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Oseltamivir (Tamiflu) Resistance in Seasonal Influenza A (H1N1) Viruses
Abstract & commentary
By Mary-Louise Scully, MD, Sansum-Santa Barbara Medical Foundation Clinic, Santa Barbara, CA. Dr. Scully reports no financial relationships relevant to this field of study. This article originally appeared in the February 2009 issue of Travel Medicine Advisor. It was edited by Frank Bia, MD, and peer reviewed by Philip Fischer, MD. Dr. Bia is Professor of Geographic and Laboratory Medicine, Co-Director, Topical Medicine and International Travelers' Clinic, Yale University School of Medicine, and Dr. Fischer is Professor of Pediatrics, Department of Pediatrics and Adolescent Medicine, Mayo Clinic, Rochester, MN. Dr. Bia is a consultant for Pfizer and Sanofi-Pasteur, and receives funds from Johnson & Johnson, and Dr. Fischer reports no financial relationship relevant to this field of study.
Synopsis: Preliminary data indicate that the prevalence of influenza A (H1N1) virus strains resistant to the antiviral medication oseltamivir is high. Therefore, interim guidelines issued by the CDC are to use zanamivir or a combination of oseltamivir and rimantidine if influenza A (H1N1) infection is suspected.
Source: CDC. Health Advisory. CDC issues interim recommendations for the use of influenza antivirals in the setting of oseltamivir resistance among circulating influenza A (H1N1) viruses, 2008-2009 season. http://www.cdc.gov/flu/professionals/antivirals/index.htm. Accessed 12/22/08.
Influenza activity has been relatively low thus far in the 2008-2009 season in the United States. However, of the influenza viruses isolated and tested to date, there is significant resistance among the influenza A (H1N1) viruses to the antiviral oseltamivir. As of mid-December 2008, 50 influenza A (H1N1) viruses from 12 states were tested. Ninety-eight percent were resistant to oseltamivir, but all were susceptible to zanamivir, amantadine, and rimantidine. Influenza A (H3N2) and B viruses remain susceptible to oseltamivir.
In light of this information, on December 19, 2008, the CDC issued interim guidelines for antiviral treatment or prophylaxis in suspected cases of influenza (see Table 2). The use of influenza tests that can distinguish influenza A from influenza B is encouraged. If a patient has a positive test for influenza A, and treatment is indicated, the use of zanamivir should be considered; alternatively, the combination of oseltamivir plus rimantidine could be used. If the patient has a positive test for influenza B, oseltamivir or zanamivir (no preference) may be given. The same recommendations hold true for persons who are candidates for chemoprophylaxis. Ideally, local or state surveillance data should be used to determine which types (A or B) and subtypes (H1N1 or H3N2) are currently circulating in a given area, but this information may not be available at the time clinical decisions need to be made.
Based on preliminary information, it does not appear that oseltamivir-resistant influenza A (H1N1) viruses cause more severe symptoms compared to oseltamivir-sensitive influenza A (H1N1) viruses. In addition, since oseltamivir-resistant influenza A (H1N1) viruses are antigenically similar to the (H1N1) virus included in the 2008-2009 influenza vaccine (A/Brisbane/59/2007), ongoing influenza vaccination remains an effective strategy to prevent influenza.
In the United States, four antiviral medications are approved for treatment and prophylaxis of influenza. The adamantanes (amantadine, rimantidine) have activity only against influenza A viruses, whereas the neuraminidase inhibitors (oseltamivir, zanamivir) have activity against both influenza A and influenza B viruses. In January 2006, when widespread resistance developed to the adamantanes among influenza A (H3N2) viruses, oseltamivir and zanamivir became the recommended influenza antiviral medications for the United States. Now we are seeing the recommendations shift again in light of the oseltamivir-resistant influenza A (H1N1) viruses circulating this year.
This development is not unique to the United States. The World Health Organization collects data from multiple laboratories participating in the Global Influenza Surveillance Network (GISN), the European Influenza Surveillance Scheme (EISS), and the European Surveillance Network for Vigilance against Viral Resistance (VirGil). In January 2008, Norway reported an increased number of influenza A (H1N1) viruses with resistance to oseltamivir. By June 2008, data from the European region of WHO indicated that 25% of the influenza A (H1N1) viruses tested were resistant to oseltamivir. Finland, France, Luxemburg, the Netherlands, Norway, the Russian federation, and Ukraine all reported a prevalence of 25% or greater, with Norway having the highest prevalence (67%).1
The trend of rising oseltamivir resistance does not appear to be correlated with oseltamivir use or abuse since the use of oseltamivir generally is quite uncommon in European countries. Moreover, it does not appear that persons with resistant viruses were in contact with, or linked to, one another. Therefore, the reason for the emergence of these resistant viruses is unknown. However, zanamivir and oseltamivir differ in certain specific aspects of their chemical structures, which explains the lack of emergence of zanamivir resistance.2 Zanamivir, available only as an inhaled formulation, is indicated for influenza treatment of patients seven years or older, but should not be used in patients with chronic underlying airway disease.
Influenza, be it avian influenza or seasonal influenza, continues to challenge the medical community worldwide. Influenza occurs in the tropics as well as colder climates, affects all age groups, and is highly contagious, placing all of us at risk, including global travelers. The 2008 southern hemisphere flu season just finished and was relatively mild, perhaps reflecting a more appropriate "match" with the vaccine viruses. Vaccination should be encouraged for both travelers and non-travelers throughout the 2009 influenza season since the oseltamivir-resistant viruses appear antigenically similar to the influenza A (H1N1) virus included in both the northern and southern hemisphere vaccines.
As this is an evolving issue, clinicians should check weekly for the updated reports and influenza information at http://www.cdc.gov/flu.
1. World Health Organization. Influenza A (H1N1) virus resistance to oseltamivir. www.who.int/csr/disease/influenza/oseltamivir_summary/en/index.html. Accessed 12/28/2008.
2. Moscona A. Oseltamivir resistance disabling our influenza defenses. N Engl J Med 2005;353:2633-2636.