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; these viruses currently include influenza A (H7N9) virus and highly pathogenic avian influenza A (H5N1) virus.¹

This guidance merges and replaces the previously posted guidance on the use of antiviral agents for treatment of human infections with avian influenza A (H7N9) and avian influenza A (H5N1). This antiviral treatment guidance is consistent with current CDC and World Health Organization (WHO) recommendations, and provides updated recommendations for treatment of novel influenza A infections associated with severe human disease in the United States.

This guidance reflects recently updated novel influenza A case definitions (see H7N9 case definitions and H5N1 case definitions).This guidance recommends antiviral treatment as soon as possible for all hospitalized cases of human infection with novel influenza A viruses associated with severe human disease, and for confirmed and probable outpatient cases.²Outpatient cases under investigation who have had recent close contact with a confirmed or probable case of human infection with a novel influenza A virus that can cause severe disease should receive antiviral treatment, whereas outpatient cases under investigation meeting only the travel exposure criteria for a case under investigation are not recommended to receive antiviral treatment. (For guidance on investigation of close contacts of confirmed or probable cases, see 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These recommendations are based on expert opinion and available published and unpublished data on the treatment of infection caused by influenza viruses, including seasonal, pandemic, and novel viruses. This guidance will continue to be updated as additional information on virus transmissibility, epidemiology, and antiviral susceptibility patterns becomes available for novel influenza A viruses that cause severe disease.

Background

Randomized controlled trials have demonstrated decreased time to symptom improvement when currently approved neuraminidase inhibitor antiviral agents (oseltamivir, peramivir and zanamivir) are used to treat otherwise healthy persons with acute uncomplicated influenza caused by seasonal influenza viruses within the first few days of illness [1-11]. Secondary analyses in some of these trials and additional meta-analyses of data from randomized controlled trials have shown that neuraminidase inhibitors reduce secondary complications associated with influenza [4, 8, 9, 12-14].

Clinical benefit is greatest when antiviral treatment is administered early, especially within 48 hours of influenza illness onset. Among patients hospitalized with seasonal influenza A or B, pandemic 2009 influenza A (H1N1), or avian influenza A (H5N1) virus infections, observational studies suggest that early treatment reduces disease severity and mortality [15-19]. Although earlier antiviral treatment results in greater clinical benefit, observational studies support the use of antiviral treatment in hospitalized patients even when started after 48 hours of illness, including in critically ill patients [15, 17-22]. 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 [10]. Neuraminidase inhibitor treatment with oseltamivir, peramivir, and zanamivir has been used for severely ill persons infected with A (H7N9) viruses, but the effectiveness for severe disease has not yet been determined [23-27].

Similar to seasonal viruses, most influenza A (H7N9) and A (H5N1) viruses are susceptible to the neuraminidase inhibitors (oseltamivir, peramivir and zanamivir), but 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

Hospitalized Patients

• Initiation of antiviral treatment with a neuraminidase inhibitor is recommended as early as possible for hospitalized patients who are confirmed cases, probable cases, or cases under investigation of human infection with novel influenza A viruses associated with severe human disease, even if more than 48 hours has elapsed since illness onset.
• For hospitalized patients and outpatients with severe, complicated, or progressive illness (e.g., development of pneumonia), treatment with oral or enterically administered oseltamivir is recommended.³ Inhaled zanamivir is not recommended because of the lack of data for use in patients with severe influenza. There is also insufficient data regarding efficacy of intravenous (IV) peramivir for hospitalized patients.
• Antiviral treatment should not be delayed while waiting for laboratory testing results. (For information regarding collection and laboratory testing, see 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 dose are uncertain for severe or complicated influenza. Influenza A (H5N1) and A (H7N9) viruses have been shown to be associated with higher virus loads and more sustained viral replication (particularly in the lower respiratory tract) than seasonal influenza [23, 26, 28-30]. Pending further data, longer courses of treatment (e.g., 10 days) should be considered for severely ill hospitalized patients with infections with novel influenza A viruses that cause severe disease.
  • 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 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; an oropharyngeal (throat) swab 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 yield negative results. 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.
  • 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 and 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, the use of IV peramivir or investigational IV zanamivir should be considered.
  • While studies have shown benefit of parenteral peramivir for treatment of uncomplicated influenza in outpatients [11, 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 viruses, 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).
  • IV zanamivir is an investigational, parenterally administered neuraminidase inhibitor product available only by enrollment in an ongoing clinical trial, or under an emergency investigational new drug (EIND) request to the manufacturer for compassionate use in hospitalized adult and pediatric patients with severe influenza. (See CDC Considerations Related to Investigational Use of Intravenous Zanamivir for 2014-2015 Influenza Season.)
• Use of zanamivir in combination with oseltamivir or peramivir is not recommended, on the basis of data which suggest antagonism may occur when they are given simultaneously.
• It is possible that some novel influenza A viruses may 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. Oseltamivir or peramivir should not be stopped until IV zanamivir can be initiated. (See CDC Considerations Related to Investigational Use of Intravenous Zanamivir for 2014-2015 Influenza Season.)
• 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).

