Synergistic Inhibition of Human Immunodeficiency Virus Type 1 Replication in Vitro by Two- and Three-Drug Combinations of Delavirdine,Lamivudine and Zidovudine

Abstract

Delavirdine (DLV), a non-nucleoside human immunodeficiency virus type 1 (HIV-1) reverse transcriptase inhibitor, was evaluated in two- and three-drug combination regimens with lamivudine (3TC) and zidovudine (ZDV). The effect of continuous drug treatment on HIV-1_JR-CSF replication in human peripheral blood mononuclear cells was measured by an ELISA for p24 core antigen. Drug synergy, estimated by the combination index method and the method of Pritchard & Shipman, was observed when DLV was combined with 3TC over a range of drug concentrations (DLV at 1, 3, 10, 30 and 100 nM; 3TC at 3, 10, 30, 100 and 300 nM). Two-drug combinations of ZDV and DLV at a 1: 3 ratio or ZDV and 3TC at a 1: 10 ratio were synergistic at greater than 75% inhibition levels. Three-drug combinations of ZDV, DLV and 3TC (ZDV at 0.3, 1, 3 and 10 nM; DLV at 1, 3, 10 and 30 nM; 3TC at 3, 10, 30 and 100 nM) at the ratio of 1: 3: 10 also yielded significant synergistic effects. None of the combinations studied showed significant additive or synergistic drug toxicity. These in vitro data suggest that DLV should be evaluated in two- and three-drug combinations with 3TC and ZDV in clinical trials.