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National Influenza Treatment Guidelines: Interim Options for Clinicians Considering Influenza Antivirals in the Context of Changing Patterns of Resistance, 2008-09 Season

The following Public Health Agency of Canada (PHAC) guidelines are based on expert scientific advice from the Seasonal Influenza Antiviral Advisory Group (SIAAG). The SIAAG provides technical, scientific and public health expert advice to the Center for Immunization and Respiratory Infectious Diseases (CIRID) and the Influenza Section of the National Microbiology Laboratory (NML).

These guidelines are based on evolving knowledge and surveillance data for the 2008-09 influenza season that show a high rate of oseltamivir resistance in A/H1N1 viruses and a continued high rate of amantadine resistance in A/H3N2 viruses. Health care providers considering the use of antivirals should consult surveillance updates to stay informed about influenza activity and antiviral resistance patterns in their area. The appropriate choice of antiviral options may change. Influenza antivirals should be used selectively and judiciously for appropriate clinical indications. Product monographs and other references should be consulted for detailed prescribing information (1-9).

Table of contents

  1.   Background
    1. General
    2. Amantadine Resistance Patterns
    3. Neuraminidase Resistance Patterns
  2. Interim Influenza Antiviral Treatment Options For 2008-09 Season
  3. Deciding on Influenza Antiviral Options Based on Surveillance & Testing
  4. Acknowledgements
  5. References
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A.  Background

1.  General

In Canada, three antiviral medications are approved for the treatment and chemoprophylaxis of influenza: oseltamivir (Tamiflu®), zanamivir (Relenza®), and amantadine[1-4]. All require medical prescription.  Oseltamivir and zanamivir are neuraminidase inhibitors; amantadine is an M2 ion channel inhibitor in the class of drugs known as adamantanes.  Rimantadine is another adamantane approved in the United States but not approved for use in Canada.  Oseltamivir and amantadine are oral medications whereas zanamivir is inhaled using a Diskhaler® device.  Oseltamivir and zanamivir are options for both influenza A and B whereas amantadine is inherently ineffective against influenza B.

Until recently, Oseltamivir has been considered the preferred antiviral option for treatment or chemoprophylaxis of influenza among people one year of age and over. Oseltamivir is approved for treatment and post-exposure prophylaxis of influenza in Canada [4]. In double-blind, placebo-controlled trials including children, young and elderly adults, the only adverse effect to occur significantly more often with oseltamivir compared to placebo was nausea or vomiting (2-17%) [7,10]. These symptoms are generally mild, are mitigated by taking oseltamivir with food and cease on discontinuation of medication.

Zanamivir is an antiviral alternative to oseltamivir that is active against current influenza A/H1N1 (including oseltamivir-resistant viruses), A/H3N2, and influenza B. Zanamivir is approved in Canada for the treatment and chemoprophylaxis of people ≥ 7 years of age [4]. In the United States, zanamivir is approved for chemoprophylaxis indication as young as 5 years of age [5]. Zanamivir is approved for both post-exposure prophylaxis and for pre-exposure prophylaxis for up to 28 days duration in Canada [4]. Diskhaler® administration of zanamivir may be difficult in some groups such as in persons with poor muscle coordination, or cognitively impaired persons [11]. No adverse effects have been significantly associated with zanamivir compared to placebo. There have been reports of bronchospasm in patients with underlying asthma/chronic obstructive pulmonary disease (COPD) taking zanamivir although a few clinical trials show no difference compared to placebo [7]. 

Amantadine is an antiviral alternative to oseltamivir that is active against current A/H1N1 strains but is no longer recommended for the treatment or prevention of influenza A/H3N2 due to high rates of amantadine resistance among circulating A/H3N2 viruses.  Amantadine is not active against influenza B[4].  Careful dosing requirements apply to amantadine used in the elderly and those with renal conditions[6].  In otherwise healthy young adults given amantadine prophylactically, 5% to 10% report difficulty concentrating, insomnia, light-headedness, and irritability[6]. These side effects are usually mild and cease shortly after the prophylaxis is stopped; however, they occur more frequently in older populations unless a reduced dosage is used. Serious side effects (e.g. marked behavioural changes, delirium, hallucinations, agitation, seizures) have been associated with high plasma drug concentrations. These have been observed most often among those with renal insufficiency, seizure disorders, or certain psychiatric disorders, and among the elderly. Lower dosages for these people reduces the severity of such side effects[6].

