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Viral Insights

Antiviral Treatment for Patients Hospitalized with 2009 Pandemic Influenza A (H1N1)

Tim Uyeki, M.D., M.P.H.

N Engl J Med 2009; 361:e110December 3, 2009

Article

With the 2009 H1N1 pandemic well under way, many clinicians are providing care to patients with influenza. Previously, although antiviral treatment was recommended,1,2 clinicians may not always have prescribed it to patients hospitalized with seasonal influenza, perhaps because of a perception that antiviral treatment had limited benefit. Controlled trials conducted among outpatients with uncomplicated seasonal influenza reported a reduction of approximately 1 day in the duration of illness and reduced severity when antiviral treatment was initiated within 48 hours of illness onset, as compared with placebo. However, evidence from observational studies supports the benefit of neuraminidase inhibitors (oseltamivir or zanamivir) in reducing complications, including deaths, among hospitalized patients with 2009 pandemic influenza A (H1N1).

The 2009 H1N1 virus is susceptible to neuraminidase inhibitors (oseltamivir, zanamivir, peramivir) but resistant to the adamantanes (amantadine, rimantadine). Therefore, neuraminidase inhibitors are recommended for antiviral treatment of 2009 H1N1.3,4 Emergence of oseltamivir-resistant 2009 H1N1 virus during or following treatment has been rarely identified.5,6 Patients with infection caused by oseltamivir-resistant virus with the H275Y mutation in the neuraminidase should be treated with zanamivir.5,6

No randomized trials of neuraminidase-inhibitor treatment of hospitalized influenza patients have been conducted. However, three observational studies suggest that oseltamivir treatment of hospitalized patients with seasonal influenza may reduce mortality. In one prospective Canadian study among hospitalized patients with seasonal influenza, (N=327; mean age, 77 years), in which 71% began oseltamivir treatment >48 hours after illness onset, oseltamivir treatment was significantly associated with a reduced risk of death (OR, 0.21; P=0.03) within 15 days after hospitalization as compared with untreated patients.7 In a subanalysis, in a Hong Kong study of hospitalized seasonal influenza patients (N=356; mean age, 70.2 years), oseltamivir treatment initiated within <96 hours after illness onset was independently associated with decreased mortality as compared with untreated patients (OR, 0.26; P=0.001).8 A retrospective chart review of hospitalized seasonal influenza patients in Thailand (N=445; mean age, 22 years), including 35% with radiographically confirmed pneumonia, reported that any oseltamivir treatment was significantly associated with survival (OR, 0.11; 95% CI, 0.04 – 0.30) as compared with untreated patients.9

Observational data from the United States and Mexico suggest that neuraminidase inhibitor treatment (primarily oseltamivir) of hospitalized patients with 2009 H1N1 may reduce disease severity and mortality. Starting treatment with a neuraminidase inhibitor within 2 days after symptom onset was significantly associated with a lower risk of ICU admission or death in hospitalized 2009 H1N1 patients (N=272; median age, 21 years), as compared with later treatment (P <0.05).10 In ICU patients with 2009 H1N1 (N=58; median age, 44 years), survivors were more likely to have received neuraminidase inhibitor treatment than nonsurvivors (OR, 8.5; P=0.04).11

Although most hospitalized 2009 H1N1 patients have been treated with oral oseltamivir, including critically ill persons, parenteral neuraminidase inhibitors (peramivir,12,13 zanamivir14) might be beneficial for some patients.13 Some critically ill 2009 H1N1 patients have been treated for twice the standard 5 days, and some have received higher oseltamivir dosing.1 There are no head-to-head clinical trials of oral or intravenous oseltamivir, inhaled or intravenous zanamivir, intravenous peramivir, or combination treatment with other antivirals among hospitalized 2009 H1N1 patients to inform clinicians, but clinical trials may be available for enrollment.15 There is an urgent need for additional clinical, virologic, time-to-treat, and pharmacokinetic studies to assess neuraminidase inhibitor effectiveness, to inform dosing and duration, and to inform optimal clinical management for hospitalized 2009 H1N1 patients.

Taken together, although data are limited, findings of observational studies all point in the same direction, suggesting benefit of early neuraminidase inhibitor treatment for hospitalized influenza patients as well as for patients presenting >48 hours after illness onset. In the setting of 2009 pandemic influenza A (H1N1) virus activity in a community, empiric neuraminidase inhibitor treatment should be started as soon as possible for any hospitalized patient who presents with influenza that is suspected (e.g., acute respiratory illness, acute exacerbation of chronic conditions, or other complications) or confirmed, in addition to initiating antibiotic treatment as indicated for suspected bacterial coinfection.

