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

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 avian influenza A(H7N9) virus and highly pathogenic avian influenza A(H5N1) and A(H5N6) viruses; visit Reported Human Infections with Avian Influenza A Viruses).

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

This guidance reflects recently updated novel influenza A case definitions (visit Avian Influenza A Virus Case Definitions). Antiviral treatment is recommended as soon as possible for outpatients and hospitalized patients who are suspected (cases under investigation), probable, or confirmed cases of human infection with novel influenza A viruses associated with severe human disease. (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.)

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.

Background

There are no data from randomized clinical trials of antiviral treatment of outpatients or hospitalized patients with novel influenza A virus infection. In otherwise healthy persons with acute, uncomplicated seasonal influenza virus infection, randomized controlled trials have demonstrated decreased time to symptom improvement with antiviral treatment by a neuraminidase inhibitor (oseltamivir, peramivir, or zanamivir) or the cap-dependent endonuclease inhibitor (baloxavir), when treatment is begun within the first few days of illness [1-11]. Clinical trials and meta-analyses of data from randomized controlled trials have shown that antiviral treatment of outpatients can reduce some complications associated with seasonal influenza [6,7,9,12,13].

Data from antiviral treatment studies of patients with seasonal influenza have reported that clinical benefit is greatest when antiviral treatment is administered early, especially within 48 hours of illness onset. Among patients hospitalized with seasonal influenza A or B, pandemic 2009 influenza A (H1N1), or highly pathogenic avian influenza A(H5N1) virus infections, observational studies suggest that early treatment reduces disease severity and mortality [14-18]. Although earlier antiviral treatment results in greater clinical benefit, observational studies support the use of antiviral treatment in hospitalized patients with seasonal influenza even when started after 48 hours of illness, including in critically ill patients [14,16-21]. Among patients with uncomplicated seasonal influenza, one randomized clinical trial in children demonstrated a modest reduction in duration of symptoms and virus shedding in patients initiated 72 hours after illness [11]. Neuraminidase inhibitor treatment with oseltamivir, peramivir, or zanamivir has been used for severely ill persons infected with A(H7N9) viruses, but their effectiveness for treatment of severe disease caused by avian influenza A virus infections has not been determined [22-26].

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.

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Recommendations

Outpatients

• Initiation of antiviral treatment with a neuraminidase inhibitor is recommended as early as possible for symptomatic outpatients who are confirmed, probable, or suspected/cases under investigation of novel influenza A virus infection associated with severe human disease. Treatment is not currently recommended for uncomplicated illness in outpatients whose exposure criteria consists only of travel to an area (e.g. country, state/province, city, county) with human cases of novel influenza A virus infection associated with severe human disease, or where these viruses are known to be circulating in animals (visit Avian Influenza A Virus Case Definitions).
• For outpatients with severe, progressive, or complicated illness, oseltamivir treatment is recommended. For other outpatients with uncomplicated mild-to-moderate illness presenting within 2 days of illness onset, oral oseltamivir, inhaled zanamivir, IV peramivir, or oral baloxavir may be used.²
• If more than 48 hours has elapsed since illness onset, oseltamivir treatment is recommended.
• For untreated outpatients who are confirmed cases, probable cases, or suspected/cases under investigation with uncomplicated disease in whom fever is absent and symptoms are nearly resolved, decisions to initiate antiviral treatment should be based on clinical judgment. Persons who are not treated with antiviral medications should be monitored for progression of illness.
• Recommended treatment duration for mild uncomplicated illness with a novel influenza A virus infection presenting within 2 days after illness onset is two doses per day of oral oseltamivir or inhaled zanamivir for 5 days, or a single dose of oral baloxavir, based on data for treatment of seasonal influenza.
  • For IV peramivir, the recommendation for treatment of uncomplicated illness is one dose of IV peramivir for 1 day based on treatment of seasonal influenza.
  • Inhaled zanamivir is not recommended for treatment of persons with underlying airway disease (e.g., asthma or chronic obstructive pulmonary disease).

For additional guidance on the use of influenza antiviral agents, including dosage recommendations for treatment by age group, please visit the Influenza Antiviral Medications: Summary for Clinicians.

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.

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 under investigation of human infection with novel influenza A viruses associated with severe human disease, regardless of time since illness onset.² 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.
• A randomized clinical trial of antiviral treatment of hospitalized patients with seasonal influenza reported that combination neuraminidase inhibitor and baloxavir treatment was not superior to neuraminidase inhibitor and placebo. No significant differences were found in the time to clinical improvement or other clinical outcomes, but the addition of baloxavir to a neuraminidase inhibitor significantly reduced duration of infectious viral shedding compared to neuraminidase inhibitor treatment alone [27].
• Antiviral treatment should not be delayed while waiting for laboratory testing results. (For information regarding 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.)
• The standard dose of oseltamivir is 75 mg twice daily for 5 days. However, the optimal duration and dosing are uncertain for patients with severe disease. Avian influenza A(H5N1) and 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) in hospitalized patients than with seasonal influenza A or B virus infection [23, 26, 28-30]. 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.
• 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 using antivirals with different mechanisms of action 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 [31]. However, oral or enterically administered oseltamivir has been reported to be adequately absorbed in critically ill adults, with standard doses producing therapeutic blood levels [32]. 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) [33, 34]. 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 [35-37].
• 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 [32, 38-44]. 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.
  • While studies have shown benefit of IV peramivir for treatment of uncomplicated influenza in outpatients [10, 45], 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. 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 [46]. 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).
• Use of inhaled zanamivir in combination with oseltamivir or peramivir is not recommended, because of data suggesting that antagonism may occur when 2 neuraminidase inhibitors are given simultaneously compared to monotherapy.
• It is possible that some novel influenza A viruses might become resistant to oseltamivir and peramivir during antiviral treatment with one of these agents and remain susceptible to zanamivir [29, 47-50]. If a hospitalized patient treated with oseltamivir and/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 [27].
• Any questions regarding arranging testing for antiviral resistance, or regarding appropriate clinical management if antiviral resistance is a concern, should be directed to the CDC Influenza Division via the CDC Emergency Operations Center (770-488-7100).

Footnotes

¹ “Outpatient” in this document refers to any patient in the ambulatory care setting, including emergency departments, urgent care and other clinics.

² Oral oseltamivir is approved by the FDA for treatment of acute uncomplicated influenza in persons ≥14 days old. Although use of oral oseltamivir for treatment of influenza in infants less than 14 days old is not part of the FDA-approved indication, it is recommended by the CDC and the American Academy of Pediatrics for treatment of influenza in patients of any age. Inhaled zanamivir is approved for treatment of acute uncomplicated influenza in persons aged 7 years and older. Clinicians may refer to the manufacturer’s package inserts for additional information regarding dosing, limitations of populations studied, contraindications, and adverse events. Please visit FDA Approved Drugs for Influenza.

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Table. Antiviral treatment recommendations according to case definition category for human infection with novel influenza A viruses associated with severe disease. (Case Definitions for Investigations of Human Infection with Avian Influenza A Viruses in the United States)

1 For hospitalized patients and outpatients with severe, progressive, or complicated disease, oral oseltamivir is recommended. Inhaled zanamivir and IV peramivir are not recommended because of the lack of data for these patients. For outpatients presenting >2 days after illness onset with mild-to-moderate illness, oral oseltamivir is recommended. For outpatients with uncomplicated influenza within 2 days of illness onset, oral oseltamivir, inhaled zanamivir, IV peramivir, or oral baloxavir may be used.