2.  Amantadine Resistance Patterns

During the 2007-08 season, 99% of the A/H3N2 isolates tested in Canada were resistant to amantadine whereas just 1% of the A/H1N1 isolates tested were amantadine-resistant (4). Since the start of the 2008-09 season (to March 19), the National Microbiology Laboratory (NML) has tested 322 influenza A isolates (160 A/H1N1 and 162 A/H3N2) for amantadine resistance. All of the A/H1N1 isolates were susceptible; however all of the A/H3N2 isolates were resistant to amantadine [12].

Resistance to amantadine emerges readily within days of starting treatment. Amantadine resistance is more likely to occur in semi-closed settings, such as within a family, facility, or institution (including nursing homes), where the drug is used for both prophylaxis and treatment, as opposed to prophylaxis alone. For this reason, simultaneous use of amantadine for prophylaxis and therapy within these settings is not recommended. People in institutions treated with amantadine should be isolated from others until 2 days after treatment has ended [6].

3. Neuraminidase Inhibitors Resistance Patterns

During the 2007-08 influenza season, oseltamivir resistance was first identified among circulating A/H1N1 viruses worldwide [4,13]. All oseltamivir-resistant strains were due to changes at position 274 in the viral neuraminidase gene (H274Y) – believed to be a spontaneous mutation conferring resistance [4,14]. The global proportion of oseltamivir-resistant A/H1N1 specimens among those tested increased from 16% during the northern hemisphere’s 2007-08 season to 31% during the southern hemisphere’s 2008 season [15]. In Canada, between August 26, 2007 and May 17, 2008, 481 influenza A/H1N1 isolates were tested for oseltamivir resistance by the NML and, of these, 125 (26%) were found to be resistant. All but one of the 125 oseltamivir-resistant A/H1N1 viruses assessed in Canada during the 2007-08 season were sensitive to amantadine (>99%); the one virus isolate resistant to both oseltamivir and amantadine was from a person who was treated with both. Testing in the United States showed that all oseltamivir-resistant A/H1N1 viruses assessed by the CDC for the 2007-08 season retained sensitivity to both zanamivir and amantadine [4,16].

This season, to March 19, 2009, the NML has tested 566 influenza isolates (125 A/H1N1, 89 A/H3N2 & 352 B) for oseltamivir resistance [12]. All of the A/H3N2 and B isolates were sensitive to oseltamivir; however all of the A/H1N1 isolates were resistant to oseltamivir due to the H274Y mutation. All A/H1N1 isolates that were oseltamivir-resistant were sensitive to amantadine. All 552 influenza isolates for the 2008-09 season to March 19 (113 A/H1N1, 88 A/H3N2 & 351 B) tested for zanamivir resistance have been found to be sensitive to zanamivir [12].

In addition, to March 16, 2009, the British Columbia Centre for Disease Control (BCCDC) virology laboratory has assessed 128 A/H1N1 viruses for the H274Y mutation denoting oseltamivir resistance using an innovative single nucleotide polymorphism (SNP) assay. Of these, 117 showed the oseltamivir resistance mutation (the other 11 specimens are indeterminate and undergoing further characterization by sequence analysis of the neuraminidase gene) [12,17].

In the United States, FluView indicates that, between October 1, 2008 and March 14, 2009, 778 influenza viruses (474 A/H1N1, 77 A/H3N2, and 227 B) have been tested for resistance to neuraminidase inhibitors. Of the A/H1N1 viruses tested, 98.9% (469/474) were resistant to oseltamivir however all were sensitive to zanamivir. All of the A/H3N2 and B viruses tested were sensitive to both oseltamivir and zanamivir. The CDC tested 553 influenza A viruses (476 H1, 77 H3) for amantadine resistance: 0.6% (3/476) of the H1N1 viruses were resistant to amantadine but 100% of the H3N2 viruses were resistant [18].

