Human Health Issues related to Avian Influenza in Canada

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10 Antivirals

The following recommendations have been developed by the National Antivirals Working Group and Public Health Measures Working Group of the Pandemic Influenza Committee, for application to avian influenza outbreaks and other situations in which AI is identified in Canada^[21]. Both of these working groups have also been involved in the development of antiviral recommendations for pandemic planning purposes. The recommendations have been reviewed and approved by the Pandemic Influenza Committee.

The use of antiviral drugs during an outbreak of avian influenza is a relatively new indication. Every effort should be made to evaluate the effectiveness of preventive measures implemented in response to an AI event, including the use of antiviral drugs. It is recommended that national systems be developed or enhanced in order to monitor antiviral susceptibility and to monitor adverse drug reactions to antivirals, under these circumstances. In addition local procedures should be put into place to maximize compliance with antiviral prophylaxis and to ensure that antiviral treatment can be initiated as soon as possible. (A sample information sheet on oseltamivir is provided in Appendix J).

The recommendations for antiviral use should be reviewed and modified as necessary at the time of the outbreak in light of the epidemiology of the specific avian influenza incident/strain. As more information about the epidemiology of avian influenza or the efficacy/safety of antiviral medications becomes available, the recommendations provided in this document may change. Additional information on antiviral drugs for influenza is available in the Antivirals Annex of the Canadian Pandemic Influenza Plan.

10.1 Background information

Neuraminidase inhibitors prevent the replication of both type A and B influenza viruses by inhibiting influenza virus neuraminidase. (Neuraminidase promotes the release of virus from infected cells.) This class of drug has a good safety profile with few side effects and is not likely to be problematic with respect to drug interactions. The protective efficacy of neuraminidase inhibitors in preventing laboratory confirmed clinical human influenza is between 60-90%. The efficacy of neuraminidase inhibitors in preventing avian influenza in humans has not been established.

Oseltamivir is a neuraminidase inhibitor that is approved for use in Canada for treatment of influenza A and B in persons 1 year of age and older. It is also approved for post-exposure prophylaxis against influenza in persons > 1 year of age, following close contact with an infected individual (index case), for a duration of up to 14 days. Oseltamivir is contraindicated in children less than one year of age and in persons with known hypersensitivity to any components of the product. Zanamivir, the other neuraminidase inhibitor, could be used as an alternative to oseltamivir; however it is not currently approved for prophylactic indications in Canada (it has been approved in other countries).

There is evidence for and experience with prophylactic use of oseltamivir for up to 8 weeks, but beyond this time frame experience is limited. Therefore, when developing these recommendations including off-label uses^[22], a risk benefit approach was taken examining the individual risk to the worker, the risk to public health, and the risk/benefit of the medication. Individuals who are being prescribed an antiviral in a way that constitutes an off-label use should be informed of that fact as part of the consent process.

10.2 Antiviral Recommendations

Since published research is lacking in the field of AI, the management of any occurrences in Canada should be used to further the knowledge base, for example through conducting serological surveys and monitoring the impact of antiviral drug use. The current objective for antiviral use is to minimize the direct risk and impact of zoonotic infection. In conjunction with other measure, antiviral prophylaxis may also reduce the risk of the emergence of a virus with pandemic potential.

10.2.1 Prophylaxis

The specific recommendations for the management of contacts, based on the human illness risk and the exposure risk, are summarized in the table 1 below. Additional recommendations follow the table. In making these recommendations it is assumed that antivirals will also be available for early treatment.

Antiviral recommendations should be guided by a risk assessment focusing on the exposure risk and the human illness risk for the specific AI virus (see section 7 for more details). If there are no data available on the human illness risk for the strain/subtype for the virus identified, antiviral prophylaxis is not recommended unless implementation of an early antiviral treatment cannot be ensured (e.g. if the worker may not accessible or able to access medical services in the 10 days following their last exposure) . The need for antiviral prophylaxis could be re-assessed if culling was indicated.

