title: Genotypic correlates of phenotypic resistance to efavirenz in virus isolates from patients failing nonnucleoside reverse transcriptase inhibitor therapy.
abstract: Efavirenz (also known as DMP 266 or SUSTIVA) is a potent nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) activity and of HIV-1 replication in vitro and in vivo. Most patients on efavirenz-containing regimens have sustained antiviral responses; however, rebounds in plasma viral load have been observed in some patients in association with the emergence of mutant strains of HIV-1. Virus isolates from the peripheral blood mononuclear cells (PBMCs) of patients with such treatment failures, as well as recombinant viruses incorporating viral sequences derived from patient plasma, show reduced in vitro susceptibility to efavirenz in association with mutations in the RT gene encoding K103N, Y188L, or G190S/E substitutions. Patterns of RT gene mutations and in vitro susceptibility were similar in plasma virus and in viruses isolated from PBMCs. Variant strains of HIV-1 constructed by site-directed mutagenesis confirmed the role of K103N, G190S, and Y188L substitutions in reduced susceptibility to efavirenz. Further, certain secondary mutations (V106I, V108I, Y181C, Y188H, P225H, and F227L) conferred little resistance to efavirenz as single mutations but enhanced the level of resistance of viruses carrying these mutations in combination with K103N or Y188L. Viruses with K103N or Y188L mutations, regardless of the initial selecting nonnucleoside RT inhibitor (NNRTI), exhibited cross-resistance to all of the presently available NNRTIs (efavirenz, nevirapine, and delavirdine). Some virus isolates from nevirapine or delavirdine treatment failures that lacked K103N or Y188L mutations remained susceptible to efavirenz in vitro, although the clinical significance of this finding is presently unclear.
authors.affiliation: DuPont Pharmaceuticals Company, Wilmington, Delaware 19880-0336, USA. lee.bacheler@dupontpharma.com
authors.forename: L
authors.initials: L
authors.lastname: Bacheler
authors.forename: S
authors.initials: S
authors.lastname: Jeffrey
authors.forename: G
authors.initials: G
authors.lastname: Hanna
authors.forename: R
authors.initials: R
authors.lastname: D'Aquila
authors.forename: L
authors.initials: L
authors.lastname: Wallace
authors.forename: K
authors.initials: K
authors.lastname: Logue
authors.forename: B
authors.initials: B
authors.lastname: Cordova
authors.forename: K
authors.initials: K
authors.lastname: Hertogs
authors.forename: B
authors.initials: B
authors.lastname: Larder
authors.forename: R
authors.initials: R
authors.lastname: Buckery
authors.forename: D
authors.initials: D
authors.lastname: Baker
authors.forename: K
authors.initials: K
authors.lastname: Gallagher
authors.forename: H
authors.initials: H
authors.lastname: Scarnati
authors.forename: R
authors.initials: R
authors.lastname: Tritch
authors.forename: C
authors.initials: C
authors.lastname: Rizzo
mesh_terms: D000480:Alkynes; D019943:Amino Acid Substitution; D019380:Anti-HIV Agents / Q000494:pharmacology* / Q000627:therapeutic use; D048588:Benzoxazines; D002478:Cells, Cultured; D017322:Clinical Trials, Phase II as Topic; D015331:Cohort Studies; D003521:Cyclopropanes; D020008:Delavirdine / Q000494:pharmacology; D004352:Drug Resistance, Microbial; D018432:Drug Resistance, Multiple; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D054303:HIV Reverse Transcriptase / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000821:virology; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D019829:Nevirapine / Q000494:pharmacology; D010078:Oxazines / Q000494:pharmacology* / Q000627:therapeutic use; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D017211:Treatment Failure
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D010078:Oxazines; D018894:Reverse Transcriptase Inhibitors; D019829:Nevirapine; D020008:Delavirdine; D054303:HIV Reverse Transcriptase; C098320:efavirenz