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: Z Gu, B Allard, J M de Muys, J Lippens, R F Rando, N Nguyen-Ba, C Ren, P McKenna, D L Taylor, R C Bethell
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 50 Issue 2 Pg. 625-31 (Feb 2006) ISSN: 0066-4804 [Print] United States
• PMID: 16436719 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-HIV Agents
• DNA, Mitochondrial
• Reverse Transcriptase Inhibitors
• Deoxycytidine
• apricitabine

Topics

• Anti-HIV Agents (pharmacology)
• Bone Marrow (drug effects)
• DNA, Mitochondrial (analysis)
• Deoxycytidine (analogs & derivatives, pharmacology, toxicity)
• HIV-1 (drug effects)
• Humans
• Mitochondria (drug effects)
• Reverse Transcriptase Inhibitors (pharmacology)