Tim Uyeki, M.D., M.P.H.
Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia

No potential conflict of interest relevant to this article was reported.

This article (10.1056/NEJMopv0910738) was published on November 18, 2009, at NEJM.org.

References

References

1. 1

   Harper SA, Bradley JS, Englund JA, et al. Seasonal influenza in adults and children -- diagnosis, treatment, chemoprophylaxis, and institutional outbreak management: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis 2009;48:1003-1032
   CrossRef | Web of Science | Medline

2. 2

   Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2008. MMWR Recomm Rep 2008;57:1-60
   

3. 3

   Updated interim recommendations for the use of antiviral medications in the treatment and prevention of influenza for the 2009-2010 season. Atlanta: Centers for Disease Control and Prevention, 2009. (Accessed November 16, 2009, at http://www.cdc.gov/H1N1flu/recommendations.htm)
   

4. 4

   WHO guidelines for pharmacological management of pandemic (H1N1) 2009 influenza and other influenza viruses. Geneva: World Health Organization, 2009. (Accessed November 16, 2009, at http://www.who.int/csr/resources/publications/swineflu/h1n1_guidelines_pharmaceutical_mngt.pdf)
   

5. 5

   Oseltamivir-resistant pandemic (H1N1) 2009 influenza virus, October 2009. Wkly Epidemiol Rec 2009;84:453-459
   Medline

6. 6

   Oseltamivir-resistant novel influenza A (H1N1) virus infection in two immunosuppressed patients -- Seattle, Washington, 2009. MMWR Morb Mortal Wkly Rep 2009;58:893-896
   Medline

7. 7

   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
   CrossRef | Web of Science | Medline

8. 8

   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
   CrossRef | Web of Science | Medline

9. 9

   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:e6051-e6051
   CrossRef | Web of Science | Medline

10. 10

    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
    Full Text | Web of Science | Medline

11. 11

    Dominguez-Cherit G, Lapinsky SE, Macias AE, et al. Critically ill patients with 2009 influenza A(H1N1) in Mexico. JAMA 2009;302:1880-1887
    CrossRef | Web of Science | Medline

12. 12

    Birnkrant D, Cox E. The emergency use authorization of peramivir for treatment of 2009 H1N1 influenza. N Engl J Med 2009:10.1056/NEJMp0910479.
    

13. 13

    Antiviral treatment options, including intravenous peramivir, for treatment of influenza in hospitalized patients for the 2009-2010 season. Atlanta: Centers for Disease Control and Prevention, 2009. (Accessed November 16, 2009, at http://www.cdc.gov/H1N1flu/EUA/peramivir_recommendations.htm)
    

14. 14

    Kidd IM, Down J, Nastouli E, et al. H1N1 pneumonitis treated with intravenous zanamivir. Lancet 2009;374:1036-1036
    CrossRef | Web of Science | Medline

15. 15

    Clinical Trials.gov home page. (Accessed November 16, 2009, at http://clinicaltrials.gov/.)
    

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   Avinash K Shetty, Leigh A Peek. (2012) Peramivir for the treatment of influenza. Expert Review of Anti-infective Therapy 10:2, 123-143
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7. 7

   A Rohn, H H Kessler, T Valentin, W Linkesch, P Neumeister. (2011) Prophylactic oseltamivir treatment for prevention of donor–recipient influenza A H1N1 virus transmission does not compromise stem cell mobilization or engraftment. Bone Marrow Transplantation 46:2, 312-313
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8. 8

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9. 9

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10. 10

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11. 11

    Brianne A. Couturier, Jeffrey M. Bender, Monica A. Schwarz, Andrew T. Pavia, Kimberly E. Hanson, Rosemary C. She. (2010) Oseltamivir-resistant influenza A 2009 H1N1 virus in immunocompromised patients. Influenza and Other Respiratory Viruses 4:4, 199-204
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12. 12

    Marc P. Girard, John S. Tam, Olga M. Assossou, Marie Paule Kieny. (2010) The 2009 A (H1N1) influenza virus pandemic: A review. Vaccine 28:31, 4895-4902
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13. 13

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