Inhibition of human immunodeficiency virus type 1 replication in vitro by the bisheteroarylpiperazine atevirdine (U-87201E) in combination with zidovudine or didanosine

The bisheteroarylpiperazine nonnucleoside Reverse Transcriptase (RT) inhibitor atevirdine effectively inhibits human immunodeficiency virus type 1 (HIV-1) in vitro. Clinical isolates with a wide range of 50% inhibitory concentrations (IC50s) of zidovudine (IC50, 0.003 to > 2.0 microM) and didanosine (IC50, 0.02 to > 10.0 microM) were inhibited by atevirdine (median IC50, 0.74 microM; range, 0.06-1.60). Cross-resistance to atevirdine in zidovudine- or didanosine-resistant isolates was not observed. Combinations of atevirdine and zidovudine were highly synergistic against zidovudine-resistant clinical isolates of HIV-1. By contrast, these combinations were mostly additive when tested against zidovudine-susceptible isolates. Combinations of atevirdine and didanosine were additive in their effects against both didanosine-susceptible and -resistant isolates. These data suggest that the interaction of atevirdine with HIV-1 RT is different than that of Other nonnucleoside RT inhibitors and that combinations of atevirdine and zidovudine may be useful in patients with AIDS who have initially received monotherapy with zidovudine.