Investigating Different Mechanisms of Action in Combination Therapy for Influenza

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.

Combinatory Treatment with Oseltamivir and Itraconazole Targeting Both Virus and Host Factors in Influenza A Virus Infection

“…Mechanistically, host-directed antiviral agents will slow down viral replication rather than eradicate the virus, and failure of HDT might result from the inappropriate time window of application (early vs. late infection stages) and a suppression rather than a complete elimination of the infectious agent, requiring long treatment duration which is often associated with poor patient compliance. Recently, combination therapies utilizing both host-and pathogen-directed strategies have been explored to overcome these limitations, as the combined use of two or more drugs might allow reduce the concentrations of the individual drugs in the cocktail [27][28][29]. As expected from established and clinically used drugs, no cytotoxic effects were observed when both, itraconazole and oseltamivir, were used individually and combined application reduced cell viability only at the highest concentrations tested.…”

“…Combination therapy, i.e., the treatment of influenza virus infection with at least two drugs with different modes of action, is considered a promising strategy for circumventing therapy resistance, based on the notion that the virus will stay susceptible to at least one of the drugs. A wide number of studies have investigated the combinatory use of antivirals belonging to the adamantanes and NA inhibitors [27][28][29]. In this study, we explored the effect of a combinatory use of the antiviral drug oseltamivir and the host-directed anti-infective drug itraconazole on IAV infection in a cell culture model of polarized bronchial cell monolayers.…”

In Vitro Combinations of Baloxavir Acid and Other Inhibitors against Seasonal Influenza A Viruses

“…The M2 ion-channel blockers (adamantanes including amantadine and rimantadine) [ 34 ], NAIs (oseltamivir, zanamivir, peramivir or laninamivir) [ 35 ] and the polymerase complex inhibitors (BXM or favipiravir) have demonstrated clinical benefits, but the emergence of viral resistance may limit the clinical efficacy of monotherapies [ 36 , 37 ]. Antiviral combinations have been suggested to prevent or delay the emergence of resistance by targeting various steps in the virus replicative process [ 38 ]. Multiple therapies may allow for dosage reduction [ 33 ], in addition to improving therapeutic effect [ 38 ].…”

“…Antiviral combinations have been suggested to prevent or delay the emergence of resistance by targeting various steps in the virus replicative process [ 38 ]. Multiple therapies may allow for dosage reduction [ 33 ], in addition to improving therapeutic effect [ 38 ]. Drug combinations already exist to treat cancer [ 39 ] and infectious diseases caused by HIV and hepatitis C [ 40 , 41 , 42 , 43 ].…”

Targeting TMPRSS2 and Cathepsin B/L Together May Be Synergistic Against SARS-CoV-2 Infection

“…Mathematical models have been developed earlier to describe receptor-dependent virus entry, with a focus on defining the entry requirements of viruses and quantifying targets of entry inhibitors and vaccines (Boianelli et al, 2015;Brandenberg et al, 2017Brandenberg et al, , 2015Kalemera et al, 2019;Magnus et al, 2009;Melville et al., 2018; Mulampaka and Dixit, 2011; Padmanabhan and Dixit, 2015, 2017, 2011; Yang et al, 2005). The models, however, have focussed typically on a single entry pathway, although multiple proteins may have been involved in mediating entry through the pathway.…”