Neuraminidase Inhibitors May Reduce Pandemic Flu Mortality

Larry Hand

March 19, 2014

Neuraminidase inhibitors (NAIs) may significantly reduce the risk for death from pandemic influenza for hospitalized adults, especially if given early, according to an article published online March 19 in the Lancet Respiratory Medicine.

Stella G. Muthuri, PhD, from the Division of Epidemiology and Public Health, University of Nottingham, United Kingdom, and colleagues conducted a systematic review and meta-analysis involving 29,234 patients from 78 studies in 38 countries. The patients were admitted to hospitals between January 2, 2009, and March 14, 2011.

The researchers reviewed studies conducted between March 1, 2009, until the World Health Organization declared the H1N1 influenza pandemic to be over in August 2010. The authors continued to receive data from ongoing studies through March 14, 2011.

After adjusting for treatment propensity and potential confounders such as corticosteroid and antibiotic treatments, the researchers found that:

  • NAI treatment was associated with a 19% reduction of mortality irrespective of timing compared with no treatment (adjusted odds ratio [OR], 0.81; 95% confidence interval [CI], 0.70 - 0.93; P = .0024).

  • NAI treatment within 2 days of symptom onset was associated with a 50% reduction in mortality compared with no treatment (adjusted OR, 0.50; 95% CI, 0.37 - 0.67; P < .0001).

  • Early NAI treatment compared with later NAI treatment was associated with more than a 50% reduction in mortality risk (adjusted OR, 0.48; 95% CI, 0.41 - 0.56).

  • The mortality hazard rate (HR) increased with each day's delay in starting NAI treatment up to day 5 compared with treatment started within 2 days of symptom onset (adjusted HR per day, 1.23; 95% CI, 1.18 - 1.28; P < .0001).

  • Reductions in mortality rates were less pronounced and not significant for children.

The researchers included laboratory-confirmed and suspected influenza cases in their analysis, but odds ratios did not change significantly when they restricted their analysis to laboratory-confirmed cases.

The most significant reductions in mortality risks were among adults in general, pregnant women, and critically ill adults. The reason for a lack of benefit in children is unclear but could be related to factors including suboptimum dosing in young children and secondary infections, the researchers write.

Without Delay

The results of the meta-analysis should bolster the confidence of governments trying to decide whether to stock up on oral oseltamivir, senior author Jonathan Nguyen-Van-Tam, DM, said in a news release.

"Since placebo-controlled trials of NAIs are not ethically feasible during a pandemic, the evidence we have assembled is likely to be the best that is available," he continued. "Our data suggest that in line with US Centers for Disease Control and Prevention recommendations, treatment guidance policies should emphasise that NAI treatment should be started as soon as possible for any hospitalised adult who presents with influenza that is suspected or confirmed. Since so many patients with severe influenza are not admitted to hospital within 48 hours of symptom onset, the same applies to adults in the community who are appreciably unwell with influenza like illness or who have underlying risk conditions. If clinical suspicion is high, one should not wait for laboratory confirmation before starting treatment."

In an accompanying comment, Alicia M. Fry, MD, from the Centers for Disease Control and Prevention's National Centers for Immunization and Respiratory Diseases, Atlanta, Georgia, characterized the current study as "a welcome addition to the previous observational evidence that NAIs reduce the risk of death associated with influenza hospital admissions, and the results support the use of NAI treatment for adults admitted to hospital during influenza pandemics and also for seasonal influenza, because thousands of hospital admissions and deaths are attributed to influenza every year."

This research was funded by F. Hoffmann-La Roche. Dr. Nguyen-Van-Tam has reported receiving consulting and lecture fees from several influenza vaccine and neuramidase inhibitor manufacturers, being a former employee of SmithKline Beecham, and receiving research funding from 2 companies and travel support from another company; one coauthor is statistical editor of the Cochrane Skin Group; one coauthor has reported receiving research and travel funding from F Hoffmann-La Roche; and one coauthor has reported receiving financial support from several pharmaceutical companies toward a research account at the Children's Hospital at Westmead, Australia. The other authors and Dr. Fry have disclosed no relevant financial relationships.

Lancet Respir Med. Published online March 18, 2014. Article abstract, Comment extract

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