title: Resistance and virulence mutations in patients with persistent infection by pandemic 2009 A/H1N1 influenza.
abstract: BACKGROUND
  Pandemic 2009 influenza A/H1N1 (H1N1v) is resistant to adamantanes, leaving neuraminidase inhibitors as the only therapeutic option. Other mutations are considered to be associated with virulence and clinical severity. However, out of the surveillance programs, few studies analyze the presence of resistance/virulent H1N1v variants in certain clinical circumstances.
  
  
  OBJECTIVE
  To define the frequency and role of resistance and virulence mutations in a specific clinical circumstance-in patients with persistent infection by H1N1v.
  
  
  METHODS
  Observational study of patients with persistent H1N1v infection admitted to our hospital.
  
  
  RESULTS
  NAI-resistance mutations were detected in 14.3% of cases with persistent infection (2/14), and in none of the non-persistent controls (0/15). These cases were initially infected with susceptible variants that acquired resistance at different time-points after therapy with oseltamivir (OTV). The first case (case 2) was an HIV-positive patient who rapidly acquired resistance 9 days after diagnosis (6 days on OTV) and whose infection resolved after standard OTV therapy. The second case (case 3) was a patient with chronic lymphocytic leukemia [corrected] and the longest viral persistence (59 days). The resistance mutation was detected in the specimen taken on day 37 after diagnosis (30 days on OTV). Once the resistance mutation was identified, OTV was substituted by zanamivir and the infection resolved. In addition to mutations encoding resistance, variants associated with virulence were also sought. The D225G mutation was not found in any case, whereas the D225E variant was identified in three persistent cases but also in two non-persistent ones. In one patient, the D225E substitution coincided with the H275 resistant mutation.
  
  
  CONCLUSIONS
  NAI-resistance mutations were detected, at rather different paces, in non-severe immunosuppressed cases with persistent infection by influenza A/H1N1v.
authors.affiliation: Servicio de Microbiología Clínica y Enfermedades Infecciosas, Hospital General Universitario Gregorio Marañón, Madrid, Spain; CIBER Enfermedades Respiratorias (CIBERES), Spain.
authors.forename: María
authors.initials: M
authors.lastname: Alonso
authors.forename: Belén
authors.initials: B
authors.lastname: Rodríguez-Sánchez
authors.forename: Maddalena
authors.initials: M
authors.lastname: Giannella
authors.forename: Pilar
authors.initials: P
authors.lastname: Catalán
authors.forename: Jorge
authors.initials: J
authors.lastname: Gayoso
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: López Bernaldo de Quirós
authors.forename: Emilio
authors.initials: E
authors.lastname: Bouza
authors.forename: Darío
authors.initials: D
authors.lastname: García de Viedma
mesh_terms: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D024882:Drug Resistance, Viral / Q000235:genetics*; D005260:Female; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics; D006801:Humans; D016867:Immunocompromised Host; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects / Q000235:genetics* / Q000472:pathogenicity; D007251:Influenza, Human / Q000188:drug therapy / Q000821:virology*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D009439:Neuraminidase / Q000235:genetics; D053139:Oseltamivir / Q000494:pharmacology / Q000627:therapeutic use; D012367:RNA, Viral / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014774:Virulence; D053243:Zanamivir / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000998:Antiviral Agents; C543345:H1N1 virus hemagglutinin; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D012367:RNA, Viral; D053139:Oseltamivir; D009439:Neuraminidase; D053243:Zanamivir