In Europe, as of week 11/2009 (18 March 2009), 272 influenza A/H3N2 isolates were tested for adamantanes susceptibility, of which 100% were resistant. Of the 81 A/H1N1 isolates tested, one was adamantane-resistant (0%). During the 2008-09 season to date, 709 isolates have been tested for resistance to neuraminidase inhibitors. Of the 204 A/H1N1 isolates tested, 200 (98%) were resistant to oseltamivir but sensitive to zanamivir. All A/H3N2 and B isolates were sensitive to both oseltamivir and zanamivir [19].

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B.  Interim Influenza Antiviral Treatment Options For 2008-09 Season

Zanamivir, although difficult to use for some people, is active against all three human influenza types or subtypes (A/H3N2, A/H1N1, B). Oseltamivir is active against influenza A/H3N2 and B viruses but is not currently an effective option for A/H1N1 viruses. Amantadine, requiring dosage adjustment (most notably in the elderly and those with renal conditions) to minimize side effects, is active against A/H1N1 only.

Antivirals used for treatment of influenza are most beneficial when started within the first two days of illness. The effectiveness of antiviral options in reducing the duration and/or complications of influenza has been summarized in published reviews[7,8,20-25].  Data for safety and effectiveness are lacking for children less than one year of age.  Treatment effectiveness data are not available for all antiviral options in all age or at-risk groups for all outcomes; more systematic evaluation is needed especially related to the benefit against serious outcomes for zanamivir and amantadine as antiviral alternatives.  In the meantime, antivirals should be used selectively and judiciously for appropriate clinical indications, most notably for individuals with severe illness and those most likely to develop complications or die as a result of influenza[7].

Position papers of the Canadian Paediatric Society and Association of Medical Microbiology and Infectious Diseases (AMMI) Canada (The Use of Antiviral Drugs for Influenza: Recommended Guidelines for Practitionerslink will open in t5he new window) and the American Pediatric Society (Antiviral Therapy and Prophylaxis for Influenza in Children PDF version ) are readily available and valuable sources of information concerning influenza antivirals.

Choice of antiviral should be based on the type/sub-type of influenza (if known), predominant viruses circulating in the community, patient age and underlying health, anticipated antiviral benefits and adverse effects, ease of administration, contraindications/warnings/precautions and, ultimately, clinician judgment.  Clinicians should consult package inserts and references for specific antiviral prescribing information[1-9]. 

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C.  Deciding on Influenza Antiviral Options Based on Surveillance & Testing

Health care providers considering influenza antivirals in the treatment of patients should take into account the following for the 2008-09 season:

  1. Immunization is the primary prevention strategy for influenza. In particular, note that the A/H1N1 component of the 2008-09 vaccine is a good antigenic match to current oseltamivir-resistant A/H1N1 viruses. Pneumococcal vaccine for eligible persons will help prevent secondary complications. Cough etiquette, hand hygiene and limiting contact with others when ill, reduces respiratory virus transmission.
  2. Surveillance for influenza antiviral resistance is ongoing in Canada. Clinicians should regularly review public health updates to determine the likelihood of type (A or B) or subtype-specific (A/H1N1, A/H3N2) influenza illness in their area. National profiles are posted at the FluWatch website. Clinicians should be alert for changes relevant to antiviral options throughout the season and consult public health as needed.
  3. Diagnostic test results, and their availability, detail and timeliness:
    1. No influenza test results available (Figure A).
    2. Rapid antigen, near patient or point-of-care (POC) testing (Figure B).
      1. Some rapid tests can distinguish between influenza A and B but do not provide subtype (A/H3N2 versus A/H1N1) detail. These tests can take 15 minutes to 2 hours and some can be used in the office setting.
      2. In general, the sensitivity of rapid tests is variable (median 70–75%) and lower than that of cell culture.  Their median specificity is 90–95%.  Test parameters may vary with age and other considerations.
      3. Because of concern related to false negative and false positive results (depending upon the stage of the season), diagnosis by rapid POC tests must be interpreted with caution and where indicated should be confirmed by direct immunofluorescence microscopy (DFA), cell culture or RT-PCR testing. Complete details regarding World Health Organization and CDC recommendations on the use of rapid influenza testing, including a review of kits, can be found at the websites in references [26,27].
    3. Laboratory confirmation with a diagnostic test capable of distinguishing influenza A/H1N1 versus A/H3N2 or B viruses with results available in a timely way (Figure C). 
      1. Local availability/timeliness, either routinely or at special request, should be explored by interested clinicians.
  4. Chemoprophylaxis may be warranted in some people [1-9]. Choice of antiviral should similarly be guided by the above considerations. Facility guidelines for institutional outbreak control have been developed separately and can be accessed here: [weblink].

