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.
RCT Entities:
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- infectedpatients 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: Masanori Kobayashi; Tomokazu Yoshinaga; Takahiro Seki; Chiaki Wakasa-Morimoto; Kevin W Brown; Robert Ferris; Scott A Foster; Richard J Hazen; Shigeru Miki; Akemi Suyama-Kagitani; Shinobu Kawauchi-Miki; Teruhiko Taishi; Takashi Kawasuji; Brian A Johns; Mark R Underwood; Edward P Garvey; Akihiko Sato; Tamio Fujiwara Journal: Antimicrob Agents Chemother Date: 2010-11-29 Impact factor: 5.191
Authors: Joseph M Custodio; Martin Rhee; Gong Shen; Kah Hiing J Ling; Brian P Kearney; Srinivasan Ramanathan Journal: Antimicrob Agents Chemother Date: 2014-02-18 Impact factor: 5.191
Authors: Rima Kulkarni; Rebecca Hluhanich; Damian M McColl; Michael D Miller; Kirsten L White Journal: Antimicrob Agents Chemother Date: 2014-08-04 Impact factor: 5.191