title: Detection of HIV-1 CXCR4 tropism and resistance in treatment experienced subjects receiving CCR5 antagonist-Vicriviroc.
abstract: BACKGROUND
  Vicriviroc (VCV), a small-molecule antagonist of the C-C chemokine receptor 5 (CCR5), blocks HIV's entry into CD4+ cells. Small studies have suggested that resistance to CCR5 antagonists is slow to develop.
  
  
  OBJECTIVE
  To examine resistance to VCV in isolates from treatment experienced patients who experienced virologic failure in two phase 3 trials.
  
  
  METHODS
  Genotypic and phenotypic susceptibility to VCV, and other antiretroviral drugs were evaluated at baseline and at defined intervals during the study. In a post hoc analysis, viral tropism at baseline was evaluated using the Trofile-ES assay. Only subjects with R5-tropic virus were included in the analysis. Viral envelope sequencing was performed on samples from subjects with emergent VCV resistance defined using a relative MPI cutoff.
  
  
  RESULTS
  71/486 subjects treated with VCV for 48 weeks met the protocol-defined virologic failure criteria. 7/71 (10%) had DM/X4 virus at the time of virologic failure; VCV resistance was identified in 4/486 treated subjects (1%). No control subject had detectable DM/X4 virus or VCV resistance at virologic failure. Clonal analysis of envelope sequences from VCV-resistant virus identified 2-5 amino acid substitutions at or near the crown of the V3 loop; however, no signature V3 mutations were identified. Changes outside the V3 loop were also observed in resistant clones; no consistent variant pattern was observed.
  
  
  CONCLUSIONS
  In these trials, use of a sensitive tropism assay and potent antiretroviral drug combinations contributed to the infrequent detection of X4-tropic virus and VCV resistance. Substitutions in the V3 loop were associated with VCV resistance, however, no specific pattern of amino acid changes were sufficient to reliably predict VCV susceptibility.
authors: Merck Research Laboratories, Kenilworth, NJ, USA.
authors: Paul
authors: P
authors: McNicholas
authors: Regis A
authors: RA
authors: Vilchez
authors: Wayne
authors: W
authors: Greaves
authors: Sushma
authors: S
authors: Kumar
authors: Chinyere
authors: C
authors: Onyebuchi
authors: Todd
authors: T
authors: Black
authors: Julie M
authors: JM
authors: Strizki
mesh_terms: D019380:Anti-HIV Agents / Q000008:administration & dosage*; D017326:Clinical Trials, Phase III as Topic; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects* / Q000302:isolation & purification / Q000502:physiology*; D006801:Humans; D008826:Microbial Sensitivity Tests; D010641:Phenotype; D010879:Piperazines / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage*; D012367:RNA, Viral / Q000235:genetics; D017422:Sequence Analysis, DNA; D017211:Treatment Failure; D056189:Viral Tropism; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics
chemical_list: D019380:Anti-HIV Agents; D010879:Piperazines; D011743:Pyrimidines; D012367:RNA, Viral; D054299:env Gene Products, Human Immunodeficiency Virus; C486781:vicriviroc