Revisiting Tamiflu Efficacy (Again)

 

 

 

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Just over two years ago in The Tamiflu Controversy Continues, we looked at the ongoing debate over the effectiveness of oseltamivir (Tamiflu ®) in the wake of the release of a Cochrane group analysis that found insufficient evidence to show whether the drug reduces influenza complications and transmission.

 

Three weeks later the CDC responded with a statement on their Have You Heard? website, which published their rationale for continuing to recommend the use of Oseltamivir for severe influenza.

 

CDC Recommendations for Influenza Antiviral Medications Remain Unchanged

February 7, 2012 -- A recent review of randomized clinical trial data for the influenza neuraminidase inhibitor antiviral medications published by the Cochrane Collaboration, and two related commentaries [“Rethinking credible evidence synthesis” and “Questions Remain over safety and effectiveness of oseltamivir”] published in the British Medical Journal, raised questions about the value of antiviral medications for the prevention and treatment of influenza. After careful consideration of all available evidence, CDC guidance on the use of antiviral medications remains unchanged. The Centers for Disease Control and Prevention (CDC) continues to recommend the use of the neuraminidase inhibitor antiviral drugs (oral oseltamivir and inhaled zanamivir) as an important adjunct in the prevention and treatment of influenza.

(Continue . . . )

Since then the CDC and the World Health Organization have continued to promote Oseltamivir and other NAI antivirals as important drugs in our limited arsenal against the influenza virus (see November 2013 CDC Research On Benefits Of Antivirals For Uncomplicated Influenza).

 

Yesterday the BMJ and the Cochrane Group published a new assessment of the antiviral drug Tamiflu, and as they have in the past, cast doubts on its efficacy and on the wisdom of governments around the world stockpiling the drug.

The entire study is available online. You’ll find the link and a small excerpt below:

 

Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments

BMJ 2014; 348 doi: http://dx.doi.org/10.1136/bmj.g2545 (Published 10 April 2014)

Cite this as: BMJ 2014;348:g2545

Tom Jefferson, reviewer, Mark Jones, senior research fellow (biostatistics), Peter Doshi, assistant professor, Elizabeth A Spencer, nutritional epidemiologist, Igho Onakpoya, research fellow in evidence-based practice and pharmacovigilance, Carl J Heneghan, professor

Conclusions In prophylactic studies oseltamivir reduces the proportion of symptomatic influenza. In treatment studies it also modestly reduces the time to first alleviation of symptoms, but it causes nausea and vomiting and increases the risk of headaches and renal and psychiatric syndromes. The evidence of clinically significant effects on complications and viral transmission is limited because of rarity of such events and problems with study design. The trade-off between benefits and harms should be borne in mind when making decisions to use oseltamivir for treatment, prophylaxis, or stockpiling.

The Cochrane Summary is available at:

 

Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children

Editorial Group: Cochrane Acute Respiratory Infections Group

Published Online: 10 APR 2014

 

While research purists may applaud their methods, the problem that I (and many others) have with this analysis is that the Cochrane group set the bar very high as to what studies they would consider, excluding many observational studies.

 

Randomized controlled trials (RCTs) are considered the `gold standard’  for drug research, but these types of studies are expensive and notoriously difficult to conduct ethically when trying to evaluate a potentially life saving drug.

 

Overnight some elements of the British press have morphed their findings into incendiary headlines, such as this one from the Daily Mail: Ministers blew £650MILLION on useless anti-flu drugs.

 

Much of this ire has been well-earned through Roche’s long-standing resistance to releasing all of the testing data on their antiviral drug, and that has led to critical editorials in the BMJ, and frequent excoriation in the British press.

 

For a different perspective, we turn to NBC’s Senior health writer Maggie Fox, who spoke to doctors whose job it is to treat patients with influenza.

 

Flu Experts Line Up to Defend Tamiflu Against New Study

By Maggie Fox

A team of researchers who have been studying the flu drugs Tamiflu and Relenza released a new report that they say raises new doubts about the benefits of the drugs. But flu experts lined up to defend the medications, which they say can help reduce the most severe and deadly effects of the virus.

The report, published jointly by the influential Cochrane Review and the British Medical Journal, seeks to cast doubt on the widespread use of the two drugs, which doctors give to treat influenza and to prevent it in people who have a high risk of complications.

