tag:theconversation.com,2011:/africa/topics/neuraminidase-inhibitors-1133/articlesNeuraminidase inhibitors – The Conversation2015-09-29T20:08:36Ztag:theconversation.com,2011:article/382872015-09-29T20:08:36Z2015-09-29T20:08:36ZControversies in medicine: the rise and fall of the challenge to Tamiflu<figure><img src="https://images.theconversation.com/files/96412/original/image-20150928-21366-d740kn.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">As part of pandemic preparation, in the early 2000s many countries amassed large stockpiles of the influenza neuraminidase inhibitor Tamiflu.</span> <span class="attribution"><a class="source" href="https://www.flickr.com/photos/hisgett/3641376785/">Tony Hisgett/Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span></figcaption></figure><p>One of the biggest recent controversies in medicine involves the effectiveness – or otherwise – of the antiviral drug Tamiflu. Governments around the world have stockpiled the drug for use in severe influenza pandemics, but many have raised doubts about its effectiveness.</p>
<p>Influenza causes annual “seasonal” epidemics in temperate countries and circulates year-round in the tropics. Pandemics occur when there’s a relatively new flu virus containing components of bird or swine flu viruses, against which the human population has little protection. </p>
<p>Global pandemic preparedness efforts were spurred in the early 2000s by the emergence of SARS, and highly pathogenic H5N1 influenza in birds, which was associated with rare but often fatal infection in humans. The problem is that the severity of pandemics can vary markedly; from the Spanish flu of 1918-19, which is estimated to have killed 20-50 million people worldwide, to the much milder 2009 swine flu, which <a href="http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1001558">resulted in between</a> 150,000 and 250,000 deaths (a similar number to the annual mortality of seasonal epidemics). </p>
<h2>Reviewing evidence</h2>
<p>Governments tend to prepare for the worst because there’s no way of knowing the impact a flu pandemic will have on the population. And, as pandemics are rare, the evidence base for public health responses has to be largely taken from studies of seasonal influenza.</p>
<p>As part of pandemic preparation, in the early 2000s many countries amassed large stockpiles of the influenza neuraminidase inhibitor Tamiflu. A 2000 clinical trial had <a href="http://jama.jamanetwork.com/article.aspx?articleid=192425">indicated modest benefits</a> from this drug, but its ability to <a href="http://jama.jamanetwork.com/article.aspx?articleid=193547">reduce disease severity and limit onward spread</a> had potential for much greater benefits in reducing death and disease at the population level.</p>
<p>In 2006 the <a href="http://www.cochrane.org/about-us">Cochrane Neuraminidase Inhibitors Review Team</a> published a review on behalf of the Cochrane Collaboration, an independent network of researchers who review evidence for medical interventions to help improve health-care decision-making. <a href="http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD001265.pub2/abstract;jsessionid=DAAC348A24E621BF48DEDF728C522519.f01t02">Its overall conclusion</a> was that the drug shouldn’t be used for treating seasonal flu, but was suitable for use as part of a suite of public health measures in pandemics.</p>
<p>But in the aftermath of the – fortunately – mild 2009 pandemic, the social and economic costs of the global public health response to this event were widely questioned. In particular, given the large amounts of money spent on Tamiflu, claims of <a href="http://www.bbc.com/news/10235558">conflict of interest</a> and <a href="http://ahrcanum.com/2009/07/01/tamiflu-linked-to-origins-of-ah1n1-swine-flu-pandemic/">conspiracy theories</a>, some <a href="http://www.dailymail.co.uk/news/article-1176743/Donald-Rumsfelds-controversial-links-drug-company-Tamiflu.html">more credible than others</a>, abounded. </p>
<p>Then, in the process of updating their 2006 Cochrane review, and in response to <a href="http://www.bmj.com/content/339/bmj.b5106.long">questions raised</a> through the Cochrane review’s feedback mechanism regarding prevention of complications and drug safety, the reviewing team requested access to Roche Tamiflu trials data in 2009. They were refused. In the years that followed, Roche came under particular scrutiny with claims that <a href="http://www.bmj.com/content/345/bmj.e7303">critical clinical trial information</a> had been withheld from publication. </p>
<p>In 2012, the <a href="http://www.bmj.com/tamiflu">BMJ launched a website</a> devoted to a public campaign, lobbying the company to release full clinical reports on all relevant studies conducted in support of the drug’s licence. The campaign was successful when, in 2013, Roche provided all the requested documentation. </p>
<h2>The question mark</h2>
