1. Recommendation for Use of Antivirals for Prophylaxis

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In considering when and how antivirals should be used during an influenza pandemic, TGAP developed a single recommendation, within which it identified specific actions to be taken during the potential spectrum of development of an influenza pandemic in Canada. Adoption of this recommendation by governments across Canada is strongly advised, to optimize its effectiveness and manageability. The proposed strategy requires a reassessment of the size of the National Antiviral Stockpile, and will likely result in a recommendation that it be increased.

a) Early Treatment for the Pandemic Period

Context: Canadian Pandemic Phases 6.1 and 6.2
Although a policy decision to provide antivirals for early treatment of influenza during a pandemic has already been made, plans for the implementation of the treatment strategy have not been completed in many jurisdictions. Adoption of the objectives proposed below for early treatment during a pandemic is assumed as a basis for TGAP’s overall recommendation on the use of antivirals.

TGAP recommends that during the implementation of the early treatment strategy, critical infrastructure sector workers have access to rapid assessment and early treatment in order to minimize societal disruption.

Rationale

In recommending these objectives, TGAP sought to encourage those who are developing implementation strategies for antiviral treatment to consider not only how to assess and treat individuals presenting for medical care, but also how to ensure that symptomatic critical infrastructure workers have rapid access to assessment and treatment.

The apparent singling out of critical infrastructure workers is not intended or expected to deprive anyone who needs antiviral treatment from receiving it. Rather it highlights the potential societal benefit of reducing absenteeism in the critical infrastructure sector. Early treatment of critical workers can be expected to shorten the duration of their illness, and restricting them from the workplace at the first indications of illness may reduce the likelihood of infection spreading from these workers to their colleagues or clients. The potential reduction of absenteeism in critical sectors would support the ongoing provision of critical services and consequently reduce potential societal disruption. Participants in the deliberative dialogues considered that the most important approach to a policy decision in this context was to keep society functioning.

Consequences and further work needed at all levels of government, to enable this to succeed, include:

• finalization of the early treatment strategy, including operational aspects;
• development of a strategic approach to antiviral stockpile acquisition and rotation;
• operational guidance regarding the consistent assessment of “need” for treatment;
• defining the core group of critical infrastructure workers and assessment of the feasibility of targeting them for early treatment;
• engagement of critical infrastructure employers in planning for implementation of the early treatment strategy for their workers; and
• consideration of how to get medication to those working in remote areas may imply a need for investment in specific strategies regarding transportation, communications and/or medical facilities to serve these areas.

A number of these requirements bring to light the importance of a well-considered, well-developed, workable implementation plan to mitigate the risks associated with the early treatment antiviral policy.

b) Early Treatment and Post-Exposure Prophylaxis for the Pandemic Alert Period

Context: Canadian Pandemic Phases 4.1, 4.2, 5.1 and 5.2
While these phases may occur due to a novel virus originating in Canada, it is considered more likely that a pandemic virus would first be seen in another country. If clusters of cases occur in other parts of the world, it is assumed that containment in those locations would have been attempted. Despite exit screening from source countries and entry screening being conducted at our international borders, cases or contacts associated with the clusters would be occurring in Canada during these phases. However, the novel influenza virus would not yet have demonstrated the efficient human-to-human transmission necessary to cause a pandemic.

TGAP recommends that early treatment of cases and post-exposure prophylaxis of close contacts should be offered in Canada during the Pandemic Alert period, specifically during phases 4 and 5, as part of a rapid response strategy. The National Antiviral Stockpile should be used for this purpose.

Rationale

Antivirals are the only medical virus-specific intervention that could be used to limit and potentially stop the spread of the novel virus in Canada, prior to development of the necessary pandemic vaccine. In clinical trials and on an annual basis during seasonal influenza, antivirals have shown a relatively high level of efficacy when used in this manner and they are approved for use in Canada for both treatment and post-exposure prophylaxis. Furthermore, during this period the number of cases would be expected to be relatively small and, if rapidly identified, timely tracing of their close contacts should be a feasible intervention.

Consequences and further work needed to enable this to succeed include:

• facilitating rapid identification of cases through a robust surveillance strategy linked to public health authorities;
• assessing the current plans for international border screening procedures;
• determining the necessity of and implications for replenishing the antivirals used for the rapid response strategy.

 

 

c) Post-Exposure Prophylaxis during the Early Pandemic Period

Context: Canadian Pandemic Phase 6.1
It is assumed that, in the early stages of pandemic influenza, efficient and sustained transmission of a pandemic virus, resulting in widespread illness and death, would be occurring in one or more locations outside Canada, and Canada would be experiencing its first cases (phase 6.1). An aggressive early treatment strategy, along with other public health measures and public education, would be implemented.

TGAP recommends that in the early stages of pandemic influenza activity in Canada (phase 6.1), post-exposure prophylaxis of close contacts of cases should not be undertaken.

