The Body Covers: The XIII International AIDS Conference
Management of Drug Resistance: Posters 3014 and 1434
July 13, 2000
In poster 3014, researchers studied the virus of 85 people who were on D4T in a combination with other antivirals, and had never taken AZT. While 14% had no mutations noted, 67% had mutations to 3TC, something commonly seen given the widespread use of this medication. In terms of other mutations seen, they noted that 28% had mutations that have in the past been seen with those resistant to AZT, including mutations at position 41, 67, 70, and 210, 215 and 219. About half of the 28% with any of these mutations had just one of these mutations seen, whereas the others had more than one seen.
A mutation that is considered linked to d4T on several resistance test interpretations, called V75T, was seen in only 4% of these samples. Some research has been done which suggests that these mutations do diminish the antiviral effects from d4T, although that was not done in this presentation. This study only looked at those who were already on treatment. Thus, we cannot be absolutely sure how often some of these mutations may have been present before therapy was started. It is reasonable to assume that a rate of 28% of these mutations is higher than what has been seen from those who were simply infected with an AZT resistant virus rather than as a result of treatment. Therefore the researchers propose calling these mutations "thymidine associated" as both AZT and d4T are thymidine analogs.
Poster 1434 studied a related issue. They report on the findings from 82 virus isolates taken from 41 patients. Here they studied the virus from those who were on d4T-containing regimens, with a history of treatment with multiple other nucleoside analogs. The focus of the study was to better characterize phenotypic resistance to stavudine. Overall they found only 5% have high level resistance to stavudine as defined by the Virco phenotype, while about 20% had intermediate resistance to it. They did see some clinical relevance to these cutoffs, as those who had a virus sensitive to d4T had a better viral load drop during treatment as compared to those with any degree of resistance. They also noted a significant phenotypic correlation of resistance to both AZT and d4T -- meaning if you were resistance to one on phenotype, you were likely to be resistant to the other one as well.
The impact of these studies suggests that when using resistance testing, it is possible that a genotype pattern that shows mutations previously linked to just AZT might also be relevant to the activity of d4T as well. Similarly a phenotype cutoff of above four-fold resistance suggests that there will be less activity from d4T. However, unanswered questions include why regimens containing d4T are less likely than AZT to generate these mutations. Similarly, it may be that these mutations can have an impact on more than just d4T, suggesting that there is some degree of cross resistance in this class of medications overall.
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