title: Investigation of causes of oseltamivir chemoprophylaxis failures during influenza A (H1N1-2009) outbreaks.
abstract: BACKGROUND
  Antiviral post-exposure prophylaxis with oseltamivir has been used as a strategy in mitigating the Influenza A (H1N1-2009) pandemic. There have been few reports of well-documented prophylaxis failures and the reasons for failure.
  
  
  OBJECTIVE
  We report herein a series of 10 cases of prophylaxis failures and explore the reasons behind their prophylaxis failure.
  
  
  METHODS
  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 sufficient 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.
authors.affiliation: Biodefence Centre, Ministry of Defence, Singapore. vernonljm@hotmail.com
authors.forename: Vernon J
authors.initials: VJ
authors.lastname: Lee
authors.forename: Jonathan
authors.initials: J
authors.lastname: Yap
authors.forename: Sebastian
authors.initials: S
authors.lastname: Maurer-Stroh
authors.forename: Raphael T C
authors.initials: RT
authors.lastname: Lee
authors.forename: Frank
authors.initials: F
authors.lastname: Eisenhaber
authors.forename: Joshua K
authors.initials: JK
authors.lastname: Tay
authors.forename: Pei Jun
authors.initials: PJ
authors.lastname: Ting
authors.forename: Jin Phang
authors.initials: JP
authors.lastname: Loh
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Wong
authors.forename: Boon Huan
authors.initials: BH
authors.lastname: Tan
authors.forename: Evelyn S C
authors.initials: ES
authors.lastname: Koay
authors.forename: Paul M
authors.initials: PM
authors.lastname: Kelly
authors.forename: Martin L
authors.initials: ML
authors.lastname: Hibberd
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use*; D004196:Disease Outbreaks; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype; D007251:Influenza, Human / Q000453:epidemiology / Q000517:prevention & control*; D008297:Male; D009154:Mutation; D017817:Nasal Lavage Fluid; D053139:Oseltamivir / Q000627:therapeutic use*; D016133:Polymerase Chain Reaction; D012367:RNA, Viral / Q000032:analysis; D017211:Treatment Failure
chemical_list: D000998:Antiviral Agents; D012367:RNA, Viral; D053139:Oseltamivir