<p>For the first time, full clinical study reports, which include tables of all study outcomes rather than those selected for publication, were made available. In addition, submissions to and correspondence with drug regulatory authorities were included. These reports, often many hundreds of pages long, formed the basis of a new meta-analysis conducted by the <a href="http://bmjopen.bmj.com/content/4/9/e005253.full">Cochrane Neuraminidase Inhibitors Review Team</a>. </p>
<p>With the new information to hand, the authors concluded the <a href="http://bmjopen.bmj.com/content/4/9/e005253.full">risk of bias</a> in several published studies was higher than had been previously assessed. This was due to missing or incomplete information, or deficiencies in study design. </p>
<p>Roche provided data on 83 studies, and regulatory authorities provided information on more than 200 trials. But only 46 studies (20 of Tamiflu and 26 of Relenza) were included in <a href="http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD008965.pub4/abstract;jsessionid=76F622C5B03F0FF262E8B76396219022.f03t01">the final analysis</a> as eligible and unbiased. </p>
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<img alt="" src="https://images.theconversation.com/files/96413/original/image-20150928-21366-19hmcgm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/96413/original/image-20150928-21366-19hmcgm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=420&fit=crop&dpr=1 600w, https://images.theconversation.com/files/96413/original/image-20150928-21366-19hmcgm.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=420&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/96413/original/image-20150928-21366-19hmcgm.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=420&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/96413/original/image-20150928-21366-19hmcgm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=528&fit=crop&dpr=1 754w, https://images.theconversation.com/files/96413/original/image-20150928-21366-19hmcgm.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=528&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/96413/original/image-20150928-21366-19hmcgm.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=528&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">A 2014 review found giving the drug to family members of an infected person prevented infections in about 15% of people.</span>
<span class="attribution"><a class="source" href="https://www.flickr.com/photos/k790i/3852576091/">Anil Jadhav/Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
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<p>Still, the <a href="http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD008965.pub4/abstract;jsessionid=76F622C5B03F0FF262E8B76396219022.f03t01">findings of this 2014 review</a> were remarkably similar to the group’s previous reports. The review showed Tamiflu hastened flu recovery by about 17 hours in adults and 29 hours in kids. Anticipated side effects of nausea and vomiting were reported in less than 5% of treated people. And giving the drug to family members of an infected person prevented infections in about 15%.</p>
<p>The meta-analysis also looked at the risk of hospitalisations and secondary infections following flu. It concluded that antivirals were ineffective for reducing these adverse outcomes. But because the trials under consideration were mostly in generally healthy people with seasonal influenza infections, the <a href="http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD008965.pub4/abstract;jsessionid=76F622C5B03F0FF262E8B76396219022.f03t01">number of hospitalisations</a> was very small, affecting only 71 of 4,400 study participants. And while the main review finding was of a 1% absolute reduction in self-reported pneumonia, this figure represented a 56% relative risk reduction in the Tamiflu-treated group.</p>
<p><a href="http://community.cochrane.org/features/tamiflu-relenza-how-effective-are-they?">Based on this evidence</a>, BMJ and Cochrane Collaboration questioned the usefulness of neuraminidase inhibitors in pandemics and called for governments to review their guidance for the drug’s use.</p>
<h2>A different view</h2>
<p>Meanwhile, another independent group, the <a href="http://www.mugas.net">Multiparty Group for Advice on Science</a>, brought together four leading academics in the field of influenza to review and oversee re-analysis of Tamiflu trials data. To support this work, they obtained an unrestricted grant from Roche. Their aim was to resolve uncertainties regarding appropriate public health use of this drug. </p>
<p>The group negotiated with Roche to gain access to not just summary reports of treatment group outcomes (as previously analysed), but individually listed patient data from nine adult Tamiflu trials involving 4,328 participants. These provided much greater statistical power to assess differences. The trials, selected on the basis they assessed the currently recommended treatment dose, would have been included among those provided to the Cochrane reviewers.</p>
