New and updated evaluations of neuraminidase inhibitors for preventing and treating influenza published

In recent months three large systematic reviews with accompanying meta-analyses assessing effectiveness and safety of the two licensed neuraminidase inhibitors oral oseltamivir (Tamiflu™) and inhaled zanamivir (Relenza™) were either published or republished with additional data; • Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data was published by Muthuri et al on March 19. This evaluated patients admitted to hospital with laboratory-confirmed or clinically diagnosed influenza A H1N1pdm09 virus infection. The meta-analysis had as its primary end point death. The analyses provide support to the evidence that neuraminidase inhibitors can reduce mortality (19% overall reduction, adjusted OR 0.81 95%CI 0.70-0.93) in hospitalized adult (25% reduction in adults, adjusted OR 0.75 95%CI 0.64–0.87) patients with influenza when reviewing individual-level data from 78 observational studies involving more than 29,000 patients. In addition, early treatment (within 48 h from symptom onset) halved the risk of death compared to no antiviral treatment (adjusted OR 0.50 95%CI 0.37-0.67) in adults. The reduction was less pronounced and not statistically significant in children.
 
• Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments was reviewed and re-published by Jefferson et al on April 9.This systematic review assessed 20 randomised placebo controlled trials. In mainly healthy adults, oseltamivir reduced the time to first alleviation of symptoms by 16.8 hours. No effect was observed in children with asthma but a significant effect was observed in otherwise healthy children (mean difference 29 hours, 95% CI 12-47). There was no significant reduction in risk of pneumonia, bronchitis, otitis media, or sinusitis. In prophylaxis trials, oseltamivir reduced symptomatic influenza in participants by 55% based on one study. Oseltamivir increases risk of nausea and vomiting in children and adults.

• Zanamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments was reviewed and re-published by Heneghan et al on April 9.This is a revised systematic review of clinical study reports from 26 randomised placebo controlled clinical trials and regulatory information found that zanamivir reduces the time to symptomatic improvement in adults (but not in children) with influenza-like illness by just over half a day (~14 hours). The authors did not identify evidence in support of reduction of the risk of complications of influenza, particularly pneumonia, or the risk of hospital admission or death. Prophylaxis treatment significantly reduced laboratory-confirmed symptomatic influenza reducing event rates from 3.26% to 1.27%.  Its harmful effects were minor (except for bronchospasm).
 
• Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children (Review) was refreshed and re-published by the Cochrane Collaboration Jefferson et al on April 10.
 
This review present the meta-analysis results from the two systematic reviews presented above in its entirety in the “parent” Cochrane review published by the Cochrane Collaboration. This was a revision of a previous meta-analysis conducted in 2011, now with new study results and access to previously unpublished clinical study results provided from Roche.

ECDC comment

While most seasonal influenza virus infections cause only mild disease, severe complications and death do occur. These are usually found in those within recognized ‘risk groups’. Recommendations by WHO and public health institutions worldwide continue to stress annual seasonal influenza vaccination, which are reviewed annually by the WHO-led global surveillance system. In the event of the emergence of a new influenza strain (a ‘pandemic’), specific pandemic vaccines targeting the emerging pandemic strain are developed. Over time the pandemic strain become part of the seasonal mix of influenza viruses which is reviewed each season and recommendations made as to global seasonal vaccines. These are the primary countermeasure against seasonal and pandemic influenza. The EU Council recommendation from 2009 supports such efforts in the European Union.
 
However, with limited influenza vaccine effectiveness (~40-60% effectiveness) observed risk groups in need of protection against influenza are in need of additional prophylactic and treatment countermeasures. Also when pandemics occur, drugs such as neuraminidase inhibitors (NAIs) represent the only available counter-measures initially until new pandemic vaccine become available, which commonly takes 5-6 months.
 
While randomised and experimental studies such as Randomized Controlled Trials (RCTs) are the preferred methodology for determining effectiveness they cannot cover every case. Hence, the study by Muthuri et al (for the PRIDE collaboration) with a sample  from 38 countries in six WHO regions provides strong evidence for use of NAIs with an observed decrease in mortality among hospitalised adults suffering from influenza A H1N1pdm09 virus infections. This influenza strain continues to cause severe disease in the world and has for the 4th season caused significant morbidity and mortality in the EU and may be alleviated by the use of NAIs.
 
