Inhibition of Human Immunodeficiency Virus Type 1 Replication In Vitro by the Bisheteroarylpiperzine Atevirdine (U-87201E) in Combination with Zidovudine

The bisheteroarylpiperazine nonnucleoside reverse transcriptase (RT) inhibitor atevirdine ef-fectively inhibits human immunodeficiency virus type 1 (HIV-I) in vitro. Clinical isolates with a wide range of 50 % inhibitory concentrations (ICsos) of zidovudine (ICso, 0.003 to> 2.0 #J,M) and didanosine (ICso, 0.02 to> 10.0 #J,M) were inhibited by atevirdine (median ICso, 0.74""M; 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 zidovudine-resistant clinical isolates of HIV-I. 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-I RT is different than that of other nonnu-cleoside RT inhibitors and that combinations of atevirdine and zidovudine may be useful in patients with AIDS who have initially received monotherapy with zidovudine. Effective therapy of human immunodeficiency virus type I (HIV-I) infection to date has relied on inhibition ofreverse transcriptase (RT) by nucleoside analogues such as zidovu