IN-VITRO COMBINATION OF PNU-140690, A HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 PROTEASE INHIBITOR, WITH RITONAVIR AGAINST RITONAVIR-SENSITIVE AND RITONAVIR-RESISTANT CLINICAL ISOLATES

PNU-140690 (sulfonamide-containing 5,6-dihydro-4-hydroxy-2-pyrone) is a potent, nonpeptidic inhibitor of the human immunodeficiency virus ty pe 1 (HIV-1) protease currently under clinical evaluation. PNU-140690 and ritonavir were studied in two-drug combinations against the replic ation of HIV-1 clinical isolates in peripheral blood mononuclear cells . A ritonavir-sensitive (301-1x) and -resistant (301-6x) isolate pair derived from an individual before and after monotherapy,vith ritonavir were used. These isolates showed no significant difference in sensiti vity to PNU-140690, but isolate 301-6x was more than 50-fold less sens itive to ritonavir than isolate 301-1x. Mathematical analysis showed t hat the combination of various concentrations of PNU-140690 with riton avir yielded additive to moderately synergistic antiviral effects agai nst the ritonavir-sensitive isolate and stronger synergy against the r itonavir-resistant isolate. The mechanism of synergy was not investiga ted, but the results suggested that both the virological and the obser ved in vitro pharmacological effects may have contributed to the obser ved synergy. Importantly, no significant antagonism was observed with the drug combinations studied. These data suggest that PNU-140690 may be useful in combination regimens with a structurally unrelated protea se inhibitor such as ritonavir.