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Antimicrobial Agents and Chemotherapy, February 2004, p. 423-429, Vol. 48, No. 2
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.2.423-429.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Treatment of Advanced Human Immunodeficiency Virus Type 1 Disease with the Viral Entry Inhibitor PRO 542

Jeffrey M. Jacobson,^1,* Robert J. Israel,² Israel Lowy,^1, Nancy A. Ostrow,^1, Linda S. Vassilatos,² Melanie Barish,² Diep N. H. Tran,² Brian M. Sullivan,^2,3 Thomas J. Ketas,^2,3 Tobias J. O'Neill,² Kirsten A. Nagashima,² Wei Huang,⁴ Christos J. Petropoulos,⁴ John P. Moore,³ Paul J. Maddon,² and William C. Olson²

Mount Sinai Medical Center, New York, New York 10029,¹ Progenics Pharmaceuticals, Inc., Tarrytown, New York 10591,² ViroLogic, Inc., South San Francisco, California 94080,⁴ Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York 10021³

Received 27 June 2003/ Returned for modification 18 September 2003/ Accepted 4 November 2003

Viral entry inhibitors represent an emerging mode of therapy for human immunodeficiency virus type 1 (HIV-1) infection. PRO 542 (CD4-immunoglobulin G2) is a tetravalent CD4-immunoglobulin fusion protein that broadly neutralizes primary HIV-1 isolates. PRO 542 binds to the viral surface glycoprotein gp120 and blocks attachment and entry of virus into CD4⁺ cells. Previously, PRO 542 demonstrated antiviral activity without significant toxicity when tested at single doses ranging to 10 mg/kg. In this study, 12 HIV-infected individuals were treated with 25-mg/kg single-dose PRO 542 and then monitored for safety, antiviral effects, and PRO 542 pharmacokinetics for 6 weeks. The study examined two treatment cohorts that differed in the extent of HIV-1 disease progression. PRO 542 at 25 mg/kg was well tolerated and demonstrated a serum half-life of 3 days. Statistically significant acute reductions in HIV-1 RNA levels were observed across all study patients, and greater antiviral effects were observed in the cohort of patients with more advanced HIV-1 disease. In advanced disease (HIV-1 RNA > 100,000 copies/ml; CD4 lymphocytes < 200 cells/mm³), PRO 542 mediated an 80% response rate and statistically significant 0.5 log₁₀ mean reductions in viral load for 4 to 6 weeks posttreatment. Similar findings were obtained in an analysis of all (n = 11) advanced disease patients treated to date with single doses of PRO 542 ranging from 1 to 25 mg/kg. In addition, a significant correlation was observed between antiviral effects observed in vivo and viral susceptibility to PRO 542 in vitro. The findings support continued development of PRO 542 for salvage therapy of advanced HIV-1 disease.

Present address: Department of Medicine, Beth Israel Medical Center, New York, NY 10003.

Present address: Medarex, Inc., Bloomsbury, NJ 08804.

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