two drugs of limited potency). He presumed the risk might be somewhat lower today, given the more highly effective combination regimens.
Dr. Kuritzkes discussed various aspects of resistance testing assays. Genotypic resistance tests rely primarily on rules-based algorithms to determine whether a patient's viral sequence has evidence of drug resistance. Phenotypic assays on the other hand, rely on the concentration of drug necessary to inhibit 50-90 percent of viral growth. The difference in drug concentration required to inhibit wild type virus (the reference strain or control) compared to a patient's virus, is known as the fold change in concentration. The fold change at which a drug is thought to no longer have activity against HIV is known as the cutoff concentration or fold change. Most of the current cutoff concentrations for the available HIV drugs were determined by sampling a very large population of HIV-drug-naive patients and were referred to as the biologic cutoff.
However, new data is emerging that suggests that these cutoffs may not be appropriate and that a better determination would be to use clinical cutoffs. Clinical cutoff concentrations are determined by looking at patient outcomes (viral load changes). Dr. Kuritzkes gave some examples in which tenofovir (TDF, Viread) and Kaletra (LPV+RTV) still demonstrated significant viral load reductions even though their phenotypic fold changes were above the biologic cutoff. He also emphasized that current phenotypic resistance assays only measure each drug's activity individually and do not take into account the activity and relative potency of combination therapy.
Dr. Kuritzkes then went on to review some of the studies which established the utility of using resistance testing in clinical practice. Several studies were presented that showed, for the most part, that the addition of either genotypic or phenotypic resistance testing resulted in greater reductions in viral load compared to standard of care without the benefit of the tests. There were also a few negative studies presented that did not show this advantage. He presented some data from the enfuvirtide (T-20, Fuzeon) studies (TORO 1 and 2) in which practitioners added either enfuvirtide or placebo to a new regimen (using genotypic or phenotypic resistance testing) in heavily HIV-drug-experienced patients. Although the active enfuvirtide arm showed greater reductions in viral load when compared to placebo, the placebo arm still managed to achieve a 0.66-log/ml reduction in viral load, which was directly correlated with a genotypic sensitivity score (GSS). A GSS is the number of drugs that have activity. Thus, subjects in this study with a GSS of 0 (no active drugs) had no viral load reduction, whereas those with a GSS of 5 (5 or more active drugs) had significant reductions in viral load.
Dr. Kuritzkes listed the situations in which one would use resistance testing in clinical practice. Testing, he said, should be considered during acute infection, in chronic infection less than two years old before initiation of any treatment, during first or after multiple failures and during pregnancy, when HIV-infected mothers have detectable viral loads.
In his final summary statements, Dr. Kuritzkes said that although resistance testing is useful, there is no substitute for a good antiretroviral history. If resistance to a drug is detected, that drug should be avoided. Absence of resistance does not mean that resistance has been ruled out. The tests have limited sensitivity, and some resistance fades into the background but does not disappear when that drug is not being used. Therefore prior exposure to a drug should raise the possibility that resistance to that drug might be present. He stressed that resistance testing was an adjunct, and not a replacement for clinical judgment when making decisions about HIV treatment.
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