title: Inhibition of human immunodeficiency virus type 1 replication in vitro by the bisheteroarylpiperazine atevirdine (U-87201E) in combination with zidovudine or didanosine.
abstract: 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.
authors.affiliation: Department of Medicine, University of Colorado Health Sciences Center, Denver 80262.
authors.forename: T B
authors.initials: TB
authors.lastname: Campbell
authors.forename: R K
authors.initials: RK
authors.lastname: Young
authors.forename: J J
authors.initials: JJ
authors.lastname: Eron
authors.forename: R T
authors.initials: RT
authors.lastname: D'Aquila
authors.forename: W G
authors.initials: WG
authors.lastname: Tarpley
authors.forename: D R
authors.initials: DR
authors.lastname: Kuritzkes
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D016049:Didanosine / Q000494:pharmacology*; D015658:HIV Infections / Q000382:microbiology; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008826:Microbial Sensitivity Tests; D010879:Piperazines / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors; D014779:Virus Replication / Q000187:drug effects; D015215:Zidovudine / Q000494:pharmacology*
chemical_list: D000998:Antiviral Agents; D010879:Piperazines; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine; D054303:HIV Reverse Transcriptase; D016049:Didanosine; C076632:atevirdine