Abstract
Combination therapy for influenza can have several benefits, from reducing the emergence of drug resistant virus strains to decreasing the cost of antivirals. However, there are currently only two classes of antivirals approved for use against influenza, limiting the possible combinations that can be considered for treatment. However, new antivirals are being developed that target different parts of the viral replication cycle, and their potential for use in combination therapy should be considered. The role of antiviral mechanism of action in the effectiveness of combination therapy has not yet been systematically investigated to determine whether certain antiviral mechanisms of action pair well in combination. Here, we use a mathematical model of influenza to model combination treatment with antivirals having different mechanisms of action to measure peak viral load, infection duration, and synergy of different drug combinations. We find that antivirals that lower the infection rate and antivirals that increase the duration of the eclipse phase perform poorly in combination with other antivirals.
Highlights
Influenza, more commonly known as the flu, is a seasonal illness that has symptoms of runny nose, cough, fever and an aching body (Khandaker et al, 2011)
We computationally evaluated combinations of theoretical influenza antivirals to assess the effect of antiviral mechanism of action on drug interactions
We found that combination therapies that include drugs that reduce the infection rate or combination therapies that include a drug that lengthens the eclipse phase show markedly different effects on peak viral load, infection duration, and synergy than other combination therapies
Summary
More commonly known as the flu, is a seasonal illness that has symptoms of runny nose, cough, fever and an aching body (Khandaker et al, 2011). There have been many experimental studies, both in vivo and in vitro, investigating the effect of different combinations of influenza antivirals (Hayden et al, 1980; Smee et al, 2002, 2009, 2010a,b; Govorkova et al, 2004; Ilyushina et al, 2006, 2007, 2008; Masihi et al, 2007; Bantia et al, 2010; Duval et al, 2010; Kim et al, 2010; Chen et al, 2011; Haasbach et al, 2013; Seo et al, 2013; Tarbet et al, 2014; Belardo et al, 2015; Morokutti-Kurz et al, 2015; Marathe et al, 2016; Beigel et al, 2017; de Mello et al, 2018), with some examining not just combinations of two drugs, but even examining triple combinations (Nguyen et al, 2009, 2010, 2012; Hoopes et al, 2011; Kim et al, 2011; Lu et al, 2015; Pavlova et al, 2018) These experimental studies are largely limited to combinations of antivirals from the two widely available classes of influenza antivirals, neuraminidase inhibitors (NAIs) and adamantanes. We find that drugs that lengthen the eclipse phase and drugs that decrease the infection rate perform poorly, using all three measures, in combination with all other drugs
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