Phase I study of high-dose, intravenous rsCD4 in subjects with advanced HIV-1 infection.
In vitro, recombinant soluble CD4 (rsCD4) attaches to and inactivates human immunodeficiency virus (HIV). To determine if prolonged therapy with high-dose intravenous rsCD4 provides an in vivo benefit, we gave three HIV-1-infected patients with AIDS, whose isolates were susceptible in vitro to rsCD4, 10 mg/kg of rsCD4 for 4 weeks, 5 mg/kg for 4 weeks, and 1 mg/kg for 2 weeks. Single-dose pharmacokinetic studies performed prior to this showed transient in vivo decreases of HIV-1 plasma viremia in all three subjects. Surrogate markers of HIV activity, clinical status, HIV-1 p24 antigen, plasma HIV-1 titers, and peripheral blood mononuclear cell (PBMC) intracellular titers of virus were measured at entry, and every other week after onset of therapy. All subjects demonstrated rsCD4 concentration-dependent reduction in plasma viremia, with two subjects having complete neutralization of cell-free virus. The third subject's isolate was relatively resistant to the in vivo effects of rsCD4 and only partial reduction in plasma virus titers was obtained, even at the highest dose of 10 mg/kg. There was no change in the PBMC intracellular viral titer or surrogate markers of HIV-1 activity (including CD4 cell count and beta 2-microglobulin). There was subjective improvement in clinical symptoms, and all subjects gained weight with the highest doses of rsCD4. rsCD4 exhibited linear pharmacokinetics over the dose range studied. We conclude that high-dose intravenous rsCD4 can be safely given for up to 10 weeks and that it has a stable pharmacokinetic profile.(ABSTRACT TRUNCATED AT 250 WORDS)
Schacker
T
T
University of Washington Department of Medicine, Seattle 98104, USA.
Collier
A C
AC
Coombs
R
R
Unadkat
J D
JD
Fox
I
I
Alam
J
J
Wang
J P
JP
Eggert
E
E
Corey
L
L
D000163:Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000628:therapy*; D000328:Adult; D015704:CD4 Antigens / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D015483:HIV Antibodies / Q000032:analysis; D016655:HIV Core Protein p24 / Q000032:analysis; D015658:HIV Infections / Q000276:immunology / Q000628:therapy*; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D009504:Neutrophils / Q000821:virology; D011994:Recombinant Proteins; D012995:Solubility; D014766:Viremia / Q000628:therapy
D015704:CD4 Antigens; D015483:HIV Antibodies; D016655:HIV Core Protein p24; D011994:Recombinant Proteins