CIDRAP News On The Lancet Oseltamivir (Tamiflu ®) Meta-Analysis

Photo Credit – Wikipedia

 

 

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I had plans this morning to write an overview of meta-analysis of Tamiflu effectiveness published January 29th in The Lancet, but I’m happy to note that last night Robert Roos of CIDRAP News has beaten me to it. Since I’m unlikely to improve upon his reportage, I’ll direct you to his excellent review – which you’ll want to read in its entirety - after which I’ll return with a little bit more.

 

Meta-analysis supports oseltamivir use in adults, notes side effects

Robert Roos | News Editor | CIDRAP News

Jan 30, 2015

A comprehensive new meta-analysis on the controversial topic of oseltamivir's effectiveness found that the drug reduces the duration of influenza symptoms and the risk of hospitalization in adults and adolescents, while increasing the risk of nausea and vomiting.

A US-British team, with Arnold S. Monto, MD, of the University of Michigan as senior author, included in the analysis all randomized controlled trials sponsored by Roche, the drug's manufacturer, as well as other relevant trials. The study, reported yesterday in The Lancet, was funded by Roche, but the researchers worked independently.

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Over the past few years we’ve seen the demonization of influenza antivirals in the media (see Daily Mail: Ministers blew £650MILLION on useless anti-flu drugs), warnings of potential aberrant psychiatric behavior (see 2007 New Worries On Tamiflu), and repeated Cochrane group analyses that have found insufficient evidence that the drug reduces influenza complications.

Add in some serious foot-dragging by manufacturer Roche in releasing all of their testing data, and Tamiflu has become an easy drug for the public, and some doctors, to distrust.

Despite all of this `baggage’  the CDC, ECDC, UK’s PHE, and other public health agencies have steadfastly supported the early use of oseltamivir in the treatment of severe flu (see this week’s CDC Antiviral Letter to Providers and ECDC Influenza Season Risk Assessment).

The reason?

Even without the `gold standard’ Randomized controlled trials (RCTs) that the Cochrane group relies on for their analyses, we’ve seen numerous observational studies that lend support to the use of antivirals in severe influenza.

 

A few I’ve written about 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 March 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 last summer, in  CID Journal: Under Utilization Of Antivirals For At Risk Flu Patients, we saw a study showing that antiviral drugs are underused for at-risk patients, while antibiotics (which don’t work against viral infections) are overused.

 

Added to this, we now have this new meta-analysis of the data from all published and unpublished clinical trials from 1997-2001, involving more than 4,300 patients. Patients with influenza (not just an ILI), who received the drug within 36 hours of onset of symptoms saw a reduction in the duration of their illness of 21% and a significant reduction in the risk of developing pneumonia or requiring hospitalization.

 

While nausea (9.9% vs 6.2% in controls) and vomiting (8.0% vs 3.3%)  were common side effects, no serious adverse reactions were reported, with no increase in psychiatric or neurological symptoms.

 

For uncomplicated influenza in a healthy individual (essentially what the Cochrane studies looked at), antivirals probably offer limited benefits.

 

But for severe influenza, or for people at risk of complications . . .

 

The preponderance of evidence shows that taking antivirals early can limit the severity and duration of symptoms – and for patients at risk of complications – that  could help keep them out of the hospital . . .  or worse.

Sandman & Lanard On The Cochrane Tamiflu Report

 

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Somehow, with all of the MERS news coming out of the Middle East, I managed to miss a terrific piece of analysis by our favorite Risk Communications experts, Dr. Peter Sandman and Dr. Jody Lanard,  published last week on the The Peter M. Sandman Risk Communication Website.

 

Their website is a repository of invaluable risk management advice, that quite frankly should be second home for anyone involved in public relations or risk communications.

 

I’ve highlighted their work often in the past,including Sandman & Lanard: WHO, Pandemic Phases & Public Preparedness, Sandman: A Tale Of Two CDCs, Lanard: China’s Risk Communication On H7N9, and Referral: Sandman On The H5N1 Moratorium.

 

Their latest analysis centers on the  recent release of (and media hype surrounding) a recent Cochrane group analysis that found insufficient evidence to show whether Oseltamivir (Tamiflu ®)  and other NAI antivirals reduces influenza complications and transmission. 

 

I wrote about  this report earlier this month in  Revisiting Tamiflu Efficacy (Again) & The CDC Responds To The Cochrane Tamiflu Study, where I posited the preponderance of evidence supports the use of NAI antivirals for severe influenza.

 

Early last week Declan Butler, writing for the Journal Nature, wrote a piece called Tamiflu report comes under fire, for which Sandman & Lanard have supplied some quotes. Building on their emailed comments to Butler, they penned and posted a longer analysis on their website the following day.

 

Since it would do an injustice to the authors to try to excerpt highlights, I would simply suggest you follow the link below to read it in its entirety. 

 

Overstated Attack Hiding Behind Scientific Assessment: An April 2014 Cochrane Review Trashes the Usefulness of Influenza Antiviral Drugs

by Peter M. Sandman and Jody Lanard

(an April 15, 2014 email responding to Declan Butler of Nature)

Declan Butler’s April 22, 2014 article drew from this email.

