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

Laetitia Canini, Jessica M. Conway, Alan S. Perelson, Fabrice Carrat

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbere1003568
JournalPLoS computational biology
Volume10
Issue number4
DOIs
StatePublished - Apr 2014

All Science Journal Classification (ASJC) codes

  • Ecology, Evolution, Behavior and Systematics
  • Modeling and Simulation
  • Ecology
  • Molecular Biology
  • Genetics
  • Cellular and Molecular Neuroscience
  • Computational Theory and Mathematics

Fingerprint Dive into the research topics of 'Impact of Different Oseltamivir Regimens on Treating Influenza A Virus Infection and Resistance Emergence: Insights from a Modelling Study'. Together they form a unique fingerprint.

  • Cite this