title: Antiviral activity, pharmacokinetics, and dose response of the HIV-1 integrase inhibitor GS-9137 (JTK-303) in treatment-naive and treatment-experienced patients.
abstract: BACKGROUND
  GS-9137 is a potent low-nanomolar strand transfer inhibitor of HIV-1 integrase.
  
  
  METHODS
  The antiviral activity, tolerability, pharmacokinetics, and pharmacodynamics of GS-9137 were evaluated in a randomized, double-blind, placebo-controlled monotherapy study in 40 HIV-1- infected patients not receiving antiretroviral therapy with an HIV-1 RNA between 10,000 and 300,000 copies/mL and a CD4 count of 200 cells/microL or greater. GS-9137 or matching placebo was administered with food for 10 days at 5 dosage regimens (200, 400, or 800 mg BID, 800 mg QD, or 50 mg+100 mg ritonavir QD; 6 active, 2 placebo per dose level). The primary end point was the maximum reduction from baseline in log10 HIV-1 RNA.
  
  
  RESULTS
  Forty patients were enrolled, with a mean baseline viral load of 4.75 log10 copies/mL and a CD4 count of 442 cells/microL. Each GS-9137 dosing regimen exhibited significant, exposure-dependent (mean reductions, -0.98 to -1.99 log10 copies/mL) antiviral activity compared with placebo (P<0.01). Twice-daily administrations of GS-9137 at doses of 400 or 800 mg or once-daily dosing of 50 mg with ritonavir demonstrated mean reductions from baseline in HIV-1 RNA of 1.91 log10 copies/mL or greater, with all patients exhibiting 1 log10 or greater and 50% having 2 log10 or greater reductions. No patient developed evidence of integrase resistance. GS-9137 showed an adverse event profile similar to placebo, and there were no study drug discontinuations.
  
  
  CONCLUSIONS
  GS-9137 demonstrated substantial short-term antiviral activity and was well tolerated as monotherapy, thus warranting further study.
authors.affiliation: Orlando Immunology Center, Orlando, FL, USA.
authors.forename: Edwin
authors.initials: E
authors.lastname: DeJesus
authors.forename: Daniel
authors.initials: D
authors.lastname: Berger
authors.forename: Martin
authors.initials: M
authors.lastname: Markowitz
authors.forename: Calvin
authors.initials: C
authors.lastname: Cohen
authors.forename: Trevor
authors.initials: T
authors.lastname: Hawkins
authors.forename: Peter
authors.initials: P
authors.lastname: Ruane
authors.forename: Richard
authors.initials: R
authors.lastname: Elion
authors.forename: Charles
authors.initials: C
authors.lastname: Farthing
authors.forename: Lijie
authors.initials: L
authors.lastname: Zhong
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Cheng
authors.forename: Damian
authors.initials: D
authors.lastname: McColl
authors.forename: Brian P
authors.initials: BP
authors.lastname: Kearney
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy*; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D015658:HIV Infections / Q000188:drug therapy*; D019427:HIV Integrase / Q000378:metabolism*; D006801:Humans; D015363:Quinolones / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*
chemical_list: D019380:Anti-HIV Agents; D004791:Enzyme Inhibitors; D015363:Quinolones; C509700:elvitegravir; D019427:HIV Integrase