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/mu L 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 logo HIV-1 RNA. Results: Forty patients were enrolled, with a mean baseline viral load of 4.75 log(10) copies/mL and a CD4 count of 442 cells/mu L. Each GS-9137 dosing regimen exhibited significant. exposure-dependent (mean reductions. -0.98 to -1.99 logo 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 log(10) copies/mL or greater, with all patients exhibiting 1 log(10) or greater and 50% having 2 log(10) 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.