The Body Covers: The 6th Conference on Retroviruses and Opportunistic Infections
Abstract No. 116: Mutations in the Reverse Transcriptase Genome of HIV I Isolates Derived from Subjects Treated with Didanosine and Stavudine in Combination
February 1, 1999
The objective of this study was to determine the nature, frequency, and significant of mutations arising during combination therapy with DDI and d4T. The study arms included DDI 200 mg b.i.d. with d4T either 40 mg or 20 mg b.i.d.; and, DDI 100 mg b.i.d. with either d4T 20 mg, 40 mg or 10 mg b.i.d.. The sensitivities of drug susceptibility of 34 baseline and follow-up isolate pairs were obtained.Abstract: Mutations in the Reverse Transcriptase Genome of HIV I Isolates Derived from Subjects Treated with Didanosine and Stavudine in Combination
No mutations classically associated with DDI monotherapy were observed. The V75T mutation associated with d4T resistant in vitro emerged in follow-up in one isolate which remained fully susceptible to d4T. Interestingly, despite the absence of prior AZT exposure, mutations associated with AZT resistance emerged in 7 of 26 isolates, including T215Y in six, M41L in two, and D67N in one. Combinations of greater than two AZT mutations were observed in follow-up in two isolates. The Q151M mutation emerged in two isolates, one of which later acquired the F116Y and then a series of further mutations. Nucleoside resistant mutations were observed to emerge as follows: in 4 of 15 (27%) of susceptible isolates, and 4 of 8 (50%) isolates resistant to greater than one drug. These findings extend previous observations of the emergence of AZT associate mutations and isolates derived in subjects treated separately with DDI, d4T, Adefovir, and, more recently, isolates derived from subjects treated with Adefovir and D14 combination. The complete Q151M multinucleoside resistant complex, previously observed to arise during combination therapy with AZT and DDI, can also emerge in retroviral naïve subjects with DDI and d4T in combination.
Finally, the authors summarize that the data highlights the complex relationship between HIV I phenotypic and phenotypic resistance and HIV viral loads in individuals treated with dual nucleoside combinations. This data has significant implications for the design of active regimens. The problem is that the amount of cross-resistance that emerges is far in excess of what many thought possible. Indeed, when switching from one regimen to another, one might feel that one is switching to two new RTI's with a new NNRTI or PI, and giving the patient a completely new and effective regimen. However, in fact, the cross-resistant pattern is so complex, that many significant mutations may have accumulated, some of which have not previously identified in the literature. I think this data should also give us pause for thought when looking at genotypic assays that are available commercially. Very often full sequences are not given, therefore emerging mutations will not be identified that have clinical significance.
Authored by: E. Coakley, J. Gillis, and S. Hammer
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