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Additional Considerations to the Interim Recommendations for the Use of Influenza Antiviral Medications in the Setting of Oseltamivir Resistance among Circulating Influenza A (H1N1) Viruses, 2008-09 Influenza Season
Among the 50 influenza A(H1N1) viruses identified in the U.S. from October 1 through December 13, 2008 and tested by CDC, 49 (98%) were resistant to oseltamivir. However, all A(H1N1) viruses tested thus far are susceptible to the adamantanes (amantadine and rimantadine). All influenza A (H3N2) and influenza B viruses tested to date have been susceptible to oseltamivir and all influenza A (H1N1) and A (H3N2) and influenza B viruses tested have been susceptible to zanamivir. Resistance to the adamantanes among A (H3N2) viruses remains high so far this season, consistent with the last three influenza seasons, with 100% of viruses tested to date found to be adamantane-resistant.
Data on the epidemiology of influenza A (H1N1) and clinical outcomes associated with influenza A (H1N1) virus infections are limited, but there are no indications of differences in severity or transmissibility of oseltamivir-resistant compared with oseltamivir-susceptible viruses (CDC, unpublished data 2008). In each community, the public health and clinical importance of oseltamivir resistance among circulating influenza viruses will depend on the level of influenza activity, the proportion influenza A (H1N1) viruses that are resistant, and the proportion of A (H1N1) viruses among all circulating influenza A and B viruses.
Since high levels of resistance to amantadine and rimantadine (i.e., adamantanes) among influenza A (H3N2) viruses emerged in 2005-06, the neuraminidase inhibitors (oseltamivir and zanamivir) have been the only antiviral medications recommended for treatment and chemoprophylaxis in the United States. However, the emergence of oseltamivir resistance among circulating influenza A (H1N1) viruses has greatly complicated the selection of antiviral medications for use in the United States,. and CDC now recommends that adamantane use be considered in certain situations when an antiviral medication may be indicated, but zanamivir can not be used. While all tested influenza viruses remain sensitive to zanamivir, this drug is not approved for use as treatment among children younger than 7 years of age or for chemoprophylaxis of influenza among persons younger than 5 years of age. In addition, zanamivir, an orally inhaled powdered medication, is not recommended for treatment or chemoprophylaxis of influenza in people with underlying airways disease (such as asthma or chronic obstructive pulmonary disease) due to risk of serious bronchospasm and it cannot effectively be used by persons who cannot use the zanamivir inhaler device. Therefore, in some patients, the use of rimantadine or amantadine might be preferred in some circumstances.
Oseltamivir, amantadine, and rimantadine are orally administered drugs, but are not approved for use in children younger than 1 year of age. Clinicians should consult the package insert of each antiviral medication for specific dosing information, approved indications and ages, contraindications/warnings/precautions, and adverse effects. Information on these drugs may be found at the Food and Drug Administration website: http://www.fda.gov/cder/drug/antivirals/influenza/
Current recommendations for antiviral use indicate that clinicians should consider whether to recommend influenza antiviral treatment based on the severity of the patient’s illness, the time since illness onset, local influenza surveillance data and influenza test results. When initiated within 48 hours of illness onset, antiviral drug treatment of influenza has been shown to reduce the time to alleviation of acute uncomplicated illness in multiple clinical trials. Limited data pooled from clinical trials suggest that treatment with neuraminidase inhibitors can reduce the risk of pneumonia when treatment is initiated within 48 hours of illness onset. In addition, limited data from recent observational studies have found that hospitalized adults (primarily elderly) who received oseltamivir had reduced mortality or hospital length of stay compared with untreated patients (McGeer et al. Clinical Infectious Diseases 2007; Lee et al. Antiviral Therapy 2007), although prospective controlled data regarding the effects of antivirals in severely ill hospitalized patients are lacking. For additional information please refer to: http://www.cdc.gov/mmwr/PDF/rr/rr5707.pdf
When available, local influenza surveillance data and results from laboratory tests can provide useful information to help guide treatment or prevention of influenza. However, the limitations of these data need to be considered. The types and influenza A subtypes of circulating virus strains can vary considerably among communities and can vary with a community over the course of the season. Local and state public health authorities might have considerable information about which viruses are circulating in some areas, and these data, if frequently updated as the season progresses, can be helpful in guiding the selection of antiviral medication.
