What to know
This page provides information about influenza antiviral medication resistance and guidance on the use of influenza antiviral medications based on excerpts from an Advisory Committee for Immunization Practices (ACIP) document. This information is provided for historical context. The text has not been updated from the ACIP document from which it was excerpted to include the more recently approved influenza antiviral medications peramivir and baloxavir.
Background
This page contains excerpts from Antiviral Agents for the Treatment and Chemoprophylaxis of Influenza – Recommendations of the Advisory Committee on Immunization Practices (ACIP). It provides guidance on the use of influenza antiviral agents. It is provided for historical context, but the text has not been updated from the ACIP document from which it was excerpted to include the more recently approved influenza antiviral medications peramivir and baloxavir. It has also not been updated to reflect current recommendations.
Oseltamivir and Zanamivir (Neuraminidase Inhibitors)
Oseltamivir or zanamivir are the primary antiviral agents recommended for the prevention and treatment of influenza123.
Because currently circulating influenza A (H3N2) and 2009 H1N1 viruses are resistant to adamantanes, these medications are not recommended for use against influenza A virus infections. However, most influenza A and B virus strains are susceptible to oseltamivir and zanamivir4. Sporadic oseltamivir-resistant 2009 H1N1 virus infections have been identified, including with rare episodes of limited transmission56789, but the public health impact has been limited to date. During the 2013- 2014 season, 98,2 % of the 2009 H1N1 viruses tested for surveillance were susceptible to oseltamivir, and 100 % of the 2009 H1N1 viruses tested were susceptible to zanamivir. Additional sporadic cases of oseltamivir-resistant 2009 H1N1 virus infection can be expected, and ongoing surveillance for oseltamivir resistance among influenza viruses is essential for public health since oseltamivir is the most widely used antiviral medication.
Development of resistance to zanamivir or oseltamivir also has been identified during treatment of seasonal influenza1011121314. One study reported that oseltamivir-resistant seasonal influenza A viruses were isolated from nine (18 %) of 50 Japanese children during treatment with oseltamivir15. Transmission of neuraminidase-inhibitor–resistant influenza B viruses has been reported among household contacts16. Development of resistance to oseltamivir during treatment was more common among seasonal influenza A (H1N1) virus infections (27 %) compared with seasonal influenza A (H3N2) (3 %) or B (0 %) viruses in another study17. Sporadic cases of resistance to oseltamivir have been observed among persons with 2009 H1N1 virus infection (e.g., immunosuppressed patients with prolonged viral replication during oseltamivir treatment and persons who developed illness while receiving oseltamivir chemoprophylaxis)818. Emergence of oseltamivir-resistant 2009 H1N1 virus strains within 48 hours after initiation of treatment has been reported19. Transmission of oseltamivir-resistant influenza B virus strains or 2009 H1N1 virus strains acquired from persons treated with oseltamivir is rare but has been documented616. Isolation of influenza A viruses with reduced susceptibility to zanamivir have been reported rarely, although the number of post-treatment isolates tested is limited11121320. Clinical isolates with reduced susceptibility to zanamivir have been obtained occasionally from immunocompromised children on prolonged therapy1221. Prolonged shedding of oseltamivir- or zanamivir-resistant virus by severely immunocompromised patients, even after cessation of oseltamivir treatment, has been reported12212223. Rare cases of infection with 2009 H1N1 virus either resistant to or with reduced susceptibility to multiple neuraminidase inhibitors in severely immunosuppressed pediatric patients with prolonged viral replication have been reported2425.
During 2007–2008, increased resistance to oseltamivir associated with a specific mutation causing a histidine to tyrosine substitution (H275Y) in neuraminidase was reported among seasonal influenza A (H1N1) virus strains in many countries and became prevalent worldwide262728. Most persons infected with oseltamivir-resistant seasonal influenza A (H1N1) virus strains had not received oseltamivir treatment previously and were not known to have been exposed to a person receiving oseltamivir treatment or chemoprophylaxis2729. Influenza caused by oseltamivir-resistant seasonal influenza A (H1N1) virus strains appears to be similar to illness caused by oseltamivir-sensitive virus strains272830. The 2013—2014 influenza season was the first since the 2009 H1N1 pandemic in which H1N1 viruses predominated (CDC 2014). During 2013-2014, all sporadic cases of oseltamivir-resistant 2009 H1N1 virus infections identified to date also have been associated with the H275Y mutation in neuraminidase; these oseltamivir-resistant H275Y virus infections have been susceptible to zanamivir.
