Inhibition of Human Immunodeficiency Virus Type 1 Replication In Vitro by the Bisheteroarylpiperzine 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 µM) and didanosine (IC₅₀, 0.02 to > 10.0µM) were inhibited by atevirdine (median IC₅₀, 0.74µM; range, 0.06-1.60). Cross-resistance to atevirdine in zidovudine- or didanosine-resistant isolates was not observed. Combinations ofatevirdine and zidovudine were highly synergistic against zidovudineresistant 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.