Abstract
The limited efficacy of existing antiviral therapies for influenza – coupled with widespread baseline antiviral resistance – highlights the urgent need for more effective therapy. We describe a triple combination antiviral drug (TCAD) regimen composed of amantadine, oseltamivir, and ribavirin that is highly efficacious at reducing mortality and weight loss in mouse models of influenza infection. TCAD therapy was superior to dual and single drug regimens in mice infected with drug-susceptible, low pathogenic A/H5N1 (A/Duck/MN/1525/81) and amantadine-resistant 2009 A/H1N1 influenza (A/California/04/09). Treatment with TCAD afforded >90% survival in mice infected with both viruses, whereas treatment with dual and single drug regimens resulted in 0% to 60% survival. Importantly, amantadine had no activity as monotherapy against the amantadine-resistant virus, but demonstrated dose-dependent protection in combination with oseltamivir and ribavirin, indicative that amantadine's activity had been restored in the context of TCAD therapy. Furthermore, TCAD therapy provided survival benefit when treatment was delayed until 72 hours post-infection, whereas oseltamivir monotherapy was not protective after 24 hours post-infection. These findings demonstrate in vivo efficacy of TCAD therapy and confirm previous reports of the synergy and broad spectrum activity of TCAD therapy against susceptible and resistant influenza strains in vitro.
Highlights
Antiviral agents are an important therapeutic strategy for adults and children infected with influenza, especially for those hospitalized and at risk for severe illness such as the immunocompromised
We found that triple combination antiviral drug (TCAD) therapy provided enhanced survival benefit and reduced maximum body weight loss relative to all double combinations in mice infected with fully susceptible, low pathogenic influenza A/H5N1 and AMT-resistant 2009 A/ H1N1 viruses
Effectiveness of delayed treatment with TCAD To assess the time dependence of the therapeutic benefit, we examined the efficacy of delayed treatment in a lethal A/H5N1 mouse model by comparing survival in mice treated with TCAD or OSL monotherapy at 4 hours pre-infection (-4 hours), or 24, 48, and 72 hours post infection
Summary
Antiviral agents are an important therapeutic strategy for adults and children infected with influenza, especially for those hospitalized and at risk for severe illness such as the immunocompromised. While antiviral therapy has been demonstrated to provide some benefit in this patient population [1,2,3,4], the benefit – with neuraminidase inhibitors – is only realized if treatment is initiated within 48 hours of symptom onset, and delaying treatment beyond this time frame is associated with decreased efficacy and greater morbidity and mortality [4,5,6]. Incomplete suppression of virus replication despite antiviral therapy may result in the emergence of resistance, which is correlated with high and prolonged viral replication such as infection in immunocompromised patients [7,8], infections with highly pathogenic avian A/H5N1 viruses [9,10] or primary infection in young children [11,12,13]. Oseltamivir resistance may emerge during treatment, resulting in dual resistance in currently circulating adamantaneresistant viruses [16,17]. There is an unmet need for new treatment regimens that can provide greater clinical benefit to those at highest risk of severe disease, and that can reduce the risk of resistance development [7,8,9,10,11,12,13,14,15]
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