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Interim Guidance on the Use of Antiviral Agents for Treatment of Human Infections with Avian Influenza A (H7N9) Virus

This document replaces “Interim Guidance on the Use of Antiviral Agents for Treatment of Human Infections with Avian Influenza A (H7N9) Virus” posted on April 18, 2013. Since that date, a Health Advisory with updated recommendations for testing and updated case definitions for H7N9 virus infection were released to reflect current epidemiology of H7N9 cases and risk assessment for infection. This guidance on antiviral treatment has been updated to be consistent with current CDC and World Health Organization recommendations, and provides updated recommendations for antiviral treatment of confirmed cases and probable cases of human infection with avian influenza A (H7N9), as well as cases under investigation for human infection with avian influenza A (H7N9) virus in the United States.

The previous guidance recommended antiviral treatment for all confirmed cases, probable cases, and cases of H7N9 under investigation. The new guidance continues to recommend treatment for all hospitalized H7N9 cases, and for confirmed and probable outpatient H7N9 cases. The primary change in the new guidance is that outpatient cases under investigation who have had recent close contact with a confirmed H7N9 case should receive antiviral treatment, whereas outpatients meeting only the travel exposure criteria for a case under investigation are not recommended to receive antiviral treatment (see Interim Guidance on Case Definitions to be Used for Novel Influenza A (H7N9) Case Investigations in the United States). For guidance on investigation of close contacts of confirmed or probable cases, see new Interim Guidance on the Use of Antiviral Medications for Chemoprophylaxis of Close Contacts of Persons with Avian Influenza A (H7N9) Virus Infection).

These recommendations are based upon expert opinion and available published and unpublished data on the treatment of other influenza viruses, including seasonal, pandemic, and zoonotic viruses. This guidance will continue to be updated as additional information on H7N9 virus transmissibility, epidemiology, and antiviral susceptibility patterns becomes available.

Summary and Background

Randomized controlled trials have demonstrated decreased time to symptom improvement when currently approved antiviral agents are used to treat healthy persons with acute uncomplicated influenza caused by circulating seasonal influenza viruses within the first few days of illness [1-9]. On the basis of these trials and additional pooled analyses and observational studies [10-12], most experts believe that when antiviral agents are given early in the course of uncomplicated influenza illness, both the duration of symptoms and the likelihood of complications are reduced. Clinical benefit is greatest when antiviral treatment is administered early, especially within 48 hours of influenza illness onset [1-16]. Among patients hospitalized with seasonal influenza A (including 2009 H1N1) or B, or avian influenza A (H5N1) virus infections, observational studies suggest that early treatment reduces disease severity and mortality [17-26]. 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 [25, 27-33]. Antiviral agents have been used for treatment of persons infected with the H7N9 virus, although the effectiveness of early neuraminidase inhibitor treatment has not yet been determined [34-37]. Laboratory testing indicates that most H7N9 viruses are susceptible to the neuraminidase inhibitors (oseltamivir and zanamivir), but similar to seasonal influenza viruses, they are resistant to the adamantanes (amantadine and rimantadine). Therefore, amantadine and rimantadine are not recommended for treatment of H7N9 virus infection

