title: Characterization of envelope glycoprotein gp41 genotype and phenotypic susceptibility to enfuvirtide at baseline and on treatment in the phase III clinical trials TORO-1 and TORO-2.
abstract: Enfuvirtide (T-20) is the first entry inhibitor approved for treatment of HIV infection and acts by inhibiting conformational changes in the viral envelope protein gp41 that are necessary for fusion of the virus and host cell membranes. Here we present genotypic and phenotypic data on viral envelopes obtained at baseline (n = 627) and after 48 weeks of enfuvirtide treatment (n = 302) from patients in the TORO (T-20 versus Optimized Regimen Only)-1 and -2 phase III pivotal studies. The amino acid sequence at residues 36-45 of gp41 was highly conserved at baseline except for polymorphism of approximately 16% at position 42. Substitutions within gp41 residues 36-45 on treatment were observed in virus from 92.7% of patients who met protocol defined virological failure criteria and occurred in nearly all cases (98.8%) when decreases in susceptibility to enfuvirtide from baseline of greater than 4-fold were observed. Consistent with previous observations, a wide range of baseline susceptibilities (spanning 3 logs) was observed; however, lower in vitro baseline susceptibility was not significantly associated with a decreased virological response in vivo. Virological response was also independent of baseline coreceptor tropism and viral subtype.
authors.affiliation: Trimeris, Durham, North Carolina, USA.
authors.forename: T
authors.initials: T
authors.lastname: Melby
authors.forename: P
authors.initials: P
authors.lastname: Sista
authors.forename: R
authors.initials: R
authors.lastname: DeMasi
authors.forename: T
authors.initials: T
authors.lastname: Kirkland
authors.forename: N
authors.initials: N
authors.lastname: Roberts
authors.forename: M
authors.initials: M
authors.lastname: Salgo
authors.forename: G
authors.initials: G
authors.lastname: Heilek-Snyder
authors.forename: N
authors.initials: N
authors.lastname: Cammack
authors.forename: T J
authors.initials: TJ
authors.lastname: Matthews
authors.forename: M L
authors.initials: ML
authors.lastname: Greenberg
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D024882:Drug Resistance, Viral / Q000235:genetics*; D005838:Genotype; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000235:genetics / Q000627:therapeutic use*; D023581:HIV Fusion Inhibitors / Q000627:therapeutic use*; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D006801:Humans; D020128:Inhibitory Concentration 50; D010641:Phenotype; D011110:Polymorphism, Genetic; D013997:Time Factors
chemical_list: D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors