title: Randomized placebo-controlled study of the safety, tolerability, antiviral activity, and pharmacokinetics of 10-day monotherapy with BMS-986001, a novel HIV NRTI, in treatment-experienced HIV-1-infected subjects.
abstract: OBJECTIVE
  To investigate the safety, tolerability, pharmacokinetics, and antiviral activity of BMS-986001 (a nucleoside reverse transcriptase inhibitor) in treatment-experienced, HIV-1-infected subjects not exposed to antiretroviral treatment in the previous 3 months.
  
  
  METHODS
  Thirty-two HIV-1-infected subjects were randomized (3:1) to receive BMS-986001 or placebo once daily for 10 days in this double-blind, placebo-controlled, dose-escalating monotherapy phase IIa study. There were 4 treatment groups (100, 200, 300, and 600 mg, all once daily) of 8 subjects each (BMS-986001, n = 6/placebo n = 2).
  
  
  RESULTS
  BMS-986001 was generally well tolerated, with no discontinuations due to adverse events and no deaths occurring. Adverse events were experienced by 22 of 24 BMS-986001-treated subjects and did not seem to be dose related. The majority were mild and considered unrelated or unlikely to be related to the study drug. The pharmacokinetics of BMS-986001 were dose proportional. Median decrease in plasma HIV-1 RNA from baseline to day 11 was 0.97, 1.15, 1.28, and 1.15 log10 copies/mL for BMS-986001 at 100, 200, 300, and 600 mg, respectively. Plasma area under the curve correlated with the antiviral activity of BMS-986001, indicating that area under the curves produced by 100-600 mg doses were on the upper end of the exposure-response curve. One subject with a single thymidine analog mutation at baseline responded well to BMS-986001.
  
  
  CONCLUSIONS
  Administration of BMS-986001 for 10 days resulted in substantial decreases in plasma HIV-1 RNA levels for all dose groups and was generally well tolerated. These data support continued clinical development of BMS-986001 at a dose of 100 mg, once daily or greater.
  
  
  BACKGROUND
  EUDRACT Number 2008-004810-29.
authors.affiliation: Service d'hépatologie et de sida, Hôtel-Dieu, Hospices Civils de Lyon and INSERM U1052, Lyon, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Cotte
authors.forename: Pierre
authors.initials: P
authors.lastname: Dellamonica
authors.forename: Francois
authors.initials: F
authors.lastname: Raffi
authors.forename: Yazdan
authors.initials: Y
authors.lastname: Yazdanpanah
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Molina
authors.forename: François
authors.initials: F
authors.lastname: Boué
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Urata
authors.forename: H Phyllis
authors.initials: HP
authors.lastname: Chan
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
authors.forename: Ih
authors.initials: I
authors.lastname: Chang
authors.forename: Richard
authors.initials: R
authors.lastname: Bertz
authors.forename: George J
authors.initials: GJ
authors.lastname: Hanna
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Grasela
authors.forename: Carey
authors.initials: C
authors.lastname: Hwang
mesh_terms: D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010919:Placebos; D012367:RNA, Viral / Q000097:blood; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013936:Thymidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D019562:Viral Load / Q000187:drug effects; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; C583040:BMS-986001; D010919:Placebos; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D013936:Thymidine