COMMENTARY

Neuraminidase Inhibitors: Ready and Able to Tackle the Flu

Alicia Fry, MD, MPH

Disclosures

April 27, 2015

Editorial Collaboration

Medscape &

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Hello. I am Alicia Fry, a physician in the Influenza Division at the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia. I am happy to speak with you today as part of the CDC Expert Commentary Series on Medscape.

Today I will be speaking with you about influenza antiviral medications—the only therapeutic drugs currently approved and recommended to treat influenza. The influenza antiviral medications I'll discuss today were approved in 1999. Since that time, a growing body of evidence has shown that early antiviral treatment can shorten the duration of fever and illness symptoms, reduce the risk for influenza complications, and reduce the risk for death in patients hospitalized with influenza. However, data from recent flu seasons indicate that antivirals are underused.[1,2] In the next few minutes, I will briefly describe CDC's antiviral recommendations, and then spend some time reviewing data supporting the benefits of treating influenza with antiviral medications.

During flu season, influenza should be high on the list of possible diagnoses for ill patients. CDC recommends that all hospitalized patients and all high-risk patients— either hospitalized or managed as outpatients —with suspected influenza should be treated as soon as possible with one of three approved influenza neuraminidase inhibitor antiviral medications. For any previously healthy (non-high risk) outpatients with suspected or confirmed influenza, neuraminidase inhibitors are licensed for use and may be prescribed on the basis of clinical judgment.

Treatment should begin as early as possible and without waiting for confirmatory influenza testing results. Although several studies suggest some therapeutic benefit even when treatment is initiated later, antiviral medications work best when given early. Waiting for laboratory confirmation not only potentially delays treatment, but results of conventional rapid influenza diagnostic tests -- immunoassays that can identify influenza viral nucleoprotein antigens in respiratory specimens may be inaccurate. Test sensitivities are 50%-70% when compared with viral culture or reverse-transcription polymerase chain reaction.

Evidence for the benefits of treatment of hospitalized patients with antiviral medications comes from observational studies.[3,4,5,6,7,8,9,10] Observational studies are especially important when data from randomized controlled trials (RCTs) are not available to address questions relevant to specific outcomes or to certain high-risk groups.

No RCTs have compared influenza antivirals with placebo alone in hospitalized patients, because antiviral treatment is recommended for all hospitalized patients with suspected influenza and having a placebo group would be considered unethical. However, results from observational studies show consistent clinical benefit of early treatment with neuraminidase inhibitor antiviral medications in reducing the risk for death in hospitalized patients with influenza.

A large meta-analysis conducted across 38 countries and involving individual patient-level data from more than 29,000 patients in 78 studies during the 2009 pandemic showed that treatment of adults with neuraminidase inhibitor antiviral drugs reduced the risk for death by 25% compared with no antiviral treatment. Early treatment (within 48 hours of symptom onset) was more effective, reducing the risk for death in adults by one half.[11] Although many studies have reported that clinical benefit is greatest when oseltamivir treatment is started within 48 hours of illness onset, a few studies suggest some clinical benefit when oseltamivir treatment is started up to 4 or 5 days after illness onset.[6,12]

For treatment of outpatients, CDC considers the evidence available from RCTs and analysis of pooled RCT data. The recently published meta-analysis by Dobson and colleagues[13] of individual patient-level data from published and unpublished trials including more than 4000 patients showed that oseltamivir treatment of laboratory-confirmed influenza in adults shortens the amount of time it takes for symptoms to resolve by about 25 hours. Findings also showed that oseltamivir treatment of influenza in adults reduces the risk for lower respiratory tract complications by 44%, and the risk for hospitalization by 63%.

The study included results for the intention-to-treat-infected population, composed of all enrolled flu-positive patients; the intention-to-treat population composed of all enrolled flu-positive and flu-negative patients; and the intention-to-treat uninfected population. As expected, no benefits from oseltamivir were observed in the patients who were not infected with influenza. This study was funded by the Multiparty Group for Advice on Science foundation and an unrestricted grant from Roche.