A subset of the influenza viruses collected by U.S. WHO collaborating laboratories are sent to CDC for further characterization, including gene sequencing, antiviral resistance testing and antigenic characterization. This information is presented in the antiviral resistance and antigenic characterization sections of the FluView report. As of September 2014, no evidence existed of ongoing transmission of oseltamivir-resistant 2009 H1N1 virus strains worldwide.
Amantadine and Rimantadine (Adamantanes)
Adamantane resistance among circulating influenza A viruses increased rapidly worldwide beginning during 2003–2004. The percentage of influenza A virus isolates submitted from throughout the world to the World Health Organization Collaborating Center for Surveillance, Epidemiology, and Control of Influenza at CDC that were adamantane-resistant increased from 0,4 % during 1994–1995 to 12,3 % during 2003–200431. During the 2005–06 influenza season, CDC determined that 193 (92 %) of 209 influenza A (H3N2) viruses isolated from patients in 26 states demonstrated a change at amino acid 31 in the M2 gene that confers resistance to adamantanes32. Resistance to adamantanes remains high among influenza A viruses currently circulating. Therefore, amantadine and rimantadine are not recommended for antiviral treatment or chemoprophylaxis of currently circulating influenza A virus strains.
Treatment Issues for Patients Hospitalized with Suspected or Confirmed Influenza
Treatment of patients with severe influenza (e.g., those requiring hospitalization) presents multiple challenges. The effect of specific antiviral strategies in serious or life-threatening influenza is not established from clinical trials conducted to support licensure of oseltamivir and zanamivir, as those studies were conducted primarily among previously healthy outpatients with uncomplicated illness. However, a number of more recent observational studies have reported that oseltamivir treatment up to 96 hours after illness onset of patients hospitalized with suspected or confirmed influenza is associated with lower risk for severe outcomes3334353637 (Muthuri, 2014). For this reason, recommendations in this report do not necessarily represent FDA-approved uses of antiviral products but are based on published observational studies and expert opinion and are subject to change as the developmental status of investigational products and the epidemiologic and virologic features of influenza change over time.
Initiation of antiviral treatment as early as possible is recommended for hospitalized patients. However, antiviral treatment might be effective in reducing morbidity and mortality in hospitalized patients even if treatment is not started until more than 48 hours after onset of illness. Data from observational studies indicates the benefit of antiviral treatment for hospitalized persons even when treatment is delayed3334383537. Careful attention to ventilator and fluid management and to the prevention and treatment of secondary bacterial pneumonia (e.g., S. pneumoniae, S. pyogenes, and S. aureus, including MRSA) also is critical for severely ill patients3940414243.
Treatment regimens might need to be altered to fit the clinical circumstances. Please see Influenza Antiviral Medications: Summary for Clinicians for further details regarding treatment recommendations for hospitalized and critically ill patients.
Patients receiving antiviral medications who do not respond to treatment might have an infection with an antiviral-resistant influenza virus. Oseltamivir resistance, sometimes occurring within 1 week of treatment initiation, has been reported particularly among immunocompromised patients with 2009 H1N1 virus infection who were receiving treatment with oseltamivir8444546. Infection-control measures are especially important for patients who are immunocompromised to reduce the risk for transmission of oseltamivir-resistant viruses347. Please see Intravenous Influenza Antiviral Medications and Use of Antivirals for further information regarding investigational parenterally administered products for treatment of influenza. Intravenous zanamivir is the recommended antiviral treatment for severely ill patients with highly suspected or confirmed oseltamivir-resistant 2009 H1N1 virus infection2454829.
