Triple Combination Antiviral Drug (TCAD) Composed of Amantadine, Oseltamivir, and Ribavirin Impedes the Selection of Drug-Resistant Influenza A Virus

Hoopes, Justin D.; Driebe, Elizabeth M.; Kelley, Erin; Engelthaler, David M.; Keim, Paul; Perelson, Alan S.; Liang, Rong; Went, Gregory T.; Nguyen, Jack

doi:10.1371/journal.pone.0029778

Cited by 51 publications

(35 citation statements)

References 37 publications

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“…Additionally, passaging influenza virus in the mutagen favipiravir did not cause the viral population to become resistant (46). Ribavirin has also been demonstrated to suppress resistance to conventional anti-influenza drugs when used in combination (67). Each of these examples, along with our results, suggests that an increased mutational burden reduces the potential for high-level resistance within an influenza virus population.…”

Section: Discussionsupporting

confidence: 54%

Effective Lethal Mutagenesis of Influenza Virus by Three Nucleoside Analogs

Pauly

Lauring

2015

J Virol

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Lethal mutagenesis is a broad-spectrum antiviral strategy that exploits the high mutation rate and low mutational tolerance of many RNA viruses. This approach uses mutagenic drugs to increase viral mutation rates and burden viral populations with mutations that reduce the number of infectious progeny. We investigated the effectiveness of lethal mutagenesis as a strategy against influenza virus using three nucleoside analogs, ribavirin, 5-azacytidine, and 5-fluorouracil. All three drugs were active against a panel of seasonal H3N2 and laboratory-adapted H1N1 strains. We found that each drug increased the frequency of mutations in influenza virus populations and decreased the virus' specific infectivity, indicating a mutagenic mode of action. We were able to drive viral populations to extinction by passaging influenza virus in the presence of each drug, indicating that complete lethal mutagenesis of influenza virus populations can be achieved when a sufficient mutational burden is applied. Population-wide resistance to these mutagenic agents did not arise after serial passage of influenza virus populations in sublethal concentrations of drug. Sequencing of these drug-passaged viral populations revealed genome-wide accumulation of mutations at low frequency. The replicative capacity of drug-passaged populations was reduced at higher multiplicities of infection, suggesting the presence of defective interfering particles and a possible barrier to the evolution of resistance. Together, our data suggest that lethal mutagenesis may be a particularly effective therapeutic approach with a high genetic barrier to resistance for influenza virus. IMPORTANCEInfluenza virus is an RNA virus that causes significant morbidity and mortality during annual epidemics. Novel therapies for RNA viruses are needed due to the ease with which these viruses evolve resistance to existing therapeutics. Lethal mutagenesis is a broad-spectrum strategy that exploits the high mutation rate and the low mutational tolerance of most RNA viruses. It is thought to possess a higher barrier to resistance than conventional antiviral strategies. We investigated the effectiveness of lethal mutagenesis against influenza virus using three different drugs. We showed that influenza virus was sensitive to lethal mutagenesis by demonstrating that all three drugs induced mutations and led to an increase in the generation of defective viral particles. We also found that it may be difficult for resistance to these drugs to arise at a population-wide level. Our data suggest that lethal mutagenesis may be an attractive anti-influenza strategy that warrants further investigation. I nfluenza virus is a single-stranded, negative-sense RNA virus with a genome consisting of 8 segments (1). Like other RNA viruses, influenza virus replicates with extremely low fidelity. Its RNA-dependent RNA polymerase (RdRp) complex, which includes the viral proteins PB1, PB2, PA, and NP (2, 3), has a mutation rate of approximately 2.3 ϫ 10 Ϫ5 substitutions per nucleotide per cell ...

