The Lancet: Effectiveness Of NAI Antivirals In Reducing Mortality In Hospitalized H1N1pdm09 Cases

 

 

# 8387

 

If you want to start a row on the Internet, simply say something positive about Roche’s neuraminidase inhibitor (NAI) antiviral Tamiflu ® (oseltamivir). 

 

Between large government outlays for stockpiles of the drug, an inherent distrust of `Big Pharma’,  a lack of Randomized Controlled Trials (RCTs) to gauge the effectiveness of the drug, a Cochrane group analysis that found insufficient evidence to show whether the drug reduces influenza complications and transmission, and the apparent reluctance of Hoffmann-La Roche  to release unpublished trial data . . .

Suffice to say its an easy drug to disparage - at least - until you need it (see Dec 2013’s Spot Shortages Of Tamiflu Reported In Some Regions). 

 

With all of this negative press (which let’s face it, sells newspapers & drives web traffic), it would be easy to assume that Tamiflu is overrated, a waste of money, and not worth risking the (usually mild) side effects.

Yet despite these critics, the CDC continues to recommend its use (as do many other public health agencies around the world), and as recently as last week, the CDC released a fresh set of antiviral guidelines for clinicians:

• UPDATED: Health Professionals - Antiviral Drugs Thursday, March 13, 2014 1:12:00 PM
• UPDATED: Influenza Antiviral Medications: Summary for Clinicians Thursday, March 13, 2014 1:06:00 PM
• UPDATED: Health Professionals - Antiviral Drug Resistance Thursday, March 13, 2014 1:05:00 PM
• UPDATED: Health Professionals - Use of Antivirals Thursday, March 13, 2014 1:04:00 PM

 

Why, you might ask, would the CDC express confidence in a drug that been so disparaged online and in the media?

 

Well, despite the critics, there are studies that show that Tamiflu can significantly reduce morbidity and mortality associated with influenza.

 

Ideally what researchers want to see are a series of well mounted Randomized controlled trials (RCTs) – long considered the `gold standard’ for drug research. But these types of studies are expensive, and difficult to conduct ethically when trying to evaluate a potentially life saving drug.

 

So what we are often left with are observational studies, which critics such as the Cochrane group often discard as being unreliable. With few studies that can meet their requirements, there is – in their opinion - insufficient evidence to show whether the drug reduces influenza complications and transmission.

 

But observational studies are not without value, and often they are the only evidence available.  Over the years we’ve looked at a number of them,  including:

 

• 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.
• 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%.

 

Today The Lancet presents a new observational study (funded by F Hoffmann-La Roche), 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 among those who received the NAI antiviral within the first 48 hours of admission, the mortality risk was halved. Pregnant women who received the drug swiftly saw a 54% reduction in mortality.

While funding was received from Roche for the study, the researchers stated that `No data were requested from nor provided by pharmaceutical companies.’ .  First a link to the study (which contains much more detail), followed by a link to an accompanying commentary from Alicia M Fry of the CDC’s Influenza Division.

 

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

Jonathan S Nguyen-Van-Tam, et. al.

EXCERPTS

Findings

We included data for 29 234 patients from 78 studies of patients admitted to hospital between Jan 2, 2009, and March 14, 2011. Compared with no treatment, neuraminidase inhibitor treatment (irrespective of timing) was associated with a reduction in mortality risk (adjusted odds ratio [OR] 0·81; 95% CI 0·70—0·93; p=0·0024). Compared with later treatment, early treatment (within 2 days of symptom onset) was associated with a reduction in mortality risk (adjusted OR 0·48; 95% CI 0·41—0·56; p<0·0001).

Early treatment versus no treatment was also associated with a reduction in mortality (adjusted OR 0·50; 95% CI 0·37—0·67; p<0·0001). These associations with reduced mortality risk were less pronounced and not significant in children. There was an increase in the mortality hazard rate with each day's delay in initiation of treatment up to day 5 as compared with treatment initiated within 2 days of symptom onset (adjusted hazard ratio [HR 1·23] [95% CI 1·18—1·28]; p<0·0001 for the increasing HR with each day's delay).