Introductory Note

In early April 2014, the Cochrane Collective published two journal articles and a news release that went out of their way to understate the value of Tamiflu and Relenza, the two antiviral drugs used against influenza. When Nature reporter Declan Butler asked for our comment, we quickly sent back the short email posted below.

 

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The Sandman site is a treasure trove of risk communications information, and you could literally spend days just hitting the highlights. 

 

Highly recommended.

The CDC Responds To The Cochrane Tamiflu Study

Photo Credit CDC

 

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Earlier today, in Revisiting Tamiflu Efficacy (Again), I wrote at some length on the BMJ –  Cochrane Library review Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children – that examined a subset of the scientific literature and cast doubt on its effectiveness in treating influenza.

While I too lamented the lack of solid, well mounted Randomized controlled trials (RCTs) proving the effectiveness of Oseltamivir (particularly in high risk patients, or with novel flu strains), I listed a number observational studies that strongly support the effectiveness of Oseltamivir.

But you don’t have to take my word for it.  This afternoon the CDC, has issued their own response. I’ve posted the link and some excerpts below.  Follow the link to read their rationale in its entirety.

 

CDC Recommendations for Influenza Antiviral Medications Remain Unchanged

April 10, 2014 -- CDC continues to recommend the use of the neuraminidase inhibitor antiviral drugs (oral oseltamivir and inhaled zanamivir) as an important adjunct to influenza vaccination in the treatment of influenza. CDC’s current influenza antiviral recommendations are available on the CDC website and are based on all available data, including the most recent Cochrane report, about the benefits of antiviral drugs in treating influenza.

 

CDC considers all of the published evidence available from Randomized Control Trials (RCT) conducted among outpatients and observational studies conducted among hospitalized patients, including benefits and risks from safety data, when issuing recommendations on antiviral treatment of influenza. These CDC recommendations emphasize early antiviral treatment as soon as possible for patients who are severely ill and for those who are at greatest risk for complications from influenza. This includes hospitalized patients with suspected or confirmed influenza, those with severe or progressive illness, and outpatients who are at high risk for influenza complications (for example, young children, people aged 65 years and older, pregnant women, and persons with certain underlying chronic medical conditions). In addition, because other reviews of RCTs and observational studies have found consistent clinical benefit of early oseltamivir treatment in reducing the risk of lower respiratory tract complications such as those requiring antibiotics, persons with uncomplicated influenza who are not in a high risk group and who present within 48 hours of illness onset can be treated with antiviral medications based upon clinical judgment.

 

One large study that was published recently, “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”, adds to the growing body of evidence which supports that neuraminidase inhibitor treatment can reduce the risk of death in hospitalized patients with influenza.  In this meta-analysis of published studies, researchers compiled individual-level data from 78 observational studies across 38 countries on more than 29,000 patients who were hospitalized with 2009 H1N1 influenza virus infection during the 2009-10 pandemic. In this study among patients aged >16 years, treatment with a neuraminidase inhibitor antiviral drug was associated with a 25% reduction in the likelihood of death compared to no antiviral treatment. Early treatment with neuraminidase inhibitor antiviral drugs (i.e., within 48 hours of development of influenza illness) halved the risk of death compared to no antiviral treatment. This confirms findings from previous observational studies in hospitalized influenza patients that the clinical benefit of neuraminidase inhibitor antiviral treatment is greatest when started within two days of influenza illness onset.

 

A review of RCT data for the influenza neuraminidase inhibitor antiviral medications published by the Cochrane Collaboration updates a previous Cochrane review published in 2012, and raises questions about the value of antiviral medications for the prevention and treatment of influenza. The updated Cochrane review assessed full internal clinical study reports from manufacturers containing published and unpublished data from 46 randomized controlled trials (RCTs) of oral oseltamivir or inhaled zanamivir versus placebo for preventing and treating outpatients with mild illness who were otherwise healthy adults and children. The review concluded that in adults and children with influenza-like illness, early oral oseltamivir treatment shortens the duration of symptoms by approximately 17 hours and 29 hours, respectively, compared to placebo. This finding is similar to results in previously published RCTs which reported a reduction of approximately one day of laboratory-confirmed uncomplicated influenza illness in outpatients by early oral oseltamivir treatment verus placebo. One RCT in outpatients who were aged 1 to 3 years with uncomplicated influenza found a reduction of 3.5 days when oral oseltamivir treatment was started within 24 hours after illness onset. The Cochrane review concluded that inhaled zanamivir reduced symptoms in adults by approximately half a day compared to placebo, but had no significant effect in children. The Cochrane review reported no significant effect of oral oseltamivir treatment of outpatients on hospitalizations for adults or children, and the authors conclude that the treatment trials do not settle the question of whether the complications of influenza are reduced by treatment in outpatients because of a lack of diagnostic definitions.

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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.

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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.

Spot Shortages Of Tamiflu Reported In Some Regions

Photo Credit – Wikipedia

 

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With the 2013-14 influenza season now well underway, and concerns over the severity of the H1N1 virus – particularly in younger patients and those with co-morbidities – the CDC is urging doctors to consider the early use of antivirals in high risk patients with suspected or confirmed influenza (see CDC HAN Advisory On Early pH1N1 Influenza Activity).

