Debunking myths on genetics and DNA

Thursday, February 14, 2013

Antiviral drugs to fight the flu: yes or no?


Disclaimer: I'm not a medical doctor. I cannot recommend taking or not taking a certain drug. However, I am a human being, I've got kids who do get sick from time to time, and I work on viruses. So when I heard that people were battling the unusually nasty flu this year with antiviral drugs, well, I had to do a bit of research.

Antiviral drugs have become increasingly popular after the highly pathogenic avian flu strain emerged. The idea is that in order to be prepared for a possible pandemic, we need to stock up on drugs, enough to treat millions of people.

Let's start with a few facts about viral infections:

A virus is made of genetic material packaged in a tiny shell. Once inside a cell, the virus hijacks the cell's proteins to replicate and create thousands of copies of itself. The new virions bud out of the cell membrane and infect new cells.

However, the infected cell has one more weapon up its sleeve: it "grasps" the virions that are budding out and tries to hold them back. In more scientific terms: there's a molecule on the cell membrane (called sialic acid) that binds to a protein on the surface of the virus (called hemagglutinin). The new virions have to break this bond in order to leave the infected cell and spread the infection. How do they do that? They use an enzyme called neuraminidase: the enzyme, found on the surface of the virus, breaks the bond between hemagglutinin and siliac acid, setting the virions free to spread out and infect new cells.

Neuraminidase inhibitors are antiviral drugs that, as the name suggests, block the neuraminadase enzyme. As a consequence, the virions remain stuck to the cell membrane and thus cannot spread the infection. Supposedly, this leads to a speedier recovery. I'm saying "supposedly" because there is an ongoing debate on whether this is true or not. Here's what I found in the literature.

Jefferson et al., 2009 [1]:
"Neuraminidase inhibitors have modest effectiveness against the symptoms of influenza in otherwise healthy adults. The drugs are effective postexposure against laboratory confirmed influenza, but this is a small component of influenza-like illness, so for this outcome neuraminidase inhibitors are not effective. Neuraminidase inhibitors might be regarded as optional for reducing the symptoms of seasonal influenza. Paucity of good data has undermined previous findings for oseltamivir's prevention of complications from influenza. Independent randomised trials to resolve these uncertainties are needed."

Wang et al., 2012 [2]:
"Oseltamivir and zanamivir appear to have modest benefit in reducing duration of illness in children with influenza. However, our analysis was limited by small sample sizes and an inability to pool data from different studies. In addition, the inclusion of data from published trials only may have resulted in significant publication bias. [...] The clinical efficacy of neuraminidase inhibitors in 'at risk' children is still uncertain. Larger high-quality trials are needed with sufficient power to determine the efficacy of neuraminidase inhibitors in preventing serious complications of influenza (such as pneumonia or hospital admission), particularly in 'at risk' groups."

Jefferson et al. 2012 [3]:
"We found a high risk of publication and reporting biases in the trial programme of oseltamivir. Sub-population analyses of the influenza infected population in the oseltamivir trial programme are not possible because the two arms are non-comparable due to oseltamivir's apparent interference with antibody production. The evidence supports a direct oseltamivir mechanism of action on symptoms but we are unable to draw conclusions about its effect on complications or transmission. We expect full clinical study reports containing study protocol, reporting analysis plan, statistical analysis plan and individual patient data to clarify outstanding issues. These full clinical study reports are at present unavailable to us."

The company that manufactures the brand name drug for oseltamivir responded here, however, according to BMJ, there hasn't been any release of data yet (source).

I have two more cautionary comments.

First: viruses mutate very rapidly and as such, they rapidly find escapes to drugs. An overuse of antiviral drugs may end up selecting drug resistant strains (for example, a flu strain that carries a neuraminadase enzyme that the inhibitor drugs cannot block). I'm not saying that antiviral drugs should not be used. Some life-threatening situations require the use of such drugs (for example, in the case of patients with immunodepression). Other non life-threatening situations don't (plain and simple).

Second: the US Food and Drug Administration recommends the use of antiviral drugs and in fact, last December they expanded the recommendation to children under one year of age (source). However, if you keep browsing the FDA website you find this very interesting Q&A page, where they report some supposed (though worrisome) adverse side effects:
"In the safety review mandated by the BPCA, a number of adverse event reports were identified associated with the use of Tamiflu in children 16 years of age or younger. These adverse event reports were primarily related to unusual neurologic or psychiatric events such as delirium, hallucinations, confusion, abnormal behavior, convulsions, and encephalitis. These events were reported almost entirely in children from Japan who received Tamiflu according to Japanese treatment guidelines (very similar but not identical to U.S. treatment guidelines). The review identified a total of 12 deaths in pediatric patients since Tamiflu's approval. All of the pediatric deaths were reported in Japanese children. In many of these cases, a relationship to Tamiflu was difficult to assess because of the use of other medications, presence of other medical conditions, and/or lack of adequate detail in the reports."