The meta-analysis by Dobson and colleagues adds to a growing body of literature that shows benefit of neuraminidase inhibitors. Some of the findings of this individual patient-level data meta-analysis are similar to those of a conventional meta-analysis of RCTs published in 2014 by the Cochrane Collaboration,[14] which analyzed only the intention-to-treat population (all flu-positive and flu-negative patients with influenza-like illness were included).

In adults with influenza-like illness, early oral oseltamivir treatment shortened the duration of symptoms by approximately 17 hours compared with placebo, and inhaled zanamivir reduced symptoms in adults by approximately one half-day compared with placebo. The Cochrane analysis also found a 45% reduction in clinical pneumonia in patients who received antibiotics, but pneumonia was not verified by chest radiography, and pneumonia lacks a consistent definition across trials.

Unlike the patient-level intention-to-treat-infected analysis conducted by Dobson and colleagues, no effect on hospitalization was found in the intention-to-treat population analyzed by the Cochrane investigators. This difference may be the result of analyzing different patient populations, or because different studies were included in the two analyses.

Evidence for the benefits of treating high-risk outpatients to prevent such future complications as hospitalization has come largely from pooled RCTs. This is because few studies enrolled high-risk patients, and early RCTs of neuraminidase inhibitors were not large enough to measure the effect on preventing influenza-associated hospitalizations. However, published studies of pooled RCT data have found that flu antiviral drugs can prevent serious flu complications in outpatients.[15,16] Pooled RCT data also have consistently shown a reduction in clinical pneumonia requiring antibiotics among patients with laboratory-confirmed flu who receive neuraminidase inhibitors.[15] In addition, some RCTs showed trends that are comparable with these pooled results, although numbers were relatively small.[17,18,19]

Published data from RCTs, observational studies, and meta-analyses provide consistent evidence of benefits from treatment of suspected and confirmed influenza with neuraminidase inhibitors, and provide the evidence base for recommendations. CDC and other groups, including the Infectious Diseases Society of America and the American Academy of Pediatrics, consider all available evidence and focus the antiviral treatment recommendations where the burden of influenza disease is the greatest—on severely ill and people at high risk for complications from influenza.

Please refer to the CDC website for a complete summary of CDC's current antiviral recommendations.

Web Resources

Antiviral Recommendations

Influenza Antiviral Medications: Summary for Clinicians

People at High Risk of Developing Flu-Related Complications

Guidance for Clinicians on the Use of Rapid Influenza Diagnostic Tests

Alicia M. Fry, MD, MPH, is a medical officer and team lead for the Influenza Prevention and Control Team, Epidemiology and Prevention Branch, Influenza Division, within CDC's National Center for Immunization and Respiratory Diseases (NCIRD). She oversees epidemiologic activities related to influenza vaccine, antiviral effectiveness, and antiviral resistance, as well as other projects related to the morbidity and mortality of influenza viruses.

Dr Fry joined the CDC in 1999 as an Epidemic Intelligence Service officer in the Respiratory Diseases Branch of the Division of Bacterial and Mycotic Diseases. In subsequent years, she served as a medical officer in the division's Foodborne and Diarrheal Disease Branch and the International Activities Branch of the Division of Tuberculosis Elimination in the National Center for HIV/AIDS, Viral Hepatitis,STD, and TB Prevention. Before her current post, Dr Fry was the medical officer and team lead for the Respiratory and Enterovirus team of the Epidemiology Branch in NCIRD's Division of Viral Diseases.

Dr Fry earned her Doctorate of Medicine from the University of Cincinnati College of Medicine in Ohio. After completing her residency in internal medicine at Johns Hopkins Hospital in Baltimore, Dr Fry completed subspecialty training in infectious diseases and a molecular medicine fellowship at the University of California, San Francisco. She subsequently earned her Master of Public Health degree from the University of California, Berkeley. She is the author of more than 100 peer-reviewed journal articles. In addition to her work at the CDC, Dr Fry serves as a clinician in the Infectious Diseases Clinic for the Veterans Affairs Medical Center in Atlanta, Georgia.

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