 

While there does not seem to be a national shortage of oseltamivir (Tamiflu ®) – the most commonly prescribed antiviral for influenza – in a few regions (mainly in the South) that have already been hit hard by the flu, some pharmacies are reporting trouble keeping the drug in stock.

 

A couple of  reports on these shortages, after which I’ll be back with a little more on Tamiflu, and this year’s H1N1 flu.

 

Shortage in flu medication worries pharmacists

LITTLE ROCK, Ark. (KTHV) - "We can't find the regular adult dose anywhere right now," Dr. Ray Turnage explained.

Turnage is one of many pharmacists dealing with a shortage of Tamiflu. He said, "There's only one manufacturer for that drug and nationwide all the wholesalers are saying it's a manufacture delay."

Tamiflu is the only medication on the market used to treat the flu and with a shortage in the drug, it could create problems for patients needing it. "Probably the demand is exceeding their supply. So that's the problem is we can't even get adult doses right now," Turnage continued.

Although there have been very minimal cases of the flu this year in Little Rock, with 3 to 4 months left in the flu season, that could change pretty quickly. If it does, Tamiflu in stock could disappear. Turnage said, "That's part of the situation is a few families can, if they can find it, can take all that the pharmacy may have."

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Shortage reports on Tamiflu in Atlanta, local pharmacies stocked – WSOC-TV

 

The bottom line is, that if you are prescribed Tamiflu, you may have to call around to more than one pharmacy to locate the drug.

While Tamiflu continues to get a strong recommendation from the CDC (see CDC Research On Benefits Of Antivirals For Uncomplicated Influenza), you’ll find no shortage of critics of the drug.  Due in large part to a prolonged reluctance on the part of Roche laboratories to release all of their clinical trial data, and a not totally undeserved reputation of `Big Pharma’ to massage test results. 

 

This has resulted in a vociferous backlash against the government stockpiling of Tamiflu in some quarters (see Dr. Ben Goldacre Opinion Piece). 

 

While academics and activists tend to have a dim view of Roche and their antiviral drug, clinicians obviously see value in oseltamivir,  and continue to prescribe it.  The CDC continues to recommend its use – particularly for high-risk influenza patients - or for the treatment of novel flu (see 2012 blog The CDC Responds To The Cochrane Group’s Tamiflu Study).

 

Although this year’s flu season is being billed in the media as `The Return of Swine Flu’, in truth, the H1N1 virus never departed.  But it has been dominated in North America by the H3N2 virus for the past couple of years.   The following snapshot of last year’s moderately severe flu season comes from last summer’s  MMWR Influenza Activity — United States, 2012–13 Season and Composition of the 2013–14 Influenza Vaccine.

 

Among the seasonal influenza A viruses, 34,922 (68%) were subtyped; 33,423 (96%) were influenza A (H3N2) viruses, and 1,497 (4%) were pH1N1 viruses. In addition, two variant influenza A (H3N2v) viruses were identified.

 

The season before that (2011-12) was the mildest flu season in decades (see 2011-2012 Flu Season Draws to a Close), that while H3N2 dominated, neither strain had a huge impact.

 

The truth is, flu seasons can vary greatly in impact from year-to-year,and with two influenza A strains in global circulation, we usually see one strain or the other dominate (although what strain is dominant in North America my differ from what is dominant in Europe, or Asia the same year).  Often we see 2 or 3 years with one strain in control, and then – as community immunity levels wane – the other takes hold.

 

The CDC’s most recent attempt to estimate the number of deaths associated with flu in the United States finds:

 

An August 27, 2010 MMWR report entitled “Thompson MG et al. Updated Estimates of Mortality Associated with Seasonal Influenza through the 2006-2007 Influenza Season. MMWR 2010; 59(33): 1057-1062.," provides updated estimates of the range of flu-associated deaths that occurred in the United States during the three decades prior to 2007. CDC estimates that from the 1976-1977 season to the 2006-2007 flu season, flu-associated deaths ranged from a low of about 3,000 to a high of about 49,000 people.

 

As much as a 16-fold difference in the number of estimated deaths between a mild flu season, and a heavy one. 

 

Thus far, its been H1N1’s year to roar, and since that strain often impacts those under the age of 65, it tends to get more publicity. The flu death of a young adult from influenza is more unexpected, and has more societal impact, than that of an octagenarian.  And this year, sadly, we are seeing a fair number of such reports (see Texas DSHS Statement On Recent Spike In Flu Activity).

 

Regardless of the strain of flu in circulation, you are much better off avoiding infection rather than treating it. So while it may only provide moderate protection, getting the flu shot each year is cheap insurance. 

That, and following good flu hygiene practices (covering coughs, washing hands frequently, staying home when sick, avoiding close contact with those who are sick),  are your best defense against our yearly flu epidemic.

CDC Research On Benefits Of Antivirals For Uncomplicated Influenza

Photo Credit – Wikipedia

 

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In clinical medicine there are a lot of things that we think we know – based on observational studies – but for which rigorous randomized controlled trials (RCTs) have not been conducted. Sometimes it is impractical (or even unethical) to subject patients to an RCT, especially if it involves withholding a potentially lifesaving drug from a `control’ cohort.

