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Interim Guidance on the Use of Antiviral Medications for Chemoprophylaxis of Close Contacts of Persons with Avian Influenza A (H7N9) Virus Infection

This document provides interim guidance to help clinicians determine when influenza antiviral agents should be used for chemoprophylaxis of close contacts of confirmed or probable cases of human infection with avian influenza A (H7N9) in the United States. (H7N9 virus updates are available at Avian Influenza A (H7N9) Virus). These recommendations are based upon expert opinion and currently available published and unpublished data for antiviral treatment and chemoprophylaxis of seasonal, pandemic, and zoonotic influenza. This guidance will be updated as additional information on H7N9 virus epidemiology and transmissibility becomes available.

These interim recommendations are based upon available information and the following considerations:

  • There is no available H7N9 vaccine at this time.
  • This virus has caused severe disease and substantial mortality among detected H7N9 cases to date.
  • Limited, non-sustained human-to-human H7N9 virus transmission cannot be excluded in some case clusters in China.
  • Sufficient supplies of antiviral agents that are expected to be effective against H7N9 are available.

The public health goal of this interim guidance is to prevent further spread of H7N9 if there is introduction/travel of infected persons into the United States. It is specific to a scenario where there are sporadic H7N9 cases associated with poultry exposure and possible limited, non-sustained human-to-human H7N9 virus transmission in China. This guidance will be updated if circumstances change.

Definition of Close Contacts

Close contacts are defined as persons within approximately 6 feet (2 meters) or within the room or care area of a confirmed or probable H7N9 case patient for a prolonged period of time, or with direct contact with infectious secretions (such as being directly in the path of a sneeze) while the patient was likely to be infectious (beginning 1 day prior to onset of signs and/or symptoms and continuing until resolution of illness). 1

In general, decisions to initiate antiviral chemoprophylaxis should be guided by the risk stratification described below,2 based on observational data for reported cases of human infections with H7N9 and H5N1 viruses, and on data from seasonal influenza studies.

  1. Highest-risk exposure groups (greatest possible risk of transmission)
    • Household or close family member contacts of a confirmed or probable case
  2. Moderate-risk exposure groups (unknown risk of transmission)
    • Health care personnel with higher-risk contact with a confirmed or probable case (e.g., during bronchoscopy or intubation; or while performing tracheal suctioning, delivering nebulized drugs, or handling inadequately screened/sealed body fluids without use of recommended personal protective equipment (PPE); or with a recognized breach in PPE procedures)
  3. Low-risk exposure groups (transmission unlikely)
    • Others who have had social contact of a short duration with a confirmed or probable case in a non-hospital setting (e.g., in a community or workplace environment)3

Follow-up of Close Contacts of an H7N9 Case-Patient

Public health personnel should attempt to identify and monitor all close contacts of all confirmed or probable cases of human infection with avian influenza A (H7N9) virus (see Interim Guidance on Case Definitions to be Used for Novel Influenza A (H7N9) Case Investigations in the United States) for new illness as soon as possible. Available data suggest that the estimated incubation period for human infection with H7N9 virus is generally 3 to 7 days, but has been reported to be as long as 10 days [1, 2].

Therefore, identified close contacts should be monitored daily for 10 days after the last known exposure to a confirmed or probable H7N9 case. Measured temperature and presence of respiratory symptoms should be assessed daily during this period. Any close contacts of a confirmed or probable H7N9 case with a measured temperature of ≥38.0°Celsius (≥100.4° F) or any new respiratory symptoms (e.g., cough, sore throat, shortness of breath, difficulty breathing) should be referred for prompt medical evaluation and testing for H7N9 virus infection. To facilitate investigation, and if resources are available, close contacts of H7N9 cases under investigation also may be identified and monitored for symptoms while the results of laboratory testing are pending.

Post-exposure Chemoprophylaxis of Asymptomatic Close Contacts

  • Oseltamivir or inhaled zanamivir chemoprophylaxis should be provided to close contacts of a confirmed or probable H7N9 case patient according to risk of exposure.
    • In high-risk exposure groups, chemoprophylaxis should be administered.
    • In moderate-risk exposure groups, chemoprophylaxis could be considered.
    • In low-risk exposure groups, chemoprophylaxis is not routinely recommended.
  • Decisions to initiate antiviral chemoprophylaxis for persons in moderate- and low-risk exposure groups should be based on clinical judgment, with consideration given to the type of exposure and to whether the close contact is at high risk for complications from influenza (see Influenza Antiviral Medications: Summary for Clinicians).
  • Administration of chemoprophylaxis should begin as soon as possible after first exposure to the confirmed or probable case.
  • The treatment dose for neuraminidase inhibitors (two doses per day) is recommended instead of the typical chemoprophylaxis regimen (1 dose per day). For dosage recommendations for treatment by age group, please see Guidance on the Use of Influenza Antiviral Agents: Dosage.
    • This recommendation for twice daily chemoprophylaxis dose is based on limited data that support higher chemoprophylaxis dosing in animals for avian influenza A (H5N1) virus [3], and on the desire to prevent development of antiviral resistance while receiving chemoprophylaxis [4-6].
  • Chemoprophylaxis with treatment doses of a neuraminidase inhibitor medication should be continued for 5 or 10 days. If exposure was time-limited and not ongoing, 5 days of medication from the last known exposure is recommended. If exposure is likely to be ongoing (e.g., household setting), 10 days is recommended because of the potential for prolonged infectiousness in the H7N9 case-patient.
  • Oral oseltamivir is recommended for persons of any age including newborn infants; inhaled zanamivir for persons aged 7 years and older.4 Inhaled zanamivir is not recommended for persons with underlying airway disease (e.g., asthma or chronic obstructive pulmonary disease). Physicians should consult the manufacturer’s package insert for dosing, limitations of populations studied, contraindications, and adverse effects.

