This information is provided by:
Grant Stiver MD, FRCPC
Editorial Board Member for the CAN-R Website

Oseltamivir resistance in influenza has emerged in the past several years, and interestingly does not correlate with previous oseltamivir use. In 2007-2008, the CDC reported that 10.9% of human H1N1 strains isolated from patients with influenza-like illness (ILI), were oseltamivir-resistant (OR).1 In 2008-2009, virtually 99.5% of human H1N1 strains were oseltamivir-resistant based on the H274Y (histidine to tyrosine) mutation in the viral neuraminidase (NA).2 Initial infections with oseltamivir-resistant viruses in animals suggested that they were less fit due to the NA mutation.3 However, this was found to be dependent on which particular mutation conveyed the resistance. The H274Y mutation does not affect virus susceptibility to the other licensed neuraminidase inhibitor zanamivir.

OR is now prevalent in virtually all human H1N1 viruses currently circulating. They still remain susceptible to adamantanes, but amantadine or rimantadine treatment induces resistance within approximately 5 days, and these resistant viruses are infectious and have not lost any virulence. Swine-origin H1N1 viruses initially isolated in Mexico in early 2009, and now occurring world-wide, remain susceptible to oseltamivir, but unlike current human H1N1, they are resistant to adamantanes.4 OR mutations are still infrequent in H3N2 influenza viruses.2

The clinical characteristics of oseltamivir-resistant human influenza was recently studied in two cohorts of patients who had either OR or oseltamivir-susceptible (OS) human H1N1 viruses isolated.5 Contrary to the previous impressions in animals, the clinical picture of OR versus OS infections was not different in terms of types of symptoms, disease severity, resultant days of work or school lost, and days of limited activity. The only significant exception was that patients with OR-virus infection reported less (70 % versus 81%) myalgia or arthralgia. Two of 36 patients infected with OR virus and taking oseltamivir within 48 hours of symptom onset, died. The comparative mortality rate for OS virus-infected patients was not reported.

This observational study suggests that OR-virus with the H274Y mutation is not any less virulent in humans, than OS-virus. Oseltamivir is the preferential influenza antiviral for use in humans. The development of OR in H1N1 occurring rapidly over a few influenza seasons, argues for continued efforts to develop improved neuraminidase inhibitors as well as other novel influenza antivirals such as favipiravir, a viral RNA inhibitor, influenza NS1 antigen inhibitors, and DAS181, an attachment inhibitor.6

1. CDC. 2007-08 US influenza summary – resistance to antiviral medications. [cited 2009 June 8]. Available from http://www.cdc.gov/flu/weekly/weeklyarchives2007-2008/07-08summary.htm.
2. CDC. Fluview–antiviral resistance. [cited 2009 June 08]. Available from http://www.cdc.gov/flu/weekly/.
3. McKimm-Breschkin JL. Resistance of influenza viruses to neuraminidase inhibitors – a review. Antiviral Res 2000;47:1-17.
4. CDC. Update: drug susceptibility of swine–origin influenza A (H1N1), April 2009. MMWR 2009;58;433-5.
5. Dharan NJ. Gubavera LV, Meyer JM, et al. Infections with oseltamivir-resistant influenza A (H1N1) virus in the United States. JAMA 2009;301:1034-41.
6. Hayden FG. Developing new antiviral agents for influenza treatment: what does the future hold? Clin Infect Dis 2009;48 Suppl:S3-13.