 

So we are often left to rely on less desirable, but still useful, observational studies to gauge the value of treatments or therapies.

 

Over the past decade one of the drugs that has fallen into this pharmaceutical limbo is oseltamivir (Tamiflu ®), a product of Roche laboratories, which has been stockpiled by many nations to combat a flu pandemic.  Observational studies have shown that this drug can significantly reduce morbidity and  mortality in severe cases of flu, and modestly reduce the duration of symptoms in uncomplicated seasonal flu.

But robust RCTs have not been conducted to quantify these benefits, and `RCT purists’ like this Cochrane group analysis – that do not consider `observational studies’ to be solid evidence - have found insufficient evidence to show whether the drug reduces influenza complications and transmission (see 2012 CIDRAP article Review renews questions about oseltamivir benefits).

 

Add to this a prolonged reluctance on the part of Roche laboratories to release all of their clinical trial data, and a not totally undeserved reputation of `Big Pharma’ to massage test results, and the result has been a vociferous backlash against the government stockpiling of Tamiflu in some quarters (see Dr. Ben Goldacre Opinion Piece).

 

While academics and activists tend to have a dim view of Roche and their antiviral drug, clinicians obviously see value in oseltamivir,  and continue to prescribe it.  The CDC continues to recommend its use – particularly for high-risk influenza patients - or for the treatment of novel flu (see 2012 blog The CDC Responds To The Cochrane Group’s Tamiflu Study). 

 

With a new avian (H7N9) virus in the wings and H5N1 still simmering in Asia and the Middle East, the CDC recently reiterated their support for the use of oseltamivir in the treatment of severe, or novel, influenza infection (See H7N9: Updated CDC Guidance For Antiviral Treatment).

 

Yesterday, the CDC published a news release on an RCT conducted in Bangladesh on the benefits of Oseltamivir in uncomplicated seasonal flu.  A category of illness where one would expect the least amount of benefit to taking an antiviral. A few excerpts, and a link to The Lancet Study, then I’ll return with a bit more.

 

CDC Research Confirms Benefits of Flu Antiviral Drugs, Even Beyond 2 Days After Symptoms Start

New research confirms benefits of the influenza antiviral medication oseltamivir in treating children with uncomplicated flu illness and shows that treatment can be beneficial even beyond the two-day window recommended as a cut-off for treatment in the drug’s package insert.

A new study on influenza (flu) antiviral drugs by CDC authors was released today in The Lancet Infectious Diseases. This study is the first clinical trial to note a significant reduction in the duration of illness and virus shedding in children when influenza antiviral treatment was initiated more than 2 days after the onset of influenza (flu) symptoms. These findings confirm the benefits of using the antiviral drug oseltamivir to treat flu illness and suggest that some children will benefit when treatment is initiated beyond 2 days, which is the recommended cut-off for treatment in the current package insert.

 

The patients in this double-blind, randomized, placebo-controlled study were mostly children (average age: 5 years) in an urban setting in Bangladesh with laboratory-confirmed influenza infection and no additional flu-related complications. Patients were treated with either oseltamivir (a type of flu antiviral drug known as a “neuraminidase inhibitor”) or a placebo (e.g., a shot of saline). Researchers observed when patients began oseltamivir treatment — either less than 48 hours or 48 hours or more after illness onset — and collected information about the duration of flu symptoms using standardized forms collected from daily household visits. In addition to documenting the duration of flu symptoms, researchers also measured viral shedding, which is virus detection at various times after the patients were enrolled. The detection of live virus in respiratory secretions is thought to be associated with how contagious a person is to others.

 

Among all children receiving oseltamivir within 5 days of illness onset, researchers found that overall flu symptoms were reduced by one day compared with those treated with placebo (3 days versus 4 days). This finding is consistent with results from other flu antiviral studies that started treatment within 2 days of illness onset. The results also show that oseltamivir treatment reduced the amount of live virus that was isolated from respiratory specimens by 12% to 50% compared with placebo regardless of whether treatment was started before or after 2 days since illness onset. This finding is especially important because no other study has shown reduced viral shedding in similar proportions regardless of whether treatment is started less than or more than 48 hours after flu symptoms begin.

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The article is available in The Lancet Infectious Diseases: “Efficacy of oseltamivir treatment started within 5 days of symptom onset to reduce influenza illness duration and virus shedding in an urban setting in Bangladesh: a randomised placebo-controlled trial.”

 

 

Of course, governments aren’t stockpiling Tamiflu for uncomplicated seasonal flu.  They have purchased millions of doses in anticipation of a severe pandemic.  And while RCTs on treating severe influenza with the drug are scant, we have seen some pretty compelling observational and anecdotal data.

 

In 2010 an observational study appearing in JAMA  (see Study: Antivirals Saved Lives Of Pregnant Women) 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%.

 

And lastly, for those who question the value of Tamiflu in an avian 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 today’s study may not completely mollify the critics, the preponderance of evidence continues to show that antivirals – including Tamiflu – can have a substantial positive therapeutic effect on influenza, particularly in high risk patients.

