H1N1 Influenza Center

From the Publishers of the New England Journal of Medicine

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

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.


  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]
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  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.)
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  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(6):e6051.
  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. [Free Full Text]
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6 Responses »

  1. We have had cases of Influenza A (H1N1) infections that did not improve much (or did not improve at all) after treatment with 5-7 days of tamiflu. We suspected these to have possible rsistant viruses, and subsequently added Amantadine for the lack of alternatives. No evidence whatsoever for our practice. I would like to hear yourcomment on that, please.

    Juan Ariel Jara Guerrero
    CMM 282860478

  3. i have a36y/o patient confirm case of h1n1 with alveolar penomonia bilatral involment after treatment with tamiflu and serial CXR show excelent result.the patient now well.but five other cases with involvment of lung because of delayed all die.i recommend serial CXR in first 48 hour of development of flu help to recognize
    the lung invlvoment and treatment if alveolar penomonia started even after 48 of disease.

  4. I have patient woman 31 yo with Flu H1N1 (SOIV) treatment Tamiflu at day 2 fever,in day 6 patient get Myocarditis and ST depressed in all leed of ECG and some bigemini or salvo.Is that resistant to tamiflu?
    Discharge from hospital at day 14 with persistant arrythmia.
    Dr. Sumardi, MD (Internist Pulmonologist)
    Pulmonary Division
    Internal Medicine Departement
    School of Medicine
    Gadjah Mada University
    Sardjito General Hospital


  6. Antiviral treatment with neuraminidase inhibitors for all patients with influenza-like illnesses during an A(H1N1)v influenza epidemic wave

    Yazdan Yazdanpanah1, 2, Sylvie Deuffic-Burban2, 3, Jean-Claude Desenclos4.

    1Service Universitaire des Maladies Infectieuses et du Voyageur, Centre Hospitalier Dron, Tourcoing, France
    2EA2694, Faculté de Médecine de Lille, Lille, France
    3INSERM U795, Faculté de Médecine de Lille, Lille, France
    4Institut de Veille Sanitaire (InVS), Saint Maurice, France

    Correspondence should be addressed to:
    Corresponding author:
    Yazdan Yazdanpanah, MD, PhD
    Service Universitaire des Maladies Infectieuses et du Voyageur
    Centre Hospitalier de Tourcoing (Faculté de Médecine de Lille)
    135, rue du Président Coty – B.P.619
    F 59208 Tourcoing, France
    Telephone: +33 320 69 46 16
    Fax: +33 320 69 46 15
    Email: yyazdan@yahoo.com

    To the editor:
    Contrary to Dr. Uyeki (1) and the United States CDC (2), we think that all patients with influenza-like illnesses (ILI) during an A(H1N1)v epidemic, not just those with severe symptoms or at high risk of complications, should initiate neuraminidase inhibitor (NI) treatment. A non-negligible proportion of severe A(H1N1)v complications occur in previously healthy young people who may benefit from early antiviral treatment (3-7). During the completed A(H1N1)v season in the Southern Hemisphere, where treatment was offered to all patients with ILI in Chile compared to hospitalized patients in Argentina, mortality rates were 0.8 and 1.44/100,000 (8). Using a decision model, we showed that early NI initiation among all patients with ILI during an A(H1N1)v epidemic is effective and cost-effective (9). One may postulate that this strategy would increase resistance to NIs. NI-resistant strains emergence may be unrelated to selective drug pressure (10). In the United Kingdom, where NI treatment is widespread, resistance rates have not increased. To date, rare cases of resistance is mostly observed in patients on prophylaxis, or with severe immunosuppression (11-13). Based on these arguments, France recently recommended treating all patients with ILI during the current A(H1N1)v epidemic (14).

    Competing Interests: Y. Yazdanpanah has received travel grants, honoraria for presentation at workshops and consultancy honoraria from Bristol-Myers Squibb, Gilead, Glaxo-SmithKline, Merck, Pfizer, Roche and Tibotec. S. Deuffic-Burban has received grants from Roche and Janssen-Cilag. None of the authors report any association that might pose a conflict of interest.

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    13. Oseltamivir-resistant novel influenza A (H1N1) virus infection in two immunosuppressed patients – Seattle, Washington, 2009. MMWR Morb Mortal Wkly Rep 2009;58:893-6.
    14. Ministère de la Santé et des Sports. Nouvelles recommandations sur la prise en charge des patients grippés (10 décembre 2009). 2009. Available from http://www.sante-sports.gouv.fr/nouvelles-recommandations-sur-la-prise-en-charge-des-patients-grippes-10-decembre-2009.html.