For patients who are intubated, use of the zanamivir disc inhaler is not possible. Suboptimal delivery to sites of infection in patients with pneumonic or extrapulmonary disease is also of concern for patients with severe respiratory illness49. Limited experimental use of an unlicensed nebulized formulation of zanamivir has been well tolerated50, but use of the nebulized preparation of the licensed powder formulation contained in the disc inhaler is not recommended because it has been demonstrated to clog ventilator tubing51.
Concerns about influenza viruses with pandemic potential, the appearance and widespread transmission of 2009 pandemic influenza A (H1N1), and the limited treatment options available for severely ill patients has prompted renewed interest in development of additional antiviral drugs with activity against influenza viruses4952. Clinicians should be alert to the future availability of new therapeutic options and recommendations. In addition, careful attention to infection-control measures is recommended347, particularly in hospital areas that house immunocompromised patients.
For current information on antiviral resistance among circulating influenza viruses in the United States, please see the FluView Weekly U.S. Influenza Surveillance Report.
Information on antiviral resistance among influenza viruses circulating globally, is available on World Health Organization (WHO) influenza virological update page. (Note: WHO periodically updates its antiviral resistance information in association with its latest influenza virological update.)
Global updates on the susceptibility of 2009 H1N1 viruses to treatment with oseltamivir, is available on WHO surveillance and monitoring influenza update page. (Note: WHO provides weekly updates on oseltamivir resistance and links to this information from its latest influenza surveillance and monitoring update).
Additional guidance on antiviral treatment of patients with suspected or documented antiviral resistant influenza virus infection (Intravenous Influenza Antiviral Medications) is available. Use of Antivirals, and the WHO guidelines for pharmacological management of pandemic (H1N1) 2009 influenza and other influenza viruses. Per WHO guidance: "Zanamivir is the treatment of choice for all patients where oseltamivir resistance is demonstrated or highly suspected. Intravenous zanamivir may be considered where available."
- CDC. Updated interim recommendations for the use of antiviral medications in the treatment and prevention of influenza for the 2009-10 season. Atlanta, GA: US Department of Health and Human Services, CDC; 2009.
- Bautista E, Chotpitayasunondh T, Gao Z, et al. Clinical aspects of pandemic 2009 influenza A (H1N1) virus infection. N Engl J Med 2010;362:1708-19.
- 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;48:1003-32.
- CDC. FluView: week ending May 20, 2010. Atlanta, GA: US Department of Health and Human Services, CDC; 2010. Accessed December 16, 2010.
- Baz M, Abed Y, Papenburg J, et al. Emergence of oseltamivir-resistant pandemic H1N1 virus during prophylaxis. N Engl J Med 2009;361:2296-7.
- Le QM, Wertheim HF, Tran ND, et al. A community cluster of oseltamivir-resistant cases of 2009 H1N1 influenza. N Engl J Med 2010;362:86-7.
- CDC. Update: influenza activity-United States, 2009-10 season. MMWR 2010;59:901-8.
- CDC. Oseltamivir-resistant novel influenza A (H1N1) virus infection in two immunosuppressed patients-Seattle, Washington, 2009. MMWR 2009;58:893-6.
- CDC. Oseltamivir-resistant 2009 pandemic influenza A (H1N1) virus infection in two summer campers receiving prophylaxis-North Carolina, 2009. MMWR 2009;58:969-72.
- Roche Laboratories Inc. Tamiflu (oseltamivir phosphate) capsules and oral suspension [package insert]. Nutley, NJ: Roche laboratories, Inc.; 2009.
- Gubareva LV, Kaiser L, Matrosovich MN, et al. Selection of influenza virus mutants in experimentally infected volunteers treated with oseltamivir. J Infect Dis 2001;183:523-31.
- Gubareva LV, Matrosovich MN, Brenner MK, et al. Evidence for zanamivir resistance in an immunocompromised child infected with influenza B virus. J Infect Dis 1998;178:1257-62.
- Barnett JM, Cadman A, Gor D, et al. Zanamivir susceptibility monitoring and characterization of influenza virus clinical isolates obtained during phase II clinical efficacy studies. Antimicrob Agents Chemother 2000;44:78-87.
- Stephenson I, Democratis J, Lackenby A, et al. Neuraminidase inhibitor resistance after oseltamivir treatment of acute influenza A and B in children. Clin Infect Dis 2009;48:389-96.
