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Neuraminidase inhibitors for preventing and treating influenza in healthy adults: systematic review and meta-analysis

BMJ 2009; 339 doi: https://doi.org/10.1136/bmj.b5106 (Published 08 December 2009) Cite this as: BMJ 2009;339:b5106

Effectiveness of neuraminidase inhibitors for the treatment of 2009 pandemic influenza A (H1N1) in severely ill and high risk patients

Dear Editor:

Jefferson, et al. and Freemantle and Calvert describe a selection of
randomised placebo controlled and observational studies respectively
regarding the use of neuraminidase inhibitors in otherwise healthy adults
infected with seasonal influenza virus. [1,2] However, in Europe, North
America, China, and South East Asia the predominant influenza virus
circulating is the new 2009 pandemic influenza A (H1N1) virus. [3,4] The
age groups and other patient population groups most severely affected
include children, pregnant women, and people with underlying conditions
that are risk factors for severe disease. The elderly are relatively
spared. The United States (U.S.) Centers for Disease Control and
Prevention estimates that hospitalisation rates are highest among children
under 18 years old. [5] Pregnant women have been affected
disproportionately compared with others and in excess of their population
distribution. [6] However, depending on the age group, 15-40% of those
who are hospitalised are without known risk factors for severe disease.
[7,8,9] The scope and magnitude of the current pandemic is greater than
that of a typical influenza season among those younger than 65 years
because all children and most adults less than 65 years of age are
immunologically naïve to this new virus and thus experience high illness
rates. The impact is also substantially affected by limited amounts of
strain-specific vaccine available prior to the fall and winter outbreaks
in northern temperate climates during the 2009-10 season and where no
vaccine was available during the 2009 influenza season in the southern
hemisphere. This is in contrast to seasonal influenza where much of the
severe morbidity and mortality occurs among the elderly, fewer persons are
immunologically naïve, and where the vast majority of vaccine, where in
use, is administered prior to increases in influenza activity.

Given limited amounts of influenza vaccine available to date to
combat 2009 pandemic influenza A (H1N1), influenza antiviral medications
have assumed a prominent role in the reducing severe influenza-related
morbidity and mortality during the pandemic. The data that indicate a
benefit from neuraminidase inhibitor treatment in reducing complications,
including death, among hospitalized patients with 2009 pandemic influenza
A (H1N1) infection have been summarized recently. [10] These data were
collected during the current pandemic in the U.S. and Mexico, with neither
investigation supported by industry
funding. [11,12] Treatment with a neuraminidase inhibitor was associated
with a lower risk for intensive care unit admission and death. These
findings are supported by data from seasonal influenza investigations that
also showed a reduced risk of death among hospitalized patients with
laboratory confirmed influenza who received a neuraminidase inhibitor,
even when initiated more than 48 hours after symptom onset. [13,14,15]

The risks associated with the use of neuraminidase inhibitors during
the pandemic are being monitored. In the United Kingdom, for example,
information on approximately 1,000,000 treatment courses of neuraminidase
inhibitors has been collected. No change has been found from the adverse
effects recognized for these drugs, and no new safety concerns have been
identified. No evidence has been found of oseltamivir being directly
responsible for any fatality. [16]

Neuraminidase inhibitors provide a modest benefit in healthy people
with mild seasonal influenza based on randomised trials. In the context of
2009 pandemic influenza A (H1N1), the benefits of treatment with
neuraminidase inhibitors clearly outweigh the risk for adverse events
among those people who present with severe disease or who have risk
factors for developing severe disease (including pregnancy). In addition
to vaccination, antiviral treatment remains an effective and essential
element of a strategy to reduce severe illness and death among patients
with 2009 pandemic influenza A (H1N1).

