Cochrane for Clinicians
Putting Evidence into Practice
Neuraminidase Inhibitors for Influenza Treatment and Prevention in Healthy Adults
Am Fam Physician. 2010 Aug 1;82(3):242-244.
A previously healthy woman presents in the middle of the influenza season with a one-day history of cough and a fever of 101° F (38.3° C). She asks if there is a medication to help treat her illness and to prevent her family members from getting ill.
Should neuraminidase inhibitors be used for preventing or treating influenza in healthy adults?
Although neuraminidase inhibitors can reduce the risk of contracting symptomatic, confirmed influenza and reduce the time to recovery for those with laboratory-confirmed influenza, they are not effective for reducing the risk of influenza-like illness or asymptomatic influenza infection in healthy adults. It is uncertain whether neuraminidase inhibitors prevent respiratory complications of influenza.1 (Strength of Recommendation = A, based on consistent, good-quality patient-oriented evidence)
Background: Neuraminidase inhibitors are recommended for use against influenza and its complications in interpandemic years and during pandemics.
Objectives: To assess the effects of neuraminidase inhibitors in preventing and treating influenza, its transmission, and its complications in otherwise healthy adults, and to estimate the frequency of adverse effects.
Search Strategy: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library 2009, issue 3), which contains the Acute Respiratory Infections Group’s specialized register; Medline (1950 to August 2009); and EMBASE (1980 to August 2009).
Selection Criteria: Randomized controlled trials (RCTs) or quasirandomized, placebo-controlled trials of neuraminidase inhibitors in healthy adults exposed to naturally occurring influenza.
Data Collection and Analysis: Two review authors independently applied inclusion criteria, assessed trial quality, and extracted data. They structured the comparisons into prophylaxis, treatment, and adverse events, with further subdivision by outcome and dose.
Main Results: The authors identified four prophylaxis, 12 treatment, and four postexposure prophylaxis trials. In prophylaxis compared with placebo, neuraminidase inhibitors had no effect against influenza-like illnesses (risk ratio [RR] ranging from 1.28 for oral oseltamivir [75 mg daily] to 0.76 for inhaled zanamivir [10 mg daily]). The effectiveness of oral oseltamivir against symptomatic influenza was 76 percent at a dosage of 75 mg daily, and 73 percent at a dosage of 150 mg daily. Inhaled zanamivir (10 mg daily) performed similarly. Neither neuraminidase inhibitor had a significant effect on asymptomatic influenza. Oseltamivir induced nausea (odds ratio = 1.79; 95% confidence interval [CI], 1.10 to 2.93). Oseltamivir for postexposure prophylaxis had an effectiveness of 58 and 84 percent in two trials for households. Zanamivir performed similarly. The hazard ratios for time to alleviation of symptoms were in favor of the treated group at 1.20 (95% CI, 1.06 to 1.35) for oseltamivir and 1.24 (95% CI, 1.13 to 1.36) for zanamivir. Because of the exclusion of a review of mainly unpublished trials of oseltamivir, insufficient evidence remained to reach a conclusion on the prevention of complications requiring antibiotics in influenza cases (RR = 0.57; 95% CI, 0.23 to 1.37). Analysis of the U.S. Food and Drug Administration and Japan’s Pharmaceuticals and Medical Devices Agency regulators’ pharmacovigilance dataset revealed incomplete reporting and description of harms, preventing the authors from reaching firm conclusions on the central nervous system toxicity of neuraminidase inhibitors.
Authors’ Conclusions: Numerous inconsistencies detected in the available evidence, followed by an inability to adequately access the data, has undermined confidence in the authors’ previous conclusions for oseltamivir. Independent RCTs to resolve these uncertainties are needed.
These summaries have been derived from Cochrane reviews published in the Cochrane Database of Systematic Reviews in the Cochrane Library. Their content has, as far as possible, been checked with the authors of the original reviews, but the summaries should not be regarded as an official product of the Cochrane Collaboration; minor editing changes have been made to the text (http://www.cochrane.org).
