title: Sustained high proportion of zidovudine-resistant HIV variants despite prolonged substitution of zidovudine by other nucleoside reverse transcriptase inhibitors.
abstract: The consequences of zidovudine (ZDV) replacement by other nucleoside reverse transcriptase inhibitors on the expression of resistance mutations at codons 215 and 41 of the reverse transcriptase (RT) gene was investigated prospectively in 66 patients harboring mutant genotypes who were changed to an effective two- or three-drug combination antiretroviral regimen. Quantitation of mutant (MUT) viral populations at codon 215 by means of RT-PCR with differential hybridization of amplicons specific for MUT and wild (WT) variants revealed no difference in the proportion of 215 MUT variants prior to (93.5 +/- 2.4%) and 12 to 20 months after (96.9 +/- 1.9%) ZDV replacement, independently of a therapeutic change for stavudine. The fitness of the variants harboring the ZDV-resistant MUT 215 genotype following drug withdrawal was calculated to be 96 to 99% of that of the variants harboring the WT 215 genotype. The apparent stability of ZDV-resistant variants in the study population may have two main complementary explanations: persistent selective pressure secondary to partial cross-resistance due to the new regimens given after the therapeutic alteration and suppression of viral replication after the therapeutic alteration that could have hampered the replacement of less fit variants by fitter variants. These findings indicate that, at least within 15 months following discontinuation of ZDV, an effective antiretroviral therapy is insufficient to allow for ZDV-resistant strains to disappear, and thus to allow for the safe re-introduction of the drug.
authors.affiliation: Laboratoire de virologie, Hôpital Européen Georges Pompidou, Paris, France. laurent.belec@egp.ap-hop-paris.fr
authors.forename: Laurent
authors.initials: L
authors.lastname: Bélec
authors.forename: Jérôme
authors.initials: J
authors.lastname: Legoff
authors.forename: Ali
authors.initials: A
authors.lastname: Si-Mohamed
authors.forename: Laurent
authors.initials: L
authors.lastname: Andréoletti
authors.forename: François-Xavier
authors.initials: FX
authors.lastname: Mbopi-Kéou
authors.forename: Janice
authors.initials: J
authors.lastname: Kolberg
authors.forename: Mathieu
authors.initials: M
authors.lastname: Matta
authors.forename: Jill
authors.initials: J
authors.lastname: Detmer
authors.forename: Christophe
authors.initials: C
authors.lastname: Piketty
authors.forename: Michel D
authors.initials: MD
authors.lastname: Kazatchkine
mesh_terms: D000222:Adaptation, Physiological / Q000235:genetics; D000328:Adult; D019380:Anti-HIV Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015224:Dideoxynucleosides / Q000494:pharmacology / Q000627:therapeutic use; D024882:Drug Resistance, Viral; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006679:HIV Seropositivity / Q000188:drug therapy / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D015995:Prevalence; D011446:Prospective Studies; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D013997:Time Factors; D015215:Zidovudine / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D019380:Anti-HIV Agents; D015224:Dideoxynucleosides; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine