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The current report summarizes the available published and unpublished data from several investigators on resistance in clinical isolates following prolonged stavudine therapy.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 sensitivity following up to 29 months of treatment. The post-treatment isolates from 15 patients exhibited an increase in EC50 value > fourfold (level above variability of assay) when compared with the corresponding pretreatment isolates. However, the vast majority (11) of these pretreatment isolates either had unexpectedly low EC50 levels and/or had post-treatment isolates that lacked any amino acid changes within their reverse transcriptase (RT) gene to account for the observed change in sensitivity. Of the four remaining isolates, two appeared to have a multi-resistant phenotype to several nucleoside analogues and two had no detectable RT amino acid changes to account for the observed change in stavudine sensitivity. To date, clinical HIV-1 isolates displaying stavudine-specific resistance have yet to be reported. Furthermore, full or partial RT sequence analysis of 194 post-treatment isolates failed to identify any consistent amino acid changes. The strain-specific V75T mutation reported to confer stavudine resistance to the HXB2 HIV-1 strain in vitro, was found in only six isolates and did not correlate with stavudine resistance. This low incidence of stavudine resistance is in striking contrast to that observed with other nucleoside analogues and further supports the use of stavudine in first-line combination therapy for HIV patients.
Lin
P F
PF
Bristol-Myers Squibb, Wallingford, Conn., USA. linp@bms.com
González
C J
CJ
Griffith
B
B
Friedland
G
G
Calvez
V
V
Ferchal
F
F
Schinazi
R F
RF
Shepp
D H
DH
Ashraf
A B
AB
Wainberg
M A
MA
Soriano
V
V
Mellors
J W
JW
Colonno
R J
RJ
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy*; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D004351:Drug Resistance; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D010641:Phenotype; D012194:RNA-Directed DNA Polymerase / Q000235:genetics; D018119:Stavudine / Q000627:therapeutic use*
D019380:Anti-HIV Agents; D018119:Stavudine; D012194:RNA-Directed DNA Polymerase