ICAAC 2013 Videos: Triple Tamiflu In ICU & Interferon For H7N9

 

 

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The 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) was held this week in Denver Colorado, and once again we’re fortunate to have videos of press conferences being webcast live and archived via MicrobeWorld’s Youtube channel.

 

Two interviews of particular interest to Flublogia concern research on the use of Triple-dose Oseltamivir (Tamiflu ®) on critically ill patients during the 2009 pandemic,  and research looking at using alpha-Interferon for the treatment of H7N9.

 

The standard adult dose of Tamiflu for uncomplicated seasonal influenza  is 75mg, twice a day for 5 days – although higher doses over longer periods of time have been proposed (and even tried) when dealing with avian or severe pandemic flu.  

 

Last May, in Delving Into The Oseltamivir Dosage Study, we looked at a BMJ study that found No benefit of double dose antiviral drug for severe influenza.   This study, however, had a number of limitations:

• Most of the patients were children under 15
• Most of the patients had low or normal BMI
• Only about 1/5th had underlying conditions
• Very few adults were included in the study
• Only 17 (of 326 cases) were H5N1, and of those, only 3 survived to day 5 of the trial.
• The average delay for treatment for H5N1 patients was 7 days vs. 5 days for seasonal flu
• All H5N1 cases met the criteria for clinical failure

 

One is left to wonder how well these results would translate to a much older population, one likely to have a higher average BMI, far more (and different) underlying conditions, and in all likelihood would seek treatment sooner than did the patients in this study (average 5-7 days).

 

While this trial found no value to doubling the dose for seasonal flu, there is insufficient evidence to judge whether doubling the dose for H5N1 (or presumably H7N9) would improve patient survival. And in an accompanying editorial, Ian Barr and Aeron Hurt of the WHO Collaborating Centre for Reference and Research on Influenza, would appear to agree:

What is clear is that double dose oseltamivir is unlikely to significantly improve the clinical outcomes of severe cases of seasonal influenza, although there were probably insufficient data to determine if this was also true for people infected with A(H5N1).

It is worth noting that last April, in CDC Interim Guidance On H7N9 Antiviral Treatment, we saw the CDC’s recommendation that for hospitalized patients:

The optimal duration and dose of therapy are uncertain in severe or complicated influenza. Pending further data, longer courses of treatment (e.g., 10 days of treatment) should be considered for severely ill hospitalized H7N9 patients.

 

Earlier this summer, we looked at the general effectiveness of oseltamivir, and the need for maintaining stockpiles in New Scientist: Don’t Stop Stockpiling Tamiflu.

 

All of which brings us to the first ICAAC video:

High Dose Therapy for Influenza Drug - Watch Now

Critically ill patients  with the pandemic H1N1 influenza who received triple the standard dose of the influenza drug oseltamivir were 7 times more likely to completely clear the virus from their system in 5 days than those who received the standard dose. This discussion will address the healthcare implications of these findings, including a rationale for high dose therapy of sensitive strains of influenza.

• Anand Kumar, Hlth. Sci. Ctr., Winnipeg, MB, Canada

 

Dr. Kumar reports that the triple dose of Tamiflu was well tolerated, and believes higher doses may be appropriate for those severely ill from influenza.   For more on the topic of antivirals, and their use for pandemic or avian flu, you may wish to revisit Study: Antiviral Therapy For H5N1  and Hong Kong Finds Success With Higher Tamiflu Doses.

 

Our next stop is an interview with William M. Mitchell, Vanderbilt University, Nashville, TN who discusses the use of interferon Alpha as a possible treatment of oseltamivir-resistant H7N9.   You may recall that just last week, in Nature: Animal Testing Of Drug Combo Shows Potential For Treating MERS Interferon was also proposed as part of a cocktail to potentially treat the MERS Coronavirus.

 

According to a press release yesterday from Hemispherx Biopharma, Inc, their findings are based on in vitro experiments, directed against inhibiting the replication of two strains of H7N9 virus in A549 cell lines.  One H7N9 strain (A/Anhui/1/2013) was a `wild type’ that was susceptible to oseltamivir, while the other (A/Shanghai/1/2013) was a patient isolate that had developed Tamiflu resistance.

 

Dr. Mitchell describes the suppression of the wild-type virus as being roughly equal with both oseltamivir and interferon, but the resistant strain (which greatly thwarted the antivirals) showed an even greater response to interferon alpha.

 

The caveat here is, these are in vitro experiments.  Clinical trials have not been conducted, but these are promising – if very early – results.  Mitchell suggests that if the need arose during a pandemic outbreak, an Emergency Use Authorization (EUA) might be issued. 

 

In the following  ICAAC video Dr. Mitchell discusses this research and the potential of using interferon-alpha as a treatment for severe influenza. Note: Mitchell is a board member and shareholder of Hemispherx Biopharma of Philadelphia, which supported this research.

