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  Q3 / 2019   Q2 / 2019  
  

Baloxavir Marboxil

Impact of the baloxavir-resistant polymerase acid (PA) I38T substitution on the fitness of contemporary influenza A(H1N1)pdm09 and A(H3N2) strains.
Viral fitness of the baloxavir-resistant I38T PA variant virus were examined in vitro and in mice. The fitness of baloxavir-resistant I38T PA mutants appears relatively unaltered in seasonal subtypesread more
 
Treatment-Emergent Influenza Variant Viruses With Reduced Baloxavir Susceptibility: Impact on Clinical and Virologic Outcomes in Uncomplicated Influenza.
The kinetics, risk factors, and effects on clinical and virologic outcomes of emergence of PA/I38X-substituted viruses was evaluated. The emergence of viruses with PA/I38X substitutions following baloxavir treatment was associated with transient rises in infectious virus titers, prolongation of virus detectability, initial delay in symptom alleviation, and uncommonly with symptom rebound...read more
 
Mutated influenza A virus exhibiting reduced susceptibility to baloxavir marboxil from an experimentally infected horse.
Baloxavir Marboxil is found to be effective against equine influenza however a PA I38T variant was recovered from one experimentally challenged horse treated with baloxivir….read more
 
Replicative fitness of seasonal influenza A viruses with decreased susceptibility to baloxavir.
The study demonstrated that substitutions I38L/M/S/T not only had a differential effect on baloxavir susceptibility (9- to 116-fold), but also on in vitro replicative fitness…read more

 

Neuraminidase Inhibitors

Characterization of substitutions in the neuraminidase of A(H7N9) influenza viruses selected following serial passage in the presence of different neuraminidase inhibitors
In vitro serial passaging of reverse engineered viruses, containing the neuraminidase from influenza A/Anhui/1/13 (H7N9) virus, in the presence of oseltamivir, laninamivir, peramivir and zanamivir was performed to determine if NAI resistant viruses would arise. oseltamivir, peramivir and laninamivir selected for (E119D, R292K and R152K) substitutions which reduced antiviral sensitivity. Zanamivir did not select for any viruses with reduced sensitivity…read more
 
Highly pathogenic avian influenza H7N9 viruses with reduced susceptibility to neuraminidase inhibitors showed comparable replication capacity to their sensitive counterparts
Recombinant A/H7N9 viruses with R292K, E119V, A246T or H274Y substitutions in the neuraminidase gene were screened for reduced antiviral susceptibility and replicative capacity. Viruses containing the R292 substitution in the neuraminidase gene were constantly lower than wildtype viruses whereas no difference in viral replication was observed with the other viruses were detectedread more
 
Effect of influenza H1N1 neuraminidase V116A and I117V mutations on NA activity and sensitivity to NA inhibitors.
The impact of V116A and I117V NA mutations on NAI susceptibility, substrate specificity, and replicative capacity was measured in vitro using normal human brochial epithelial cells in A/California/07/2009 virus backgroundread more
 
Viral Kinetics and Resistance Development in Children Treated with Neuraminidase Inhibitors: The Influenza Resistance Information Study (IRIS).
A total of 2131 children infected with influenza (683 A/H1N1pdm09; 825 A/H3N2; 623 influenza B) were investigated. Children aged 1>5 years had a higher total viral burden with prolonged virus shedding and had an increased risk of acquiring resistance mutations following antiviral treatmentread more

 

Clinical reports

Baloxavir marboxil in Japanese pediatric patients with influenza: safety and clinical and virologic outcomes
A single, oral dose of baloxavir marboxil was well-tolerated, and rapidly reduced viral titers, but the common emergence of PA/I38T/M-substituted viruses warrants consideration of alternative dosing regimens in young childrenread more
 
Rapid detection and clinical spectrum of the novel influenza H1N1 strain in a diabetic paediatric population
Influenza infected children with type 1 diabetes mellitus tested positive for diabetic ketoacidosis and higher levels of leukocytes were present in these patients when compared to hyperglycaemic individuals. Treatment with oseltamivir within 48 hours after infection was recommended for diabetic patients… read more
 
Genetic diversity of influenza A(H3N2) viruses in Northern Cameroon during the 2014-2016 influenza seasons
This study set out to better understand the genetic diversity and potential resistance to antivirals in circulating A/H3N2 viruses in Northern Cameroon. Analysis of HA sequences revealed that the majority of viruses grouped together with the vaccine strains and within clade 3C.2a sequences mostly grouped with sub-clade A3. No NA sequences had genetic markers of resistance to NA antivirals but all samples had the S31N substitution in the M gene corresponding to adamantine resistance...read more
 
A network meta-analysis of the efficacy and safety of baloxavir marboxil versus neuraminidase inhibitors for the treatment of influenza in otherwise healthy patients
Network meta-analysis evaluating the efficacy and safety of baloxavir marboxil compared to currently licensed neuraminidase inhibitors was conducted in otherwise healthy patients. The study found that baloxavir significantly reduced viral shedding when compared to the neuraminidase inhibitors and safety was comparable amongst all compounds tested… read more

 

Investigational antivirals

Brevilin A, a Sesquiterpene Lactone, Inhibits the Replication of Influenza A Virus In Vitro and In Vivo.
Brevillin A,  a sesquiterpene lactone isolated from C. minim inhibited viral replication of influenza A H1N1, H3N2, H9N2 viruses in vitro and delayed death in mice… read more
 
Novel N-Substituted oseltamivir derivatives as potent influenza neuraminidase inhibitors: Design, synthesis, biological evaluation, ADME prediction and molecular docking studies
This study described the design and synthesis of novel N-substituted oseltamivir derivatives for probing the 150-cavity which is nascent to the activity site of NAread more

Review articles

Antivirals targeting the polymerase complex of influenza viruses.
A review which discusses newly licenced, early and late phase antivirals (Baloxavir, favipiravir, pimodivir and AL-794) in clinical trials… read more
 
One hundred years after the 1918 pandemic: new concepts for preparing for influenza pandemics
A review which focuses on advances in preparing for influenza pandemics and how new antivirals may improve treatment in ill patients… read more
 
Overview of Current Therapeutics and Novel Candidates Against Influenza, Respiratory Syncytial Virus, and Middle East Respiratory Syndrome Coronavirus Infections.
In this review, we will describe some of the novel therapeutics currently under development for the treatment of  infections with Influenza, RSV and MERS-coV..read more
 

 

Prepared by: Dr. Edin Mifsud and Ms Rubaiyea Farrukee (WHO Collaborating Centre for Influenza, Melbourne)