Antiviral Drug-Resistant Strains of Seasonal Influenza Virus

Note: On December 19, 2008, CDC issued Interim Recommendations for the Use of Influenza Antivirals for the 2008-09 Season.

Oseltamivir and Zanamivir (Neuraminidase Inhibitors)

Among 2,287 isolates obtained from multiple countries during 1999—2002 as part of a global viral surveillance system, eight (0.3%) had a more than ten fold decrease in susceptibility to oseltamivir, and two (25%) of these eight also were resistant to zanamivir. In Japan, where more oseltamivir is used than in any other country, resistance to oseltamivir was identified in three (0.4%) A (H3N2) viruses in 2003—04, no A (H3N2) viruses in 2004—05, and no A (H3N2) viruses in 2005—06 influenza seasons. In 2005—06, four (2.2%) A (H1N1) viruses were identified to have oseltamivir resistance with a specific genetic marker. Neuraminidase inhibitor resistance remained low in the United States through the 2006—07 influenza season.

In 2007—08, increased resistance to oseltamivir was reported among A (H1N1) viruses in many countries. Persons infected with oseltamivir resistant A (H1N1) viruses had not previously received oseltamivir treatment and were not known to have been exposed to a person undergoing oseltamivir treatment. In the United States, approximately 10% of influenza A (H1N1) viruses, no A (H3N2) viruses, and no influenza B viruses were resistant to oseltamivir during the 2007—08 influenza season, and the overall percentage of influenza A and B viruses resistant to oseltamivir in the United States was less than 5%. No viruses resistant to zanamivir were identified. Oseltamivir or zanamivir continue to be the antiviral agents recommended for the prevention and treatment of influenza. Although recommendations for use of antiviral medications have not changed, enhanced surveillance for detection of oseltamivir-resistant viruses is ongoing and will enable continued monitoring of changing trends over time.

Development of viral resistance to zanamivir or oseltamivir during treatment has also been identified but does not appear to be frequent. One limited study reported that oseltamivir-resistant influenza A viruses were isolated from nine (18%) of 50 Japanese children during treatment with oseltamivir. Transmission of neuraminidase inhibitor-resistant influenza B viruses acquired from persons treated with oseltamivir is rare but has been documented. No isolates with reduced susceptibility to zanamivir have been reported from clinical trials, although the number of post-treatment isolates tested is limited. Only one clinical isolate with reduced susceptibility to zanamivir, obtained from an immunocompromised child on prolonged therapy, has been reported. Prolonged shedding of oseltamivir- or zanamivir-resistant virus by severely immunocompromised patients, even after cessation of oseltamivir treatment, has been reported.

Amantadine and Rimantadine (Adamantanes)

Adamantane resistance among circulating influenza A viruses increased rapidly worldwide over the past several years, and these medications are no longer recommended for influenza prevention or treatment, although in some limited circumstances use of adamantanes in combination with a neuraminidase inhibitor medication might be considered (see Prevention and Treatment of Influenza when Oseltamivir Resistance is Suspected). The proportion of influenza A viral isolates submitted from throughout the world to the World Health Organization Collaborating Center for Surveillance, Epidemiology, and Control of Influenza at CDC that were adamantane-resistant increased from 0.4% during 1994—1995 to 12.3% during 2003—2004. During the 2005—06 influenza season, CDC determined that 193 (92%) of 209 influenza A (H3N2) viruses isolated from patients in 26 states demonstrated a change at amino acid 31 in the M2 gene that confers resistance to adamantanes. Preliminary data from the 2007—08 influenza season indicates that resistance to adamantanes remains high among influenza A isolates, with approximately 99% of tested influenza A(H3N2) isolates and approximately 10% of influenza A(H1N1) isolates resistant to adamantanes. Amantadine or rimantidine should not be used alone for the treatment or prevention of influenza in the United States until evidence of susceptibility to these antiviral medications has been reestablished among circulating influenza A viruses. Adamantanes are not effective in the prevention or treatment of influenza B virus infections.

Prevention and Treatment of Influenza when Oseltamivir Resistance is Suspected

Testing for antiviral resistance in influenza viruses is not available in clinical settings. Because the proportion of influenza viruses that are resistant to oseltamivir remains less than 5% in the United States, oseltamivir or zanamivir remain the medications recommended for prevention and treatment of influenza. Influenza caused by oseltamivir-resistant viruses appears to be indistinguishable from illness caused by oseltamivir-sensitive viruses. When local viral surveillance data indicates that oseltamivir-resistant viruses are widespread in the community, clinicians have several options. Consultation with local health authorities to aid in decision-making is recommended as a first step. Persons who are candidates for receiving chemoprophylaxis as part of an outbreak known to be caused by oseltamivir-resistant viruses or who are being treated for influenza illness in communities where oseltamivir-resistant viruses are known to be circulating widely can receive zanamivir. However, zanamivir is not licensed for chemoprophylaxis indications in children aged younger than 5 years, and is not licensed for treatment in children younger than 7 years of age. In addition, zanamivir is not recommended for use in persons with chronic cardiopulmonary conditions, and can be difficult to administer to critically ill patients because of the inhalation mechanism of delivery. In these circumstances, a combination of oseltamivir and either rimantadine or amantadine can be considered, because influenza A (H1N1) viruses characterized to date that were resistant to oseltamivir have usually been susceptible to adamantane medications. However, adamantanes should not be used for chemoprophylaxis or treatment of influenza A unless they are part of a regimen that also includes a neuraminidase inhibitor, because viral surveillance data has documented that adamantane resistance among influenza A viruses is common. Influenza B viruses are not sensitive to adamantane drugs.

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NOTE: The text above is taken from Prevention & Control of Influenza - Recommendations of the Advisory Committee on Immunization Practices (ACIP) 2008. MMWR 2008 Jul 17; Early Release:1-60. (Also available as PDF, 586K).