Antiviral Drug Resistance among Influenza Viruses

Oseltamivir and Zanamivir (Neuraminidase Inhibitors)

Oseltamivir or zanamivir are the primary antiviral agents recommended for the prevention and treatment of influenza [28, 51, 105].

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 zanamivir [110]. Sporadic oseltamivir-resistant 2009 H1N1 virus infections have been identified, including with rare episodes of limited transmission [111–115], 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 influenza [116–120]. One study reported that oseltamivir-resistant seasonal influenza A viruses were isolated from nine (18%) of 50 Japanese children during treatment with oseltamivir [121]. Transmission of neuraminidase-inhibitor–resistant influenza B viruses has been reported among household contacts [122]. 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 study [123]. 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) [114, 124]. Emergence of oseltamivir-resistant 2009 H1N1 virus strains within 48 hours after initiation of treatment has been reported [125]. Transmission of oseltamivir-resistant influenza B virus strains or 2009 H1N1 virus strains acquired from persons treated with oseltamivir is rare but has been documented [112, 122]. Isolation of influenza A viruses with reduced susceptibility to zanamivir have been reported rarely, although the number of post-treatment isolates tested is limited [117–119, 126]. Clinical isolates with reduced susceptibility to zanamivir have been obtained occasionally from immunocompromised children on prolonged therapy [118, 127]. Prolonged shedding of oseltamivir- or zanamivir-resistant virus by severely immunocompromised patients, even after cessation of oseltamivir treatment, has been reported [118, 127–129]. 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 reported [130, 131].

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 worldwide [132–134]. 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 chemoprophylaxis [133, 135]. Influenza caused by oseltamivir-resistant seasonal influenza A (H1N1) virus strains appears to be similar to illness caused by oseltamivir-sensitive virus strains [133, 134, 136]. 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.

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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 2003–2004 [137]. 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 adamantanes [138]. 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 outcomes [12, 23, 27, 65, 150] (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 delayed [12, 23, 26–28, 150]. 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 patients [66, 158–161].

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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 oseltamivir [114, 168–170]. Infection-control measures are especially important for patients who are immunocompromised to reduce the risk for transmission of oseltamivir-resistant viruses [104, 105]. 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 infection [51, 169, 174].

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 illness [171]. Limited experimental use of an unlicensed nebulized formulation of zanamivir has been well tolerated [175], 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 tubing [176].

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 viruses [171, 177]. Clinicians should be alert to the future availability of new therapeutic options and recommendations. In addition, careful attention to infection-control measures is recommended [104, 105], particularly in hospital areas that house immunocompromised patients.

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For current information on antiviral resistance among circulating influenza viruses in the United States, please see the FluView Weekly U.S. Influenza Surveillance Report.

For information on antiviral resistance among influenza viruses circulating globally, see the World Health Organization (WHO) influenza virological update page. (Note: WHO periodically updates its antiviral resistance information in association with its latest influenza virological update.)

For global updates on the susceptibility of 2009 H1N1 viruses to treatment with oseltamivir, see the 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).

For additional guidance on antiviral treatment of patients with suspected or documented antiviral resistant influenza virus infection, see the Intravenous Influenza Antiviral Medications, Use of Antivirals, and the WHO guidelines for pharmacological management of pandemic (H1N1) 2009 influenza and other influenza viruses. PDF Version [540 KB, 32 pages]. 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.”

Review the complete references cited in this guidance.

Selected References

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; 10.1016/ 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.

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