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Antiviral Activity, Pharmacokinetics, and Dose Response of the HIV-1 Integrase Inhibitor GS-9137 (JTK-303) in Treatment-Naive and Treatment-Experienced Patients

DeJesus, Edwin MD*; Berger, Daniel MD; Markowitz, Martin MD; Cohen, Calvin MD§; Hawkins, Trevor MD; Ruane, Peter MD; Elion, Richard MD#; Farthing, Charles MD**; Zhong, Lijie PhD††; Cheng, Andrew K. MD, PhD††; McColl, Damian PhD††; Kearney, Brian P. PharmD††for the 183-0101 Study Team

JAIDS Journal of Acquired Immune Deficiency Syndromes: September 2006 - Volume 43 - Issue 1 - p 1-5
doi: 10.1097/01.qai.0000233308.82860.2f
Rapid Communication

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/μL 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/μL. 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.

From the *Orlando Immunology Center, Orlando, FL; †NorthStar Medical Center, Chicago, IL; ‡The Aaron Diamond AIDS Research Center, Rockefeller University, New York, NY; §Community Research Initiative of New England, Boston, MA; ∥Southwest Comprehensive AIDS-Care, Research & Education, Santa Fe, NM; ¶Light Source Medical, Los Angeles, CA; #Clinical Alliance for Research and Education-Infectious Diseases, Washington, DC; **AIDS Healthcare Foundation Research Center, Beverly Hills, CA; and ††Gilead Sciences, Foster City, CA.

Received for publication April 14, 2006; accepted July 13, 2006.

This study was supported by Gilead Sciences, Inc.

Drs Edwin DeJesus, Daniel Berger, Martin Markowitz, Calvin Cohen, Trevor Hawkins, Peter Ruane, Richard Elion, and Charles Farthing are clinical investigators for Gilead Sciences, Inc. Some or all of these investigators may also speak for and/or may have received research grant support from Gilead Sciences, Inc. Dr Daniel Berger owns shares of stock in Gilead Sciences.

Reprints: Brian P. Kearney, PharmD, 333 Lakeside Dr, Foster City, CA, 94404 (e-mail:

© 2006 Lippincott Williams & Wilkins, Inc.