References:

1. Jefferson T, Jones M, Doshi P, Del Mar C. Neuraminidase inhibitors
for preventing and treating influenza in healthy adults: systematic review
and meta-analysis BMJ 2009;339:b5106 Available from:
http://www.bmj.com/cgi/content/full/339/dec07_2/b5106

2. Freemantle N, Calvert M. What can we learn from observational
studies of oseltamivir to treat influenza in healthy adults? BMJ
2009;339:b5248 Available from:
http://www.bmj.com/cgi/content/full/339/dec07_2/b5248

3. World Health Organization [Internet]. Geneva. Pandemic (H1N1) 2009
- update 75. Available from:
http://www.who.int/csr/don/2009_11_20a/en/index.html

4. Weekly Influenza Surveillance Overview Accessed 9 December 2009
(Week 48) Available from:
http://www.ecdc.europa.eu/en/activities/surveillance/EISN/Pages/EISN_Bul...

5. U.S. Centers for Disease Control and Prevention [Internet].
Atlanta, GA, U.S. CDC Estimates of 2009 H1N1 Influenza Cases,
Hospitalizations and Deaths in the United States, April – October 17, 2009
Available from: http://www.cdc.gov/h1n1flu/estimates_2009_h1n1.htm

6. Jamieson DJ, Honein MA, Rasmussen SA, et al. H1N1 2009 influenza
virus infection during pregnancy in the USA. Lancet. 2009 Aug
8;374(9688):451-8.

7. Cullen G, Martin J, O’Donnell J et al Surveillance of the first
205 confirmed hospitalised cases of pandemic H1N1 influenza in Ireland, 28
April – 3 October 2009 Eurosurveillance 2009; 14, 44
http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19389

8. Domínguez-Cherit G, Lapinsky SE, Macias AE, et al. Critically Ill
patients with 2009 influenza A(H1N1) in Mexico. JAMA. 2009 Nov
4;302(17):1880-7.

9. Louie JK, Acosta M, Winter K, et al. Factors associated with death
or hospitalization due to pandemic 2009 influenza A(H1N1) infection in
California. JAMA. 2009 Nov 4; 302(17):1896-902.

10. Uyeki T. Antiviral Treatment for Patients Hospitalized with 2009
Pandemic Influenza A (H1N1). N Eng J Med. (10.1056/NEJMopv0910738) 18
November 2009. Available from: http://h1n1.nejm.org/?p=1188

11. Jain S, Kamimoto L, Bramley AM, et al. Hospitalized patients with
2009 H1N1 influenza in the United States, April-June 2009. N Engl J Med
2009;361:1935-1944

12. Domínguez-Cherit G, Lapinsky SE, Macias AE, et al. Critically ill
patients with 2009 influenza A(H1N1) in Mexico. JAMA 2009;302:1880-1887

13. McGeer A, Green KA, Plevneshi A, et al. Antiviral therapy and
outcomes of influenza requiring hospitalization in Ontario, Canada. Clin
Infect Dis 2007;45:1568-1575

14. Lee N, Cockram CS, Chan PK, Hui DS, Choi KW, Sung JJ. Antiviral
treatment for patients hospitalized with severe influenza infection may
affect clinical outcomes. Clin Infect Dis 2008;46:1323-1324

15. Hanshaoworakul W, Simmerman JM, Narueponjirakul U, et al. Severe
human influenza infections in Thailand: oseltamivir treatment and risk
factors for fatal outcome. PLoS One 2009;4(6):e6051

16. UK Suspected Adverse Drug Reaction (ADR) Analysis Influenza
antivirals - oseltamivir (Tamiflu) and zanamivir (Relenza) 26th November
2009 Available from:

http://www.mhra.gov.uk/home/idcplg?IdcService=GET_FILE&dDocName=CON06290...

Competing interests:
None declared

Competing interests: No competing interests

10 December 2009
J. Todd Weber, MD
Influenza Division, U.S. Centers for Disease Control and Prevention assigned to the ECDC
Angus Nicoll, MB, Influenza Programme, European Centre for Disease Prevention and Control (ECDC), Stockholm, Sweden; Carolyn B. Bridges, MD, Influenza Division, CDC, Atlanta, GA, USA; and Bruno C. Ciancio, MD, Influenza Programme, ECDC, Stockholm, Sweden
171 83 Stockholm, Sweden