3rd International AIDS Society Conference on HIV Pathogenesis and Treatment Rio de Janeiro - July 24 - 27, 2005

ANTI-HIV-1 ACTIVITY OF A FOSCARNET ANALOGUE, SYNERGY WITH ZIDOVUDINE AND ANALYSIS OF RESISTANCE VARIANTS SELECTED IN VITRO

IAS Conf HIV Pathog Treat 2005 Jul 24-27;3rd: Abstract No. TuPe6.1B16

Waninger S., Ramos S., Robbins J.
Adventrx Pharmacueticals, Inc, San Diego, United States of America

INTRODUCTION: Thiovir is an oral replacement for foscarnet, a highly effective, broad-spectrum antiviral with limited usage due to toxicity and low bioavailability. Improved efficacy and bioavailability make thiovir an attractive clinical candidate. We have investigated antiviral activity of thiovir alone and in combination with zidovudine against wild type and drug resistant HIV-1 strains and analyzed thiovir resistant variants selected for in vitro.

METHODS: Anti-HIV-1 activity of thiovir was evaluated against a panel of NRTI and NNRTI resistant virus with multiple mutations using Phenosense assay. Synergistic interactions were investigated between thiovir or foscarnet plus zidovudine by MAGI assay and median-effect principle. In order to examine drug resistance properties of HIV-1 to thiovir, resistant virus was selected by passage of H9 cells with escalating concentrations of drug. Resistant virus was analyzed for changes in IC₅₀ by MAGI assay and sequenced to determine genotypic changes.

RESULTS: All HIV-1 variants examined were sensitive to thiovir and foscarnet with a fold change (IC₅₀ variant/IC₅₀ wt) of less than 0.5 in most cases indicating hypersensitivity. Efficacy was increased in thiovir over foscarnet by approximately 2-fold. Combinations of foscarnet and zidovudine exhibit only mild synergistic to antagonistic behavior while thiovir combined with zidovudine results in a high degree of synergism. Wild type virus has undergone thirteen rounds of selection with thiovir resulting in virus with a five fold increase in IC₅₀ of both thiovir and foscarnet. Changes in sequence are compared to zidovudine and foscarnet resistant strains.

CONCLUSIONS: Results of efficacy studies indicate high antiviral activity against several complex NRTI and NNRTI resistant strains. Synergy results suggest that the dosage of thiovir may be decreased allowing for suitable drug regimens combining thiovir with an NRTI. Potent HIV-1 inhibition activity combined with increased bioavailability and strong synergistic behavior with zidovudine make thiovir a promising candidate for a therapeutic.

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050724
Basic | TuPe6.1B16 | Shani Waninger
New antiretroviral targets and compounds

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