There is no direct evidence that the deaths were linked to the use of the drug. In fact, often it's high risk children that need to take the drug, which means they are likely to have other conditions and take additional medications. If we can't be certain of what one drug alone can do, imagine multiple ones combined. You can read more about the Japan reports here. I also found a reference [4].

Bottom line: drugs are wonderful things. They save lives. Drugs can also mess up with our body chemistry in ways that we don't always understand. The key point is to read, be informed, and use sparingly (as needed, not just as recommended).

NOTE: I strive to make these commentaries as objective as possible. If you feel I've missed some part of the story or you have more references to add to make a rounder point, please let me know in the comments. 

[1] Jefferson, T., Jones, M., Doshi, P., & Del Mar, C. (2009). Neuraminidase inhibitors for preventing and treating influenza in healthy adults: systematic review and meta-analysis BMJ, 339 (dec07 2) DOI: 10.1136/bmj.b5106

[2] Kay Wang, Matthew Shun-Shin, Peter Gill, Rafael Perera, Anthony Harnden (2012). Neuraminidase inhibitors for preventing and treating influenza in children (published trials only) The Cochrane Library DOI: 10.1002/14651858.CD002744.pub4

[3] Tom Jefferson, Mark A Jones, Peter Doshi, Chris B Del Mar, Carl J Heneghan, Rokuro Hama, Matthew J Thompson (2012). Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children The Cochrane Library DOI: 10.1002/14651858.CD008965.pub3

[4] Urushihara, H., Doi, Y., Arai, M., Matsunaga, T., Fujii, Y., Iino, N., Kawamura, T., & Kawakami, K. (2011). Oseltamivir Prescription and Regulatory Actions Vis-à-Vis Abnormal Behavior Risk in Japan: Drug Utilization Study Using a Nationwide Pharmacy Database PLoS ONE, 6 (12) DOI: 10.1371/journal.pone.0028483


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5 comments:

  1. antisocialbutterflieFebruary 14, 2013 at 8:42 PM

    Logically I agree with all the points against the use of antivirals. It seems unlikely that they would be used responsibly in a clinical setting. The general population doesn't understand the flu enough to even tell when they have it versus a cold. And if you think about it how likely is it that you will get to the doctor early enough for the drug to be effective? As fast as the flu mutates it's a recipe for disaster.

    However the last time I had the actual flu all I wanted to do was curl into a ball and die. I haven't missed a vaccine since. I would have given anything to make it stop. I can't really blame anyone for wanting the drugs if there was even a fraction of a chance to reduce the misery.

    I don't think there is really a winner in this debate.

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  2. Those are excellent points. I thought about that exactly, by the time you "know" you have the flu, it's already too late. It's the doctor's responsibility, though, to tell you what the drug can and, most importantly, CANNOT do for you. Of course you want it to go away fast, but if the drug has a low chance of making it happen, and a low chance to harm you, why take the risk?

    The flu vs. cold thing is quite worrisome too, however, it's my understanding that they test for flu before prescribing the drug. I haven't looked this up -- do you happen to know how reliable the flu test is, in terms of false positive rate?

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  3. antisocialbutterflieFebruary 14, 2013 at 9:09 PM

    I'd like to believe that doctors would be responsible but even in the face of antibiotic resistance many give out antibiotics like candy if the patient whines enough. I don't have a lot of hope on that front.

    As for the false positive/false negative thing my google-fu led me to the FDA website ( http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/TipsandArticlesonDeviceSafety/ucm109385.htm ). It was updated in November so I'm guessing it's a fairly accurate assessment of the current state of flu detection.

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  4. Ack, now I have to dust off my epidemiology book... specificity and sensitivity, shoot, could never get them straight... BRB. :-)

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  5. Thank goodness for wikipedia:

    http://en.wikipedia.org/wiki/Sensitivity_and_specificity

    OK, so:

    sensitivity = probability of correctly identifying a positive
    specificity = probability of correctly identifying a negative

    Thanks, Kat, that's really interesting. I pick the wash/aspirate. :-)

    ReplyDelete

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