Interim Guidance on the Use of Antiviral Medications for the Treatment of Human Infections with Pandemic Influenza A(H7N9) Virus – September 13, 2018

Summary

This document provides guidance for antiviral treatment of human infection with pandemic influenza A(H7N9) virus.

This guidance merges and replaces the previously posted guidance on the use of antiviral agents for treatment of human infections with pandemic influenza A(H7N9). This guidance recommends antiviral treatment as soon as possible for all outpatients and hospitalized patients with suspected or confirmed pandemic A(H7N9) virus infection. These recommendations are based on expert opinion and available published and unpublished data on the treatment of infection caused by influenza viruses, including seasonal, novel, and pandemic viruses. This guidance will continue to be updated as additional information on virus transmissibility, epidemiology, and antiviral susceptibility patterns becomes available for the pandemic influenza A(H7N9) virus.

Background

Randomized controlled trials have demonstrated decreased time to symptom improvement when currently FDA-approved neuraminidase inhibitor (NAI) antiviral agents (oral oseltamivir, IV peramivir and inhaled 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 NAIs 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]. NAI treatment with oral oseltamivir, IV peramivir, and inhaled 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.

Investigational non-NAI antivirals including baloxavir and pimodivir provide alternative mechanisms to treating influenza. Baloxavir selectively inhibits influenza cap-dependent endonuclease. In recent Phase 2 clinical trials in adults and adolescents with uncomplicated influenza, single dose baloxavir was effective in reducing the time to alleviation of seasonal influenza symptoms similar to oseltamivir and was associated with greater reduction in seasonal influenza viral load than oseltamivir or placebo at 1 day after initiation²⁸. Pimodivir is a novel, non-nucleoside polymerase basic protein 2 subunit inhibitor and in early studies has been shown to effectively reduce seasonal influenza viral load in Phase 1 clinical trials^{29, 30}.

Similar to seasonal influenza viruses, the current circulating pandemic influenza A(H7N9) virus is susceptible to the NAIs (oseltamivir, peramivir and zanamivir), but resistant to the adamantanes (amantadine and rimantadine). Therefore, amantadine and rimantadine are not recommended for treatment of pandemic influenza A(H7N9) virus infections.

Recommendations

Hospitalized Patients

• Initiation of antiviral treatment with a NAI is recommended as early as possible for hospitalized patients who are suspected or confirmed cases of pandemic influenza A(H7N9) virus infection, 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.²
• Antiviral treatment should be empiric and not delayed for laboratory testing. 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. The pandemic influenza A(H7N9) virus has 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, 31-33]. Pending further data, longer courses of treatment (e.g., 10 days) should be considered for severely ill hospitalized patients with confirmed or suspected pandemic influenza A(H7N9) virus infections.
  • Clinical judgment should guide decisions to consider treatment regimens longer than 5 days for patients with severe and prolonged illness.
  • 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 patients³⁴. However, oral or enterically administered oseltamivir has been reported to be adequately absorbed in critically ill adults, with standard doses producing therapeutic blood levels³⁵. Although the higher dose was generally well-tolerated and not associated with severe adverse events, available data suggest that higher dosing may not provide additional clinical benefit for seasonal influenza and for pandemic 2009 influenza A(H1N1) ^{36, 37}. 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^38-40. Therefore, higher dosing is not recommended at this time.
• 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 ^{35, 41-47}. 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 is recommended.
  • While studies have shown benefit of parenteral peramivir for treatment of uncomplicated influenza in outpatients ^{11, 48}, 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 [49]. If used to treat hospitalized patients with pandemic 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 NAI product available through an emergency EUA/IND (placeholder link for more info). IV zanamivir has been studied in hospitalized adults and children at a dose of 600 mg twice daily in adults and children at a comparable dose. Outcomes of these studies showed a favorable virologic response and clinical improvement during the treatment course in clinical trials and during emergency use during the 2009 pandemic H1N1 virus [27, 50-52].
• 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.
• Critically ill patients in intensive care units who are significantly immunocompromised (e.g., hematopoietic stem cell transplant recipients) at high risk of prolonged influenza viral replication . Such patients are at risk of developing antiviral-resistant virus.
  • For these patients, oral baloxavir is recommended in combination with an NAI (oral oseltamivir, IV peramivir, or IV zanamivir). Baloxavir is available through an emergency IND. One dose should be given and repeat dosing may be considered after 5 days.
• It is possible that the pandemic influenza A(H7N9) virus may become resistant to NAIs and/or baloxavir during antiviral treatment with one of these agents [32, 53-58]. Although this is tested for by CDC on a subset of surveillance specimens, there is no clinical diagnostic testing available for antiviral resistance of pandemic influenza A(H7N9) virus at this time.