Rationale

It is considered likely that the pandemic virus will retain the characteristics of seasonal influenza and the number of cases resulting from a single case will double approximately every three days, with the potential for transmission prior to onset of symptoms or from asymptomatic cases. In this scenario, Phase 6.1 will be very short in duration and may be missed altogether if the first cases in Canada are not rapidly identified. Given this, post-exposure prophylaxis could not be expected to control the spread of a pandemic virus in the population in the real world once Phase 6 has begun.

Such control would require extensive use of antivirals in individuals infected with the pandemic virus but not yet able to spread the illness to others. Considerable time and resources would be required to identify, assess and administer drugs to the ever-increasing number of these contacts, which would not be feasible on a population basis during a pandemic. Management of the situation, requiring tracing of each contact network and administration of post-exposure prophylaxis potentially within every regional or local health authority in which the first cases are identified, would be a major challenge offering limited benefits to the population.

TGAP took these dynamics into consideration in concluding that the implementation of post-exposure prophylaxis by public health authorities in phase 6.1, followed by the relatively rapid discontinuation of this measure when Canada reaches phase 6.2, would confront the public health system with operational and communication challenges. It might create confusion and threaten public confidence in public health authorities at a critical time.

It is recognized that some of the strongest efficacy data is for post-exposure prophylaxis of household contacts of cases. However, the concern remains that the effectiveness of this measure on a population basis is significantly limited for the reasons stated above. The clinical care system may be in a position to provide post-exposure prophylaxis on an individual basis to some close contacts of cases during phase 6.1. However, rapid provision of this service would require re-direction of clinical care resources at a time of pandemic response ramp-up, with imminent increased demand for services.

Finally, broadening the criteria for administering post-exposure prophylaxis, for example by requiring only self-identification of exposure to a case, would likely result in extensive uncontrolled use of antiviral drugs, with the potential for previously unidentified and possibly unmonitored side effects, and misuse of the drug.

Therefore, TGAP does not support the use of publicly-funded NAS supplies for post-exposure prophylaxis during phase 6.1.

An acknowledged weakness of this decision might be the public perception that no action is being taken to stop the spread of the disease. This could be managed by appropriate communication of the limitations of this approach, and of actions that are in fact being taken, including the use of antivirals for treatment and other public health measures. Development of a pandemic vaccine and preparations for its administration would be under way. Consistency of response among jurisdictions is essential to successful implementation of this decision and the perception of the public.

Consequences and further work needed to enable this to succeed include:

• monitoring relevant scientific developments and international decisions that may influence these conclusions;
• public education and communications to manage expectations.

 

d) Post-Exposure Prophylaxis During the Pandemic Period

Context: Canadian Pandemic Phase 6.2

In phase 6.2, many cases of pandemic influenza would be occurring in Canada. Governments and health systems would be in pandemic response mode aimed at optimal management of cases, with implementation of the early antiviral treatment strategy, infection control and other public health measures including enhanced surveillance. Vaccine production, distribution and administration would be planned or under way. There would be a focus on maintaining essential health care and other services, and professional and public communications and education measures would be under way or in place.

TGAP recommends that general post-exposure antiviral prophylaxis of close contacts of cases during pandemic phase 6.2 not be undertaken, and that antiviral use be focused on treatment of those with influenza.

Rationale

As described in situation c), a post-exposure prophylaxis strategy, requiring identification of close contacts of a case, is resource-intensive, untimely and unsustainable. The level of resources (human, material, financial) needed to sustain an effective strategy cannot be predicted. From the scientific perspective, randomized control trial (RCT) data supporting post-exposure prophylaxis has only been generated in household settings, and could not be assumed to be an effective strategy on a population basis.

Public health staff would be focusing on other essential rapid response tasks during this phase, and diverting health care resources to contact tracing to enable post-exposure prophylaxis, could seriously deplete the resources necessary to manage the health sector response. Additionally, there would be multiple potential exposure sites, probably including most community settings. The response would be better supported by the most effective use of the health system, that is in providing treatment, maintaining public health measures, and preparing for and administering pandemic vaccine.

Consequences and further work needed to enable this to succeed include:

• consideration of the impact of this recommendation on vulnerable persons, as identified in the CPIP;
• specifically, focused examination of issues regarding the provision of prophylaxis to immunocompromised persons, with an emphasis on additional research to guide decision-making.

e) Outbreak Control During the Pandemic Period

Context: Canadian Pandemic Phases 6.1 and 6.2

It is assumed that pandemic phase 6 has been reached and that the contextual circumstances would be the same as those identified in situation d).

TGAP recommends that outbreak control, involving treatment of cases and post-exposure prophylaxis of contacts, in closed health care facilities and other closed facilities in which high risk persons reside, be offered or continue to be offered during pandemic phases 6.1 and 6.2.

During a pandemic, there would be severe disease, with transmission known to be occurring in closed settings, such as Long Term Care (LTC) facilities or hospital wards. A closed setting is a facility or institution in which an outbreak can be identified in time and place and for which outbreak control protocols exist to protect high risk populations who are living in these settings. Outbreak control would involve the use of antiviral medications to treat cases and to provide post-exposure prophylaxis to contacts, that is, to residents, staff and potentially others, such as volunteers who provide services in these institutions.

