Peer-reviewed literature

21 December 2012

Supply of Neuraminidase Inhibitors Related to Reduced Influenza A (H1N1) Mortality during the 2009–2010 H1N1 Pandemic: An Ecological Study

The influenza A(H1N1)pdm09 pandemic of 2009 infected millions, prompting widespread government responses to formulate preparedness plans. Clinical trials have shown that neuraminidase inhibitors (NAI) have been effective in reducing morbidity (1), resulting in the World Health Organization (WHO) to recommend their widespread use during pandemics (2). It is less clear, however, whether NAIs have had a meaningful impact on the mortality rates during the pandemic. The objective of Miller et al.’s (3) investigation was to examine the relationship between the mortality rates attributed to pandemic H1N1 and the supply of NAIs from a cohort of WHO Member States so as to suggest an evidence-based policy on the use of NAIs in any subsequent influenza pandemics. Estimates for the total use of NAIs (Oseltamivir and Zanamivir) by country were used to predict the mortality rates (per 100,000) from influenza A(H1N1)pdm09 infection between the periods July 2009 and August 2010. Confounding factors that might be associated with mortality were controlled for. Three broad categories were identified: health indicators, health-related indicators and socio-economic indicators. Broad-ranging health and economic indicators were assessed as potential explanations for the variation in mortality including under-5 mortality rate, total per capita health spending, population density etc. NAI use was calculated from the weight (kg) distribution per country using data supplied by Intercontinental Medical Statistics (IMS) (an auditor that records transactions between pharmaceutical companies and purchasing users), with population estimates from the United Nations Statistics Division. Mortality rates were based on laboratory confirmed fatal cases reported to the WHO. Regression was then used to model the A(H1N1)pdm09 mortality rate controlling for all variables. Limitations to this study were accounted for where possible; however, the scope of the investigation was such that not all confounders that may bias results could be considered. For example, the data supplied by the IMS makes the assumption that NAI supply reflects its administration, whilst it is known that some countries have not fully distributed their stockpiles. Miller et al. found that mortality rate during the pandemic was negatively associated with the per capita supply of both Oseltamivir and Zanamivir but not other health or economic indicators. A 10% increase in kg of Oseltamivir supply per 100 000 was associated with a 1.6% decrease in mortality resulting from H1N1, and a 10% increase in Zanamivir per 100 000 was associated with a 0.3% decrease in mortality.


The H1N1 pandemic of 2009 resulted in widespread use of neuraminidase inhibitors (NAI) as a means to reduce mortality rate (4, 5). However, there was a diverse adoption of their use according to the health policies of each country. Regionally, the Americas and the Eastern Mediterranean countries were found to have the lowest supply of NAIs, while Europe and the Western Pacific region had the highest. As the pandemic progressed, the WHO recommended that all but the most severe cases be laboratory tested for H1N1 to ease the burden on the laboratory network, leading to reporting of mortality rate instead of the H1N1 case fatality rate. In spite of the inevitable limitations, the authors of this study have made every reasonable attempt to factor in the confounders to produce a robust and conclusive analysis, demonstrating a statistically significant correlation between the supply of NAIs and decreased mortality due to influenza A(H1N1)pdm09 during the pandemic. Antiviral therapy appears to be effective in the treatment of influenza symptoms, but its use should be combined with other public health strategies, such as vaccination, travel restrictions, effective monitoring and reporting, public health awareness campaigns and speedy decision making on the ground levels to close down areas of large human gathering e.g. schools. The findings of this study, (along with others (1, 6, 7, 8), can be used to support the use of NAIs as one method of reducing the mortality rates in future influenza pandemics.


(1) Hernan, N. A. & Lipsitch, M. (2011). Oseltamivir and risk of lower respiratory tract complications in patients with flu symptoms: A meta-analysis of 11 clinical trials. Clin Infect Dis. 53: 277-279
(2) World Health Organization. (2010). WHO guidelines for pharmacological management of pandemic influenza A(H1N1) 2009 and other influenza viruses.
(3) Miller PE, Rambachan A, Hubbard RJ, Li J, Meyer AE, et al. (2012) Supply of Neuraminidase Inhibitors Related to Reduced Influenza A (H1N1) Mortality during the 2009–2010 H1N1 Pandemic: An Ecological Study. PLoS ONE 7(9): e43491. doi:10.1371/journal.pone.0043491
(4) Sugaya, N. (2011). Widespread use of neuraminidase inhibitors in Japan. J Infect Chemother. Oct;17(5):595-601.
(5) Smith, S. M. & Gums, J. G. (2010). Antivirals for influenza: strategies for use in pediatrics. Paediatr Drugs. Oct 1;12(5):285-99.
(6) Higuera Iglesias, A.L. et al. (2011). Reducing occurrence and severity of pneumonia due topandemic H1N1 2009 by early oseltamivir administration: a retrospective study in Mexico. PLoS ONE 6: e21838.
(7) Chowell, G. et al. (2012). Impact of antiviral treatment and hospital admission delay on risk of death associated with 2009 A/H1N1 pandemic influenza in Mexico. BMC Infect Dis. Apr 20; 12:97
(8) Sugaya, N. et al. (2012). Very low pandemic influenza A (H1N1) 2009 mortality associated with early neuraminidase inhibitor treatment in Japan: analysis of 1000 hospitalized children. J Infect. Oct;63(4):288-94.


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