title: In vitro antiretroviral activity and in vitro toxicity profile of SPD754, a new deoxycytidine nucleoside reverse transcriptase inhibitor for treatment of human immunodeficiency virus infection.
abstract: SPD754 (AVX754) is a deoxycytidine analogue nucleotide reverse transcriptase inhibitor (NRTI) in clinical development. These studies characterized the in vitro activity of SPD754 against NRTI-resistant human immunodeficiency virus type 1 (HIV-1) and non-clade B HIV-1 isolates, its activity in combination with other antiretrovirals, and its potential myelotoxicity and mitochondrial toxicity. SPD754 was tested against 50 clinical HIV-1 isolates (5 wild-type isolates and 45 NRTI-resistant isolates) in MT-4 cells using the Antivirogram assay. SPD754 susceptibility was reduced 1.2- to 2.2-fold against isolates resistant to zidovudine (M41L, T215Y/F, plus a median of three additional nucleoside analogue mutations [NAMs]) and/or lamivudine (M184V) and was reduced 1.3- to 2.8-fold against isolates resistant to abacavir (L74V, Y115F, and M184V plus one other NAM) or stavudine (V75T/M, M41L, T215F/Y, and four other NAMs). Insertions at amino acid position 69 and Q151M mutations (with or without M184V) reduced SPD754 susceptibility 5.2-fold and 14- to 16-fold, respectively (these changes gave values comparable to or less than the corresponding values for zidovudine, lamivudine, abacavir, and didanosine). SPD754 showed similar activity against isolates of group M HIV-1 clades, including A/G, B, C, D, A(E), D/F, F, and H. SPD754 showed additive effects in combination with other NRTIs, tenofovir, nevirapine, or saquinavir. SPD754 had no significant effects on cell viability or mitochondrial DNA in HepG2 or MT-4 cells during 28-day exposure at concentrations up to 200 microM. SPD754 showed a low potential for myelotoxicity against human bone marrow. In vitro, SPD754 retained activity against most NRTI-resistant HIV-1 clinical isolates and showed a low propensity to cause myelotoxicity and mitochondrial toxicity.
authors.affiliation: Shire Biochem, Inc., Laval, Québec, Canada.
authors.forename: Z
authors.initials: Z
authors.lastname: Gu
authors.forename: B
authors.initials: B
authors.lastname: Allard
authors.forename: J M
authors.initials: JM
authors.lastname: de Muys
authors.forename: J
authors.initials: J
authors.lastname: Lippens
authors.forename: R F
authors.initials: RF
authors.lastname: Rando
authors.forename: N
authors.initials: N
authors.lastname: Nguyen-Ba
authors.forename: C
authors.initials: C
authors.lastname: Ren
authors.forename: P
authors.initials: P
authors.lastname: McKenna
authors.forename: D L
authors.initials: DL
authors.lastname: Taylor
authors.forename: R C
authors.initials: RC
authors.lastname: Bethell
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D001853:Bone Marrow / Q000187:drug effects; D004272:DNA, Mitochondrial / Q000032:analysis; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008928:Mitochondria / Q000187:drug effects; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; D004272:DNA, Mitochondrial; D018894:Reverse Transcriptase Inhibitors; D003841:Deoxycytidine; C508042:apricitabine