High risk of poor outcome of pandemic influenza would be defined as high likelihood of serious illness or death, based on the epidemiology of the pandemic. At the time of the pandemic, the available epidemiological data would be reviewed to identify the factors which might influence risk of poor outcome. These risk factors would be used to characterize persons identified as high risk, and thus settings in which these individuals reside together. The recommendation is setting-based, not based on the person, so would not include prophylaxis of high risk individuals outside of these facilities or institutions.

Rationale

TGAP determined that the established standard of care for those in certain closed facilities, primarily long-term care facilities, should continue. Specifically, influenza outbreak control in LTC facilities is currently a standard of practice across Canada and usually includes the use of antiviral drugs. In some jurisdictions, outbreak control using antivirals for treatment and prophylaxis is also conducted in other health care facilities, in order to reduce morbidity and mortality in these facilities.

From a scientific perspective, there are limited Randomized Control Trial (RCT) data and some case series data supporting use of antivirals in these settings during influenza outbreaks.

Logistically, it is easier to identify contacts in such closed facilities than in the population at large. Medical records are available to assess for contraindications and compliance, and occurrence of adverse events can be more readily monitored and managed.

It was concluded that this recommendation could be supported on many levels, especially if risk factors were consistent with those observed in seasonal influenza (those over age 65, and/or with underlying circulatory and respiratory conditions). During seasonal influenza outbreaks, residents of closed facilities such as LTC facilities are often at highest risk for poor outcome. They are seen as more vulnerable, a group which the deliberative dialogue sessions indicated should be protected.

Consequences and further work needed to enable this to succeed include:

• Estimates of the quantity of antivirals needed to provide this limited prophylaxis. While it would be difficult to determine how much drug might be required, it may be possible to come up with a reasonable estimate based on past annual usage.
• Recognition that there may be closed facilities or institutions other than LTC facilities, in which high risk persons reside, where outbreak control may be indicated during pandemic phase 6. Defining these settings would be a more challenging task than identification of LTC facilities which are already known to relevant authorities in the context of current practice. In addition, applying this recommendation to facilities or institutions beyond those in which antivirals are currently used would not be a continuation of current practice but an extension of it, and, therefore, not supported by the “standard of practice” rationale. For closed facilities or institutions not within the health care system, in which individuals who are defined as at higher risk of morbidity and mortality reside, it would be important both to provide an initial assumption of where those closed facilities or institutions are and then to develop an operational plan on how to provide treatment and post-exposure prophylaxis.
• In the post-exposure prophylaxis protocol, it may be appropriate to include family members and/or friends who visit and provide much of the personal patient care in these facilities. Whereas past practice has often been to restrict visitors or patient transfers to limit the spread of the disease, enabling them to access the facility and provide support may be beneficial during a time of potentially overwhelming demands on health care workers. Furthermore, medical ethics dictates that all persons should have access to proper care and consolation during illness, deprivation of which would constitute unsound medical practice.

 

f) Pre-exposure Prophylaxis During the Pandemic Period

Context: Canadian Pandemic Phase 6.1 and 6.2

The context continues to be that of a full pandemic in Canada.

TGAP recommends that antivirals for pre-exposure prophylaxis not be stockpiled by F/P/T governments for use during pandemic phases 4.1, 4.2, 5.1, 5.2, 6.1 and 6.2

Rationale

It is TGAP’s assessment that population-based interventions for prophylaxis represent a different type of practice than one-on-one patient care, and that any decision to undertake pre-exposure prophylaxis as a population-based intervention would require stronger scientific evidence, such as population-based trials. In addition, Tamiflu^® is not approved for pre-exposure prophylaxis in Canada and studies done on this have been for short periods only.

Compliance with the extended use of drugs, even in emergency situations, has historically been poor and interventions to improve compliance have not proven to be effective. Analysis of the progression of a virus during a pandemic suggests that more widespread use of antivirals could lead to development of resistant strains of the virus, potentially providing only short-lived protective benefits of pre-exposure prophylaxis.

Resistance is also a risk. Analysis of the progression of a virus during a pandemic suggests that more widespread use of antivirals could lead to development of resistant strains of the virus, potentially providing only short-lived protective benefits of pre-exposure prophylaxis. Typically, the risk of resistance increases with increased use and/or improper use (like such as missing doses, or not finishing the prescription). If resistance develops from widespread use for of pre-exposure prophylaxis, we would no longer be able to use antivirals for early treatment.

Logistically, the efficient and effective use of pre-exposure prophylaxis is very difficult to achieve. It would be difficult to determine the optimal time to start using these drugs, to identify who should receive them in order to achieve the greatest societal benefit, and how to ensure appropriate and consistent use across Canada.

That said, it is known that antivirals have been purchased by some organizations. Given this reality, some Canadians may have access to antivirals for pre-exposure prophylaxis.

Consequences and further work needed to enable this to succeed include:

• Development of communications strategies and messages to be used both before and during a pandemic for decision-makers to explain to the public the approach that is being adopted by governments, while acknowledging that other decisions and approaches may have been made in some organizations.

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