Table 1: Summary Recommendations for Antiviral Use for AI virus exposures

(Note: As the situation evolves and additional information becomes available the recommendations for individuals may change i.e., they may move between the cells in this table)

See section 7.2 for details regarding these risk categories.		Exposure Risk
		Low risk groups	Moderate risk groups	High risk groups
Human Illness Risk	Subtype has previously been identified and is not known to have caused human illness	- no prophylaxis	- no prophylaxis	- no prophylaxis (see note below table re. cullers*)
	Subtype is known to cause predominantly mild human illness	- no prophylaxis	- consider prophylaxis	- prophylaxis
	Subtype is known to cause predominantly severe human illness	- no prophylaxis(see note below table re. cullers**)	- prophylaxis	- prophylaxis

Specific considerations for cullers:

* If culling is implemented, given the potentially high concentration of virus and unique situation of a mass cull, prophylaxis may be considered for the cullers in this situation.

** With respect to cullers of asymptomatic presumably non-infected birds, this recommendation for "no prophylaxis" is intended for the situation in which a pro-active cull has been ordered in out lying areas (i.e., not within the infected zone) and is dependent on this designation being made based on a thorough risk assessment with ongoing monitoring of indicators of viral spread. Any illness in presumably non-infected flocks should prompt an immediate repeat risk assessment with concurrent (repeat) exposure assessments for the individuals involved. Post-exposure prophylaxis should be considered for individuals identified "retrospectively" as potentially belonging to a moderate or high risk group.

Additional prophylaxis recommendations:

1. When indicated oseltamivir prophylaxis should continue for the duration of exposure plus an additional 7 days. The maximum duration of time for continuous prophylactic should be 8 weeks. Consideration may be given to extending oseltamivir prophylaxis beyond 8 weeks on a case-by-case basis after consultation with a physician.
2. For persons not on continuous prophylaxis, post-exposure prophylaxis (7-10 day course) may be recommended based on the specific exposure risk category (see section 7). Post-exposure prophylaxis should only be offered to household and other close contacts of human cases of avian influenza, if the risk assessment suggested that it is prudent^[23].
3. Zanamivir should be considered a suitable alternative to oseltamivir, especially for pregnant women.
4. Amantadine could be considered for prophylaxis if the virus is known to be susceptible, however oseltamivir is preferable.
5. Prophylaxis of infants less than 1 year of age should only be considered after a thorough risk assessment and consultation with a physician as there are limited data on this age group and this would constitute an off-label use.

10.2.2 Treatment

1. a. Oseltamivir treatment is recommended for persons one year of age and over, who develop compatible illness following avian exposure. For H7 this can include conjunctivitis and/or influenza-like illness (ILI), specifically fever and cough.
2. b. Zanamivir may be considered for treatment of pregnant women if viral replication is believed to be confined to the respiratory tract (as with typical annual influenza). Zanamivir is not indicated if the virus is replicating outside of the respiratory tract (i.e., systemic infection)
3. c. Treatment of infants less than 1 year of age should only be considered after a thorough risk assessment and consultation with a physician as there are limited data on this age group and this would constitute an off-label use.
4. d. Clinical benefit has been shown when treatment with neuraminidase inhibitors has been initiated as late as 48 hours after onset of symptoms; however, in light of evidence showing continuing replication of avian influenza virus beyond 48 hours⁽²⁾ after onset of symptoms and therefore a potentially beneficial treatment effect with antivirals, consideration should be given to treating individuals presenting at any point during their illness (i.e., not just during the first 48 hours).^[24]

Oseltamivir Dosage[25]:

			Treatment	Prophylaxis[26]
Adults			75 mg bid x 5 days	75 mg daily
Children (≥ 1 year of age)	weight	≤ 15 kg	30 mg bid x 5 days	30 mg daily
		> 15-23 kg	45 mg bid x 5 days	45 mg daily
		> 23-40 kg	60 mg bid x 5 days	60 mg daily
		> 40 kg	75 mg bid x 5 days	75 mg daily

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