Efficacy of constant infusion of A-77003, an inhibitor of the human immunodeficiency virus type 1 (HIV-1) protease, in limiting acute HIV-1 infection in vitro.
A-77003, a human immunodeficiency virus type 1 (HIV-1) protease inhibitor, is effective for both acute and chronic infection in vitro and was evaluated clinically by continuous intravenous infusion administration. The minimum effective dose (the concentration required to completely inhibit viral replication) was determined in vitro in a population of uninfected (99%) and HIV-infected (1%) cells exposed to A-77003 by continuous infusion in hollow-fiber bioreactors. The production of infectious HIV and release of p24 antigen from infected cells were completely inhibited in cultures exposed to A-77003 at or above a concentration of 0.5 microM. Measurement of unintegrated HIV-1 DNA synthesis and flow cytometric analysis for cells expressing HIV p24 antigen demonstrated that the spread of HIV to uninfected cells was also blocked at 0.5 microM A-77003. Dose deescalation to 0.25 microM or removal of A-77003 resulted in the limited spread of the virus throughout the culture, the resumption of viral DNA synthesis, and release of p24. HIV produced after exposure to 0.5 microM A-77003 was noninfectious for a period of 72 h after the removal of the drug. Addition of 1 mg of alpha 1-acid glycoprotein per ml to this in vitro system completely ablated the anti-HIV effect of 0.5 microM A-77003. These data suggest that determination of the minimum effective dose under conditions which simulate human pharmacodynamic patterns may be useful in determining the initial dose and schedule for clinical trials. However, other factors, such as serum protein binding, may influence the selection of a therapeutic regimen.
Bilello
J A
JA
Department of Medicine, Albany Medical College, New York 12208, USA.
Bilello
P A
PA
Kort
J J
JJ
Dudley
M N
MN
Leonard
J
J
Drusano
G L
GL
D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002460:Cell Line; D004279:DNA, Viral / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D016655:HIV Core Protein p24 / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008782:Methylurea Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D009961:Orosomucoid / Q000378:metabolism / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000821:virology; D014633:Valine / Q000031:analogs & derivatives; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D004279:DNA, Viral; D016655:HIV Core Protein p24; D017320:HIV Protease Inhibitors; D008782:Methylurea Compounds; D009961:Orosomucoid; D011725:Pyridines; C079555:Abbott 77003; D014633:Valine