<p>This <a href="http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2814%2962449-1/abstract">new analysis found</a>, similarly to the Cochrane review, that the drugs hastened recovery from influenza infection by about a day, with the side effects of nausea and vomiting in a minority of patients. It said that in people with confirmed flu, Tamiflu <a href="http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2814%2962449-1/abstract">reduced the risk of secondary respiratory infections</a> requiring antibiotics by 44%. Hospitalisations in the Tamiflu group were down by 63%. </p>
<p>These findings were more in keeping with observational studies of “real world” Tamiflu use among patients hospitalised with a clinical or laboratory diagnosis of influenza during the 2009 pandemic. While this broader clinical definition of flu is less specific than in a randomised trial, it does represent the basis on which doctors make treatment decisions in everyday practice. </p>
<h2>Other research</h2>
<p>A <a href="http://www.ncbi.nlm.nih.gov/pubmed/23204175">meta-analysis of published data from 90 such studies</a> published in 2012 demonstrated a 60% reduction in the odds of intensive care unit admission and death among hospitalised influenza patients who received prompt antiviral therapy. This study was also funded by an unrestricted grant from Roche. </p>
<p>And <a href="http://www.thelancet.com/journals/lanres/article/PIIS2213-2600%2814%2970041-4/abstract">a follow-up 2014 analysis</a> of individual patient data from nearly 30,000 participants who took part in studies identified through the 2012 meta-analysis found a 50% reduction in the odds of death among those treated within 48 hours of symptom onset, compared with no treatment. It was also funded by Roche.</p>
<p>Given that randomised controlled trials are logistically and ethically challenging to conduct in pandemic events, it’s <a href="http://www.nature.com/news/analysis-of-trial-data-revives-flu-drug-row-1.16820">unlikely there will ever be a consensus</a> on Tamiflu’s effectiveness for use in pandemics. But observational studies conducted during the 2009 pandemic seem to reinforce the initial clinical trials evidence base on which Tamiflu was recommended for stockpiling against pandemic threats. </p>
<p>Indeed, <a href="http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2815%2960074-5/abstract">the drug’s benefits</a> appear to be greatest in severe influenza seasons and pandemics.</p><img src="https://counter.theconversation.com/content/38287/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Jodie McVernon is a member of the Australian Technical Advisory Group on Immunisation and has provided advice to the Australian Government Office of Health Protection on pandemic planning, including on antiviral stockpiling and distribution; she is also a Director of the Influenza Specialist Group. </span></em></p>One of the biggest recent controversies in medicine involves the effectiveness of the antiviral drug Tamiflu. Governments have stockpiled the drug but many have raised doubts about its usefulness.Jodie McVernon, Associate Professor, Population Health, The University of MelbourneLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/324312014-10-07T03:45:05Z2014-10-07T03:45:05ZWhat kind of research can we trust?<figure><img src="https://images.theconversation.com/files/60976/original/bpdqn58n-1412643107.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Conflicting recommendations about flu drugs has made it difficult for doctors to decide whether to prescribe them. </span> <span class="attribution"><a class="source" href="https://www.flickr.com/photos/stanrandom/3754123623">Andrew Wales/Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span></figcaption></figure><p>Research involving pharmaceutical company input is notoriously compromised. While not all industry ties lead to biased research, and not all biases are a consequence of industry ties, <a href="http://www.ncbi.nlm.nih.gov/pubmed/23235689">many studies show</a> industry influence can make drugs look safer and more effective than they really are. So where can doctors and indeed the public turn to for reliable information?</p>
<p>One favoured option is research known as systematic reviews, which sift through evidence, evaluate their quality and synthesise conclusions and recommendations for clinical practice. Systematic reviews are considered to be the highest level of medical evidence because they summarise large volumes of evidence and follow strict processes to avoid biases. </p>
<p>Systematic reviews form the basis of evidence-based medicine, but there’s now growing doubt about whether these reviews are as untouched by industry influence as many of us expect them to be.</p>
<h2>A particular case</h2>
<p>Consider the case of a class of drugs known as neuraminidase inhibitors, which has been <a href="https://theconversation.com/the-tamiflu-saga-shows-why-all-research-data-should-be-public-13951">causing controversy</a> in the last few years. These drugs are said to minimise the impact of the flu; you’ll know them by their commercial names Tamiflu and Relenza. </p>
