Stavudine resistance: an update on susceptibility following prolonged therapy

The current report summarizes the available published and unpublished data from several investigators on resistance in clinical isolates following pro longed stavudine therapy. Results suggest that stavudine resistance is both modest in degree and infrequent in appearance. Phenotypic evaluation of 61 patients on stavudine therapy showed only modest changes in drug sensitivi ty following up to 29 months of treatment. The post-treatment isolates from 15 patients exhibited an increase in EC50 value >fourfold (level above var iability of assay) when compared with the corresponding pretreatment isolat es. However, the vast majority (11) of these pretreatment isolates either h ad unexpectedly low EC50 levels and/or had post-treatment isolates that lac ked any amino acid changes within their reverse transcriptase (RT) gene to account for the observed change in sensitivity. Of the four remaining isola tes, two appeared to have a multi-resistant phenotype to several nucleoside analogues and two had no detectable RT amino acid changes to account for t he observed change in stavudine sensitivity To date. clinical HIV-1 isolate s displaying stavudine-specific resistance have yet to be reported. Further more, full or partial RT sequence analysis of 194 post-treatment isolates f ailed to identify any consistent amino acid changes. The strain-specific V7 5T mutation reported to confer stavudine resistance to the HXB2 HIV-1 strai n in vitro, was found in only six isolates and did not correlate with stavu dine resistance. This low incidence of stavudine resistance is in striking contrast to that observed with other nucleoside analogues and further suppo rts the use of stavudine in first-line combination therapy for HIV patients .