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Interim Guidance on the Use of Antiviral Medications for Treatment of Human Infections with Novel Influenza A Viruses Associated with Severe Human Disease

What to know

This guidance provides recommendations for treatment of novel influenza A virus infections associated with severe human disease in the United States.

Summary

This document provides guidance for antiviral treatment of human infection with novel influenza A viruses associated with severe human disease (examples include but are not limited to highly pathogenic avian influenza (HPAI) A(H5N1) and A(H5N6) viruses and avian influenza A(H7N9) virus). These recommendations are based on available data on the treatment of infections caused by influenza viruses, including seasonal, pandemic, and novel influenza A viruses, and expert opinion.

Antiviral treatment is recommended as soon as possible for outpatients and hospitalized patients who are suspected, probable, or confirmed cases of human infection with novel influenza A viruses associated with severe human disease.

This guidance reflects recently updated novel influenza A case definitions (visit Avian Influenza A Virus Case Definitions). CDC will continue to evaluate new information as it becomes available and will update this guidance as needed. Updated information will be provided on CDC's Avian Influenza Current Situation Summary.

For guidance on investigation of close contacts of case-patients, visit Interim Guidance on Follow-up of Close Contacts of Persons Infected with Novel Influenza A Viruses Associated with Severe Human Disease and the Use of Antiviral Medications for Chemoprophylaxis. CDC has issued information about Emergency Use Instructions (EUI) for oseltamivir treatment or post-exposure prophylaxis (PEP) of pandemic influenza A viruses and novel influenza A viruses with pandemic potential Emergency Use Instructions (EUI) for Oseltamivir | Bird Flu | CDC.

Background

To date, novel influenza A viruses such as highly pathogenic avian influenza (HPAI) A(H5N1) and A(H5N6) viruses and avian influenza A(H7N9)es virus that have infected people have been susceptible to antivirals recommended for treatment of seasonal influenza. There are no data from randomized clinical trials of antiviral treatment of outpatients or hospitalized patients with novel influenza A virus infections. Antiviral treatment recommendations are based upon available observational studies (see Rationale section) and indirect evidence from studies of antiviral treatment of seasonal influenza.

Most avian influenza A(H7N9), A(H5N1), and A(H5N6) viruses are susceptible to the neuraminidase inhibitors (oseltamivir, peramivir and zanamivir) and baloxavir, but are often resistant to the adamantanes (amantadine and rimantadine). Therefore, amantadine and rimantadine are not recommended for treatment of novel influenza A virus infections.

Outpatients

  • Initiation of antiviral treatment with oseltamivir is recommended as soon as possible for symptomatic outpatients who are confirmed, probable, or suspected cases of infection with a novel influenza A virus associated with severe human disease.
    • The standard dose of oseltamivir for adolescents and adults is 75 mg twice daily for 5 days.
    • For information on oseltamivir dosage recommendations for treatment by age group, please visit: Emergency Use Instructions (EUI) for Oseltamivir | Bird Flu | CDC and Influenza Antiviral Medications: Summary for Clinicians.
    • For a patient who is immunocompromised, combination antiviral treatment (e.g., oseltamivir and baloxavir) can be considered because of the increased potential for emergence of antiviral resistance in immunocompromised persons treated with monotherapy for influenza.
    • Decisions to initiate antiviral treatment for untreated outpatients who are confirmed, probable, or suspected cases with uncomplicated disease, in whom fever is absent and symptoms are nearly resolved, should be based on clinical judgment. Because of the potential for progression to severe disease, oseltamivir treatment is recommended as soon as possible for persons with conjunctivitis or acute respiratory illness.
    • For questions regarding clinical management, antiviral dosing, including if antiviral resistance is a concern, contact the CDC Influenza Division for consultation with a medical officer via the CDC Emergency Operations Center (770-488-7100).