Interpretation

We advocate early instigation of neuraminidase inhibitor treatment in adults admitted to hospital with suspected or proven influenza infection.

(Continue Reading Full Text)

The related commentary may be read at:

 

Effectiveness of neuraminidase inhibitors for severe influenza

Alicia M Fry a

The neuraminidase inhibitors (NAIs) were licensed for use for the treatment of uncomplicated influenza on the basis of results from phase 3 placebo-controlled, randomised clinical trials and are the only influenza-specific treatment option recommended for use. 1 However, the greatest potential clinical and public health benefits of NAI treatment are associated with more severe influenza-associated illness and outcomes, including admission to hospital and death. Thus, in the absence of placebo-cont ...

(Continue . . . )

Today’s study adds to the preponderance of evidence that oseltamivir (and other NAI antivirals) provide substantial benefits – particularly when administered early and in cases of severe influenza.  For on this topic you may wish to review these earlier blogs.

CDC Research On Benefits Of Antivirals For Uncomplicated Influenza

New Scientist: Don’t Stop Stockpiling Tamiflu

The CDC On The Value Of Antivirals

 

CHP CDW Report On Antiviral Resistant Influenza In Hong Kong

Photo Credit – Wikipedia

 

 

# 8354

 

Last January, we looked at a Eurosurveillance journal reports (see Community Cluster Of Antiviral Resistant pH1N1 in Japan) that detailed a recent (between November and December 2013) cluster of resistant pH1N1 (with the H275Y mutation) in Sapporo, Japan.  Six genetically similar viruses were detected, although none of the patients had known contact with each other, which suggests a resistant strain may be starting to spread in that region.

 

The most common cause of  Neuraminidase Inhibitor (NAI) antiviral drugs (like oseltamivir aka Tamiflu ®) is the H275Y mutation - where a single amino acid substitution (histidine (H) to tyrosine (Y)) occurs at the neuraminidase position 275 (Note: some scientists use 'N2 numbering' (H274Y)).

 

Up until 2006 we only saw a smattering of oseltamivir resistant seasonal H1N1 cases, almost always attributed to `spontaneous mutations’  within a patient already receiving the drug.  While of concern to the patient being treated, it appeared to be poorly transmissible, and less than 1% of cases exhibited resistance.

 

But in 2008 the profile of antiviral resistant seasonal flu changed, and by the spring roughly 25% of European samples tested showed the H275Y mutation (see Increased Tamiflu Resistance In Seasonal Influenza).

 

By the end of 2008, nearly all of the samples tested in the United States were resistant to oseltamivir and the CDC was forced to issue major new guidance for the use of antivirals (see CIDRAP article With H1N1 resistance, CDC changes advice on flu drugs).

 

One benefit of the arrival of the H1N1 pandemic strain the following spring was that it effectively removed this resistant strain from circulation.  Despite some scattered clusters of resistance reported in Asia and Australia (see NEJM: Oseltamivir Resistant H1N1 in Australia), nearly 99% of the  pH1N1 viruses tested around the globe have remained sensitive to NA inhibiting drugs. 

 

The latest FluView report (week 8) indicated that of 3733 viruses tested this flu season in the United States, only 28 (0.8%) showed signs of NA Inhibitor resistance.

 

Today, Hong Kong’s CHP has a report in their Communicable Diseases Watch  (CDW) that indicates a slightly higher (but still < 2%) incidence rate of Oseltamivir resistance detected over the past several years, but reassuring finds that the overwhelming majority of viruses tested still remain sensitive to the drug, and reports no signs of community transmission.

 

Human Infections with Oseltamivir-resistant Influenza A(H1N1)pdm09 Virus in Hong Kong

Reported by Dr Henry YH Mou, Medical and Health Officer, Respiratory Disease Office, Surveillance and
Epidemiology Branch, CHP.

