Antiviral activity, pharmacokinetics, and dose response of the HIV-1 integrase inhibitor GS-9137 (JTK-303) in treatment-naive and treatment-experienced patients.
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.
DeJesus
Edwin
E
Orlando Immunology Center, Orlando, FL, USA.
Berger
Daniel
D
Markowitz
Martin
M
Cohen
Calvin
C
Hawkins
Trevor
T
Ruane
Peter
P
Elion
Richard
R
Farthing
Charles
C
Zhong
Lijie
L
Cheng
Andrew K
AK
McColl
Damian
D
Kearney
Brian P
BP
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*
D019380:Anti-HIV Agents; D004791:Enzyme Inhibitors; D015363:Quinolones; C509700:elvitegravir; D019427:HIV Integrase