Activity of T-705 in a hamster model of yellow fever virus infection in comparison with that of a chemically related compound, T-1106

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Antimicrob Agents Chemother



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Treatment with the nucleoside analog T-1106 was previously shown to be effective in a hamster model of yellow fever virus (YFV) disease, even though it had only slight activity in cell culture. In the study described in this report, the activity of T-705, a chemically related compound currently undergoing clinical trials for the treatment of influenza (FDANews 4:1, 2007), was tested against YFV in cell culture and in the hamster model. The antiviral efficacy of T-705 in cell culture occurred at a concentration of 330 μM, which was more than threefold lower than the concentration at which T-1106 had antiviral efficacy, as determined by a virus yield reduction assay and confirmed by a luciferase-based ATP detection assay. Time-of-addition studies revealed that addition of T-705, T-1106, or ribavirin at 0, 4, 8, or 12 h after virus challenge was effective in inhibiting virus in Vero cells, suggesting that these three agents have similar mechanisms of action in cell culture. Because of its more potent activity in cell culture, it was anticipated that T-705 treatment of hamsters infected with YFV would result in protection from disease. Significant improvements in survival and disease parameters were seen in infected animals when T-705 was administered orally at a dose of 200 or 400 mg/kg of body weight per day when it was given twice a day for 8 days. Significant improvements were also observed with a dose of 400 mg/kg/day when treatment initiation was delayed as late as 3 days after virus inoculation. Although the dose of T-705 required for efficacy in hamsters is higher than that of T-1106 required for efficacy, T-705 treatment is effective in significantly improving disease parameters in YFV-infected hamsters, which may indicate its potential utility in the treatment of YFV disease in humans.

Yellow fever virus (YFV) is a flavivirus that is spread by mosquitoes in areas of endemicity in Africa and South America. Despite the availability of an effective vaccine, this virus continues to cause periodic outbreaks and significant morbidity and mortality (16, 24). Cases of clinical disease after adverse vaccination events have also been reported, resulting in life-threatening illness (3, 9, 12, 13, 25). Cases of YFV disease outside the natural range have been documented and were contracted after travel into the natural range of YFV (1, 14, 24). Although there is a great need for therapies, no antiviral agents are approved for use for the treatment of YFV disease.

The rhesus macaque (Macacus rhesus) has been used as a model of YFV infection and disease. Infection of these primates usually results in a fulminating disease similar to fatal cases of the disease in humans (2, 15, 17). Due to the increased restrictions on the use of primates as laboratory models, a small-animal model of viscerotropic YFV disease was needed. A hamster model of YFV disease has recently been characterized, and the infection in hamsters is similar in many regards to that in humans (20, 23, 26). This hamster model has served as a useful tool for the evaluation of antiviral agents for the treatment of YFV disease (11, 19). The hamster-adapted Jimenez strain of YFV used in this model causes disease and death after intraperitoneal (i.p.) injection of hamsters (23). Useful parameters for the evaluation of antiviral compounds include the rate of survival; the YFV titer in the liver; serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels; weight change; and several serum parameters, including elevated bilirubin and blood urea nitrogen levels (10, 11, 19).

T-1106, a pyrazine nucleoside analog, was recently shown to significantly improve the rates of survival and disease parameters in hamsters infected with YFV (10). Doses as low as 32 mg/kg of body weight per day (120 μmol/kg/day) were effective against the virus. Despite the lack of cell culture activity at concentrations below 100 μg/ml (369 μM), testing was performed with the hamster model because of activity against the polymerase of hepatitis C virus in vitro (7). T-705 (6-fluoro-3-hydroxy-2-pyrazinecarboxamide), a substituted pyrazine compound that is chemically similar to T-1106 (Fig. 1), has been shown to have potent activity in vitro and in vivo against influenza virus and other RNA viruses (5, 6, 8, 21, 22). This compound is also currently undergoing phase II clinical trials for the treatment of human influenza virus infection. The purpose of this study was to compare the efficacy of T-705 with that of T-1106 in cell culture and in the hamster model.

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