- Kiso M, Mitamura K, Sakai-Tagawa Y, et al. Resistant influenza A viruses in children treated with oseltamivir: descriptive study. Lancet 2004;364:759-65.
- Hatakeyama S, Sugaya N, Ito M, et al. Emergence of influenza B viruses with reduced sensitivity to neuraminidase inhibitors. JAMA 2007;297:1435-42.
- Stephenson I, Democratis J, Lackenby A, et al. neuraminidase inhibitor resistance after oseltamivir treatment of acute influenza a and b in children. Clin Infect Dis 2009;48:389-96.
- CDC. Update: influenza activity-United States, August 30, 2009-March 27, 2010, and composition of the 2010-11 influenza vaccine. MMWR 2010;59:423-30.
- Inoue M, Barkham T, Leo YS, et al. Emergence of oseltamivir-resistant pandemic (H1N1) 2009 virus within 48 hours. Emerg Infect Dis 2010;16:1633-6.
- Gubareva LV, Fry AM. Current challenges in the risk assessment of neuraminidase inhibitor-resistant influenza viruses. J Infect Dis 2010;201:656-8.
- Ison MG, Gubareva LV, Atmar RL, et al. Recovery of drug-resistant influenza virus from immunocompromised patients: a case series. J Infect Dis 2006;193:760-4.
- Baz M, Abed Y, McDonald J, et al. Characterization of multidrug-resistant influenza A/H3N2 viruses shed during 1 year by an immunocompromised child. Clin Infect Dis 2006;43:1555-61.
- Weinstock DM, Gubareva LV, Zuccotti G. Prolonged shedding of multidrug-resistant influenza A virus in an immunocompromised patient. N Engl J Med 2003;348:867-8.
- van der Vries E, Stelma FF, Boucher CA. Emergence of a multidrug-resistant pandemic influenza A (H1N1) virus. N Engl J Med 2010;363:1381-2.
- Nguyen HT, Fry AM, Loveless PA, et al. Recovery of a multidrug-resistant strain of pandemic influenza A 2009 (H1N1) virus carrying a dual H275Y/I223R mutation from a child after prolonged treatment with oseltamivir. Clin Infect Dis 2010;51:983-4.
- World Health Organization. Influenza A (H1N1) virus resistance to oseltamivir. Geneva, Switzerland: World Health Organization; 2009.
- Dharan NJ, Gubareva LV, Meyer JJ, et al. Infections with oseltamivir-resistant influenza A(H1N1) virus in the United States. JAMA 2009;301:1034-41.
- Hauge SH, Dudman S, Borgen K, et al. Oseltamivir-resistant influenza viruses A (H1N1), Norway, 2007-08. Emerg Infect Dis 2009;15:155-62.
- Kramarz P, Monnet D, Nicoll A, et al. Use of oseltamivir in 12 European countries between 2002 and 2007-lack of association with the appearance of oseltamivir-resistant influenza A(H1N1) viruses. Euro Surveill 2009;14.
- Meijer A, Lackenby A, Hungnes O, et al. Oseltamivir-resistant influenza virus A (H1N1), Europe, 2007-08 season. Emerg Infect Dis 2009;15:552-60.
- Bright RA, Medina MJ, Xu X, et al. Incidence of adamantane resistance among influenza A (H3N2) viruses isolated worldwide from 1994 to 2005: a cause for concern. Lancet 2005;366:1175-81.
- Bright RA, Shay DK, Shu B, et al. Adamantane resistance among influenza A viruses isolated early during the 2005-2006 influenza season in the United States. JAMA 2006;295:891-4.
- Siston AM, Rasmussen SA, Honein MA, et al. Pandemic 2009 influenza A(H1N1) virus illness among pregnant women in the United States. JAMA 2010;303:1517-25.
- McGeer A, Green KA, Plevneshi A, et al. Antiviral therapy and outcomes of influenza requiring hospitalization in Ontario, Canada. Clin Infect Dis 2007;45:1568-75.
- Lee N, Cockram CS, Chan PKS, et al. Antiviral treatment for patients hospitalized with severe influenza infection may affect clinical outcomes. Clin Infect Dis 2008;46:1323-4.
