Selection of Zidovudine Resistance Mutations and Escape of Human Immunodeficiency Virus Type 1 from Antiretroviral Pressure in Stavudine-Treated Pediatric Patients

• Published in: The Journal of infectious diseases 2002-04, Vol.185 (8), p.1070-1076
• Main Authors: Maxeiner, Horst-Guenter, Keulen, Wilco, Schuurman, Rob, Bijen, Marc, Graaf, Loek de, van Wijk, Albert, Back, Nicole, Kline, Mark W., Boucher, Charles A. B., Nijhuis, Monique
• Format: Article
• Language: English
• Subjects: Acquired Immunodeficiency Syndrome - drug therapy; Acquired Immunodeficiency Syndrome - virology; Anti-HIV Agents - therapeutic use; Antiretrovirals; Antivirals; Biological and medical sciences; Child; Child, Preschool; Drug Resistance, Viral; Genetic mutation; HIV; HIV 1; HIV Reverse Transcriptase - genetics; HIV-1 - drug effects; Human immunodeficiency virus 1; Human viral diseases; Humans; Infant; Infectious diseases; Inhibitory concentration 50; Major Articles; Medical sciences; Mutagenesis, Site-Directed; Mutation; RNA; RNA, Viral - blood; Stavudine - therapeutic use; Transponders; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids; Viral Load; Virology; Viruses; Zidovudine - therapeutic use
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1086/339817

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 IC50 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.