December 18, 2001
The ZORRO study was an open-label 16-week study to evaluate the safety and virologic efficacy of using abacavir (ABC) in a HAART regimen. Patients were either drug-naive or had previous HIV drug experience that had not included abacavir.
Abacavir is a very potent nucleoside analogue which has some unique HIV-1 reverse transcriptase (RT) gene mutations. The use of abacavir can produce a unique set of mutations that confer drug resistance. In addition, resistance can be conferred to abacavir when other common mutations are present. Mutations known to confer resistance to abacavir include 184V, 65R, 74V and 115F. In addition resistance occurs when the 184V is combined with thymidine-associated mutations (TAMs or AZT-type mutations). This study used the virtual phenotype to determine the level of phenotypic resistance. The virtual phenotype utilizes a real genotype generated from the patient's sample, that is then matched through a software program with real phenotypes in an existing database. The merger of these two sets of data creates a virtual phenotype that is relatively accurate compared to real phenotypic information. The definition of resistance (or reduced susceptibility) in this assay is a more than four-fold increase in the concentration of abacavir necessary to suppress viral growth, when compared to wild-type (or nonresistant) virus. This study was performed to evaluate the utility of the virtual phenotype in predicting the effects of RT mutations on abacavir activity and other HIV drugs.
This study analyzed baseline samples from 179 patients. The poster shows several figures illustrating virtual phenotype data for AZT, d4T, and abacavir in the presence of different mutation combinations. The results demonstrate that abacavir retains activity when there are fewer than 4 TAMs in the presence of a 184V mutation, and that 184V mutation reverses the resistance effect of TAMs on AZT and d4T activity. The results suggest there is a complex interplay between resistance mutations in the RT gene. If one were to view the mutations in a single-drug level, one might come up with different conclusions about the activity of a drug in combination. For instance, we have traditionally thought of a mutation or series of mutations as only affecting that activity of a single drug. This data and some other data presented at this conference now suggest that not only is there cross resistance among certain NRTI drugs (like AZT and d4T), but that other mutations which confer resistance to a particular drug like 3TC (184V mutation) can rescue back activity of drugs like AZT or d4T. This adds a new complex dimension to the interpretation of resistance tests and suggests the possibility of reusing drugs that were thought to be inactive because of resistance. Abacavir appears to retain activity in the presence of a certain level of AZT and/or 3TC resistance. This is again important in how we position this drug in rescue regimens after people have failed on regimens containing AZT or 3TC. The clinical significance of these mutational interactions is still being defined.
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