Hospitalized Patients

  • Initiation of antiviral treatment with oral or enterically administered oseltamivir is recommended as soon as possible for hospitalized patients who are confirmed, probable, or suspected cases of infection with novel influenza A virus associated with severe human disease, regardless of time since illness onset.
  • Antiviral treatment should not be delayed while waiting for laboratory testing results. (For information regarding specimen collection and laboratory testing, visit the Interim Guidance for Specimen Collection, Processing, and Testing for Patients with Suspected Infection with Novel Influenza A Viruses Associated with Severe Disease in Humans.)
  • For information on oseltamivir dosage recommendations for treatment by age group, please visit: Emergency Use Instructions (EUI) for Oseltamivir | Bird Flu | CDC and Influenza Antiviral Medications: Summary for Clinicians.
  • The standard dose of oseltamivir for adolescents and adults is 75 mg twice daily for 5 days. However, the optimal duration and dosing are uncertain for patients with severe disease.
    • Human infections with HPAI A(H5N1) and avian influenza A(H7N9) viruses have been shown to be associated with higher virus levels and longer duration of viral replication (particularly in the lower respiratory tract disease) in hospitalized patients than with seasonal influenza A or B virus infection 12345
    • Pending further data, longer courses of treatment (e.g., 10 days) should be considered for severely ill hospitalized patients with novel influenza A virus infections.
  • Combination antiviral treatment (e.g., oseltamivir and baloxavir) can be considered for hospitalized patients with novel influenza A virus infection because it is possible that some novel influenza A viruses might become resistant to oseltamivir and peramivir during antiviral treatment with one of these agents 36789
    • Oseltamivir resistance has been reported in hospitalized patients with HPAI A(H5N1) virus infection, resulting in fatal outcome 3. If a hospitalized patient treated with oseltamivir or peramivir manifests progressive lower respiratory disease, the presence of a resistant virus should be considered. After consultation with CDC's Influenza Division, investigation for antiviral resistance should be performed.
    • Combination treatment with a neuraminidase inhibitor and baloxavir did not have clinical benefit compared with neuraminidase inhibitor and placebo in a randomized clinical trial in hospitalized patients with seasonal influenza, but the addition of baloxavir reduced duration of infectious viral shedding 10
  • Limited data suggest that oseltamivir administered orally or by oro/naso gastric tube is well absorbed in critically ill influenza patients, including those in the intensive care unit, on continuous renal replacement therapy, and/or on extracorporeal membrane oxygenation 1112131415161718. However, for patients who cannot tolerate or absorb oral or enterically-administered oseltamivir because of suspected or known gastric stasis, malabsorption, or gastrointestinal bleeding, IV peramivir is an alternative.
  • Any questions regarding arranging testing for antiviral resistance, combination antiviral treatment dosing, or regarding appropriate clinical management if antiviral resistance is a concern, should be directed to the CDC Influenza Division for consultation with a medical officer via the CDC Emergency Operations Center (770-488-7100).

Rationale

Oseltamivir is recommended as soon as possible for treatment of symptomatic patients who are suspected, confirmed, or probable cases of infection with novel influenza A viruses associated with severe human disease based on observational studies of patients with HPAI A(H5N1) virus infection.

  • An observational study of HPAI A(H5N1) patients in Indonesia (N=127) reported that oseltamivir treatment started within 2 days of symptom onset was significantly associated with lower mortality compared to patients who received oseltamivir treatment started later (e.g., ≥5-6 days after symptom onset) 19.
  • An observational study of a multi-country registry of HPAI A(H5N1) patients reported that oseltamivir treatment (n=98) was significantly associated with survival compared with no treatment (n=123), and survival was highest when oseltamivir was started within 2 days of symptom onset 20.
  • An observational study of an expanded multi-country registry of HPAI A(H5N1) patients reported that oseltamivir treatment initiated within 2 days of symptom onset in patients without respiratory failure when treatment was started (n=113) was significantly associated with survival 21.

There are no data for baloxavir treatment of patients with HPAI A(H5N1) virus infection or avian influenza A(H7N9) virus infection.

  • One small case series (n=5) in critically ill hospitalized patients infected with HPAI A(H5N6) virus, clade 2.3.4.4b, who were treated daily with oseltamivir (median time from symptom onset to starting oseltamivir: 5 days) and baloxavir was added every 3 days (median time from symptom onset to starting baloxavir: 11 days) reported that the addition of baloxavir reduced A(H5N6) viral RNA levels in sputum and levels of some cytokines in sputum and serum, although 3 of the 5 patients died 22.

