Identification of Reversible Oseltamivir Resistance in 2009 H1N1 Influenza A Virus in a Critically Ill, Immunocompromised Patient

Background: The H1N1 influenza A virus has thus far been susceptible to oseltamivir.  Sporadic cases of oseltamivir resistant H1N1 influenza A virus have been reported during the 2009 pandemic.

Objective: Describe reversion of oseltamivir resistance in a patient with 2009 H1N1 influenza A virus.

Index Patient: 69 year old man with leukemia undergoing chemotherapy admitted with neutropenic fever, cough, and clear chest radiograph tested positive for influenza A in July.  He was treated with oseltamivir 75 mg bid on hospital days (HD) 4-10.  Subsequently he required intubation due to respiratory failure and oseltamivir was increased to 150mg bid, along with the addition of rimantadine 100mg bid on HD 11.  On HD 26, he had completed 22 days of anti-viral therapy with clinical improvement.  On HD 30, his respiratory status declined leading to another test for influenza that was again positive and high dose oseltamivir therapy was restarted on HD 31.  The patient was discharged after 48 days of hospitalization.

Methods: The index patient underwent testing for influenza A by two methodologies at our institution.  Real time reverse transcription polymerase chain reaction was done using the ProFlu+ assay (Prodesse, Inc.) This RT-PCR is able to identify all influenza A positive specimens including the 2009 H1N1 influenza A virus.  Viral cultures were done using R mix testing.  Confirmatory testing for H1N1 influenza A performed by the Ohio Department of Health.  Three specimens positive for influenza A by RT-PCR were sent for antiviral resistance testing (VIRACOR, Lee's Summit, MO).  DNA sequencing analysis confirmed oseltamivir resistance by the detection of a single base mutation (H275Y) in the neuraminidase gene. 

Results: Results of testing are shown in Table 1.  Positive test results were identified over a 6 week time period.  The patient's initial isolate was confirmed as H1N1 influenza A virus.  Three positive nasopharyngeal swabs were sent for oseltamivir resistance testing because of the prolonged shedding and suspected resistance.  The oseltamivir resistance gene (H275Y) was not detected on HD 8, was detected HD 16, and then not detected on HD 43.

Conclusions: We report an immunocompromised patient with H1N1 influenza A infection with prolonged viral shedding who developed oseltamivir resistance while on therapy.  Wild type virus later re-emerged after therapy was completed. This example suggests that routine use of influenza resistance testing would provide a benefit for patient care inform efforts to mitigate nosocomial transmission.