 

Human Interferon Kills Resistant H7N9 Influenza - Watch Now
During the April 2013 avian influenza A (H7N9) outbreak, more than 130 human infections with H7N9 were reported. Most patients had severe respiratory illness and 44 people have died. Studies suggest that the H7N9 virus has developed resistance to oseltamivir. A human interferon already in use for treatment of genital warts, alpha-n3, has been found to be active against the virus, even the oseltamivir-resistant isolate. Participants will discuss these findings and implications.

 

 

 

You’ll find more videos from this year’s ICAAC on this page, and many more offerings from the American Society for Microbiology Youtube Channel.

New Scientist: Don’t Stop Stockpiling Tamiflu

 

 

UPDATED :  My thanks to Debra MacKenzie  for her comment, and link to New Scientist article from last week (Evidence that Tamiflu reduces deaths in pandemic flu) that adds even more evidence of the value of oseltamivir in severe, or complicated, influenza infection.

 

 

# 7430

 

 

There’s a short opinion piece appearing in the New Scientist today that implores governments to ignore the side-bar controversies over Roche’s release of clinical trials, and continue to stockpile (and replace) their Tamiflu ® (oseltamivir) supplies.

 

Don't stop stockpiling Tamiflu

• 27 June 2013

SHOULD countries continue to stockpile the flu drug Tamiflu in case there is a pandemic? Until now many governments have been happy to do so. But as stockpiles reach their "replace by" dates, cash-strapped politicians may be having second thoughts.

 

Their uncertainty may be being fuelled by a campaign against Tamiflu (oseltamivir), motivated by the entirely reasonable beef that manufacturer Roche has not released all of its clinical trial data.

(Continue . . . )

 

 

The stockpiling and use of oseltamivir (Tamiflu) has engendered a good deal of controversy over the past decade, but it is only partially deserved. Over the years Its value has been questioned by Cochrane meta-studies, medical journals, conspiracy theorists, pundits, and the press.

 

Roche Pharmaceuticals has been justifiably criticized for their past refusals to release all of the testing data on their best selling antiviral drug, and that has led to critical editorials in the BMJ, and excoriation in the British press.

 

We’ve seen media reports of aberrant psychiatric behavior in adolescents taking the drug (see 2007 New Worries On Tamiflu), and there’s been a paucity of `gold standard’ Randomized control trials (RCTs) proving its effectiveness.

 

Yet, despite these negatives, there is plenty of evidence to suggest that Tamiflu does work, that it can be lifesaving with severe influenza, and that the risks of side effects have been overstated.

 

Which is why the CDC continues to recommend its use – particularly for high-risk influenza patients - or for the treatment of novel flu (see  The CDC Responds To The Cochrane Group’s Tamiflu Study).

 

Regardless of one’s feeling about `Big Pharma’, the money they have made, or their parsimonious dispersal of clinical trial data, there are really only two factors that governments should consider. 

 

1. Is oseltamivir safe?
2. Does it reduce morbidity and mortality in severe influenza?

 

First the safety issue.

Everybody seems to remember the press reports of abnormal behavior in adolescents in Japan while taking the drug, but few recall that a study in 2008 found no link between the drug and these events (see Japan: No Link Between Tamiflu And Abnormal Behavior).

 

In 2010 a review in the journal Eurosurveillance: Adverse Effects of Oseltamivir in Children, looked at the antiviral treatment of a number of students at a primary school in Sheffield, UK during the 2009 pandemic.

 

While none of the side effects reported were life-threatening, the nausea, vomiting, abdominal pain and other symptoms were bothersome enough that a minority of those who started the Tamiflu (< 10% ) stopped taking the drug.

 

More recently, in Study: Adverse Events Associated With Oseltamivir Outpatient Treatment, researchers writing in the journal Pharmacoepidemiology and Drug Safety, found that `no evidence was identified for an increased risk of neuropsychiatric or other AEs following oseltamivir treatment.’

 

The safety record of Tamiflu has been reassuring enough that last December the FDA approved its use in infants as young as two-weeks (see FDA expands Tamiflu’s use to treat children younger than 1 year).

 

Admittedly, all drugs have side effects, even over-the-counter medications.  But the side effects of Tamiflu appear, for the most part, to be mild and manageable.

 

The second issue, does Tamiflu work? 

 

While it’s value for `seasonal flu’ in healthy adults appears marginal – showing only a slight reduction in symptoms and duration of illness - for those with comorbidities, the benefits appear greater.

 

In 2010 an observational study appearing in JAMA  (see Study: Antivirals Saved Lives Of Pregnant Women) 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.

 

Quite recently, 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%.

 

 

And lastly, for those who question the value of Tamiflu in an avian 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.

 

Despite the critics, the preponderance of evidence continues to show that antivirals – including Tamiflu – can have a substantial positive therapeutic effect on influenza, particularly in high risk patients.

Delving Into The Oseltamivir Dosage Study

 

Photo Credit – Wikipedia

 

# 7344

 

One of the concerns during a severe pandemic is our finite supply of antiviral medications. The standard adult dose of oseltamivir (Tamiflu ®) is 75mg twice a day for 5 days, or a course of 10 pills.

But as we’ve seen in Southeast Asia with H5N1 (and more recently with H7N9), many patients have required larger antiviral doses for a longer period of time, and yet many still do not survive.