The neuraminidase inhibitors oseltamivir (Tamiflu) and zanamivir (Relenza) have been available for more than 10 years for the prevention and treatment of influenza. Because influenza A and B viruses depend on neuraminidase for viral replication, neuraminidase inhibitors are effective against both types. Older adamantanes (amantadine and rimantadine [Flumadine]) are only effective against influenza A subtypes. Neuraminidase inhibitors were recommended for the treatment of influenza-like illness and 2009 H1N1 influenza (swine flu) during the 2009 to 2010 influenza season, and for prophylaxis of exposed persons, based on resistance of 2009 H1N1 influenza to adamantanes.2
The authors of this Cochrane review1 set out to update information on the effectiveness of neuraminidase inhibitors against influenza from their earlier Cochrane review on this subject,3 and to address the risk of adverse events from treatment with neuraminidase inhibitors. Consistent with the earlier review, they found evidence supporting the effectiveness of neuraminidase inhibitors for preventing symptomatic, laboratory-confirmed influenza; reducing household transmission of influenza; reducing sick days in those who contracted influenza from household members; and reducing time to alleviation of symptoms in those with influenza. However, neuraminidase inhibitors did not prevent influenza-like illness (i.e., constitutional symptoms and fever with cough or sore throat) or asymptomatic influenza infection.
The earlier Cochrane review reported that oseltamivir prevented lower respiratory tract complications.3 The authors noted that this conclusion depended heavily on one review that included unpublished industry data. When they were unable to obtain these data from the manufacturer, the authors excluded this review from analysis for the current Cochrane review.1 They found the remaining evidence inadequate to demonstrate whether neuraminidase inhibitors reduce complications of influenza, such as pneumonia, bronchitis, or other respiratory infections requiring treatment with antibiotics. This issue was addressed by one of the authors in a separate commentary.4
Two other limitations in published data affected the authors’ ability to fully appraise the risk-benefit balance for using neuraminidase inhibitors to treat influenza.1 First, they were unable to completely assess rates of severe adverse events, including psychiatric events, because of inconsistencies in reporting of adverse events across databases. Second, they noted that some of the trials demonstrating the effectiveness of neuraminidase inhibitors had an unusually high prevalence of influenza among participants, which might give overly optimistic estimates of effectiveness.
Neuraminidase inhibitors appear effective for reducing sick days in those with influenza and those who contracted influenza from persons in their household. However, neuraminidase inhibitors do not prevent influenza-like illness during influenza season or asymptomatic infection with influenza virus, and there is insufficient evidence to determine whether they meaningfully reduce the risk of influenza respiratory complications requiring antibiotics. Thus, it is unclear if neuraminidase inhibitors can actually decrease the spread of influenza and the rate of serious complications during an epidemic or pandemic, or if they serve mainly to relieve symptoms in those infected.
The Advisory Committee on Immunization Practices has recommended annual influenza vaccination to include all persons who are six months and older,5 and the evidence in this Cochrane review reinforces the importance of relying on vaccination rather than prophylaxis with neuraminidase inhibitors for reducing influenza transmission.1
Address correspondence to William E. Cayley, Jr., MD, MDiv, at firstname.lastname@example.org. Reprints are not available from the author.
Author disclosure: Nothing to disclose.
1. Jefferson T, Jones M, Doshi P, Del Mar C, Dooley L, Foxlee R. Neuraminidase inhibitors for preventing and treating influenza in healthy adults. Cochrane Database Syst Rev. 2010;(2):CD001265.
2. Centers for Disease Control and Prevention. Updated interim recommendations for the use of antiviral medications in the treatment and prevention of influenza for the 2009–2010 season. December 2009. http://cdc.gov/H1N1flu/recommendations.htm. Accessed June 14, 2010.
3. Jefferson TO, Demicheli V, Di Pietrantonj C, Jones M, Rivetti D. Neuraminidase inhibitors for preventing and treating influenza in healthy adults. Cochrane Database Syst Rev. 2006;(3):CD001265.
4. Doshi P. Neuraminidase inhibitors—the story behind the Cochrane review. BMJ. 2009;339:b5164.
5. CDC’s Advisory Committee on Immunization Practices (ACIP) recommends universal annual influenza vaccination [news release]. Atlanta, Ga.: CDC Division of Media Relations; February 24, 2010. http://cdc.gov/media/pressrel/2010/r100224.htm. Accessed June 14, 2010.
The Cochrane Abstract is a summary of a review from the Cochrane Library. It is accompanied by an interpretation that will help clinicians put evidence into practice. Dr. Cayley presents a clinical scenario and question based on the Cochrane Abstract, followed by an evidence-based answer and a critique of the review. The practice recommendations in this activity are available at http://www.cochrane.org/reviews/en/ab001265.html.
The series coordinator for AFP is Clarissa Kripke, MD, Department of Family and Community Medicine, University of California, San Francisco.
A collection of Cochrane for Clinicians published in AFP is available at http://www.aafp.org/afp/cochrane.
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