<p>Tens of millions of prescriptions for these drugs have been dispensed and governments worldwide have stockpiled them in preparation for a flu pandemic at the cost of billions of dollars. But there are conflicting views about both their safety and their efficacy – and they’re fuelled by conflicting systematic reviews. </p>
<p>One <a href="http://www.ncbi.nlm.nih.gov/pubmed/24815805">systematic review published this year</a>, for instance, encouraged early use of the drugs in any patient who looks appreciably unwell. <a href="http://www.bmj.com/content/348/bmj.g2545">Another cautioned</a> about their safety and questioned whether they should be used in practice at all.</p>
<p>In an article <a href="http://www.annals.org/article.aspx?doi=10.7326/M14-0933">published today in the Annals of Internal Medicine</a>, we tried to make sense of how such discrepancies arise despite the strict processes that underpin systematic reviews. </p>
<p>Given what we already know about industry influence on research, we suspected the differences might be associated with reviewers’ financial ties to companies that make the drugs. To test our hypothesis, we examined 26 systematic reviews published about neuraminidase inhibitors. </p>
<h2>Sleight of hand?</h2>
<p>We found reviewers with financial ties to drug companies were more likely to present evidence in favourable ways and recommend use of the drugs. In the reviews written by researchers with such ties, 88% of the conclusions were favourable. In the absence of financial links, just 17% were positive.</p>
<p>In other words, reviewers with financial ties to drug manufacturers overwhelmingly decided the drugs were safe and effective while those without ties were considerably more reserved about their value.</p>
<p>So how did the systematic reviews arrive at such different conclusions?</p>
<p>While we were unable to examine the differences statistically, one part of the review process stood out as the point where biases could be more easily introduced: generalising from results to recommendations.</p>
<p>For some systematic reviews, the recommendations made in the discussion sections didn’t match the evidence in the results. That suggests reviewers may have generalised in ways that aligned with predetermined views rather than what the evidence showed.</p>
<h2>What can be done?</h2>
<p>Ours is not the only study that has identified this type of problem. Last year, researchers identified the same association in <a href="http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1001578">systematic reviews of sweetened beverages and weight gain</a>.</p>
<p>While this may make it tempting to ignore all evidence reported by researchers who receive industry funding, we don’t think that’s the answer. There’s much to be gained from collaborations with industry. What we need are <a href="http://www.futuremedicine.com/doi/pdf/10.2217/cer.14.31">better strategies for managing conflicts of interest</a>.</p>
<p>Being able to detect the kind of polarisation in the conclusions of systematic reviews we did is one step towards managing the effects of conflicts of interest. And one way to mitigate these effects may be to ask independent researchers to interpret results and formulate recommendations.</p>
<p>As with other drugs, conflicting recommendations about neuraminidase inhibitors has made it difficult for doctors to decide whether to prescribe them. The most authoritative reviews now show these drugs have small benefits and some risks. These reviews have led to <a href="http://www.theguardian.com/world/2014/apr/10/uk-wasted-560m-stockpiling-flu-drugs">suggestions</a> that <a href="http://www.smh.com.au/federal-politics/political-news/antiviral-drug-stockpile-a-waste-of-money-says-study-20140410-zqt3i.html">stockpiling them</a> may have <a href="http://www.theatlantic.com/magazine/archive/2009/12/the-truth-about-tamiflu/307801/">been unjustified</a>.</p>
<p>To be able to make informed decisions together, doctors and patients need research that’s trustworthy. If systematic reviews are to remain the pinnacle of evidence-based medicine, then the processes underpinning them need to be continually reassessed to ensure they meet the highest of standards.</p><img src="https://counter.theconversation.com/content/32431/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Adam Dunn receives funding from the National Health & Medical Research Council.</span></em></p><p class="fine-print"><em><span>Florence Bourgeois receives funding from the National Institute of Health in the USA.</span></em></p>Research involving pharmaceutical company input is notoriously compromised. While not all industry ties lead to biased research, and not all biases are a consequence of industry ties, many studies show…Adam Dunn, Senior Research Fellow, UNSW SydneyFlorence Bourgeois, Assistant Professor of Pediatrics, Harvard UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/49552012-01-18T00:04:40Z2012-01-18T00:04:40ZTamiflu is stockpiled globally as a defence against pandemic influenza … but does it work?