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Phase I study of high-dose, intravenous rsCD4 in subjects with advanced HIV-1 infection
T Schacker1, A C Collier, R Coombs
1University of Washington Department of Medicine, Seattle 98104, USA.
Insights
High-dose intravenous recombinant soluble CD4 (rsCD4) therapy showed safe, dose-dependent reductions in human immunodeficiency virus (HIV) plasma viremia in AIDS patients. While not affecting intracellular virus, rsCD4 improved clinical symptoms and weight.
Area of Science:
- Virology
- Immunology
- Pharmacology
Background:
- Recombinant soluble CD4 (rsCD4) demonstrates in vitro capacity to bind and neutralize human immunodeficiency virus (HIV).
- Previous studies indicated transient in vivo reduction of HIV viremia following single rsCD4 doses.
Purpose of the Study:
- To evaluate the in vivo efficacy and safety of prolonged, high-dose intravenous rsCD4 therapy in patients with Acquired Immunodeficiency Syndrome (AIDS).
- To assess the impact of rsCD4 on viral load, surrogate markers, and clinical status in HIV-1 infected individuals.
Main Methods:
- Three HIV-1 infected patients with AIDS received escalating doses of intravenous rsCD4 (10 mg/kg for 4 weeks, 5 mg/kg for 4 weeks, 1 mg/kg for 2 weeks).
- Measurements included plasma HIV-1 titers, p24 antigen, peripheral blood mononuclear cell (PBMC) intracellular viral titers, CD4 cell counts, and beta-2 microglobulin.
- Pharmacokinetic studies were conducted to evaluate rsCD4 behavior in vivo.
Main Results:
- All patients showed rsCD4 concentration-dependent reductions in plasma viremia; two achieved complete neutralization of cell-free virus.
- One patient's HIV isolate exhibited partial resistance to in vivo rsCD4 effects.
- No significant changes were observed in PBMC intracellular viral titers or key surrogate markers, but subjective clinical improvement and weight gain occurred at higher doses.
Conclusions:
- High-dose intravenous rsCD4 can be safely administered for up to 10 weeks with a predictable pharmacokinetic profile.
- rsCD4 demonstrates potential for reducing plasma HIV viremia, although efficacy may vary based on viral isolate susceptibility.
- Further research is warranted to explore rsCD4's therapeutic role in managing HIV infection.
Abstract:
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)