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 H7N9 cases under investigation, even if more than 48 hours has elapsed since illness onset.
  • For hospitalized patients and patients with severe or complicated illness, treatment with oral or enterically administered oseltamivir is recommended. Inhaled zanamivir is not recommended because of the lack of data for use in patients with severe influenza disease.
  • Laboratory testing and initiation of antiviral treatment should occur simultaneously; treatment should not be delayed while waiting for laboratory testing results. (For information regarding collection and laboratory testing, please see Interim Guidance for Specimen Collection, Processing, and Testing for Patients Who May Be Infected with Avian Influenza A (H7N9) Virus.)
  • The recommended treatment course for uncomplicated influenza is two doses per day of a neuraminidase inhibitor medication for 5 days; however, the optimal duration and dose are uncertain for severe or complicated influenza. Pending further data, longer courses of treatment (e.g., 10 days of treatment) should be considered for severely ill hospitalized H7N9 patients.
    • Clinical judgment and virologic testing of lower respiratory tract specimens by rRT-PCR should guide decisions to consider treatment regimens longer than 5 days for patients with severe and prolonged illness, until clearance of viral shedding. For patients with lower respiratory tract disease, lower respiratory tract specimens, such as bronchoalveolar lavage or endotracheal aspirate, are preferred; an oropharyngeal (throat) swab may be collected if lower respiratory specimens are not available.
    • Longer treatment regimens might be necessary in immunosuppressed persons who may have prolonged viral replication and also 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) for treatment of influenza in immunocompromised patients and in severely ill hospitalized patients, although it is unknown if this provides clinical benefit [38-40].
  • Although oral or enterically delivered oseltamivir is well absorbed in critically ill influenza patients [41-45], for patients who cannot tolerate or absorb oral oseltamivir because of suspected or known gastric stasis, malabsorption, or gastrointestinal bleeding, the use of investigational intravenous (IV) zanamivir should be considered. IV zanamivir is an investigational parenterally administered neuraminidase inhibitor product available by enrollment in a clinical trial or compassionate use under an emergency investigational new drug (EIND) request to the manufacturer. An IV zanamivir compassionate use request may be made by contacting the GSK Clinical Support Help Desk via email (gskclinicalsupportHD@gsk.com) or by calling 1-877-626-8019 or 1-866-341-9160. The GSK Clinical Support Help Desk will provide information and instructions on obtaining IV zanamivir, assess eligibility for clinical trials, and provide the EIND form that needs to be completed to obtain FDA approval of release of the drug.
  • It is possible that some H7N9 viruses may rapidly become oseltamivir-resistant and remain zanamivir-susceptible [46]. If a hospitalized patient treated with oseltamivir manifests progressive lower respiratory symptoms, resistant virus should be considered, and, after consultation with the CDC Influenza Division, investigation for antiviral resistance should be performed and oseltamivir should be stopped when IV zanamivir can be initiated.
  • 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).

Uncomplicated Illness in 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 H7N9 case. Treatment is not currently recommended for outpatients whose exposure criteria consists only of travel to an area with H7N9 cases (see Interim Guidance on Case Definitions to be Used for Novel Influenza A (H7N9) Case Investigations in the United States).
  • When warranted, antiviral treatment should be initiated as early as possible, even if more than 48 hours has elapsed since illness onset. For H7N9, 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. Please see link for complete list of people considered to be at higher risk for influenza complications at Influenza Antiviral Medications: Summary for Clinicians.
  • For outpatients 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 duration of treatment for uncomplicated illness is 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 Guidance on the Use of Influenza Antiviral Agents: Dosage.

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. 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.

CDC will continue to evaluate new information as it becomes available and will update this guidance as needed. Updated information will be provided on the CDC website at Avian Influenza A (H7N9) Virus).

Table. Antiviral treatment recommendations according to case definition category.

Case categoryDefinitionAntiviral treatment1
Confirmed caseAvian influenza A (H7N9) 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 avian influenza A (H7N9) viruses may be made by public health laboratories following CDC-approved protocols for detection of avian influenza A (H7N9) virus, or by laboratories using an FDA-authorized test specific for detection of avian influenza A (H7N9) virus.Recommended for hospitalized patients and outpatients
Probable caseIllness 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 hospitalized patients and outpatients
Case under investigationIllness 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 avian influenza A (H7N9) virus infection. 

Exposed during travel

Patients with recent travel (within <10 days of illness onset) to areas where human cases of avian influenza A (H7N9) virus infection have become infected or to areas where avian influenza A (H7N9) viruses are known to be circulating in animals. 2Recommended for hospitalized patients

Exposed to confirmed case

Patients who have had recent close contact (within <10 days of illness onset) with confirmed cases of human infection with avian influenza A (H7N9) 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. 3Recommended for hospitalized patients and outpatients

1 For specific guidance on medications recommended for treatment of H7N9 infections, see Interim Guidance on the Use of Antiviral Agents for Treatment of Human Infections with Avian Influenza A (H7N9) Virus – September 30, 2013. For specific dosage recommendations for treatment by age group, please see Guidance on the Use of Influenza Antiviral Agents: Dosage.

2 As of September 30, 2013, China was the only country where avian influenza A (H7N9) viruses were known to be circulating in animals or where human cases have become infected. For more information, including updates on countries affected, please see the CDC Avian Influenza A (H7N9) Virus information page.

3 Limited data are available for avian influenza A (H7N9); however, limited person-to-person transmission of avian influenza A (H5N1) virus has been demonstrated only with close, prolonged physical contact.

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