<figure><img src="https://images.theconversation.com/files/7014/original/mxckq3bd-1326925334.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Billions of dollars have been spent, but the safety and effectiveness of Roche's drug remain uncertain.</span> </figcaption></figure><p><em><strong>A <a href="http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD008965/full">Cochrane review published today</a> has again raised questions about the efficacy of <a href="http://www.roche-australia.com/fmfiles/re7229005/downloads/anti-virals/tamiflu-cmi.pdf">Tamiflu</a>, the antiviral drug that has been stockpiled by countries across the world as the first line of defence against pandemic influenza. Tamiflu is on the <a href="http://www.who.int/medicines/publications/essentialmedicines/en/">World Health Organisation’s List of Essential Medicines</a> but reviewers have found inconsistencies with published reports and possible under-reporting of side effects.</strong></em></p>
<p><em><strong>Professor Chris Del Mar, one of the review’s authors, spoke to us about the review’s findings and their implications.</strong></em></p>
<p>On the face of it, this research is just an update of a Cochrane review about the effectiveness against influenza of a group of drugs called <a href="http://www.nejm.org/doi/full/10.1056/NEJMra050740">neuraminidase inhibitors</a>. These drugs include the very famous <a href="http://www.nlm.nih.gov/medlineplus/druginfo/meds/a699040.html">oseltamivir</a>, also known by its trade name of Tamiflu, and <a href="http://www.nlm.nih.gov/medlineplus/druginfo/meds/a699021.html">zanamivir</a>, which is also know as Relenza. </p>
<p>These are the two most famous neuraminidase inhibitors but there are other drugs in this group as well. Both work on the same principle, but there are some important differences. The main one of these is that oseltamivir is taken orally or intravenously whereas zanamivir has to be breathed in, and that’s made it less attractive because people who are very sick with influenza often have trouble breathing so they might not be able to get the stuff down.</p>
<p>Neuraminidase inhibitors are antiviral drugs, specific for influenza and they work by inhibiting an enzyme that the virus has the host cell generate, which is important for the virus to escape from the cell it invades. The importance of research comes from the fact that the world has stockpiled billions of dollars worth of Tamiflu, made by the pharmaceutical and diagnostic manufacturer <a href="http://www.roche-australia.com/portal/eipf/australia/au/corporate">Roche</a>.</p>
<p>The reason there’s such an interest in this drug is because it was stockpiled after claims by its manufacturer that it not only relieves symptoms but also reduces the complications of influenza. These complications include those that are the reasons people end up in hospital, such as developing secondary infections like pneumonia.</p>
<p>So stockpiling Tamiflu seemed to be an important public health intervention. It could be very important in case of a pandemic where large sections of the population gets infected with influenza. And that’s why Tamiflu got distributed and stored for such an event.</p>
<p>Then of course we had the avian flu scare and, following that, the swine flu scare. Neither of these were as severe as had been anticipated but they showed that there were good reasons to have such a drug around.</p>
<h2>Cochrane reviews</h2>
<p><a href="http://www.cochrane.org/about-us/newcomers-guide">Cochrane reviews</a> work in the following way: world literature is reviewed and systematically analysed in a special statistical way to combine different studies and come up with a summary result. </p>
<p>The first review talked about how the complications from flu infection could be reduced by using neuraminidase inhibitors. We use an open process at Cochrane and someone wrote in and said that we didn’t do the first part of the analysis properly because we relied on secondary data, and we should get the primary data.</p>
<p>We took that on board and discovered the primary data weren’t available. We wrote to the author of the <a href="http://archinte.ama-assn.org/cgi/content/abstract/163/14/1667">secondary review (Professor Kaiser Laurent from Geneva)</a> that we took the data from – all quite proper – and asked, please can we have the primary data because we’ve had this criticism and we need to look at it and analyse it carefully.</p>
<p>He told us he didn’t have it, which was unexpected. It was extraordinary that he didn’t have the data, and he referred us to Roche. </p>
<p>Roche weren’t particularly helpful to us. That made us start wondering: where are these data? We realised that some of the data used for the assertion about oseltamivir reducing influenza’s complications belonged to a set of trials that had never been published. They were only published in this secondary form, from which we couldn’t look at the primary data.</p>
<p>So we asked Roche for the primary data and they said: “yes, we will give them to you,” but they’ve never given us the full data we would like. </p>