Observational studies of antiviral treatment of patients with avian influenza A(H7N9) virus infection have yielded mixed results.

  • An observational study of 1220 patients with avian influenza A(H7N9) virus infection hospitalized over 5 epidemics in China during 2013-2017 reported that patients started on antiviral treatment >2 days after symptom onset had a higher risk of death than patients who started antiviral treatment ≤2 days of symptom onset, but this difference was not statistically significant in adjusted analyses 23.
  • An observational study of 305 patients with avian influenza A(H7N9) virus infection hospitalized in a single province in China during 2013-2017 that used time-dependent survival models reported no significant association between time to starting antiviral treatment with neuraminidase inhibitors and survival 24.
  • A single center observational study of 160 patients with avian influenza A(H7N9) virus infection hospitalized during 2013-2017 in China reported that starting antiviral treatment with oseltamivir within 2 days of symptom onset was significantly associated with decreased risk of death 25.

Other Considerations

  • Clinical judgment and virologic testing of lower respiratory tract specimens by RT-PCR should guide decisions to consider treatment regimens longer than 5 days for hospitalized patients with severe and prolonged illness. For patients with lower respiratory tract disease, lower respiratory tract specimens such as bronchoalveolar lavage fluid or endotracheal aspirate are preferred; a combined nasal and oropharyngeal (throat) swab specimen may be collected if lower respiratory specimens are not available. Lower respiratory tract specimens may yield the diagnosis when testing of upper respiratory tract specimens produce negative results in hospitalized patients with severe disease. Multiple respiratory tract specimens collected on different days should be tested if novel influenza A virus infection associated with severe disease is suspected without another definitive diagnosis.
  • Longer treatment regimens might be necessary in severely immunosuppressed persons (e.g., hematopoietic stem cell transplant recipients) who may have prolonged influenza viral replication. Such patients are at risk of developing antiviral-resistant virus infection with monotherapy. Although no data from clinical trials are available, combination treatment of immunocompromised patients using antivirals with different mechanisms of action (e.g., oseltamivir and baloxavir) can be considered.
  • Limited data do not suggest clinical benefit of higher antiviral dosing. A higher dose of oseltamivir has been recommended by some experts (e.g., 150 mg twice daily in adults with normal renal function instead of the standard 75 mg twice daily dose) for treatment of influenza in immunocompromised patients and in severely ill hospitalized patients 26. However, oral or enterically administered oseltamivir has been reported to be adequately absorbed in critically ill adults, with standard doses producing therapeutic blood levels 11. Although the higher dose was generally well-tolerated and not associated with severe adverse events, limited data suggest that higher dosing may not provide additional clinical benefit for seasonal influenza or for pandemic 2009 influenza A (H1N1) 2728. Studies indicate that the exposure to oseltamivir carboxylate (the active metabolite of oseltamivir) is similar between obese and non-obese subjects for both 75 mg and 150 mg doses given twice daily 293031.
  • Inhaled zanamivir is not recommended because of the lack of data for use in patients with severe seasonal influenza. There are insufficient data regarding the efficacy or effectiveness of intravenous (IV) peramivir for hospitalized seasonal influenza patients.
  • Use of two neuraminidase inhibitors (e.g., inhaled zanamivir in combination with oseltamivir or peramivir, or use of oseltamivir and peramivir) is not recommended because of data suggesting that antagonism may occur when 2 neuraminidase inhibitors are given simultaneously compared to monotherapy in outpatients 32.
  • While studies have shown benefit of IV peramivir for treatment of uncomplicated influenza in outpatients 33, a randomized trial of treatment of seasonal influenza in hospitalized patients aged >6 years failed to demonstrate significant clinical benefit for intravenous peramivir plus standard of care compared with placebo plus standard of care 34. However, peramivir was generally safe and well tolerated at a dosage of 600 mg once daily (10 mg/kg once daily in children) for 5 days. If used to treat hospitalized patients with novel influenza A virus infection, this dose of IV peramivir is recommended for a minimum of 5 days (not a single dose as is recommended for outpatients with uncomplicated illness).
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