(Continue . . . )

 

Despite its critics, there are studies that show that Tamiflu can significantly reduce morbidity and mortality associated with influenza – particularly with severe, or novel infections. Some we’ve looked at in the past include:

 

• In 2010 we saw an observational study that appeared in JAMA  (see Study: Antivirals Saved Lives Of Pregnant Women) that strongly suggested that Tamiflu was life saving for some patients with pandemic flu.
• And again in 2010, in BMJ: Efficacy of Oseltamivir In Mild H1N1, we saw a study which suggested that the administration of oseltamivir may have significantly reduced the incidence of pneumonia among otherwise healthy pandemic H1N1 patients.
• In December of 2012, in Study: The Benefits Of Antiviral Therapy During the 2009 Pandemic we looked at a meta-analysis of 90 observational studies that appeared in the  Journal of Infectious Diseases that spanned nearly 35,000 patients, 85% of whom has laboratory confirmed H1N1.

Their main finding was antiviral therapy - principally oseltamivir - initiated within 48 hours of onset, reduced the likelihood of severe outcomes, namely admission to a critical care unit or death, by 49 to 65%.

• Last month in The Lancet: Effectiveness Of NAI Antivirals In Reducing Mortality In Hospitalized H1N1pdm09 Cases we looked at yet another observational study conducted by researchers at The University of Nottingham – that reviewed more than 29,000 hospitalized H1N1pdm cases across 38 countries between 2009 and 2011, and found that the administration of NAI antivirals was associated with a 19% reduction in mortality compared to receiving no NAI treatment at all.

 

And finally, for those who question the value of Tamiflu in novel flu pandemic, in Study: Antiviral Therapy For H5N1, we saw the largest study to date on outcomes of H5N1 patients who either received, or did not receive, antiviral treatment. The research appears in the IDSA’s Journal of Infectious Diseases. The bottom line is essentially out of 308 cases studied, the overall survival rate was a dismal 43.5%.

 

But . . . of those who received at least one dose of Tamiflu . . .  60% survived . . .  as opposed to only 24% who received no antivirals.

 

While we would all prefer to have rock-solid, indisputable evidence based on well-mounted RCTs proving the effectiveness of Oseltamivir, the preponderance of evidence we have today still indicates that NAIs can have a substantial positive therapeutic effect on influenza, particularly in high risk patients or with novel flu strains.

Besides, unless and until better therapeutic options become available, they pretty much the only game in town.

The Great Mask Debate Revisited

Photo Credit PHIL (Public Health Image Library)

 

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Fears over the MERS coronavirus (and avian flu), and the recent call by the Saudi government for pilgrims to wear face masks during Ramadan and the Hajj, will no doubt reawaken the debate over the appropriateness, effectiveness and logistics of mask wearing in public to prevent infection during a pandemic. 

 

As you’ll see, while it may seem like a no-brainer, there’s conflicting evidence of their effectiveness, the supply of face-masks is finite, and governments and public health agencies around the world are not all on the same page with their advice.

 

Our primary defense against any pandemic (until a vaccine can be developed and deployed) are called NPIs (non-pharmaceutical interventions).

NPI’s can be as simple as hand hygiene, covering your coughs, and avoiding crowds, or can involve the use of personal protective barriers like N95 or surgical masks, latex or vinyl gloves, and eye protection.

 

School closures, public education, staying home when sick, and engineered barriers to avoid exposure are also examples of NPIs.

 

There are two basic types of masks available to the public; surgical or medical masks and N95 respirators. Given the higher costs, and their likely limited supply during a pandemic or epidemic, N95 masks are less likely to be used by the general public.

 

 

Surgical Facemask N-95 Respirator 

 

The simple surgical mask has the advantage of being cheap (a box of 50 is usually under $4), easy to don, and easier to breath through than the N95 respirator. Its role has traditionally been to protect others from the coughs or sneezes of someone who may be infected.

 

A 2008 NIOSH Science blog called Influenza Pandemic and the Protection of Healthcare Workers with Personal Protective Equipment describes their effectiveness thusly:

 

Medical masks are not designed or certified to protect the wearer from exposure to airborne hazards. They may offer some limited, as yet largely undefined, protection as a barrier to splashes and large droplets.

 

However, because of the loose-fitting design of medical masks and their lack of protective engineering, medical masks are not considered personal protective equipment.

 

This of course assumes a healthcare setting, where HCWs are in close, prolonged contact with probable or confirmed infected patients, and a higher standard of protection is required.

 

• The evidence for the protective qualities of surgical masks is mixed, but in 2010 we looked at a study (see (see Efficacy of Facemasks Vs. Respirators), that suggests that inexpensive facemasks may be more effective than previously thought in protecting against the H1N1 virus.

 

• And in 2009 (see JAMA: Surgical Masks vs N95 Respirators) we looked a report that HCWs using surgical masks experienced `noninferior rates of laboratory-confirmed influenza’. The implication here, according to the authors, is that surgical masks provide similar protection to N95 respirators in a routine health care setting.

 

Other studies have been less sanguine about the effectiveness of surgical masks to prevent infection in the wearer (see PPEs & Transocular Influenza Transmission), although they do appear to provide some degree of protection.  