<p>From this point, we began to wonder whether the data that weren’t published would give as optimistic a result about the drug’s effect on complications as those that were published.</p>
<p>In our subsequent review, two years ago, we said we were uncertain about the effect. Since then, we’ve been able to get hold of some of the data Roche wouldn’t give us from regulatory authorities, specifically the FDA (USA) and EMA (Europe). So we’ve looked at some of the data Roche did give us and some they didn’t.</p>
<p>These authorities are the Federal Drug Administration (FDA) in the United States, and the European Medicines Agency (EMA), the Australian equivalent of whom is the Therapeutic Goods Administration (TGA). They had more information about the performance of the drug in trial evaluation because it’s required before they approve the drug. All drugs have to be approved for use as a drug for specific indications. </p>
<p>We went to the FDA and the EMA and they supplied us with some of the information, not all of what we wanted, perhaps because they themselves didn’t have it all. So we managed to get hold of some of the information that way. </p>
<p>And this review that we’ve published today is the result of the analysis from those data. It was a very difficult analysis because we didn’t have complete information and there was an awful lot of it. Even though it wasn’t complete, there were thousands and thousands of pages of reports, which we’ve been going through.</p>
<h2>A clouded diagnosis?</h2>
<p>We’re still not sure Tamiflu is effective for the complications of influenza. It looks to us as if it is reasonably effective at reducing symptoms – a little bit – but that in itself isn’t reason enough to have nations around the world stockpile billions of dollars worth of the drug as had happened.</p>
<p>In terms of its effectiveness in reducing symptoms, when you start thinking of a disease that gets better by itself, the difference between being less ill (“cured”) and feeling less ill is theoretical. </p>
<p>What’s more, there has been some criticism of this drug regarding its side effects. In Japan, there have been some reports of children, in particular, and adolescents who <a href="http://iospress.metapress.com/content/54581l6w5n31w818/">became psychiatrically very unwell after using it</a>.</p>
<p>It’s very difficult to separate out an adverse effect like that as something that is the consequence of the drug, or something that this consequent on the illness that the drug is being used for. That’s always difficult to sort out but we’ve started to look at some of the data to try to work it out and we’ve got a new plan of analysis where we might be able to disentangle that.</p>
<p>At the moment there are certainly some indications that there are more adverse events being reported in the unpublished data while published summaries say they don’t exist. That is, some published reports declare no adverse effects while we’ve found some unpublished data reporting adverse effects, and some of them are attributed to oseltamivir itself.</p>
<p>Roche has funded nearly every single study on this drug; they are expensive studies to perform so they’re nearly always funded by the drug industry. Not only have they not been forthcoming with the data, they have never told us good reasons for not sharing it. </p>
<p>The company talks in vague terms about commercial-in-confidence reasons. That’s a very interesting argument to run because, although we think there are some aspects of the drug’s development that are commercial in confidence – particularly to do with its development in the earlier stages of a drug’s development when you could imagine competitors might get an advantage if they could get access to the information – the effectiveness and efficacy of the stuff, how well it performs in trials, is something that should be publicly available. This information should be in the public domain transparently because it’s to do with the public good. </p>
<p>In terms of pandemic preparation, having access to these data is about making sure that we’re not wasting our money on something. That if we’ve got a drug that’s not effective, that isn’t effective in reducing the spread of the disease, which is the most important thing in a pandemic, or in saving lives or saving people from having to go to hospital, then it’s absolutely vital that we have that information. </p>
<p>If it’s not effective on these important outcomes, it may be better for us to resort to something we do know works, like barrier methods – wearing masks, washing your hands a lot and quarantining people. </p><img src="https://counter.theconversation.com/content/4955/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Chris Del Mar has received funding from the National Institute for Health research (NIHR) in the United Kingdom and the NHMRC in Australia.
He has previously done some consultancy work on an unrelated area – a vaccine for middle-ear infections – for GSK, the manufacturer of zanamivir.
