HUMAN-IMMUNODEFICIENCY-VIRUS TYPE 1 (HIV-1) INHIBITORY INTERACTIONS BETWEEN PROTEASE INHIBITOR RO 31-8959 AND ZIDOVUDINE, 2',3'-DIDEOXYCYTIDINE, OR RECOMBINANT INTERFERON-ALPHA-A AGAINST ZIDOVUDINE-SENSITIVE OR ZIDOVUDINE-RESISTANT HIV-1 INVITRO

Protease inhibitor Ro 31-8959, a compound that interrupts human immunodeficiency virus (HIV)-specific formation of infectious virions, was evaluated in two-drug combined regimens with zidovudine, 2,3-dideoxycytidine (ddC), or recombinant interferon-alphaA (rIFN-alphaA) against HIV-1 replication in vitro. By using peripheral blood mononuclear cells infected with HIV-1, drug interactions were evaluated by the median-effect principle and the isobologram technique. A zidovudine-sensitive and -resistant HIV-1 isolate pair was studied. Additive to synergistic anti-HIV-1 interactions were seen with 7.5-30 nM Ro 31-8959 and 0.005-0.02 muM zidovudine (for the zidovudine-sensitive HIV-1 isolate), 0.25-1.0 muM zidovudine (for the zidovudine-resistant HIV-1 isolate), 0.025-0.1 muM ddC, and 8-32 units/mL rIFN-alphaA, without additive toxicity. Phase I/II clinical trials of Ro 31-8959 for therapy of HIV-1 infection are in progress. If results are favorable, combined regimens including Ro 31-8959 deserve consideration for future clinical trials.