Outpatients

• Initiation of antiviral treatment with a neuraminidase inhibitor is recommended as early as possible for outpatients with suspected or confirmed pandemic influenza A(H7N9) virus infection. For illness caused by pandemic influenza A(H7N9) virus, 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.
• Clinical benefit is greatest when antiviral treatment is administered early, especially within 48 hours of influenza illness onset. However, antiviral treatment might have some benefits in outpatients with severe, complicated or progressive illness, and in outpatients who are at high risk for complications.
  • For outpatients with severe, progressive, or complicated illness, oral oseltamivir is recommended.
  • Oral oseltamivir is preferred for treatment of pregnant women [59, 60]. Pregnant women are recommended to receive the same antiviral dosing as non-pregnant persons. Multiple recent studies have reported safe use of neuraminidase inhibitors during pregnancy [61-68]. See Recommendations for Obstetric Health Care Providers Related to Use of Antiviral Medications in the Treatment and Prevention of Influenzafor additional information.
  • For other outpatients, oral oseltamivir or inhaled zanamivir may be used.²
  • For outpatients who are confirmed or suspected cases 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 pandemic influenza A(H7N9) virus 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 the pandemic influenza A(H7N9) virus that causes severe disease. The recommendation for uncomplicated seasonal influenza is one dose of IV peramivir for 1 day. For treatment of pandemic influenza A(H7N9) virus, 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).

To facilitate early initiation of treatment, when feasible, an antiviral prescription can be provided without testing and before an office visit. Patients at high risk of influenza complications (children <5 years old, adults age 65 and over, pregnant women, people with high-risk conditions (link to ACIP list) should be advised to call their provider promptly if they have acute respiratory symptoms. It may be useful for providers to implement phone triage lines to enable high-risk patients to discuss symptoms over the phone. Please see Algorithm to Assist in Medical Office Telephone Evaluation of Patients with Possible 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 CDC’s pandemic H7N9 website.

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 see FDA Approved Drugs for Influenza.

* Please see interim guidance for chemoprophylaxis in long-term care facilities/nursing home outbreaks (placeholder link).

¹ Oral oseltamivir is approved by the FDA for treatment of acute uncomplicated influenza within 2 days of illness onset in persons 14 days and older, and for chemoprophylaxis in persons 1 year and older. Although not part of the FDA-approved indications, use of oral oseltamivir for treatment of influenza in infants less than 14 days old, and for chemoprophylaxis in infants 3 months to 1 year of age, is recommended by the CDC and the American Academy of Pediatrics. If a child is younger than 3 months old, use of oseltamivir for chemoprophylaxis is not recommended unless the situation is judged critical due to limited data in this age group.

² Self-injury or delirium; mainly reported among Japanese adolescents and adults.

³ Inhaled zanamivir is approved by the FDA for treatment of acute uncomplicated influenza within 2 days of illness onset in persons aged 7 years and older, and for chemoprophylaxis of influenza in persons aged 5 years and older. Inhaled zanamivir is contraindicated in patients with history of allergy to milk protein.

⁴ Intravenous peramivir is approved by the FDA for treatment of acute uncomplicated influenza within 2 days of illness onset in persons aged 2 years and older. Peramivir efficacy is based on clinical trials in which the predominant influenza virus type was influenza A; a limited number of subjects infected with influenza B virus were enrolled.

⁵FDA has granted approval for EUIs to allow for treatment of hospitalized patients with oseltamivir and peramivir

⁶Baloxavir is an investigational drug and is not currently FDA-approved

⁷Zanamivir (IV) is an investigational drug and is not currently FDA-approved

* Please see interim guidance for chemoprophylaxis in long-term care facilities/nursing home outbreaks (placeholder link).

¹ Baloxavir is an investigational drug and is not currently FDA-approved; clinical data including laboratory values, hospital course, and outcomes will be collected regarding use through the emergency IND mechanism

² Zanamivir (IV) is an investigational drug and is not currently FDA-approved

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