Evolution of genotypic and phenotypic resistance during chronic treatment with the fusion inhibitor T-1249.
T-1249 is a peptide HIV fusion inhibitor (FI) previously under development for use in FI-naive and experienced patients. Here we present prospectively planned longitudinal analyses of FI resistance during 48 weeks of T-1249 dosing in patients with extensive prior FI exposure. T1249-105 was a single-arm rollover study in patients with prior resistance to enfuvirtide (ENF) and 10 days of T-1249 functional monotherapy exposure. The phenotype and genotype of plasma virus envelopes were analyzed at baseline and at study weeks 8, 16, and 48. At study entry, viruses had a geometric mean decrease in susceptibility to ENF of 51.8-fold but to T-1249 of 1.8-fold; extensive genotypic resistance to ENF was observed. A median viral load response of - 1.5 log(10) copies/ml was observed at week 2 that was partially sustained (- 0.5 log(10) copies/ml) through 48 weeks. Resistance to T-1249 gradually increased to a geometric mean 92.7-fold decrease from FI-naive baseline; this occurred concomitant with further evolution of gp41 amino acids 36-45, most commonly the G36D (n = 6, 16%) or N43K (n = 9, 24%) substitutions. A novel substitution, A50V (n = 12, 32%), was also common, as were the N126K and S138A substitutions in heptad-repeat 2 (HR-2). These data point toward a primary role for the gp41 36-45 locus in modulating FI binding and suggest that residues in HR-2 may contribute in a more limited manner to development of peptide FI resistance. These data also point toward a substantial genetic barrier and fitness cost to development of resistance to next-generation fusion inhibitors.
Melby
T
T
Trimeris, Inc., Morrisville, North Carolina 07560, USA.
Demasi
R
R
Cammack
N
N
Miralles
G D
GD
Greenberg
M L
ML
D019943:Amino Acid Substitution / Q000235:genetics; D024882:Drug Resistance, Viral; D000077560:Enfuvirtide; D006678:HIV / Q000187:drug effects* / Q000235:genetics; D015700:HIV Envelope Protein gp41 / Q000009:adverse effects / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use*; D023581:HIV Fusion Inhibitors / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D006801:Humans; D008137:Longitudinal Studies; D008826:Microbial Sensitivity Tests; D010446:Peptide Fragments / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*
D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments; C474741:peptide T1249; D000077560:Enfuvirtide