Figure A: No Influenza Test Results Available but Clinical Suspicion of Influenza and Strong Indication for Treatment (1)

Figure Bb: Rapid point of care test results for Influenza A or B available but subtype results not available and strong indication for treatment(1)

1 Antivirals used for influenza treatment are most beneficial when started within the first two days of illness. Antivirals should be used selectively and judiciously for appropriate clinical indications, most notably for individuals with severe illness and those most likely to develop complications or die as a result of influenza.  See narrative section B of these guidelines and consult specific antiviral package insert and/or references for prescribing detail including dose/indications/contraindications/precautions/warnings. 

2 Surveillance data may be driven by younger age groups.  Circulating A/H1N1 may be more likely to cause classic influenza illness and/or be reported in younger compared to elderly people and this requires consideration in treatment choice. 

3 Data for safety and effectiveness are lacking for children < 1 year of age and no influenza antivirals are yet approved for use in that very young age group.  Expert infectious disease consultation is advised in considering pediatric antiviral treatment options, especially for hospitalized children or those with severe illness.

4 Combined therapy with (amantadine plus oseltamivir) will address A/H1N1 (amantadine), A/H3N2 (oseltamivir) and B (oseltamivir), if multiple influenza types/subtype may be circulating. Human data are lacking to support the benefits of combination antiviral treatment of influenza; however, these interim recommendations are intended to assist clinicians treating patients who might be infected with oseltamivir-resistant influenza A/H1N1 virus when individual subtype-specific laboratory confirmation is lacking. 

b See Narrative in Section C3b of these guidelines related to rapid antigen, point of care tests. If there is strong clinical suspicion of influenza and strong indication for treatment and the rapid test is negative, consider treatment options per Figure A above.

Figure C: Laboratory confirmation able to distinguish influenza A/H3 versus A/H1 versus B and Strong Indication for Treatment (c1,2)

c1 Antivirals used for influenza treatment are most beneficial when started within the first two days of illness. Antivirals should be used selectively and judiciously for appropriate clinical indications, most notably for individuals with severe illness and those most likely to develop complications or die as a result of influenza. See narrative section B of these guidelines and consult specific antiviral package insert and/or references for prescribing detail including dose/indications/contraindications/precautions/warnings.

c2 When submitting a specimen for laboratory testing to a virology laboratory, there will be added transportation and processing time and subtype or oseltamivir resistance results may not be routinely available/reported or provided in a timely way to guide clinical decision-making. Antiviral treatment options are time-sensitive.  Local availability and timeliness of such diagnostic testing, either routinely or at special request, should be explored by interested clinicians. In such cases, treatment options can be considered per Figure A or B and revised with the availability of test results if clinically warranted.

c3 Data for safety and effectiveness are lacking for children < 1 year of age and no influenza antivirals are yet approved for use in that very young age group. Expert infectious disease consultation is advised in considering pediatric antiviral treatment options, especially for hospitalized children or those with severe illness.

D. Acknowledgements

These guidelines were adapted with permission from the document developed by the BC Centre for Disease Control entitled “Interim Options for Clinicians Considering Influenza Antivirals in the Context of Changing Patterns of Resistance, 2008-09 Season”.

