title: DPC 817: a cytidine nucleoside analog with activity against zidovudine- and lamivudine-resistant viral variants.
abstract: Highly active antiretroviral therapy (HAART) is the standard treatment for infection with the human immunodeficiency virus (HIV). HAART regimens consist of protease inhibitors or nonnucleoside reverse transcriptase inhibitors combined with two or more nucleoside reverse transcriptase inhibitors (NRTIs). DPC 817, 2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine (PSI 5582 D-D4FC) is a potent inhibitor of HIV type 1 replication in vitro. Importantly, DPC 817 retains activity against isolates harboring mutations in the reverse transcriptase gene that confer resistance to lamivudine (3TC) and zidovudine (AZT), which are frequent components of initial HAART regimens. DPC 817 combines this favorable resistance profile with rapid uptake and conversion to the active metabolite DPC 817-triphosphate, which has an intracellular half-life of 13 to 17 h. Pharmacokinetics in the rhesus monkey suggest low clearance of parent DPC 817 and a plasma half-life longer than that of either AZT or 3TC. Together, these properties suggest that DPC 817 may be useful as a component of HAART regimens in individuals with resistance to older NRTI agents.
authors.affiliation: Veterans Affairs Medical Center, Atlanta, Georgia 30033, USA. rschina@emory.edu
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Schinazi
authors.forename: John
authors.initials: J
authors.lastname: Mellors
authors.forename: Holly
authors.initials: H
authors.lastname: Bazmi
authors.forename: Sharon
authors.initials: S
authors.lastname: Diamond
authors.forename: Sena
authors.initials: S
authors.lastname: Garber
authors.forename: Karen
authors.initials: K
authors.lastname: Gallagher
authors.forename: Romas
authors.initials: R
authors.lastname: Geleziunas
authors.forename: Ron
authors.initials: R
authors.lastname: Klabe
authors.forename: Michael
authors.initials: M
authors.lastname: Pierce
authors.forename: Marlene
authors.initials: M
authors.lastname: Rayner
authors.forename: Jing-Tao
authors.initials: JT
authors.lastname: Wu
authors.forename: Hangchun
authors.initials: H
authors.lastname: Zhang
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hammond
authors.forename: Lee
authors.initials: L
authors.lastname: Bacheler
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Manion
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Otto
authors.forename: Lieven
authors.initials: L
authors.lastname: Stuyver
authors.forename: George
authors.initials: G
authors.lastname: Trainor
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Liotta
authors.forename: Susan
authors.initials: S
authors.lastname: Erickson-Viitanen
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D003562:Cytidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000188:drug therapy; D054303:HIV Reverse Transcriptase / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D019259:Lamivudine / Q000493:pharmacokinetics / Q000494:pharmacology; D008253:Macaca mulatta; D009705:Nucleosides / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D016047:Zalcitabine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D015215:Zidovudine / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D009705:Nucleosides; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D015215:Zidovudine; D003562:Cytidine; D016047:Zalcitabine; D054303:HIV Reverse Transcriptase; C099405:dexelvucitabine