title: Treatment of advanced human immunodeficiency virus type 1 disease with the viral entry inhibitor PRO 542.
abstract: 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/mm(3)), PRO 542 mediated an 80% response rate and statistically significant approximately 0.5 log(10) 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.
authors.affiliation: Mount Sinai Medical Center, New York, New York 10029. Progenics Pharmaceuticals, Inc., Tarrytown, New York 10591, USA. jjacobson@chpnet.org
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Jacobson
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Israel
authors.forename: Israel
authors.initials: I
authors.lastname: Lowy
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Ostrow
authors.forename: Linda S
authors.initials: LS
authors.lastname: Vassilatos
authors.forename: Melanie
authors.initials: M
authors.lastname: Barish
authors.forename: Diep N H
authors.initials: DN
authors.lastname: Tran
authors.forename: Brian M
authors.initials: BM
authors.lastname: Sullivan
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Ketas
authors.forename: Tobias J
authors.initials: TJ
authors.lastname: O'Neill
authors.forename: Kirsten A
authors.initials: KA
authors.lastname: Nagashima
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.forename: Christos J
authors.initials: CJ
authors.lastname: Petropoulos
authors.forename: John P
authors.initials: JP
authors.lastname: Moore
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Maddon
authors.forename: William C
authors.initials: WC
authors.lastname: Olson
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D016860:CD4 Immunoadhesins / Q000009:adverse effects / Q000627:therapeutic use*; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects* / Q000254:growth & development; D006801:Humans; D008297:Male; D008875:Middle Aged; D012367:RNA, Viral / Q000032:analysis / Q000096:biosynthesis; D019562:Viral Load; D014771:Virion / Q000737:chemistry
chemical_list: D019380:Anti-HIV Agents; D016860:CD4 Immunoadhesins; C096753:CD4-IgG(2); D012367:RNA, Viral