The following current and past members of the Seasonal Influenza Antiviral Advisory Group (SIAAG) have contributed to the development of these guidelines: Upton Allen, Fred Aoki, Samina Aziz, Nathalie Bastien, Tim Booth, Michel Couillard, Shalini Desai, Gaston deSerres, Kathleen Dunn, Myrna Dyck, Travis Hottes, Naveed Janjua, Yan Li, Allison McGeer, Jennifer.McTaggart, Louise Pelletier, George Samuel, Shelly Sarwal, Claire Sevenhuysen, Tammy Simpson, Danuta Skowronski, Grant Stiver, Susan Tamblyn, Anne-Luise Winter.

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E. References

  1. Health Canada Drug Product Database. Oseltamivir product monograph, Hoffman-La Roche. 2008 [updated 2009 Mar 04, cited 2009 Mar 20]. Available at: http://webprod.hc-sc.gc.ca/dpd-bdpp/index-eng.jsp
  2. Health Canada Drug Product Database. Zanamivir product monograph, GlaxoSmithKline. 2008 [updated 2009 Mar 04, cited 2009 Mar 20]. Available at: http://webprod.hc-sc.gc.ca/dpd-bdpp/index-eng.jsp
  3. Health Canada Drug Product Database. Amantadine product monograph, Pharmel. 2004 [updated 2009 Mar 04, cited 2009 Mar 20]. Available at: http://webprod.hc-sc.gc.ca/dpd-bdpp/index-eng.jsp
  4. Statement on influenza vaccination for the 2008-2009 season. An Advisory Committee Statement (ACS). Can Commun Dis Rep 2008 Jul 15;34(ACS-3):1-46.  Available at:  http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/08pdf/acs-3.pdf
  5. Centers for Disease Control and Prevention. Antiviral agents for seasonal influenza:  dosage. 2009 [updated 2009 Feb 11, cited 2009 Mar 20]. Available at: http://www.cdc.gov/flu/professionals/antivirals/dosage.htm
  6. Statement on influenza vaccination for the 2005-2006 season.  An Advisory Committee Statement (ACS).  Can Commun Dis Rep 2006 Jun 15; 31(ACS-6):  1-32.  Available at:  http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/05pdf/acs-dcc3106.pdf
  7. Allen UD, Aoki F, Stiver HG et al. The use of antiviral drugs for influenza: Recommended guidelines for practitioners. Can J Infect Dis Med Microbiol 2006;17:273-79.  Available at:  http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=18382639
  8. American Academy of Pediatrics Committee on Infectious Diseases.  Antiviral therapy and prophylaxis for influenza in children.  Pediatrics 2007;119:852-860.  Available at:  http://aappolicy.aappublications.org/cgi/reprint/pediatrics;119/4/852.pdf
  9. Centers for Disease Control and Prevention. Interim Recommendations for the Use of Influenza Antiviral Medications in the Setting of Oseltamivir Resistance among Circulating Influenza A (H1N1) Viruses, 2008-09 Influenza Season. 2008 Dec 19 [cited 2009 Mar 20]. Available at: http://www.cdc.gov/flu/professionals/antivirals/index.htm
  10. Dutkowski R, Thakrar B, Froehlich E et al. Safety and pharmacology of oseltamivir in clinical use. Drug Safety 2003;26:787-801.
  11. Lee C, Loeb M, Phillips A, Nesbitt J, Smith K, Fearon M, McArthur MA, Mazzulli T, Li Y, McGeer A. Zanamivir use during transmission of amantadine-resistant influenza A in a nursing home. Infect Control Hosp Epidemiol. 2000 Nov;21(11):700-4. available at: http://www.journals.uchicago.edu/doi/pdf/10.1086/501727
  12. Public Health Agency of Canada. FluWatch weekly report. 2008-09 season [updated 2009 Mar 14, cited 2009 Mar 20]. Available at: http://www.phac-aspc.gc.ca/fluwatch/
