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Antiretroviral Therapy
(Part XXV)

Clinical Implications of Resistance To Antiretroviral Drugs

November 21, 1997

AIDS INFORMATION NEWSLETTER AIDS Information Center
VA Medical Center, San Francisco

Definition and Measures of Resistance

Drug resistance can be more appropriately termed "altered drug susceptibility." It is a phenomenon that can occur in vivo and in vitro, in response to the exposure of HIV to a drug or to a combination of drugs. The phenotypic resistance of HIV can be assessed in vitro. It is roughly represented by the need to use increased concentrations of drugs (inhibitor concentration, or IC) to inhibit the growth of the resistant virus, as compared with the concentrations generally needed for the inhibition of a "reference" virus (or the "wild" virus isolated from the patient before the start of a particular drug regimen).

Phenotypic susceptibility is usually quantified in terms of IC50 or IC90 (a measure of the concentration of drug needed to inhibit 50% or 90%, respectively, of viral growth). If the IC50 (or IC90) characteristic of the so-called wild-type virus is known, the IC50 (or IC90) for a resistant virus will be X-fold greater. The increase in IC50 needed to define a virus as resistant to a particular drug is often established empirically. For example, a virus highly resistant to AZT is assumed to have an IC50 or at least greater than 1.00 uM, whereas wild-virus generally has an IC50 of 0.01uM to 0.05uM.

The molecular mechanism underlying phenotypic susceptibility can be identified in changes in the sequence of the gene coding for the enzyme target of our antiviral intervention (so far, the reverse transcriptase or the protease). The characteristic genetic changes (at the codon level) that predict the subsequent resistant phenotype are referred to as genotypic resistance.

Determination of phenotypic resistance (assessment of the drug susceptibility of the virus harbored by an HIV-infected individual) can be accomplished by growing out the virus (preferably isolated from plasma, which has a better representation of the actively growing virus population) in the presence of various concentrations of the drug under study. However, because phenotypic resistance is the consequence of specific mutations in target genes (e.g. the reverse transcriptase gene or the protease gene), PCR and gene- sequencing methods to directly detect these mutations have been developed to analyze genotypic resistance. Moreover, although phenotypic and genotypic resistance are often found on analysis to be directly related, in some cases the relation is altered by the fact that the emergence of resistance is a dynamic process, and multiple strains of virus, with various sensitivities, often coexist in an organism.

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A rather controversial issue is whether determination of the resistance pattern in patient isolates would be useful in current clinical practice, now that a number of relatively easy and reproducible techniques (at least for viral genotyping) have become available. In a case of documented antiviral therapy failure in a patient taking a three-drug combination, identifying the drug to which the virus has become resistant could aid the design of salvage therapy and prevent the need to change all three drugs. This may be considered a very reasonable option, if we consider the scarcity of available therapeutic options. However, some experts feel strongly that all components of a failing combination should be changed; this strategy would not benefit from the availability of quick genotypic resistance testing.

Current data suggest that the evaluation of drug resistance in individual patients might best be used in the near future as a data point collected before starting treatment, to be used as a baseline against which to measure efficacy of therapy. In other words, treatment could be planned on the basis of baseline susceptibility or cross-resistance profiles. In fact, mutations that confer resistance to nucleoside analog reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, and protease inhibitors, have all been identified in persons who have never been treated with antiretroviral drugs, perhaps as a consequence of transmission of already resistant strains, or of natural polymorphism. With the wider use of antiretrovirals, pretreatment resistance will probably occur with increasing frequency.


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