 

In 2007, at the height of the H5N1’s expansion, some doctors began treating patients with double the dose for double the time, essentially 40 pills over 10 days (see Prudence and the Pill). 

 

A rate that is sustainable when cases are few, but would quickly exhaust our stockpiles of antivirals in a severe pandemic.

 

Which makes the headline being carried by the media this morning, stemming from a study that appeared in the BMJ yesterday, of particular interest:

 

 

No benefit of double dose antiviral drug for severe influenza

Findings have major implications for stockpiling drugs during pandemics, say experts

 

And if you stop there, or simply read the press release, you might come away with the idea that a double dose of oseltamivir (Tamiflu ®) is a waste of time, and valuable resources, when treating an avian flu patient.

But that’s not exactly what the study says.

 

First, a link to the open access double-blind randomized trial, conducted across 13 hospitals in four southeast Asian countries between 2007 and 2010, comparing the relative effectiveness of the standard dose of oseltamivir (Tamiflu ®) vs a double dose.

 

Effect of double dose oseltamivir on clinical and virological outcomes in children and adults admitted to hospital with severe influenza: double blind randomised controlled trial

BMJ 2013; 346 doi: http://dx.doi.org/10.1136/bmj.f3039 (Published 30 May 2013)

Cite this as: BMJ 2013;346:f3039

 

 

This is actually an impressive, well mounted study, certainly worth reading in its entirety. There were 326 patients, mostly children under the age of 15, enrolled in the trial.

 

The press release describes their methodology:

 

Patients received either standard dose oseltamivir (75 mg twice a day or children's equivalent) or double dose (150 mg twice a day or children's equivalent) for five days. Nose and throat swabs were then taken to test for virus levels.

 

Other outcomes including death, admission to intensive care, and help with breathing (mechanical ventilation) were also assessed.

 

The researchers found no differences between the treatment groups in virus levels on day five. There were also no differences in deaths or rates of adverse events between the different doses.

 

The authors mention a few important limitations to this study, including:

 

• Most of the patients were children under 15
• Most of the patients had low or normal BMI
• Only about 1/5th had underlying conditions
• Very few adults were included in the study
• Only 17 (of 326 cases) were H5N1, and of those, only 3 survived to day 5 of the trial.
• The average delay for treatment for H5N1 patients was 7 days vs. 5 days for seasonal flu
• All H5N1 cases met the criteria for clinical failure

 

The authors caution:

 

Thus, our findings are applicable primarily to the region where the study was conducted and other settings with similar characteristics of influenza epidemiology.

 

 

One is left to wonder how well these results would translate to a much older population, one likely to have a higher average BMI, far more (and different) underlying conditions, and in all likelihood would seek treatment sooner than did the patients in this study (average 5-7 days).

 

But assuming that these factors would not make huge differences in outcomes, the biggest limitation remains the lack of data on H5N1 avian influenza.

 

Only 17 patients were enrolled, treatment began (on average) a week after falling ill – well beyond the optimal `48 hour window’ - and only three patients survived.

 

So, while this trial found no value to doubling the dose for seasonal flu, there is insufficient evidence to judge whether doubling the dose for H5N1 (or presumably H7N9) would improve patient survival.

 

And in an accompanying editorial, Ian Barr and Aeron Hurt of the WHO Collaborating Centre for Reference and Research on Influenza, would appear to agree:

 

What is clear is that double dose oseltamivir is unlikely to significantly improve the clinical outcomes of severe cases of seasonal influenza, although there were probably insufficient data to determine if this was also true for people infected with A(H5N1).

 

It is worth noting that last month, in CDC Interim Guidance On H7N9 Antiviral Treatment, we saw the CDC’s recommendation that for hospitalized patients:

 

The optimal duration and dose of therapy are uncertain in severe or complicated influenza. Pending further data, longer courses of treatment (e.g., 10 days of treatment) should be considered for severely ill hospitalized H7N9 patients.

 

And in a discussion this morning on this study between Gregory Hartl – spokesperson for the World Health Organization and FluTrackers – Hartl had this to say.

 

 

While the success rate of treatment with oseltamivir for avian flu has been less than stellar, 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.

 

And importantly, most of these patients did not receive antivirals within the first critical 48 to 72 hours of infection.

 

Over the next few months I suspect we’ll get a much better idea of the efficacy of oseltamivir for treating avian flu, and optimal dosing in adult patients, from China’s experience with the H7N9 virus.

The Taiwan H7N9 Patient & Antiviral Resistance

Photo Credit – Wikipedia

 

 

 

# 7322

 

The good news - that Taiwan’s first and only H7N9 patient was released from the hospital earlier this week - is tempered somewhat by reports that his viral infection proved at least partially resistant to our first line antiviral drug; oseltamivir.

 

Two reports.  First this one from a week ago, before he was released.

 

H7N9 case has drug- and non-resistant strains

Sunday, May 19, 2013
The China Post/Asia News Network

TAIPEI, Taiwan - The only H7N9 patient so far in Taiwan was carrying two strains of the same virus, with one being drug resistant and the other not, making it tricky to treat to him, doctors said.