Although several laboratory tests are available to detect influenza virus infection in respiratory specimens, not all tests may be available to clinicians to yield timely results to influence treatment decisions. It should be recognized that reverse-transcriptase polymerase chain reaction (RT-PCR) can provide highly accurate results, but testing may not be widely available to provide timely results to influence clinical management. Immunoflourescence can distinguish between influenza A and B and may be available at hospital laboratories and can produce results in 2-4 hours. Influenza viral culture results may take 2 or more days. Commercially available rapid antigen tests can produce results within 15 minutes, are widely available, have good specificity (low rate of false positive tests), but are only 50%-70% sensitive (i.e., these tests have relatively high rate of false negative tests) when compared to RT-PCR or viral culture. Many but not all rapid influenza tests can distinguish influenza A viruses from influenza B viruses. Positive rapid test results are most reliable when influenza activity is high in a community and are useful in deciding whether to initiate antiviral treatment. Negative rapid test results are less helpful in making treatment decisions during influenza season. When local influenza activity is high, people with severe respiratory symptoms or acute respiratory illness who are at higher risk for influenza complications should still be considered for influenza antiviral treatment despite a negative rapid influenza test result unless illness can be attributed to another cause. None of the currently FDA-cleared rapid antigen tests can distinguish between influenza A subtypes. A rapid antigen test that cannot distinguish influenza A from influenza B will not help guide the selection of treatment if oseltamivir resistance is of concern, but a positive result remains helpful in informing treatment decisions. More sophisticated laboratory tests capable of distinguishing between influenza A subtypes might be available in some areas, including from state public health laboratories and some research laboratories, but the results of such testing are not likely to be available quickly enough to guide clinical decisions for individual patients.
Antiviral resistance testing is not commercially available to guide clinical management of individual patients. However, local and statewide influenza virus surveillance data available form public health laboratories might be helpful for decision-making about antiviral use since the resistance patterns are thus far type and influenza A subtype specific.
Information on use of zanamivir and oseltamivir use is available in Prevention and Control of Influenza, Recommendations of the Advisory Committee on Immunization Practices, 2008 http://www.cdc.gov/mmwr/PDF/rr/rr5707.pdf However, information on adamantane use has not been included in recent recommendations and details on specific dosages and administration can be found at http://www.cdc.gov/flu/professionals/antivirals/index.htm
Both amantadine and rimantadine are approved for antiviral therapy of influenza A in people aged 1 year or older. Both amantadine and rimantadine can cause central nervous system (CNS) and gastrointestinal side effects. However, incidence of CNS side effects (e.g., nervousness, anxiety, insomnia, difficulty concentrating, and lightheadedness) is higher among persons taking amantadine than among those taking rimantadine, and clinicians might prefer to use rimantadine based on this side effect profile. Seizures have been reported among persons with a history of seizures who were not receiving anticonvulsant medication while taking amantadine or rimantadine. Careful observation is advised when amantadine is administered concurrently with drugs that affect CNS, including CNS stimulants. Concomitant administration of amantadine and antihistamines or anticholinergic drugs can increase the incidence of adverse CNS reactions. No clinically substantial interactions between rimantadine and other drugs have been identified. Clinicians should consult the package insert for guidance on adamantane therapy in elderly and persons with renal disease.
Influenza A viruses resistant to amantadine are cross-resistant to rimantadine and vice versa. Adamantane-resistant viruses can appear in approximately one-third of patients when either amantadine or rimantadine is used for therapy. During the course of amantadine or rimantadine therapy, resistant influenza A virus strains can replace susceptible strains within 2 to 3 days of starting therapy. Resistant viruses have been isolated from persons who live at home or in an institution where other residents are taking or have recently taken amantadine or rimantadine as therapy. The emergence and spread of adamantane resistant influenza A viruses among patients in facilities in which these drugs were used for outbreak control has been previously documented.
When viral surveillance data indicates that the predominant viruses in circulation are influenza A (H3N2) or influenza B viruses, oseltamivir alone remains an option for treatment or chemoprophylaxis. However, when local viral surveillance data indicates that H1N1 viruses are widespread in the community, zanamivir or a combination of oseltamivir and rimantadine would be more likely to provide effective treatment or chemoprophylaxis, unless circulating influenza A (H1N1) viruses have been shown to be sensitive to oseltamivir.
Note: The information above has been provided as "Additional Considerations" to a Health Alert Advisory issued on December 19, 2008 entitled "Interim Recommendations for the Use of Influenza Antiviral Medications in the Setting of Oseltamivir Resistance among Circulating Influenza A (H1N1) Viruses, 2008-09 Influenza Season." Visit http://www.cdc.gov/flu/professionals/antivirals/index.htm for the full content of the interim recommendations.
- Page last updated December 19, 2008
- Content Source: Coordinating Center for Infectious Diseases (CCID)
- National Center for Immunization and Respiratory Diseases (NCIRD)