 

Use of the N95 mask, which the CDC recommends for HCWs who may be exposed to the MERS coronavirus or H7N9 (along with gloves, gown, & eye protection – see CDC: Interim Infection Control Guidelines For MERS-CoV) would be somewhat problematic for the general public.

 

• They are uncomfortable to wear for long periods of time. 
• They saturate with exhaled moisture relatively quickly, and must be changed out every couple of hours. 
• The must be fit tested for each wearer (see Survival Of The Fit-tested)
• They are 10 times more expensive than surgical masks.
• They are considered a `last line of defense’ by the CDC and are really only effective when combined with gloves, hand hygiene, and eye protection.   
• They must be removed and disposed of properly, to avoid contamination
• And lastly, our national supply of N-95s is likely inadequate to supply even our Health Care Workers during a prolonged severe pandemic wave.

 

The bottom line is that surgical masks (and N95 respirators) may be somewhat protective for the wearer, but they will be in short supply during a severe pandemic, and are certainly not guaranteed to protect the wearer.

 

Which is why the World Health Organization has been reluctant to recommend the wearing of masks by the general public (see WHO: MERS, Masks, And The Media and More From WHO on MERS & Masks).

 

Credit @WHO June 13th, 2013

 

In Advice on the use of masks in the community setting in Influenza A (H1N1) outbreaks Interim guidance  - while not recommending the public use of masks - WHO doesn’t come out strongly against them, either. And should the threat from MERS change, WHO could very well adjust their recommendations down the line.

 

The HHS issued guidance in 2007, as part of their H5N1 and pandemic flu preparedness push, on the use of facemasks by the public during a pandemic.

 

 

Interim Public Health Guidance for the Use of Facemasks and Respirators in Non-Occupational Community Settings during an Influenza Pandemic

May 2007

This document describes interim guidance for the use of facemasks and respirators in certain public settings during an influenza pandemic. Very little information is available about the effectiveness of facemasks and respirators in controlling the spread of pandemic influenza in community settings. In the absence of scientific data, this document offers interim recommendations that are based on public health judgment and on the historical use of facemasks and respirators in other settings. In brief, these interim recommendations advise the following:

• Whenever possible, rather than relying on the use of facemasks or respirators, close contact and crowded conditions should be avoided during an influenza pandemic.
• Facemasks should be considered for use by individuals who enter crowded settings, both to protect their nose and mouth from other people's coughs and to reduce the wearers' likelihood of coughing on others.  The time spent in crowded settings should be as short as possible.
• Respirators should be considered for use by individuals for whom close contact with an infectious person is unavoidable. This can include selected individuals who must take care of a sick person (e.g., family member with a respiratory infection) at home.

Facemasks and respirators should be used in combination with other preventive measures, such as hand hygiene and social distancing, to help reduce the risk for influenza infection during a pandemic. This interim guidance will be updated as new information becomes available.

(Continue . . . )

In 2008 (see The HHS Revised Mask Recommendations) new draft guidance for mask use by the public was released with even stronger recommendations, but that document appears to be no longer online. Although it wasn’t formally adopted, the interim advice offered by the HHS in 2008 still seems prudent to me:

 

Pandemic outbreaks in communities may last 6 to 12 weeks.[3]  Persons who cannot avoid commuting on public transit may choose to purchase 100 facemasks for use when going to and from work.  An additional supply of facemasks also could be purchased for other times when exposure in a crowded setting is unavoidable or for use by an ill person in the home when they come in close contact with others.[4]

The problem, of course, is supply.

 

Our Strategic National Stockpile contains more than 100 million  N95 and surgical masks (see Caught With Our Masks Down), but the demand for PPEs during a serious pandemic would far exceed the supply. 

 

At one time the HHS estimated the nation would need 30 billion masks (27 billion surgical, 5 Billion N95) to deal with a major pandemic (see Time Magazine A New Pandemic Fear: A Shortage of Surgical Masks).

 

Which means that if you intend to avail yourself of the (admittedly limited) protection of face masks during a pandemic, your best bet is to buy any supplies well before a pandemic erupts.

 

Another alternative (offered without recommendation) was published in the CDC’s Journal of Emerging Infectious Diseases back in 2006 (see The Man In The Ironed Mask); A homemade reusable mask made out of Tee-shirt material.

 

Emerging Infectious Diseases Volume 12, Number 6, June 2006

Simple Respiratory Mask

Virginia M. Dato, David Hostler & Michael E. Hahn

Figure. Prototype mask. A) Side view, B) Face side. This mask consisted of 1 outer layer (≈37 cm × 72 cm) rolled and cut as in panel B with 8 inner layers (<18 cm²) placed inside (against the face). The nose slit was first placed over the bridge of the nose, and the roll was tied below the back of the neck. The area around the nose was adjusted to eliminate any leakage. If the seal was not tight, it was adjusted by adding extra material under the roll between the cheek and nose or by pushing the rolled fabric above or below the cheekbone. Tie b was tied over the head. A cloth extension was added if tie b was too short. Finally, tie c was tied behind the head. The mask was then fit tested.

