title: Prediction of virological response and assessment of resistance emergence to the HIV-1 attachment inhibitor BMS-626529 during 8-day monotherapy with its prodrug BMS-663068.
abstract: BACKGROUND
  BMS-663068 is the phosphonooxymethyl prodrug of BMS-626529, a small-molecule attachment inhibitor that targets the HIV-1 envelope glycoprotein gp120 preventing it from binding to CD4 T cells. In vitro investigations have demonstrated considerable variation in susceptibility of different HIV-1 isolates to BMS-626529. BMS-663068 monotherapy in HIV-1-infected subjects produced a mean maximum change from baseline of -1.64 log10 copies per milliliter, but the response was variable.
  
  
  METHODS
  In this analysis, baseline and day 8 samples were analyzed for susceptibility to BMS-626529 and the presence of known HIV-1 attachment inhibitor resistance mutations. In addition, predictors of virological response (maximal HIV-1 RNA decline ≥1 log10 copies per milliliter) and resistance selection were investigated.
  
  
  RESULTS
  The only factor associated with reduced virological response was low baseline susceptibility to BMS-626529. There was no apparent relationship between virological response and baseline treatment experience, coreceptor tropism, plasma HIV-1 RNA level, or CD4 T-cell count. Examination of all positions with known BMS-626529 resistance mutations based on in vitro selection studies showed that gp120 M426L was the primary substitution most clearly associated with nonresponse to BMS-663068. There was minimal change in susceptibility to BMS-626529 over the course of the study and no clear evidence of emergence of a known HIV-1 attachment inhibitor resistance mutation in the majority of subjects as measured by standard population-based phenotypic and genotypic approaches.
  
  
  CONCLUSIONS
  Nonresponse to BMS-663068 was associated with low baseline susceptibility to BMS-626529 and the presence of M426L. In this short-term trial, there was minimal evidence of selection for BMS-626529 high-level resistance over 8 days of monotherapy with BMS-663068 by population-based approaches.
authors.affiliation: Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543-4000, USA. neelanjana.ray@bms.com
authors.forename: Neelanjana
authors.initials: N
authors.lastname: Ray
authors.forename: Carey
authors.initials: C
authors.lastname: Hwang
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Healy
authors.forename: Jeannette
authors.initials: J
authors.lastname: Whitcomb
authors.forename: Max
authors.initials: M
authors.lastname: Lataillade
authors.forename: Megan
authors.initials: M
authors.lastname: Wind-Rotolo
authors.forename: Mark
authors.initials: M
authors.lastname: Krystal
authors.forename: George J
authors.initials: GJ
authors.lastname: Hanna
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology* / Q000627:therapeutic use; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D004198:Disease Susceptibility; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000235:genetics; D005260:Female; D015699:HIV Envelope Protein gp120 / Q000187:drug effects*; D023581:HIV Fusion Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D015658:HIV Infections / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D015497:HIV-1 / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010755:Organophosphates / Q000627:therapeutic use*; D010879:Piperazines / Q000627:therapeutic use*; D011355:Prodrugs / Q000494:pharmacology* / Q000627:therapeutic use; D012367:RNA, Viral / Q000097:blood; D016896:Treatment Outcome; D014230:Triazoles / Q000627:therapeutic use*; D019562:Viral Load / Q000187:drug effects*
chemical_list: D019380:Anti-HIV Agents; C584152:BMS-626529; D015699:HIV Envelope Protein gp120; D023581:HIV Fusion Inhibitors; D010755:Organophosphates; D010879:Piperazines; D011355:Prodrugs; D012367:RNA, Viral; D014230:Triazoles; C576364:fostemsavir