  13. Lackenby A, Hungnes O, Dudman SG, et al. Emergence of resistance to oseltamivir among influenza A(H1N1) viruses in Europe. Euro Surveill 2008 [cited 2009 Feb 20];13(5). Available at: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=8026
  14. Rameix-Welti MA, Enouf V, Cuvelier F, Jeannin P, van der Werf S. Enzymatic properties of the neuraminidase of seasonal H1N1 influenza viruses provide insights for the emergence of natural resistance to oseltamivir. PLoS Pathog. 2008 Jul 25;4(7):e1000103.
  15. World Health Organization. Influenza A(H1N1) virus resistance to oseltamivir - 2008 influenza season, southern hemisphere. 2008 Oct 14 [cited 2009 Feb 20]. Available at: http://www.who.int/csr/disease/influenza/H1N1200801013.pdf 
  16. Centers for Disease Control and Prevention. 2007-08 U.S. Influenza Season Summary. 2008 [updated 2008 Oct 06, cited 2009 Feb 20]. Available at: http://www.cdc.gov/flu/weekly/weeklyarchives2007-2008/07-08summary.htm
  17. BC Centre for Disease Control. Influenza Surveillance Updates. 2009 [updated 2009 Mar 14, cited 2009 Mar 20]. Available at: http://www.bccdc.org/content.php?item=35 
  18. Centers for Disease Control and Prevention. FluView – A weekly influenza surveillance report prepared by the influenza division. 2009 [updated 2009 Mar 14, cited 2009 Mar 20]. Available at:  http://www.cdc.gov/flu/weekly/
  19. European Influenza Surveillance Scheme. EISS Weekly Bulletin. 2009 [updated 2009 Mar 14, cited 2009 Mar 20]. Available at: http://www.eiss.org/cgi-files/bulletin_v2.cgi?season=2008 
  20. Alves Galvão MG, Rocha Crispino Santos MA, Alves da Cunha AJL. Amantadine and rimantadine for influenza A in children and the elderly. Cochrane Database Syst Rev. 2008;Issue 1. Art. No.: CD002745. DOI: 10.1002/14651858.CD002745.pub2.
  21. Jefferson T, Demicheli V, Di Pietrantonj C, Rivetti D. Amantadine and rimantadine for influenza A in adults. Cochrane Database Syst Rev. 2006 Apr 19;(2):CD001169. Review.
  22. Jefferson T, Demicheli V, Rivetti D, et al. Antivirals for influenza in healthy adults: systematic review. Lancet 2006;367:303-313.
  23. Matheson NJ, Harnden A, Perera R, Sheikh A, Symmonds-Abrahams M. Neuraminidase inhibitors for preventing and treating influenza in children. Cochrane Database Syst Rev. 2007;Issue 1. Art. No.: CD002744. DOI: 10.1002/14651858.CD002744.pub2.
  24. Jefferson T, Demicheli V, Di Pietrantonj C, Jones M, Rivetti D. Neuraminidase inhibitors for preventing and treating influenza in healthy adults. Cochrane Database Syst Rev. 2008;Issue 4. DOI: 10.1002/14651858.CD001265.pub2
  25. Ambrozaitis A, Gravenstein S, van Essen GA, Rubinstein E, Balciuniene L, Stikleryte A, Crawford C, Elliott M, Shult P.  Inhaled zanamivir versus placebo for the prevention of influenza outbreaks in an unvaccinated long-term care population. J Am Med Dir Assoc. 2005 Nov-Dec;6(6):367-74.
  26. World Health Organization. WHO recommendations on the use of rapid testing for influenza diagnosis. 2005 Jul [cited 2009 Feb 20]. Available at: http://www.who.int/csr/disease/avian_influenza/guidelines/rapid_testing/
    en/index.html
  27. Centers for Disease Control and Prevention. Rapid diagnostic testing for influenza – information for health care professionals.  2009 [updated 2009 Jan 22, cited 2009 Feb 20]. Available at:  http://www.cdc.gov/flu/professionals/diagnosis/rapidclin.htm
Date Modified: 2009-04-18

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