Outpatients

• Initiation of antiviral treatment with a neuraminidase inhibitor is recommended as early as possible for outpatients who are confirmed cases, probable cases, or cases under investigation based on exposure criteria consisting of contact with a confirmed human novel influenza A case or unprotected exposure in a laboratory. Treatment is not currently recommended for uncomplicated illness in outpatients whose exposure criteria consists only of travel to an area with human cases of H7N9 or H5N1, or where these viruses are known to be circulating in animals (see H7N9 case definitions and H5N1 case definitions).
• For outpatients with severe, progressive, or complicated illness, oseltamivir is recommended. For other outpatients, oral oseltamivir, inhaled zanamivir, or IV peramivir may be used.³
• When warranted, antiviral treatment should be initiated as early as possible, even if more than 48 hours has elapsed since illness onset. For illness caused by novel influenza A viruses associated with severe disease, treatment is recommended even for otherwise healthy persons, but is especially important for those at higher risk of influenza complications: this includes children <5 years, with highest risk for those aged <2 years old, adults aged ≥65 years, pregnant women, and persons with certain underlying medical conditions. (See the complete list of people considered to be at higher risk for influenza complications in the Influenza Antiviral Medications: Summary for Clinicians.)
• For outpatients who are confirmed cases, probable cases, or 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 uncomplicated influenza with a novel influenza A virus associated with severe human disease is two doses per day of oral oseltamivir or inhaled zanamivir for 5 days.
  • For IV peramivir, there are insufficient data for use in outpatients with infection with novel influenza A viruses that cause severe disease. The recommendation for uncomplicated seasonal influenza is one dose of IV peramivir for 1 day. For treatment of novel influenza A viruses, a single IV infusion is not recommended. Until evidence is available, if peramivir treatment is chosen, it should be given for at least 5 days.
• Inhaled zanamivir is not recommended for 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 see 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 website.

¹ This guidance is intended to address human infections with novel influenza A viruses that cause severe or progressive disease in otherwise healthy persons resulting in hospitalization and/or death. A number of different subtypes of novel influenza A viruses have been reported to cause severe pneumonia and death, including H5N1, H7N9, H7N2, H7N7, H9N2, H10N8, and H3N2v viruses; however, currently only H5N1 and H7N9 have caused severe illness in a high proportion of cases and have been reported in substantial numbers.

² “Outpatient” in this document refers to any patient in the ambulatory care setting, including emergency departments, urgent care and other clinics.

³ 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 see 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. (See H7N9 case definitions and H5N1 case definitions.)

Case category	Definition	Antiviral treatment1
Confirmed case	Novel influenza A virus infection in a patient that is confirmed by CDC’s Influenza Laboratory or a CDC certified public health laboratory using methods agreed upon by the CDC and the Council of State and Territorial Epidemiologists. Confirmation of novel influenza A viruses may be made by public health laboratories following CDC-approved protocols for detection of novel influenza A viruses, or by laboratories using an FDA-authorized test specific for detection of novel influenza A viruses.	Recommended for all (hospitalized patients and outpatients)
Probable case	Illness compatible with influenza in a patient meeting any of the exposure criteria below and for whom laboratory diagnostic testing is positive for influenza A, negative for H1, negative for H1pdm09, and negative for H3 by real-time reverse transcription polymerase chain reaction (RT-PCR) and therefore unsubtypeable.	Recommended for all (hospitalized patients and outpatients)
Case under investigation	Illness compatible with influenza in a patient meeting any of the exposure criteria below and for whom laboratory confirmation is not known or pending or for whom test results do not provide a sufficient level of detail to confirm novel influenza A virus infection.
Exposed during travel	Patients with recent travel (within <10 days of illness onset) to areas where human cases of novel influenza A virus infection have become infected or to areas where novel influenza A viruses are known to be circulating in animals.2	Recommended for hospitalized patients
Exposed to confirmed or probable case	Patients who have had recent close contact (within <10 days of illness onset) with confirmed or suspected3 cases of human infection with novel influenza A virus. Close contact may be regarded as coming within about 6 feet (2 meters) of a confirmed case while the case was ill (beginning 1 day prior to illness onset and continuing until resolution of illness). This includes healthcare personnel providing care for a confirmed case, family members of a confirmed case, persons who lived with or stayed overnight with a confirmed case, and others who have had similar close physical contact.4	Recommended for all (hospitalized patients and outpatients)
Exposure to birds infected with avian influenza	Patients who have had recent contact5 (within <10 days of illness onset) to infected sick or dead birds, or infected flocks.	Recommended for all (hospitalized patients and outpatients)
Unprotected laboratory exposure	Patients who have had recent (within <10 days of illness onset) unprotected exposure to live novel influenza A virus in a laboratory.	Recommended for all (hospitalized patients and outpatients)
1 For hospitalized patients and outpatients with severe, progressive, or complicated disease, oseltamivir is recommended. Inhaled zanamivir and IV peramivir are not recommended because of the lack of data for these patients. For outpatients with uncomplicated influenza, oseltamivir, inhaled zanamivir, or IV peramivir may be used. For specific dosage recommendations for treatment by age group, please see https://www.cdc.gov/flu/professionals/antivirals/antiviral-dosage.htm. 2 As of March 19, 2015, China was the only country where H7N9 viruses were known to be circulating in animals (poultry) or where human cases have become infected. For H5N1, please see WHO website. http://www.who.int/influenza/human_animal_interface/EN_GIP_20131210CumulativeNumberH5N1cases.pdf [39 KB, 2 pages] and link to countries with animal cases. For more information, including updates on countries affected, please see the CDC Novel/Avian Influenza A Virus Home Page. 3 Patients suspected of having infection with a novel influenza A virus can include probable cases, cases under investigation for infection with novel influenza A virus, and other patients for whom available clinical and epidemiologic information support a diagnosis of infection with novel influenza A virus. 4 Limited non-sustained person-to-person transmission of H7N9 virus could not be excluded in some family clusters [51]. Limited non-sustained person-to-person transmission of H5N1 virus has been reported in several countries following close, prolonged unprotectedcontact with a severely ill H5N1 patient, including in household and hospital settings. 5 May include: contact with birds (e.g., handling, slaughtering, defeathering, butchering, preparation for consumption); direct contact with surfaces contaminated with feces or bird parts (carcasses, internal organs, etc.); or prolonged exposure to birds in a confined space.

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