 

Another study, which appeared in PLoS One  in 2008 (see What Everyone Will Be Wearing During The Next Pandemic Flu Season), found that homemade masks – while not as effective as N95s – could offer some degree of protection against viral infection.

 

Professional and Home-Made Face Masks Reduce Exposure to Respiratory Infections among the General Population

Marianne van der Sande, Peter Teunis, Rob Sabel

 

Although I would certainly prefer the protection of an N95 mask (and eye protection), I’ve always believed that in an potentially infectious environment, any mask beats having no mask at all.

 

But as always, your mileage may vary.

Another Entry Into The H5N1 Lethality Debate

 

 

 

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With the announcement last fall that two researchers had successfully created a ferret-transmissible (and in one case, lethal), version of the H5N1 virus there have been fresh calls to regulate and restrict just how, and where, this sort of research should be conducted.

 

While not guaranteed - successful adaptation to ferrets (which have respiratory systems similar to humans) is assumed by many researchers to be a pretty good indication it would transmit in humans as well.

 

Suddenly labs that have been working with variants of the H5N1 virus are under new scrutiny, and regulators are questioning just how much biosecurity is needed to work on these viruses.

 

Last month Canada decided to restrict H5N1 research to labs with the highest biosecurity measures (see  Canada Issues Biosafety Advisory For H5N1 Research), and other countries are considering similar measures.

 

In an attempt to assuage fears over the risks of H5N1 research (and the publication of the results), several well respected scientists have challenged the notion that the bird flu virus is as lethal in humans as is commonly portrayed.

 

One high profile paper appeared in Science last month -Seroevidence for H5N1 Influenza Infections in Humans: Meta-analysis - authored by Professor Peter Palese et. al., that argues that we are likely missing a great many uncounted H5N1 infections, and that the virus is far less lethal than has been assumed in the past.

 

This is similar to the argument that Vincent Racaniello offered last January in his blog Should we fear avian H5N1 influenza?

 

While stating that we don’t have definitive numbers, Palese writes that if one assumes a 1-2% infection rate among exposed populations, there would likely be millions of people who have been infected by the H5N1 virus.

 

Palese grants that deaths from the virus may also be undercounted, and calls for better studies (something that I think everyone, regardless of where they stand on this issue, would agree with).

 

A counter argument appeared last month in mBio, authored by CIDRAP director Michael T. Osterholm and Nick Kelley. 

 

They found little evidence to support the notion that we are missing `millions’ of uncounted H5N1 infections (see mBio: Mammalian-Transmissible H5N1 Influenza: Facts and Perspective), and find that the H5N1 virus has the potential to be highly virulent in humans.

 

 

Mammalian-Transmissible H5N1 Influenza: Facts and Perspective

Michael T. Osterholm Nicholas S. Kelley

 

All of which serves as prelude to a new analysis, authored by Eric S. Toner and Amesh A. Adalja (both of the Center for Biosecurity at the University of Pittsburgh Medical Center (UPMC)) published last week in Biosecurity and Bioterrorism: Biodefense Strategy, Practice, and Science.

 

Is H5N1 Really Highly Lethal?

Eric S. Toner and Amesh A. Adalja.

Biosecurity and Bioterrorism: Biodefense Strategy, Practice, and Science. doi:10.1089/bsp.2012.022

 

I would invite you to read the entire study (it is reasonably short), but an excerpt from the press release sums it up nicely:

 

The authors review the available evidence: the distinctions between different clades of H5N1, the clinical series of human H5N1 cases, and the seroepidemiological and laboratory studies. They conclude that the preponderance of evidence argues that H5N1 virus is indeed highly lethal in humans compared to other influenza viruses.

 

Author Eric Toner said, “Our review of the evidence underscores what so many experts have been saying for years: Wild-type H5N1 is a very dangerous virus. We are quite fortunate it has not yet become contagious between humans.”

 

 

Dueling opinion pieces obviously won’t settle this argument, and regrettably, the amount of hard data available to support either position is limited.

 

While I suspect the virus is less deadly than the `official numbers’ suggest  - given the stakes - it would seem to this humble blogger that if we err, we ought to err in favor of overestimating the threat of this virus.

 

At least in the short run.

 

We can always relax policies later when we have more accurate data and a better handle on the threat. 

 

 

But underestimating this virus now, before we have solid answers, could lead to an irrevocable error.