RETENTION OF MARKED SENSITIVITY TO HYLTHIOMETHYL)-3,4-DIHYDROQUINOXALINE-2(1H)-THIONE (HBY-097) BY AN AZIDOTHYMIDINE (AZT)-RESISTANT HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 (HIV-1) STRAIN SUBCULTURED IN THE COMBINED PRESENCE OF QUINOXALINE HBY-097 AND 2',3'-DIDEOXY-3'-THIACYTIDINE (LAMIVUDINE)

An azidothymidine (AZT)-resistant virus strain (HIV-1/AZT) (containing the 67 Asp --> Asn, 70 Lys --> Arg, 215 Thr --> Phe and 219 Lys --> G in mutations into its reverse transcriptase) was grown in the combined presence of 2',3'-dideoxy-3'-thiacytidine (3TC, lamivudine) and the n onnucleoside reverse transcriptase inhibitor -isopropoxycarbonyl-6-met hoxy-3-(methylthiomethyl) -3,4-dihydroquinoxaline-2(1H)-thione (quinox aline HEY 097). Replication of HIV-1/AZT was inhibited to a significan tly greater extent by the combination of 3TC and quinoxaline HBY 097 t han by either drug alone. Virus breakthrough was markedly delayed in t he combined presence of 3TC and HEY 097 at drug concentrations as low as 0.05 mu g/mL and 0.0025 mu g/mL, respectively. The virus that was r ecovered after exposure to the compounds (3TC and HEY 097) individuall y had acquired, in the genetic AZT-resistance background of HIV-1/AZT, 103 Lys --> Glu and 106 Val -->,Ala mutations. The 103 Lys -->,Glu mu tation had not been observed before. However, both virus mutants retai ned marked sensitivity to HEY 097. In all cases, the genotypic AZT-res istance mutations were maintained in the mutant virus RT genomes, and the viruses also remained phenotypically resistant to AZT. Given the e xquisite potency of a concomitant combination of 3TC and HEY 097 in su ppressing virus replication, this drug combination should be further p ursued in clinical trials in HIV-1-infected individuals. (C) 1998 Else vier Science Inc.