- Lee EH, Wu C, Lee EU, et al. Fatalities associated with the 2009 H1N1 influenza A virus in New York city. Clin Infect Dis 2010;50:1498-504.
- Lee N, Choi KW, Chan PK, et al. Outcomes of adults hospitalised with severe influenza. Thorax 2010;65:510-5.
- Lee N, Chan PK, Choi KW, et al. Factors associated with early hospital discharge of adult influenza patients. Antivir Ther 2007;12:501-8.
- Shieh WJ, Blau DM, Denison AM, et al. 2009 pandemic influenza A (H1N1): pathology and pathogenesis of 100 fatal cases in the United States. Am J Pathol 2010;177:166-75.
- Hageman JC, Uyeki TM, Francis JS, et al. Severe community-acquired pneumonia due to Staphylococcus aureus, 2003-04 influenza season. Emerg Infect Dis 2006;12:894-9.
- Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007;44(Suppl 2):S27-72.
- Mauad T, Hajjar LA, Callegari GD, et al. Lung pathology in fatal novel human influenza A (H1N1) infection. Am J Respir Crit Care Med 2010;181:72-9.
- Finelli L, Fiore A, Dhara R, et al. Influenza-associated pediatric mortality in the United States: increase of Staphylococcus aureus coinfection. Pediatrics 2008;122:805–11.
- Tramontana AR, George B, Hurt AC, et al. Oseltamivir resistance in adult oncology and hematology patients infected with pandemic (H1N1) 2009 virus, Australia. Emerg Infect Dis 2010;16:1068-75.
- Gaur AH, Bagga B, Barman S, et al. Intravenous zanamivir for oseltamivir-resistant 2009 H1N1 influenza. N Engl J Med 2010;362:88-9.
- Kidd IM, Down J, Nastouli E, et al. H1N1 pneumonitis treated with intravenous zanamivir. Lancet 2009;374:1036.
- CDC. Interim guidance on infection control measures for 2009 H1N1 influenza in healthcare settings, including protection of healthcare personnel. Atlanta, GA: US Department of Health and Human Services, CDC; 2010. Accessed December 16, 2010.
- Dulek DE, Williams JV, Creech CB, et al. Use of intravenous zanamivir after development of oseltamivir resistance in a critically ill immunosuppressed child infected with 2009 pandemic influenza A (H1N1) virus. Clin Infect Dis 2010;50:1493-6.
- Hayden F. Developing new antiviral agents for influenza treatment: what does the future hold? Clin Infect Dis 2009;48(Suppl 1):S3-13.
- Ison MG, Gnann JW Jr, Nagy-Agren S, et al. Safety and efficacy of nebulized zanamivir in hospitalized patients with serious influenza. Antivir Ther 2003;8:183-90.
- Kiatboonsri S, Kiatboonsri CTheerawit P. Fatal respiratory events caused by zanamivir nebulization. Clin Infect Dis 2009;50:620.
- National Institutes of Allergy and Infectious Diseases and Biomedical Advanced Research and Development Authority. NIAID influenza antiviral development workshop: new generation, March 26-27, 2009, Conference summary. Accessed December 16, 2010.
- CDC. Influenza Activity - United States, 2013-14 Season and Composition of the 2014-15 Influenza Vaccines. 2014. MMWR 2014: 63(22);483-490.
- Chan-Tack KM, Gao A, Himaya AC, et al. Clinical experience with intravenous zanamivir under an emergency investigational new drug program in the United States. J Infect Dis. 2013; 207(1): 196-8.
- Chen LF, Dailey NJ, Rao AK, Fleischauer AT, Greenwald I, Deyde VM, Moore ZS, Anderson DJ, Duffy J, Gubareva LV, Sexton DJ, Fry AM, Srinivasan A, Wolfe CR. Cluster of oseltamivir-resistant 2009 pandemic influenza A (H1N1) virus infections on a hospital ward among immunocompromised patients-North Carolina, 2009. J Infect Dis. 2011 Mar 15;203(6):838-46.
