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Impact of Different Oseltamivir Regimens on Treating Influenza A Virus Infection and Resistance Emergence: Insights from a Modelling Study

Journal Article · · PLoS Computational Biology (Online)
 [1];  [2];  [2];  [3]
  1. Institut Pierre Louis d’Epidemiologie et de Sante Publique, Paris (France). INSERM; Sorbonne Univ., Paris (France). Institut Pierre Louis d’Epidemiologie et de Sante Publique; Los Alamos National Lab. (LANL), Los Alamos, NM (United States); DOE/OSTI
  2. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  3. Institut Pierre Louis d’Epidemiologie et de Sante Publique, Paris (France). INSERM; Sorbonne Univ., Paris (France). Institut Pierre Louis d’Epidemiologie et de Sante Publique; Hopital Saint Antoine, Paris (France). Assistance Publique Hopitaux de Paris
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Several studies have proven oseltamivir to be efficient in reducing influenza viral titer and symptom intensity. However, the usefulness of oseltamivir can be compromised by the emergence and spread of drug-resistant virus. The selective pressure exerted by different oseltamivir therapy regimens have received little attention. Combining models of drug pharmacokinetics, pharmacodynamics, viral kinetics and symptom dynamics, we explored the efficacy of oseltamivir in reducing both symptoms (symptom efficacy) and viral load (virological efficacy). We simulated samples of 1000 subjects using previously estimated between-subject variability in viral and symptom dynamic parameters to describe the observed heterogeneity in a patient population. We simulated random mutations conferring resistance to oseltamivir. We explored the effect of therapy initiation time, dose, intake frequency and therapy duration on influenza infection, illness dynamics, and emergence of viral resistance. Symptom and virological efficacies were strongly associated with therapy initiation time. The proportion of subjects shedding resistant virus was 27-fold higher when prophylaxis was initiated during the incubation period compared with no treatment. It fell to below 1% when treatment was initiated after symptom onset for twice-a-day intakes. Lower doses and prophylaxis regimens led to lower efficacies and increased risk of resistance emergence. We conclude that prophylaxis initiated during the incubation period is the main factor leading to resistance emergence.
Research Organization:
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
Sponsoring Organization:
European Union (EU); National Institutes of Health (NIH); USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division
Grant/Contract Number:
AC52-06NA25396
OSTI ID:
1627233
Journal Information:
PLoS Computational Biology (Online), Journal Name: PLoS Computational Biology (Online) Journal Issue: 4 Vol. 10; ISSN 1553-7358
Publisher:
Public Library of ScienceCopyright Statement
Country of Publication:
United States
Language:
English

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In-host modeling journal May 2017
Understanding the within-host dynamics of influenza A virus: from theory to clinical implications journal June 2016
The therapeutic effects of sodium cromoglycate against influenza A virus H5N1 in mice journal December 2015
Innate Immunity and the Inter-exposure Interval Determine the Dynamics of Secondary Influenza Virus Infection and Explain Observed Viral Hierarchies journal August 2015
Coadministration of Hedera helix L. Extract Enabled Mice to Overcome Insufficient Protection against Influenza A/PR/8 Virus Infection under Suboptimal Treatment with Oseltamivir journal June 2015
Oseltamivir Population Pharmacokinetics in the Ferret: Model Application for Pharmacokinetic/Pharmacodynamic Study Design journal October 2015
Modelling the emergence of influenza drug resistance: The roles of surface proteins, the immune response and antiviral mechanisms journal July 2017
Assessing the oseltamivir-induced resistance risk and implications for influenza infection control strategies journal July 2017
Oseltamivir PK/PD Modeling and Simulation to Evaluate Treatment Strategies against Influenza-Pneumococcus Coinfection journal June 2016
Mathematical Analysis of Viral Replication Dynamics and Antiviral Treatment Strategies: From Basic Models to Age-Based Multi-Scale Modeling journal July 2018
Investigating Different Mechanisms of Action in Combination Therapy for Influenza journal October 2018
Neuraminidase Inhibitors in Influenza Treatment and Prevention–Is It Time to Call It a Day? journal August 2018
The Mechanisms for Within-Host Influenza Virus Control Affect Model-Based Assessment and Prediction of Antiviral Treatment journal July 2017
Mathematical analysis of a mouse experiment suggests little role for resource depletion in controlling influenza infection within host preprint January 2017
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Simulation modelling for immunologists journal December 2019
Determining drug efficacy parameters for mathematical models of influenza journal August 2014
Neuraminidase inhibitors — is it time to call it a day? posted_content January 2018
Interferon Lambda Inhibits Bacterial Uptake during Influenza Superinfection journal May 2019
A comparison of RSV and influenza in vitro kinetic parameters reveals differences in infecting time journal February 2018

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