The Cochrane review provides evidence for limited effects on reducing time to alleviation of symptoms among adults while no evidence of any effect against hospitalisation or serious complications from influenza was observed. However, oseltamivir use was observed to be associated with a reduction of self-reported pneumonia.
 
The questions debated and the analyses presented in the studies in question are highly complex and require careful deliberation. The PRIDE and Cochrane reviews have individual strengths and limitations. ECDC is looking to arrange a small expert workshop later this year to assess the available evidence and identify knowledge gaps to be addressed in future studies.
 
Further studies are needed to assess neuraminidase inhibitor effectiveness in groups that are rarely included in randomized clinical trials (RCTs). Often these are those who suffer from severe disease and are excluded from many RCTs. Well-designed observational studies, such as PRIDE, are therefore especially important and may contribute to important policy decisions.
 
The new review results are valuable and provide limited new evidence on effectiveness of antivirals against severe disease caused including that resulting from other influenza strains more pathogenic than influenza A H1N1pdm09. But they do not give reasons for changing the current approach to public health use of antivirals, including prophylaxis, pandemic preparedness, stockpiling or use in outbreaks. While their publication represents a ‘signal event’ we clearly have a long way to go in this field.
 
Therapeutic indications as specified in Specific Product characteristics for neuraminidase inhibitors in the EU
Tamiflu (EMA)Treatment of influenza In patients one year of age and older, who present with symptoms typical of influenza, when influenza virus is circulating in the community. Efficacy has been demonstrated when treatment is initiated within two days of first onset of symptoms. This indication is based on clinical studies of naturally occurring influenza in which the predominant infection was influenza A (see section 5.1).
Tamiflu is indicated for the treatment of infants less than 1 year of age during a pandemic influenza outbreak (see section 5.2). The treating physician should take into account the pathogenicity of the circulating strain and the underlying condition of the patient to ensure there is a potential benefit to the child.
Prevention of influenza Post-exposure prevention in individuals 1 year of age or older following contact with a clinically diagnosed influenza case when influenza virus is circulating in the community.
The appropriate use of Tamiflu for prevention of influenza should be determined on a case by case basis by the circumstances and the population requiring protection. In exceptional situations (e.g. in case of a mismatch between the circulating and vaccine virus strains, and a pandemic situation) seasonal prevention could be considered in individuals one year of age or older.
Tamiflu is indicated for post-exposure prevention of influenza in infants less than 1 year of age during a pandemic influenza outbreak (see section 5.2).
 
Relenza (UK MHRA)
Relenza is authorised individually by all EU Member States.
 
Treatment of influenzaRelenza is indicated for treatment of both influenza A and B in adults and children (≥ 5 years) who present with symptoms typical of influenza when influenza is circulating in the community.
 
Prevention of influenzaRelenza is indicated for post-exposure prophylaxis of influenza A and B in adults and children (≥ 5 years) following contact with a clinically diagnosed case in a household (see section 5.1 for children aged 5-11 years). In exceptional circumstances, Relenza may be considered for seasonal prophylaxis of influenza A and B during a community outbreak (e.g. in case of a mismatch between circulating and vaccine strains and a pandemic situation).
 
In addition, EMA issued in 2011 a Summary on Compassionate use for IV Zanamivir

Compassionate use of  IV Zanamivir should be considered only to treat critically ill adults and children having a life-threatening condition due to suspected or confirmed pandemic A(H1N1)v infection or infection due to seasonal influenza A or B virus and answering to the following criteria:1. patients not responding to either oral or inhaled authorised antiviral medicinal products, or2. patients for whom drug delivery by a route other than IV (e.g. oral oseltamivir or inhaled zanamivir) is not expected to be dependable or is not feasible, or3. patients infected with documented oseltamivir-resistant influenza virus and not suitable for therapy with inhaled zanamivir.