Antiviral medications for influenza

Clinical question

Do the neuraminidase inhibitors (NIs) oseltamivir or zanamivir improve clinical outcomes in influenza?

Bottom line

Biased, poor-quality, mostly unpublished evidence suggests that oseltamivir and zanamivir shorten the duration of influenza symptoms by 0.6 to 0.7 of a day. Pneumonia and hospitalizations are not decreased.

Evidence

Three 2014 systematic reviews of placebo-controlled RCTs (including > 160 000 pages of previously unreleased clinical study reports)^1–3 found the following when treating otherwise healthy adults with influenza or influenzalike illness with oseltamivir (11 RCTs)^1,2 or zanamivir (14 RCTs)^1,3:

• Time to symptom improvement was 0.6 to 0.7 days (about 10%) better^1–3; the benefit of zanamivir was similar to “relief medications” (like acetaminophen).^1,3

• There was no benefit for pneumonia (x-ray scan confirmed)^1–3 and hospitalizations were not reported^1,3 or there was no benefit.^1,2

• Adverse events included the following:

  • -For oseltamivir,^1,2 the number need to harm was 28 for nausea and 22 for vomiting.
  • -Postmarketing surveillance reports (frequency unknown) identified bronchospasm with zanamivir⁴ and delirium and self-injury with oseltamivir.⁵

A 2015 systematic review⁶ concluded adults receiving oseltamivir had faster symptom alleviation, and fewer lower respiratory tract complications and hospitalizations.

• The review used similar studies^1,2 but the conclusion was based on a subgroup with documented influenza.

• The review was funded by, and 2 authors had pre-existing financial affiliations with, the manufacturer of oseltamivir.

From 26 systematic reviews,⁷ authors with financial conflicts of interest were 5 times more likely to report benefits of NI use (this includes a systematic review of cohort studies from the 2009–2010 pandemic suggesting that NIs decreased mortality in hospitalized patients⁸) and less likely to report on publication bias and the quality of included studies.

• Other concerns¹: unpublished protocols; inconsistent outcome definition; “placebos” with potential adverse effects; and incomplete reporting (eg, missing symptom cards).

Context

• Oseltamivir sales are > $18 billion, half from government and company stockpiling. Most have not been used.⁹

• The NIs are not recommended if symptoms have lasted longer than 48 hours.^4,5 Zanamivir is contraindicated in asthma and COPD.⁴ There is limited evidence for oseltamivir in underlying cardiac or respiratory disease.⁵

• Limited data suggest NIs are likely safe in pregnancy,¹⁰ but the manufacturers do not recommend (zanamivir)⁴ or conclude that there are insufficient data and to use them only when the potential benefit justifies the potential risk to the fetus (oseltamivir).⁵

Implementation

Headache or muscle aches do not reliably differentiate influenza from other respiratory infections. Cough with fever might have the greatest diagnostic value,¹¹ but knowledge of current local influenza rates is more important. In outbreaks, 79% of patients with fever and cough have influenza,¹² but influenza accounts for only 10% of identified respiratory pathogens in a typical winter.¹³ Trials of NIs generally exclude the very young, the old, and those with comorbidity. Targeting those at greatest risk of complications during influenza outbreaks might provide greater utility. High-quality trials enrolling such patients are needed.

Tools for Practice articles in Canadian Family Physician (CFP) are adapted from articles published on the Alberta College of Family Physicians (ACFP) website, summarizing medical evidence with a focus on topical issues and practice-modifying information. The ACFP summaries and the series in CFP are coordinated by Dr G. Michael Allan, and the summaries are co-authored by at least 1 practising family physician and are peer reviewed. Feedback is welcome and can be sent to toolsforpractice@cfpc.ca. Archived articles are available on the ACFP website: www.acfp.ca.