title: Failure of short-term CD4-PE40 infusions to reduce virus load in human immunodeficiency virus-infected persons.
abstract: The safety, immunologic, and antiviral effects of a recombinant biologic product that combines the second and third domains of the CD4 molecule and Pseudomonas exotoxin A (PE40) were evaluated in 21 human immunodeficiency virus (HIV)-infected subjects in a phase III open-label dose-ranging study. Subjects with CD4+ lymphocyte counts of 100-500/mm3 received CD4-PE40 at 40, 80, or 160 micrograms/m2 by infusion three to seven times over 10 days. At the maximum tolerated dose (80 micrograms/m2), peak CD4-PE40 levels were 65-130 ng/mL with a serum half-life of 3.6 +/- 1.5 h. Toxicity, primarily increased hepatic transaminases, was dose-related and reversible. HIV DNA proviral levels in peripheral blood mononuclear cells and plasma HIV RNA remained stable during and after CD4-PE40 infusions. The relative resistance of clinical isolates of HIV, limits of the tolerated dose, and the immunogenicity and short half-life of the protein may explain the lack of in vivo antiviral effect of CD4-PE40.
authors.affiliation: Center for AIDS Research, Stanford University Medical Center, California 94305.
authors.forename: R V
authors.initials: RV
authors.lastname: Ramachandran
authors.forename: D A
authors.initials: DA
authors.lastname: Katzenstein
authors.forename: R
authors.initials: R
authors.lastname: Wood
authors.forename: D H
authors.initials: DH
authors.lastname: Batts
authors.forename: T C
authors.initials: TC
authors.lastname: Merigan
mesh_terms: D036002:ADP Ribose Transferases; D000328:Adult; D001427:Bacterial Toxins; D015704:CD4 Antigens; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D004279:DNA, Viral / Q000097:blood; D004334:Drug Administration Schedule; D005098:Exotoxins / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006678:HIV / Q000302:isolation & purification; D006679:HIV Seropositivity / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D000922:Immunotoxins / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007262:Infusions, Intravenous; D011533:Proviruses / Q000302:isolation & purification; D011550:Pseudomonas aeruginosa; D012367:RNA, Viral / Q000097:blood; D017211:Treatment Failure; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
chemical_list: D036002:ADP Ribose Transferases; D001427:Bacterial Toxins; D015704:CD4 Antigens; D004279:DNA, Viral; D005098:Exotoxins; D000922:Immunotoxins; D012367:RNA, Viral; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A