Antiviral Treatment of Symptomatic Close Contacts (H7N9 Cases under Investigation)

New Symptoms after Use of an Antiviral Agent

  • If a close contact becomes symptomatic or has worsening of symptoms after or during use of an antiviral agent, contact with other persons should be minimized, appropriate infection prevention and control measures should be used in health care settings (see Interim Guidance for Infection Control Within Healthcare Settings When Caring for Patients with Confirmed, Probable, or Cases Under Investigation of Avian Influenza A(H7N9) Virus Infection), and respiratory specimens should be collected for H7N9 virus testing at the state health department as soon as possible.
  • If a close contact tests positive for H7N9 and had taken oseltamivir chemoprophylaxis for more than 2 days [7], oseltamivir should be stopped as soon as possible when treatment with inhaled zanamivir (twice daily) can be initiated, because it is possible that some H7N9 viruses may rapidly become oseltamivir-resistant and remain zanamivir-susceptible. If the patient manifests progressive lower respiratory symptoms, the patient should be promptly hospitalized for treatment with investigational intravenous zanamivir, available by enrollment in a clinical trial or compassionate use under an emergency investigational new drug (EIND) request. 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.
  • Investigation for antiviral resistance should be initiated immediately (in conjunction with the CDC Influenza Division), and infection prevention and control measures recommended for patients with H7N9 infection should be implemented (see Interim Guidance for Infection Control Within Healthcare Settings When Caring for Patients with Confirmed, Probable, or Cases Under Investigation of Avian Influenza A(H7N9) Virus Infection).
  • 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).

CDC will provide updated information as it becomes available on the CDC website at Avian Influenza A (H7N9) Virus).

1 Limited data are available regarding risk of transmission for H7N9 virus; however, limited non-sustained person-to-person transmission of avian influenza A (H5N1) virus has been demonstrated only with close, prolonged, unprotected exposure to a symptomatic H5N1 patient either at home or in a hospital. To define a close contact, this document uses “within approximately 6 feet of an ill person” to include the potential for transmission by small particle droplet nuclei within the vicinity of the patient or large droplets. Three feet has often been used by infection control professionals to define close contact and is based on studies of respiratory virus infections; however, for practical purposes, this distance may range up to 6 feet or more. The World Health Organization defines close contact as "approximately 1 meter;" the U.S. Occupational Safety and Health Administration uses "within 6 feet." For consistency with infection control recommendations for healthcare settings, this document also defines “within the room or care area of an H7N9 patient” as close contact for a health care provider or caregiver.

2 Exposure groups adapted from the stratification of risks for human H5N1 infection from the “World Health Organization Rapid Advice Guidelines on pharmacological management of humans infected with avian influenza A (H5N1) virus, 2006” (WHO Rapid Advice Guidelines on pharmacological management of humans infected with avian influenza A (H5N1) virus)

3 Recommendations for special situations (e.g., travelers potentially exposed to H7N9 influenza virus during air travel) will be made in the setting of specific contact investigation protocols.

4 Oral oseltamivir is approved by the FDA for treatment of acute uncomplicated influenza with twice-daily dosing in persons >14 days old, and for prophylaxis with once-daily dosing in persons 1 year and older. Although use of oral oseltamivir for treatment of influenza in infants less than 14 days old, and for prophylaxis in infants less than 1 year of age, are not part of the FDA-approved indications, this use is recommended by the CDC and the American Academy of Pediatrics. Inhaled zanamivir is approved for treatment of acute uncomplicated influenza with twice-daily dosing in persons aged 7 years and older, and for prophylaxis with once-daily dosing in persons aged 5 years and older. Because this guidance recommends chemoprophylaxis using the twice-daily dosing studied in clinical trials of influenza treatment rather than the once-daily dosing studied in clinical trials supporting approval for influenza prophylaxis, it is recommended than inhaled zanamivir be used only in persons aged 7 years and older.

 

References

1. Li Q, Zhou L, Zhou M, et al. Preliminary Report: Epidemiology of the Avian Influenza A (H7N9) Outbreak in China. The New England journal of medicine 2013.

2. Chen Y, Liang W, Yang S, et al. Human infections with the emerging avian influenza A H7N9 virus from wet market poultry: clinical analysis and characterisation of viral genome. Lancet 2013; 381(9881): 1916-25.

3. Boltz DA, Rehg JE, McClaren J, Webster RG, Govorkova EA. Oseltamivir prophylactic regimens prevent H5N1 influenza morbidity and mortality in a ferret model. The Journal of infectious diseases 2008; 197(9): 1315-23.

4. Centers for Disease C, Prevention. Oseltamivir-resistant 2009 pandemic influenza A (H1N1) virus infection in two summer campers receiving prophylaxis--North Carolina, 2009. MMWR Morbidity and mortality weekly report 2009; 58(35): 969-72.

5. Baz M, Abed Y, Papenburg J, Bouhy X, Hamelin ME, Boivin G. Emergence of oseltamivir-resistant pandemic H1N1 virus during prophylaxis. The New England journal of medicine 2009; 361(23): 2296-7.

6. Cane A, Casanueva E, Iolster T, et al. First isolation of a oseltamivir-resistant influenza A (H1N1) strain in Argentina. The Pediatric infectious disease journal 2010; 29(4): 384.

7. Hu Y, Lu S, Song Z, et al. Association between adverse clinical outcome in human disease caused by novel influenza A H7N9 virus and sustained viral shedding and emergence of antiviral resistance. Lancet 2013.

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