</span></em></p>A Cochrane review published today has again raised questions about the efficacy of Tamiflu, the antiviral drug that has been stockpiled by countries across the world as the first line of defence against…Chris Del Mar, Professor of Public Health, Bond UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/19812011-08-30T01:16:59Z2011-08-30T01:16:59ZMarvellous mutants: how nimble flu viruses outsmart drugs<figure><img src="https://images.theconversation.com/files/2708/original/409745082_384a876452_b.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Mutations of the flu virus render drugs ineffective for treating infected patients.</span> <span class="attribution"><span class="source">Leonid Mamchenkov</span></span></figcaption></figure><p>The <a href="http://www.abc.net.au/am/content/2011/s3305219.htm">United Nations Food and Agricultute Organisation is warning authorities to be on high alert</a> after a mutant strain of bird flu was found to be spreading across Asia. While bird flu hasn’t traditionally spread easily to humans, it’s know to be very virulent, killing half of the 600 people infected since it was first detected in 2003. </p>
<p>Fortunately in Australia we don’t have the highly pathogenic bird flu known as A(H5N1), although many of us of course experience colds and sniffles as a result of other influenza A viruses during the winter months. </p>
<p>Influenza accounts for over 300,000 general practitioner consultations and over 18,000 hospitalisations in a typical year in Australia. </p>
<h2>Man vs flu</h2>
<p>While most people are aware that the influenza vaccine prevents infection, many don’t know about the antiviral drugs available for either treatment or short-term prevention of influenza infection in both children and adults.</p>
<p>These antivirals can be particularly useful during a pandemic (a worldwide epidemic caused by the introduction of a new influenza A virus into the human population). </p>
<p>More specifically, they can play a key role during the period while a new vaccine is being made. </p>
<p>The most common class of influenza antiviral drugs is known as <a href="http://www.nejm.org/doi/full/10.1056/NEJMra050740">neuraminidase inhibitors (NAIs)</a>, and includes Tamiflu (<a href="http://www.nlm.nih.gov/medlineplus/druginfo/meds/a699040.html">oseltamivir</a>) and Relenza (<a href="http://www.nlm.nih.gov/medlineplus/druginfo/meds/a699021.html">zanamivir</a>). </p>
<p>NAIs are designed to inhibit the <a href="http://www.pdb.org/pdb/101/motm.do?momID=113">neuraminidase</a>, a spike on the surface of the influenza virus that plays a key role in infection. These inhibitors fit precisely into a cavity on top of the neuraminidase, mimicking how a key fits into a lock. </p>
<p>Once locked in, the inhibitors block its function and reduce the capacity of the virus to multiply and spread from cell to cell. But genetic mutations in the virus lead to changes in the cavity of the neuraminidase, altering the shape of the “lock” so the inhibitors no longer fit as well. </p>
<p>Some mutations in the neuriminidase can cause such large changes in the shape of the cavity that drugs may bind very poorly. This can result in the virus becoming drug resistant and the NAIs becoming ineffective for treating a patient infected with this virus. </p>
<p>Other mutations can cause smaller changes in the shape of the “lock” so the “key” only partially fits and the drug’s effectiveness is reduced but not completely eliminated.</p>
<h2>Resistance becomes fertile</h2>
<p>Before 2007, resistance to neuraminidase inhibitors was rare. </p>
<p>Even more importantly, of the influenza viruses that <em>were</em> resistant, the majority had impaired fitness as a result of the altered shape of their neuraminidase cavity. (“Fitness” is used to describe the ability of the virus to multiply, replicate and spread.)</p>
<p>In other words, the mutation that was causing resistance was at the same time affecting the ability of the neuraminidase to function normally and restricting viral fitness. </p>
<p>This was the ideal scenario because the resistant viruses that emerged from time to time in individual patients were unlikely to spread widely throughout the community. </p>
<p>But this human-friendly state of affairs was about to be challenged. </p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/2686/original/Screen_shot_2011-08-05_at_5.14.42_PM.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/2686/original/Screen_shot_2011-08-05_at_5.14.42_PM.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=522&fit=crop&dpr=1 600w, https://images.theconversation.com/files/2686/original/Screen_shot_2011-08-05_at_5.14.42_PM.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=522&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/2686/original/Screen_shot_2011-08-05_at_5.14.42_PM.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=522&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/2686/original/Screen_shot_2011-08-05_at_5.14.42_PM.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=656&fit=crop&dpr=1 754w, https://images.theconversation.com/files/2686/original/Screen_shot_2011-08-05_at_5.14.42_PM.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=656&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/2686/original/Screen_shot_2011-08-05_at_5.14.42_PM.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=656&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">The head of four neuraminidase molecules with their cavities in red. Jason Roberts.</span>
