Pan-canadian public health network council report and policy recommendations on the use of antivirals for prophylaxis during an influenza pandemic

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Key Considerations and Expert Reviews

1.Scientific Considerations

Extensive research and analysis of current scientific findings related to antivirals and their potential value for prophylaxis during an influenza pandemic were conducted. The PHNC requested an arm’s length, systematic review of the literature on the efficacy and safety of antivirals. The Canadian Agency for Drugs and Technologies in Health (CADTH) was commissioned to conduct the reviews. In addition, TGAP assessed the absolute risk reduction and “efficiency” of both pre-exposure and post-exposure prophylaxis, and conducted additional reviews of adverse events, compliance, and the risk of resistance. (see Annex 3.1).

Key Findings

A systematic review of amantadine undertaken by CADT noted that although it was a lower-cost drug, the side effects associated with amantadine and its potential to develop resistant strains made its use “questionable”. Thus, TGAP focused the rest of its review on neuraminidase inhibitors (oseltamivir and zanamivir).

Safety, Efficacy and Absolute Risk Reduction

The arm’s length systematic review of Tamiflu^® (oseltamivir) and Relenza^® (zanamivir) concluded that neuraminidase inhibitors are generally safe in so far as that they are “well-tolerated, by healthy humans and those whose health is compromised (e.g., the elderly and those living in LTC facilities)”. Serious side effects are rare, and in general adverse events are less frequent during a daily prophylactic dose, than in a twice-daily treatment dose.

The CADTH review concluded that there is “enough evidence to conclude that the antiviral drugs zanamivir [Relenza^®] and oseltamivir [Tamiflu^®] are effective in preventing the acquisition of common laboratory-confirmed influenza”. This conclusion is based on the analysis of 12 publicly available randomized controlled trials (RCT) on pre-exposure and post-exposure prophylaxis. For Tamiflu^®, there were 2 excellent quality trials to support the use of pre-exposure prophylaxis, no trials in LTC facility outbreaks, and 2 good quality trials to support the use of post-exposure prophylaxis. For Relenza^® there were 2 excellent quality trials to support the use of pre-exposure prophylaxis, two very good quality trials in LTC outbreaks (one positive and one negative) and 2 excellent and 1 fair quality trials to support the use of post-exposure prophylaxis. There was only one trial that received a poor quality score. Relative efficacy for both types of prophylaxis were similar with a range of 67-91% for pre-exposure prophylaxis and 68-81% for post-exposure prophylaxis. In contrast, there was a difference in absolute risk reduction (difference between drug and placebo) between pre and post-exposure. Absolute risk reduction of seasonal influenza ranged from 1.1 to 4% for pre-exposure prophylaxis to 10-15% for post-exposure prophylaxis. This was likely due to the increased risk of exposure to the influenza virus in the post-exposure prophylaxis group.

There was no RCT evidence for efficacy of antivirals for prophylaxis among many of the vulnerable populations, such as the elderly, the immunocompromised, and pregnant women (see Table 5 in Annex 3.1). Nor did the review find data for specific occupational groups such as health care or other critical infrastructure workers, although it is expected that the data on healthy people would apply to most occupational groups.

There were two intervention studies in long term care facilities that reported a beneficial effect of using Tamiflu^® for both treatment and prophylaxis during an institutional outbreak of influenza, and one that suggested a beneficial effect for Relenza^®.

Population-based considerations

There is adequate RCT evidence to support the use of neuraminidase inhibitors for prophylaxis under the conditions studied. However, it is uncertain how these findings will translate to widespread use on a population basis during a pandemic. To supplement this evidence TGAP undertook further assessments in the area of efficiency, safety, compliance, and the risk of resistance.

Additional safety considerations

Due to the difficulties in standardizing and reporting safety data, and the relatively few trials that have been done that have collected safety data, it would not be surprising if new adverse events were noted if these drugs were to be used widely in the general population during a pandemic. Rare and serious adverse events, such as Stevens Johnson Syndrome, may occur if there is widespread use in Canada, and the risks in a healthy population taking prophylaxis must be weighed against the likely benefits.

Following the completion of the systematic review, concerns regarding safety were raised when a 2007 Health Canada Advisory noted that “Canadian labelling for Tamiflu^® has recently been updated to include new safety information resulting from adverse reaction reports of abnormal or

suicidal behavior in Japanese children or teenagers taking Tamiflu^®”. These adverse events occurred following the use of Tamiflu^® for treatment of influenza illness. The etiology of these observations is not clear, nor is the likelihood that this would occur following prophylactic use. However, this is an example of a temporally associated effect that if caused by Tamiflu^® may become more evident with widespread use.

Efficiency considerations

Studies of new interventions do not necessarily give a sense of the investment of resources needed to obtain the beneficial effect. “Number needed to treat” is calculated to achieve this end – it indicates how many people need an intervention to reach a desired outcome. Based on the pre-exposure prophylaxis trials, 26.5 people would need to take antivirals for 6 weeks to prevent one case of influenza (>1000 doses). Based on the post-exposure prophylaxis trials, 9 people would need to take antivirals for 10 days to prevent one case of influenza (90 doses). During a pandemic when the clinical attack rate would be higher, the number requiring prophylaxis to prevent one case would be lower. However it is likely that post-exposure prophylaxis would continue to be more efficient than pre-exposure prophylaxis.

Compliance considerations

A supplementary review showed that compliance is a problem with all medications, regardless of age, sex, race, or education. Compliance is lower in the absence of symptoms, and when adverse events increase, and compliance continues to decrease the longer the medication is taken. Whereas one might expect compliance to increase with increased perceived risk to self and to one’s close contacts, variable compliance was still recorded, for example, in postal workers following the anthrax exposure in the United States, and in responders to the avian influenza outbreaks in Europe and British Columbia. Efforts to improve compliance have not been very effective. Based on these trends, TGAP would anticipate that compliance may be an issue with the prophylactic use of antivirals and would likely be more of an issue with pre-exposure prophylaxis (taken for 6-8 weeks or more) vs. post-exposure prophylaxis (taken for 10 days).

Resistance considerations

In the systematic review, of the five RCTs that reported on antiviral resistance testing, no evidence of resistance was found. As noted in the Product Monograph, the incidence of viral resistance in treatment studies is approximately 0.33% in adults and 4% in pediatric patients. To date, mostly non-transmissible virus strains have been identified, suggesting that that the current risk of Tamiflu^®-resistant influenza is low. However, it is possible that resistance would increase during a pandemic with more widespread, community-based use.

Conclusions

Tamiflu^® and Relenza^® are efficacious in preventing seasonal influenza given either as pre-exposure or post-exposure prophylaxis in healthy populations. Policy recommendations related to the use of antivirals for prophylaxis during a pandemic can only be based on extrapolation from the limited scientific data available at this time, and should include a risk-benefit assessment based on population-based considerations. More research is needed into the efficacy of antivirals, especially for vulnerable populations, as well as population-based effectiveness studies. Modeling studies may further inform the development of population-based policies. Early detection of resistant strains will be important and real time surveillance for adverse events needs to be established well in advance of a pandemic.

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