Characterization of emergent HIV resistance in treatment-naive subjects enrolled in a vicriviroc phase 2 trial.
BACKGROUND
Vicriviroc is a C-C motif chemokine receptor 5 (CCR5) antagonist that is in clinical development for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. This study explored the molecular basis for the development of phenotypically resistant virus.


METHODS
HIV-1 RNA from treatment-naive subjects who experienced virological failure in a phase 2 dose-finding trial was evaluated for coreceptor usage and susceptibility. For viruses that exhibited reduced susceptibility to vicriviroc, envelope clones were phenotypically and genotypically characterized.


RESULTS
Twenty-six vicriviroc-treated subjects experienced virological failure; for 24 the virus remained CCR5-tropic, and 2 had dual/X4 virus. Reduced susceptibility to vicriviroc, manifested as decreases in the maximum percent inhibition value (no increase in median inhibitory concentration), was detected in 4 of the 26 subjects who experienced virological failure. Clonal analysis of envelopes in samples from these 4 subjects revealed multiple sequence changes in gp160, principally within the variable domain 1/variable domain 2, variable domain 3, and variable domain 4 loops. However, no consistent pattern of mutations was observed across subjects.


CONCLUSIONS
In this study, only a small proportion of treatment failures were associated with tropism changes or reduced susceptibility to vicriviroc. Genotypic analysis of cloned env sequences revealed no specific mutational pattern associated with reduced susceptibility to vicriviroc, although numerous changes were observed in the variable domain 3 loop and in other regions of gp160.
McNicholas
Paul
P
Merck Research Laboratories, Kenilworth, New Jersey 07033, USA.
Wei
Yi
Y
Whitcomb
Jeannette
J
Greaves
Wayne
W
Black
Todd A
TA
Tremblay
Cecile L
CL
Strizki
Julie M
JM
D019380:Anti-HIV Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D024882:Drug Resistance, Viral / Q000235:genetics*; D019302:HIV Envelope Protein gp160 / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000145:classification / Q000187:drug effects*; D006801:Humans; D010879:Piperazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D012367:RNA, Viral / Q000235:genetics; D019562:Viral Load
D019380:Anti-HIV Agents; D019302:HIV Envelope Protein gp160; D010879:Piperazines; D011743:Pyrimidines; D012367:RNA, Viral; C486781:vicriviroc