 

Huang Li-min, a doctor from National Taiwan University Hospital (NTUH), explained that it was possible the avian flu virus was not drug resistant when the patient was first infected, but mutated later to become resistant to Tamiflu.

(Continue . . . )

 

And this one today, where Taiwan media is reporting:

 

Drug-resistant H7N9 strains to change treatment: researcher

2013/05/26 17:46:26

Taipei, May 26 (CNA) The discovery that some H7N9 bird flu virus strains have developed drug resistance will affect the strategies for dealing with future cases, a researcher said Saturday.

 

Some H7N9 strains found in a Taiwanese businessmen who became the first and only confirmed case outside China in late April after returning from there, were resistant to Tamiflu, a drug used to prevent and treat flu, said Shih Shin-ru, director of Chang Gung University's Research Center for Emerging Viral Infections.

(continue . . . )

 

 

We’ll have to await the publication of this researcher’s results to learn the whole story, but for now it appears that this patient’s recovery was delayed because his infection did not respond satisfactorily to Tamiflu.

 

While it is possible this patient was infected by an already resistant strain, It is not uncommon for a small percentage of patients who are treated with antivirals to spontaneously generate resistant strains of the virus. 

 

Essentially, when the drug inhibits the replication of susceptible strains – any viable resistant mutations that arise are given an opportunity to proliferate.

 

A good example of this phenomenon is described in an October, 2010 EID Journal article called:

 

Emergence of Oseltamivir-Resistant Pandemic (H1N1) 2009 Virus within 48 Hours

Masafumi Inoue, Timothy Barkham, Yee-Sin Leo, Kwai-Peng Chan, Angela Chow, Christopher W. Wong, Raphael Tze-Chuen Lee, Sebastian Maurer-Stroh, Raymond Lin, and Cui Lin

Abstract

An oseltamivir-resistant influenza A pandemic (H1N1) 2009 virus evolved and emerged from zero to 52% of detectable virus within 48 hours of a patient’s exposure to oseltamivir. Phylogenetic analysis and data gathered by pyrosequencing and cloning directly on clinical samples suggest that the mutant emerged de novo.

 

While this can be bad news for the patient, most of these spontaneous mutations have been poorly transmissible, meaning they haven’t been able to spread widely in the community.

 

The CDC, in their H7N9 FAQ has this to say about antiviral treatment options for this emerging virus.

 

Are there medicines to treat illness associated with this virus?

CDC recommends oseltamivir (Tamiflu®) and zanamivir (Relenza®) for treatment of H7N9. Most of the H7N9 viruses that have been studied are likely susceptible (sensitive) to the two influenza antiviral drugs that are used to treat seasonal flu. Those drugs are oseltamivir (Tamiflu®) and zanamivir (Relenza®) (neuraminidase inhibitors). Like seasonal influenza viruses, avian A(H7N9) viruses are resistant to the influenza antiviral drugs known as the adamantanes.

 

It’s important to note that influenza viruses may acquire genetic changes which can make one or more influenza antiviral drugs less effective. This happens with seasonal influenza viruses and could happen with H7N9 viruses found in China. As new H7N9 virus isolates are received, CDC will conduct ongoing testing to determine the susceptibility of other H7N9 viruses to existing antiviral drugs. More information about antiviral resistance is available at Influenza Antiviral Drug Resistance: Questions & Answers.

 

 

Of course, we have seen flu strains develop antiviral resistance and - over time - manage to spread widely. 

 

By 2006 we had only seen a small number of oseltamivir (Tamiflu ®) resistant seasonal H1N1 cases, and they were almost always attributed to `spontaneous mutations’ within a patient receiving the drug. 

 

During the 2006-2007 flu season, laboratories reported no resistant strains in Europe or Japan, and they were found in fewer than 1% of samples from the United States.

 

This resistance was caused by a mutation called H275Y, where a single amino acid substitution (histidine (H) to tyrosine (Y)) occurs at the neuraminidase position 275.

 

(Note: some scientists use 'N2 numbering' (H274Y) and some use 'N1 numbering' (H275Y))

 

The following year, during the 2007-2008 flu season, oseltamivir resistant viruses suddenly took off, and by the spring of 2008 roughly 25% of European samples tested showed the H275Y mutation (see Increased Tamiflu Resistance In Seasonal Influenza).   

 

By the end of the year, resistant seasonal H1N1 has become dominant around the world.

 

And had the old seasonal H1N1 virus not been replaced by the pandemic H1N1 virus in the spring of 2009 – which was (and still is) overwhelmingly sensitive to oseltamivir – our pharmacological options for treating seasonal flu today would be greatly impaired.

 

Since 2009 we’ve seen sporadic cases of antiviral resistance show up in the new H1N1 virus, but only rarely (see NEJM: Oseltamivir Resistant H1N1 in Australia) have we seen clusters that suggest limited community spread.

 

But we know that pharmacological victories over viruses and bacteria have always been fleeting at best.

 

Pathogens – given enough time – have demonstrated a keen ability to evade each new generation of drugs we throw at them. 

 

A reminder that in our ongoing battle against infectious diseases, that nature always bats last.