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Section: Discussionsupporting

confidence: 54%

Effective Lethal Mutagenesis of Influenza Virus by Three Nucleoside Analogs

Pauly

Lauring

2015

J Virol

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“…During an infection virus can be released from the cell without the presence of neuraminidase171819, so we might expect the efficacy of NAIs at blocking an infection to be lower than the efficacy measured in an inhibition assay. To account for this, the efficacy of NAIs is sometimes measured through a reduction in viral yield20, cytopathic effect2122, or plaque formation2023. Knowledge of the within host antiviral efficacy will help in estimating the effect of NAI treatment at the population level, through the use of multiscale models242526, allowing public health officials to manage their stockpiles more effectively.…”

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confidence: 99%

The in vivo efficacy of neuraminidase inhibitors cannot be determined from the decay rates of influenza viral titers observed in treated patients

Palmer

Dobrovolny

Beauchemin

2017

Sci Rep

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Antiviral therapy is a first line of defence against new influenza strains. Current pandemic preparations involve stock- piling oseltamivir, an oral neuraminidase inhibitor (NAI), so rapidly determining the effectiveness of NAIs against new viral strains is vital for deciding how to use the stockpile. Previous studies have shown that it is possible to extract the drug efficacy of antivirals from the viral decay rate of chronic infections. In the present work, we use a nonlinear mathematical model representing the course of an influenza infection to explore the possibility of extracting NAI drug efficacy using only the observed viral titer decay rates seen in patients. We first show that the effect of a time-varying antiviral concentration can be accurately approximated by a constant efficacy. We derive a relationship relating the true treatment dose and time elapsed between doses to the constant drug dose required to approximate the time- varying dose. Unfortunately, even with the simplification of a constant drug efficacy, we show that the viral decay rate depends not just on drug efficacy, but also on several viral infection parameters, such as infection and production rate, so that it is not possible to extract drug efficacy from viral decay rate alone.

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“…Similar to the treatment of HIV or HCV, a combination of various drugs should provide synergistic effects and reduce resistances. Combinations of NA inhibitors with adamantanes, favipiravir, or the nucleoside analogue ribavirin have already been demonstrated to cause additive to synergistic inhibition of influenza virus infection in vitro and to enhance survival of infected mice more efficiently than either drug used alone, even in the case of amantadine-or oseltamivir-resistant viruses [149][150][151][152]. However, the clinical benefits of such combinatorial treatments have to be demonstrated in controlled trials in man; a number of studies are ongoing [36].…”

Section: Discussionmentioning

confidence: 99%

Strategies for the Development of Influenza Drugs: Basis for New Efficient Combination Therapies

Steinmetzer¹,

Hardes²,

Böttcher‐Friebertshäuser³

et al. 2014

Topics in Medicinal Chemistry

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Only four drugs are approved for the specific treatment of acute influenza infections worldwide. These drugs address either the viral neuraminidase or the M2-channel but suffer from poor efficacy and the rapid emergence of drug resistances. Some additional drugs are launched in few countries, but their efficacy is relatively low and often limited to certain influenza strains. Ideally, new drugs should possess a broad potency against all influenza viruses and be less susceptible to the development of resistances. The propagation cycle of the influenza virus offers many possibilities for the development of new anti-influenza drugs. Various compounds addressing viral targets reached clinical development, from which the most-advanced candidate is the polymerase inhibitor favipiravir. A promising strategy could be also the inhibition of host targets and signaling pathways, e.g., by already approved kinase inhibitors, anti-inflammatory drugs, or immunomodulatory agents. However, the benefit of these agents has to be demonstrated in controlled clinical trials. A broader arsenal of approved drugs will offer the possibility for more efficient combinatorial therapies in the future. The first proof of concept studies for such multiple drug therapies in infected mice revealed beneficial effects. Moreover, this strategy should reduce the rapid emergence of resistant influenza strains.

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Triple Combination Antiviral Drug (TCAD) Composed of Amantadine, Oseltamivir, and Ribavirin Impedes the Selection of Drug-Resistant Influenza A Virus

Cited by 51 publications

References 37 publications

Effective Lethal Mutagenesis of Influenza Virus by Three Nucleoside Analogs

Effective Lethal Mutagenesis of Influenza Virus by Three Nucleoside Analogs

The in vivo efficacy of neuraminidase inhibitors cannot be determined from the decay rates of influenza viral titers observed in treated patients

Strategies for the Development of Influenza Drugs: Basis for New Efficient Combination Therapies

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