Selection of zidovudine resistance mutations and escape of human immunodeficiency virus type 1 from antiretroviral pressure in stavudine-treated pediatric patients.
The relationship between clinical changes in stavudine activity and stavudine resistance was investigated in 16 human immunodeficiency virus (HIV)-infected children who received stavudine monotherapy for 18 months. Seven patients responded well to stavudine therapy, 3 experienced transient reductions in virus load, and all others had no detectable virologic response. In both the responders and nonresponders, no changes in stavudine susceptibility or specific baseline/emergent mutations in reverse transcriptase were observed. Only posttherapy HIV isolates from transient responders had elevated IC(50) values for stavudine. In 2 of the 3 transient responders, substitutions at codons 41, 210, and 215 were selected. The significance of these mutations was confirmed in viral competition experiments, site-directed mutagenesis, and in vitro selection. Selection of mutations previously associated with zidovudine resistance can be an important mechanism through which HIV may escape stavudine. The effect of these mutations on phenotypic stavudine susceptibility is relatively small but apparently large enough to be clinically significant.
Maxeiner
Horst-Guenter
HG
Department of Virology, University Medical Center, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
Keulen
Wilco
W
Schuurman
Rob
R
Bijen
Marc
M
de Graaf
Loek
L
van Wijk
Albert
A
Back
Nicole
N
Kline
Mark W
MW
Boucher
Charles A B
CA
Nijhuis
Monique
M
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000821:virology; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D024882:Drug Resistance, Viral; D054303:HIV Reverse Transcriptase / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007223:Infant; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D012367:RNA, Viral / Q000097:blood; D018119:Stavudine / Q000627:therapeutic use*; D019562:Viral Load; D015215:Zidovudine / Q000627:therapeutic use*
D019380:Anti-HIV Agents; D012367:RNA, Viral; D015215:Zidovudine; D018119:Stavudine; D054303:HIV Reverse Transcriptase