Journal of Clinical Virology 50 (2011) 104–108 Contents lists available at ScienceDirect Journal of Clinical Virology j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / j c v Investigation of causes of oseltamivir chemoprophylaxis failures during influenza A (H1N1-2009) outbreaks Vernon J. Lee a,b,c,d,∗ , Jonathan Yap a , Sebastian Maurer-Stroh e,f , Raphael T.C. Lee e , Frank Eisenhaber e,g,h , Joshua K. Tay a , Pei Jun Ting i , Jin Phang Loh i , Christopher W. Wong j , Boon Huan Tan i , Evelyn S.C. Koay k,l , Paul M. Kelly d , Martin L. Hibberd j a Biodefence Centre, Ministry of Defence, Singapore b Centre for Health Services Research, National University of Singapore, Singapore c Department of Epidemiology and Public Health, National University of Singapore, Singapore d National Center for Epidemiology and Population Health, Australian National University, Australia e Bioinformatics Institute, Agency for Science, Technology and Research, Singapore f School of Biological Sciences, Nanyang Technological University, Singapore g Department of Biological Sciences, National University of Singapore, Singapore h School of Computer Engineering, Nayang Technological University, Singapore i Defence Medical and Environmental Research Institute, DSO National Laboratories, Singapore j Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore k Department of Pathology, National University of Singapore, Singapore l Molecular Diagnosis Centre, Department of Laboratory Medicine, National University Hospital, Singapore a r t i c l e i n f o Article history: Received 23 March 2010 Received in revised form 5 October 2010 Accepted 6 October 2010 Keywords: Influenza A (H1N1-2009) Oseltamivir prophylaxis Resistance a b s t r a c t Background: Antiviral post-exposure prophylaxis with oseltamivir has been used as a strategy in mitigat- ing the Influenza A (H1N1-2009) pandemic. There have been few reports of well-documented prophylaxis failures and the reasons for failure. Objectives: We report herein a series of 10 cases of prophylaxis failures and explore the reasons behind their prophylaxis failure. Study design:In the early pandemic phase, the military employed oseltamivir post-exposure ring- prophylaxis of affected units. From June 22 to July 30, 2009, cases of laboratory-confirmed prophylaxis failures were identified.Nasopharyngeal swabs were collected and tested by PCR. Samples with suffi- cient RNA material were sent for whole genome sequencing,and screened for mutations that confer oseltamivir resistance, especially the H275Y mutation. Results: Ten cases of laboratory-confirmed prophylaxis failure were identified, with a mean age of 22.3 years. One case was asymptomatic; the remaining 9 had fever or cough but without severe complications. The mean duration of exposure before starting oseltamivir was 1.9 days (SD 0.9), while the mean duration of oseltamivir consumption before symptom onset was 1.9 days (SD 1.4). None of the samples had the H275Y mutation or other known mutations that confer resistance. From the whole genome sequencing, several mutations at the HA (T220S, E275V, T333A, D239G); PB2 (K660R, L607V, V292I); NS1 (F103S), and NP (W104G) gene segments were detected, but none of them were likely to result in anti-viral resistance. Conclusions: Primary prophylaxis failures exhibited mild symptoms without complications; all did not have the H275Y mutation and were unlikely to result from other mutations. © 2010 Elsevier B.V. All rights reserved. Abbreviations: PCR, polymerase chain reaction; DNA,deoxyribonucleic acid; RNA, ribonucleic acid; PDB, Protein Data Bank; BMI, body mass index; SD, standard deviation; NP, nucleoprotein; NS1,non-structural protein 1; WT, wild-type; MT, mutant-type; AA, amino acids. ∗ Corresponding author at: 701 Transit Road #04-01, Singapore 778910, Singapore. Tel.: +65 97928896; fax: +65 64531015. E-mail address: vernonljm@hotmail.com (V.J. Lee). 1. Background The Influenza A (H1N1-2009) pandemic resulted in the activa- tion of response measures worldwide, 1,2 with oseltamivir antiviral prophylaxis used frequently. Oseltamivir protects against sea- sonal influenza when used as post-exposure prophylaxis 3,4 or pre-exposure prophylaxis. 5,6 However, resistance to oseltamivir has been developing,especially in seasonal H1N1 viruses,largely due to the H275Y mutation. 7,8 1386-6532/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.jcv.2010.10.004