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Although antivirals had some positive effects on the treatment of severe influenza and prevention of the flu, many effects on outcomes were uncertain, according to two World Health Organization-funded systematic reviews and network meta-analyses.

In the first analysis, treatment of severe influenza with oseltamivir (Tamiflu) and peramivir (Rapivab) appeared to reduce the length of hospital stays, but overall the effects of antivirals on key clinical outcomes -- such as mortality -- remained questionable, reported Qiukui Hao, MD, of McMaster University in Hamilton, Ontario, and colleagues in .

from Hao and colleagues found that post-exposure prophylaxis (PEP) with a range of antivirals probably decreased risk of severe disease in high-risk individuals after exposure to seasonal influenza viruses and may have also reduced the risk of zoonotic infection after exposure to novel influenza A viruses, Hao and researchers reported.

"The optimal antiviral drugs for treatment of severe influenza and post-exposure prophylaxis for influenza are unclear," David Hui, MD, of the Chinese University of Hong Kong, wrote in . "Many knowledge gaps remain that need to be filled."

Treatment of Severe Flu

In the first systematic review and network meta-analysis of randomized controlled trials, Hao and colleagues analyzed eight trials that included a total of 1,424 participants.

Researchers found only low certainty of evidence that duration of hospitalization for seasonal flu was reduced with oseltamivir and peramivir when compared with standard care or placebo, although statistically significant with a mean reduction in hospitalization of 1.63 and 1.73 days for the two drugs, respectively.

There was no significant difference in time to symptom alleviation with either drug, although again with low certainty of evidence.

Researchers were unable to draw any other conclusions about the use of antivirals and key patient outcomes. For example, in a network meta-analysis of mortality that included four trials of oseltamivir, peramivir, or zanamivir (Relenza) for the treatment of severe seasonal influenza, the impact on mortality varied from a reduction of 18 per 1,000 patients to an increase of four per 1,000 patients for seasonal influenza when compared with standard care or placebo. Mortality also varied from 232 fewer to 51 more per 1,000 patients infected with zoonotic influenza A viruses. The evidence for both findings was of very low certainty.

"Great uncertainty remains regarding the effects of oseltamivir, peramivir, and zanamivir on mortality in patients with severe seasonal influenza or zoonotic influenza," Hao and colleagues wrote.

The study had several limitations, the authors acknowledged. There were only eight trials in the analysis, and none looked at effects of antivirals versus placebo or standard care on any adverse events or severe adverse events, making it impossible to draw any firm conclusions about most outcomes for patients with severe influenza. Also, data were scarce on the effects of antivirals on patients over the age of 60, nor was there enough data to perform prespecified subgroup analyses.

Flu PEP?

In this systematic review, researchers analyzed 33 trials that evaluated the efficacy and safety of six antivirals for the prevention of influenza: zanamivir, oseltamivir, baloxavir (Xofluza), amantadine (Symmetrel), rimantadine (Flumadine), and laninamivir (never approved in the U.S.).

In 19 trials that reported on laboratory-confirmed seasonal asymptomatic infections, zanamivir, oseltamivir, laninamivir, and baloxavir probably reduced symptomatic influenza in high-risk individuals when given within 48 hours after exposure to seasonal influenza. The four antivirals had similar, statistically significant risk reductions of 0.35 to 0.43 when compared with placebo.

However, the antivirals fell below the threshold of importance for reducing symptomatic influenza in people at low risk for severe disease.

Rimantadine did not significantly reduce risk for symptomatic influenza A virus infection; no data was available for amantadine.

Of note, researchers found that when given promptly after exposure, zanamivir, oseltamivir, laninamivir, and baloxavir might reduce the development of symptomatic infection from exposure to novel zoonotic influenza A viruses that are often associated with severe disease in people.

According to the Infectious Diseases Society of America (IDSA), for severely immunocompromised asymptomatic adults and children ages 3 months or older who are at very high risk of developing complications from influenza and for whom influenza vaccination is contraindicated or unavailable after household exposure to influenza.

Also, the PEP with oseltamivir in people exposed to novel influenza A viruses, including H5N1 (bird flu).

Hao and colleagues also found that in studies evaluating both asymptomatic and symptomatic illness, oseltamivir, laninamivir, baloxavir, and amantadine probably decreased the risk of all influenza infection. Results were driven by reduction of symptomatic influenza.

"Antivirals probably have little or no effect on prevention of asymptomatic influenza virus infection," the researchers concluded.

The findings of the analysis "support the use of baloxavir, laninamivir, oseltamivir, or zanamivir for post-exposure prophylaxis of seasonal influenza in people at high risk of severe influenza, and they also provide some indirect support for the use of these antivirals for post-exposure prophylaxis of zoonotic influenza," Hui wrote in his editorial.

However, four of the 33 trials looked at the effects of oseltamivir administered as PEP and found it had little to no effect on preventing hospital admission from seasonal influenza.

In addition, 15 studies provided evidence that zanamivir, oseltamivir, laninamivir, and baloxavir as PEP probably had little to no effect on all-cause mortality. Absolute risk reductions ranged from zero fewer deaths to one more per 1,000 patients.

On one reassuring note, in an analysis of 13 trials that reported adverse drug-related events, zanamivir, laninamivir, and rimantadine appeared to result in few drug-related adverse events, with risk ratios ranging from 1.01 to 1.40. Baloxavir also appeared to have little or no effect on drug-related adverse events.

Hao and researchers acknowledged several limitations of this analysis, including lack of outcomes data on length of hospitalization, ICU admission, invasive mechanical ventilation, and disease severity. Also the mean age of participants varied widely, from about 7 years to over age 81 years. There were few data on pregnant individuals or young infants. Studies also varied in terms of drug administration, dosage, and duration of PEP.