Monday, August 14, 2017

ECDC: Expert Opinion On Use Of Neuraminidase Inhibitor Antivirals For Influenza


For more than a decade critics have demonized NAI antivirals (particularly Tamiflu) as being either useless, or in some extreme cases, even dangerous. The British press, in particular, has promoted these notions using hyperbolic headlines such as the Daily Mail's: Ministers blew £650MILLION on useless anti-flu drug.

Fueling this controversy have been a number of Cochrane group analyses that found insufficient evidence that oseltamivir substantially reduces seasonal influenza complications in healthy adults.
A conclusion based primarily on the fact that the Cochrane group routinely excludes observational studies in favor of more rigorous, but difficult to mount RCTs (Randomized Controlled Trials), of which few exist for Tamiflu.

Earlier this year the WHO downgraded Oseltamivir (Tamiflu) on their list of essential medicines from a “core” drug to “complementary” status — which has led to new claims that these drugs don't work or are a waste of money - despite ample evidence to the contrary.

The WHO defines `core' vs. `complementary'  drugs as:
The core list presents a list of minimum medicine needs for a basic health-care system, listing the most efficacious, safe and cost–effective medicines for priority conditions. Priority conditions are selected on the basis of current and estimated future public health relevance, and potential for safe and cost-effective treatment.
The complementary list presents essential medicines for priority diseases, for which specialized diagnostic or monitoring facilities, and/or specialist medical care, and/or specialist training are needed. In case of doubt medicines may also be listed as complementary on the basis of consistent higher costs or less attractive cost-effectiveness in a variety of settings.

No where does it claim that these drugs don't work, or offer substantial benefits.   But you wouldn't know that by some of the media coverage.

With a potentially difficult flu season ahead (see The Enigmatic, Problematic H3N2 Influenza Virus), the ECDC has published a new expert opinion on the value, and use of Neuraminidase Inhibitor Antivirals for the treatment and prevention of influenza. 
Expert opinion on Neuraminidase inhibitors for the prevention and treatment of influenza - review of recent systematic reviews and meta-analyses

expert opinion
14 Aug 2017

This ECDC expert opinion confirms earlier assessments by ECDC and national authorities that there is no significant new evidence to support any changes to the approved indications and recommended use of neuraminidase inhibitors (NAIs) in EU/EEA Member States.
Recommendations to treat patients with severe influenza – or those at high risk of the complications of influenza – and provide prophylaxis to the most vulnerable and their families are based on the evidence from randomised controlled trials, evidence from observational studies, extrapolation from studies, and a generally benign safety profile of these medicines.

With respect to stockpiling of neuraminidase inhibitors, evidence reviewed by the expert group supports the practice of stockpiling NAIs as part of national preparedness plans.

Executive summary

The neuraminidase inhibitors oseltamivir and zanamivir, currently authorised in the European Union/European Economic Area for treatment and prophylaxis of influenza disease (including seasonal, pandemic and zoonotic influenza), have been the subject of debate concerning their effectiveness and safety, and as a consequence, also the appropriateness of stockpiling these drugs for use in future influenza pandemics.

Three large systematic reviews and meta-analyses assessing efficacy, effectiveness and safety of two licensed neuraminidase inhibitors, oral oseltamivir and inhaled zanamivir, were reviewed: The 2014 Cochrane Collaboration report (Jefferson et al.), the 2015 MUGAS study (Dobson et al.) and the 2014 PRIDE study (Muthuri et al.). Additional reviews and studies were considered where appropriate.

The reviews by Jefferson et al. and Dobson et al. conclude that, for adults, oseltamivir decreases the time to first alleviation of symptoms of influenza-like illness (ILI) by 16.8 hours (95% CI 8.4–25.1) and 17.8 hours (95% CI 27.1 to 9.3), respectively. The time to alleviation of all symptoms among the sub-population with laboratory confirmed influenza infection was decreased by 25.2 hours 95% CI 16.0–36.2 in the Dobson et al. analysis.

Additional analyses within the Jefferson et al. and Dobson et al. reviews documented a statistically significant reduction in patient-reported pneumonia, a reduction in lower respiratory tract infections and a decrease in hospital admissions following influenza diagnosis among oseltamivir-treated groups.

All three reviews point to the importance of initiating treatment early, ideally within 48 hours (within 36 hours in the case of zanamivir in children) of onset of symptoms.

With regard to prophylaxis, the review by Jefferson et al. assessing pre- or post-exposure prophylactic oseltamivir observed a 3.05% reduction in absolute risk for laboratory-confirmed influenza A among groups receiving oseltamivir in four RCTs (RR 0.45; 95% CI 0.30–0.67). The trials were conducted in ambulatory community members and nursing home residents. Similarly, Okoli et al. reported an association in an RCT between reduction in laboratory-confirmed influenza A(H1N1) infection and prophylactic treatment with oseltamivir (OR 0.11; 95% CI 0.06–0.20), and in four observational studies of zanamivir (0.23; 95% CI 0.16–0.35).

The most commonly reported adverse effect was an increased risk of nausea and vomiting; Jefferson et al. reported the risk in adults receiving oseltamivir for vomiting (RR 2.43; CI 95% 1.75–3.38) and children (1.70; 95% CI 1.23–2.35), and Dobson et al. in adults (RR 2.43; 95% CI 1.83–3.23).

Limitations were identified for all three systematic reviews and meta-analyses.

While the reviews considered for this expert opinion add to the evidence on the beneficial and adverse impacts of neuraminidase inhibitors, it is clear that further studies are needed to strengthen the evidence base overall.

This ECDC expert opinion confirms earlier assessments by ECDC and national authorities that there is no significant new evidence from RCTs to support any changes to the approved indications and recommended use of neuraminidase inhibitors in EU/EEA Member States.

Available evidence provides support for the use of NAIs as prophylaxis and treatment and thus they can be considered a reasonable public health measure during seasonal influenza outbreaks, pandemics and zoonotic outbreaks caused by susceptible influenza virus strains.

Over the past couple of years we've seen other expert opinions offered that come to similar conclusions, including:

Wellcome Trust/AMS Report On Antivirals For Influenza

The CDC Responds To The Cochrane Group’s Tamiflu Study

The Conversation: The Rise & Fall Of The Challenge To Tamiflu

CID Journal: Outcomes Of Prompt Influenza Antiviral Treatment Of Older Adults 

While the benefits of these antivirals when used on healthy adults who are experiencing mild or moderate seasonal flu symptoms may not be huge, for high risk patients - or when dealing with severe (or novel) influenza - the evidence shows they can be life saving.

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