- Dulek DE, Williams JV, Creech CB, Schulert AK, Frangoul HA, Domm J, Denison MR, Chappell JD. Use of intravenous zanamivir after development of oseltamivir resistance in a critically Ill immunosuppressed child infected with 2009 pandemic influenza A (H1N1) virus. Clin Infect Dis. 2010 Jun 1;50(11):1493-6.
- Gaur AH, Bagga B, Barman S, Hayden R, Lamptey A, Hoffman JM, Bhojwani D, Flynn PM, Tuomanen E, Webby R. Intravenous zanamivir for oseltamivir-resistant 2009 H1N1 influenza. N Engl J Med. 2010 Jan 7;362(1):88-9.
- Härter G, Zimmermann O, Maier L, Schubert A, Mertens T, Kern P, Wöhrle J. Intravenous zanamivir for patients with pneumonitis due to pandemic (H1N1) 2009 influenza virus. Clin Infect Dis. 2010 May 1;50(9):1249-51.
- Hurt AC, Hardie K, Wilson NJ, Deng YM, Osbourn M, Leang SK, Lee RT, Iannello P, Gehrig N, Shaw R, Wark P, Caldwell N, Givney RC, Xue L, Maurer-Stroh S, Dwyer DE, Wang B, Smith DW, Levy A, Booy R, Dixit R, Merritt T, Kelso A, Dalton C, Durrheim D, Barr IG. Characteristics of a widespread community cluster of H275Y oseltamivir-resistant A(H1N1)pdm09 influenza in Australia. J Infect Dis. 2012 Jul 15;206(2):148-57.
- Hurt AC, Hardie K, Wilson NJ, Deng YM, Osbourn M, Gehrig N, Kelso A. Community transmission of oseltamivir-resistant A(H1N1)pdm09 influenza. N Engl J Med. 2011 Dec 29;365(26):2541-2.
- Hurt AC, Chotpitayasunondh T, Cox NJ, Daniels R, Fry AM, Gubareva LV, Hayden FG, Hui DS, Hungnes O, Lackenby A, Lim W, Meijer A, Penn C, Tashiro M, Uyeki TM, Zambon M; WHO Consultation on Pandemic Influenza A (H1N1) 2009 Virus Resistance to Antivirals. Antiviral resistance during the 2009 influenza A H1N1 pandemic: public health, laboratory, and clinical perspectives. Lancet Infect Dis. 2012 Mar;12(3):240-8.
- Kidd IM, Down J, Nastouli E, Shulman R, Grant PR, Howell DC, Singer M. H1N1 pneumonitis treated with intravenous zanamivir. Lancet. 2009 Sep 19;374(9694):1036.
- Le QM, Wertheim HF, Tran ND, van Doorn HR, Nguyen TH, Horby P; Vietnam H1N1 Investigation Team. A community cluster of oseltamivir-resistant cases of 2009 H1N1 influenza. N Engl J Med. 2010 Jan 7;362(1):86-7.
- Moore C, Galiano M, Lackenby A, Abdelrahman T, Barnes R, Evans MR, Fegan C, Froude S, Hastings M, Knapper S, Litt E, Price N, Salmon R, Temple M, Davies E. Evidence of person-to-person transmission of oseltamivir-resistant pandemic influenza A(H1N1) 2009 virus in a hematology unit. J Infect Dis. 2011 Jan 1;203(1):18-24.
- Muthuri SG, Venkatesan S, Myles PR, et al. Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to a hospital with influenza A H1N1 pdm09 virus infection: a meta-analysis of individual participant data. Lancet Res Med. 2014 Mar; 10.1/ S2213-2600(14)70041-4.
- Nguyen HT, Fry AM, Gubareva LV. Neuraminidase inhibitor resistance in influenza viruses and laboratory testing methods. Antivir Ther. 2012;17(1 Pt B):159-73.
- Stephenson I, Democratis J, Lackenby A, McNally T, Smith J, Pareek M, Ellis J, Bermingham A, Nicholson K, Zambon M. Neuraminidase inhibitor resistance after oseltamivir treatment of acute influenza A and B in children. Clin Infect Dis. 2009 Feb 15;48(4):389-96.