EFFICACY OF CONSTANT INFUSION OF A-77003, AN INHIBITOR OF THE HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 (HIV-1) PROTEASE, IN LIMITING ACUTE HIV-1INFECTION IN-VITRO

A-77003, a human immunodeficiency virus type 1 (HIV-1) protease inhibi tor, is effective for both acute and chronic infection in vitro and wa s evaluated clinically by continuous intravenous infusion administrati on. The minimum effective dose (the concentration required to complete ly 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 inf ectious HIV and release of p24 antigen from infected cells were comple tely inhibited in cultures exposed to A-77003 at or above a concentrat ion of 0.5 mu M, Measurement of unintegrated HIV-1 DNA synthesis and f low cytometric analysis for cells expressing HIV p24 antigen demonstra ted that the spread of HIV to uninfected cells was also blocked at 0.5 mu M A-77003. Dose deescalation to 0.25 mu M or removal of A-77003 re sulted in the limited spread of the virus throughout the culture, the resumption of viral DNA synthesis, and release of p24, HIV produced af ter exposure to 0.5 mu M A-77003 was noninfectious for a period of 72 h after the removal of the drug, Addition of 1 mg of alpha(1)-acid gly coprotein per mi to this in vitro system completely ablated the anti-H IV effect of 0.5 mu M A-77003, These data suggest that determination o f the minimum effective dose under conditions which simulate human pha rmacodynamic patterns may be useful in determining the initial dose an d schedule for clinical trials, However, other factors, such as serum protein binding, may influence the selection of a therapeutic regimen.