<span class="attribution"><span class="source">Jason Roberts</span></span>
</figcaption>
</figure>
<h2>The plot thickens</h2>
<p>In early 2008, laboratories in Europe began <a href="http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=8026">reporting an increasing frequency of resistance</a> to Tamiflu in the influenza subtype A(H1N1), due to a neuraminidase mutation called H275Y. </p>
<p>In Norway, the frequency of resistance in tested influenza viruses had increased from the normal level of less than 1%, to more than 70%. That means 70 out of 100 A(H1N1) viruses circulating in Norway at the time were resistant to Tamiflu. </p>
<p>Relenza, due to its different chemical structure to Tamiflu, remained effective. </p>
<p>Laboratories throughout Europe rapidly <a href="http://www.ncbi.nlm.nih.gov/pubmed/19331731">tested influenza viruses within their countries and demonstrated</a> retrospectively that the resistant virus had emerged in late 2007 and spread throughout Europe within just a few months. </p>
<p>It didn’t take long for this virus to spread to the southern hemisphere – first to South Africa and then South-East Asia, Australia and New Zealand. </p>
<p>By the end of the 2008 southern hemisphere winter – a mere nine months after the resistant virus first emerged in Europe – it had spread so widely that almost all of the circulating A(H1N1) viruses detected worldwide were resistant to Tamiflu. </p>
<p>Significantly, this virus didn’t conform to the accepted viral behaviour theory - not only was it resistant but its mutation didn’t appear to affect its ability to multiply and spread in humans. </p>
<p>This Tamiflu-resistant virus continued to circulate globally during late 2008 and early 2009, but its fate was about to change. </p>
<h2>Saved by the pandemic?</h2>
<p>In April 2009, the world experienced the first influenza pandemic of the 21st century with the emergence of a new influenza A strain that apparently crossed from pigs into the human population – the swine flu.</p>
<p>The new pandemic strain, called “A(H1N1)2009” was of the same influenza subtype as the “seasonal A(H1N1)” Tamiflu-resistant virus, but it was a very different beast.</p>
<p>In past pandemics (1957 and 1968), the newly-emerged pandemic strain out-competed the previously circulating influenza A strain, driving the “older” virus into history. </p>
<p>And fortunately, the same was about to occur in the 2009 pandemic. In less than a year, the new pandemic A(H1N1)2009 virus had “out-muscled” the Tamiflu-resistant seasonal A(H1N1) virus from human circulation. </p>
<p>It’s impact was such that the earlier resistant strain is now virtually extinct. And since then, <a href="http://www.eurosurveillance.org/viewarticle.aspx?articleid=19770">resistance has been detected in only a few circulating influenza strains</a>.</p>
<p>But the experience of the rapid spread of the “fit” Tamiflu resistant A(H1N1) strain in 2008 raises concerns about this scenario being repeated in the now widely circulating pandemic A(H1N1)2009 strain. </p>
<p><a href="http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19884">Recent analysis of viruses from the Asia-Pacific region</a> during the early months of 2011 found that more than a third of pandemic A(H1N1)2009 strains from Northern Australia and more than a tenth in Singapore contained a new neuraminidase mutation, called S247N.</p>
<p>Importantly, the S247N mutation has a relatively mild effect on the binding of Tamiflu, compared to the large effect of the previous H275Y mutation. </p>
<p>Nevertheless, the mutation had modified the shape of the “lock” and while it’s expected that the inhibitors will remain effective, any additional mutations may mean that at least one of the “keys” may no longer work.</p>
<p>Of greater concern is the very recent <a href="http://www.promedmail.org/pls/apex/f?p=2400:1001:8812035519322363::NO::F2400_P1001_BACK_PAGE,F2400_P1001_PUB_MAIL_ID:1010,89966">detection of pandemic A(H1N1)2009 strains with the highly resistant H275Y mutation in community cases in the region of Newcastle, New South Wales</a>. </p>
<p>At this stage, the resistant virus has been detected in 14% of the pandemic A(H1N1)2009 strains from the Newcastle area.</p>
<p>So now scientists in Australia and around the world are actively monitoring both the movement drug-resistant human influenza viruses and new mutant bird flu strains. It seems there’s never a quiet day in the world of influenza.</p><img src="https://counter.theconversation.com/content/1981/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Aeron Hurt does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>The United Nations Food and Agricultute Organisation is warning authorities to be on high alert after a mutant strain of bird flu was found to be spreading across Asia. While bird flu hasn’t traditionally…Aeron Hurt, Senior Researh Scientist & Head of Anti-viral Sensitivity Analysis, WHO Collaborating Centre for Reference and Research on InfluenzaLicensed as Creative Commons – attribution, no derivatives.