Prolonged influenza virus shedding and emergence of antiviral resistance in immunocompromised patients and ferrets

Erhard van der Vries; Koert J Stittelaar; Geert van Amerongen; Edwin J B Veldhuis Kroeze; Leon de Waal; Pieter L A Fraaij; Roland J Meesters; Theo M Luider; Bart van der Nagel; Birgit Koch; Arnold G Vulto; Martin Schutten; Albert D M E Osterhaus

doi:10.1371/journal.ppat.1003343

Prolonged influenza virus shedding and emergence of antiviral resistance in immunocompromised patients and ferrets

PLoS Pathog. 2013;9(5):e1003343. doi: 10.1371/journal.ppat.1003343. Epub 2013 May 23.

Authors

Erhard van der Vries¹, Koert J Stittelaar, Geert van Amerongen, Edwin J B Veldhuis Kroeze, Leon de Waal, Pieter L A Fraaij, Roland J Meesters, Theo M Luider, Bart van der Nagel, Birgit Koch, Arnold G Vulto, Martin Schutten, Albert D M E Osterhaus

Affiliation

¹ Department of Virology, ErasmusMC, Rotterdam, The Netherlands.

Abstract

Immunocompromised individuals tend to suffer from influenza longer with more serious complications than otherwise healthy patients. Little is known about the impact of prolonged infection and the efficacy of antiviral therapy in these patients. Among all 189 influenza A virus infected immunocompromised patients admitted to ErasmusMC, 71 were hospitalized, since the start of the 2009 H1N1 pandemic. We identified 11 (15%) cases with prolonged 2009 pandemic virus replication (longer than 14 days), despite antiviral therapy. In 5 out of these 11 (45%) cases oseltamivir resistant H275Y viruses emerged. Given the inherent difficulties in studying antiviral efficacy in immunocompromised patients, we have infected immunocompromised ferrets with either wild-type, or oseltamivir-resistant (H275Y) 2009 pandemic virus. All ferrets showed prolonged virus shedding. In wild-type virus infected animals treated with oseltamivir, H275Y resistant variants emerged within a week after infection. Unexpectedly, oseltamivir therapy still proved to be partially protective in animals infected with resistant virus. Immunocompromised ferrets offer an attractive alternative to study efficacy of novel antiviral therapies.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antiviral Agents / administration & dosage*
Disease Models, Animal
Drug Resistance, Viral* / drug effects
Drug Resistance, Viral* / immunology
Female
Ferrets
Humans
Immunocompromised Host*
Influenza A Virus, H1N1 Subtype / immunology*
Influenza, Human* / drug therapy
Influenza, Human* / epidemiology
Influenza, Human* / immunology
Male
Oseltamivir / administration & dosage*
Pandemics*
Retrospective Studies
Virus Shedding* / drug effects
Virus Shedding* / immunology

Substances

Antiviral Agents
Oseltamivir

Grants and funding

Part of this work was funded by Hoffmann-La Roche Ltd. Hoffmann-La Roche did not participate in any of the work leading to this manuscript. For the immunocompromised ferret model a PCT application has been filed (PCT/EP2012/063497). ADMEO is chief science officer of Viroclinics Biosciences BV, a contract research organisation that collaborates with pharmaceutical companies. PF and AO are financially supported by the Virgo consortium, which is funded by the Dutch government project number FES0908 and the Netherlands Genomics Initiative (NGI) project number 050-060-452. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.