GENOTYPIC AND PHENOTYPIC ANALYSIS OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 ISOLATES FROM PATIENTS ON PROLONGED STAVUDINE THERAPY

Development of stavudine resistance was studied using human immunodefi ciency virus type 1 isolates from 13 patients treated with stavudine f or 18-22 months. Drug sensitivity testing on 11 of these pre- and post therapy isolates identified only 2 posttreatment isolates with decreas ed stavudine sensitivity (ED(50)s <4-fold higher than the average pret reatment ED(50)). Genotypic analysis of all 13 pairs of isolates ident ified multiple mutations in the reverse transcriptase (RT) gene. Howev er, no genetic basis was identified to account for the observed change s in stavudine susceptibility. A recombinant virus containing the enti re RT gene of the posttherapy isolate displaying the greatest resistan ce remained sensitive to stavudine. Five of the stavudine posttreatmen t isolates developed resistance (9- to 176-fold) to zidovudine, althou gh the relationship between stavudine treatment and the appearance of zidovudine resistance remains unexplained. Analysis of 10 additional p airs of isolates did not confirm this relationship. The low frequency and modest degree of change in stavudine sensitivity following prolong ed treatment is very encouraging.