(EXCERPT)

From May 2009 to February 2014, more than 2,700 influenza A(H1N1)pdm09 viruses were tested for oseltamivir resistance in Hong Kong. Among them, a total of 46 reports (<2% of tested samples) of oseltamivir-resistant influenza A(H1N1)pdm09 virus were detected. The cases affected 26 males and 20 females with a male to female ratio of 1.3:1. Their ages ranged from 5 months to 85 years (median: 16 years). Most of them (87%) were known to acquire the infection locally. No epidemiological linkage was identified among the cases. The annual number of cases detected ranged from 1 to 17 during the period between 2009 and 2013. The monthly number of cases ranged from 0 to 6.

Fifteen cases (33%) had known exposure to a full course of oseltamivir before the collection of specimens. Among the 44 cases with information available, 26 cases (59%) enjoyed good past health. The remaining 18 cases had one or more underlying medical conditions such as hypertension, diabetes, chronic lung diseases, malignant conditions, etc. There was one fatal case affecting a 52 years old female who had multiple chronic medical conditions including hypertension, diabetes and depression. It was also noted that five cases were known to have conditions that resulted in immunosuppressed or immunocompromised state. Viral replication may persist in such patients for prolonged periods of time despite antiviral treatment and this can create a favourable environment for selection of drug-resistant strain.

Molecular tests showed the presence of nucleotide mutation resulting in H275Y amino acid substitution in the neuraminidase protein (N1) of all the oseltamivir-resistant viruses isolated. All were found to be sensitive to another neuraminidase inhibitor zanamivir.

So far, the vast majority of influenza A(H1N1)pdm09 viruses tested in Hong Kong remained sensitive to oseltamivir. Cases of oseltamivir-resistant viruses were sporadic and infrequently found and there is no evidence of onward transmission of oseltamivir-resistant influenza A(H1N1)pdm09 viruses in Hong Kong. Zanamivir remains a treatment option in patients with severe or deteriorating illness caused by oseltamivir-resistant virus. The CHP will continue to monitor the global and local situation of oseltamivir-resistant influenza viruses and remain vigilant for any further changes in influenza viruses that may have public health significance.

(Continue . . .)

While surveillance for antiviral resistance continues to be reassuring, scientists remember the remarkable speed by which seasonal influenza went from being almost 100% sensitive to being nearly 100% resistant.

 

So, as the report says, continued vigilance is required. 

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 Lancet: Antiviral Resistance In Two H7N9 Patients

 

# 7328

 

On Sunday, in The Taiwan H7N9 Patient & Antiviral Resistance, we looked at Taiwan’s only H7N9 patient, who spend more than a month in the hospital, and who developed resistance to oseltamivir while undergoing treatment.

 

Today, the Lancet carries a report of two more cases (out of 14 studied) – this time in Shanghai – who developed resistance to our first line antivirals during their course of treatment for the H7N9 virus.

 

The authors found that a mutation R292K (Arginine to Lysine at position 292 in the NA) – also known as Arg292Lys – already known to confer antiviral resistance to seasonal flu (see Resistant influenza A viruses in children treated with oseltamivir: descriptive study), appeared in two patients after several days of oseltamivir therapy.

 

The article, which is available as a PDF file, is called:

 

Association between adverse clinical outcome in human disease caused by novel influenza A H7N9 virus and sustained viral shedding and emergence of antiviral resistance

Yunwen Hu, Shuihua Lu, Zhigang Song, Wei Wang, Pei Hao, Jianhua Li, Xiaonan Zhang, Hui-Ling Yen, Bisheng Shi, Tao Li, Wencai Guan, Lei Xu, Yi Liu, Sen Wang, Xiaoling Zhang, Di Tian, Zhaoqin Zhu, Jing He, Kai Huang, Huijie Chen, Lulu Zheng, Xuan Li, Jie Ping, Bin Kang, Xiuhong Xi, Lijun Zha,Yixue Li, Zhiyong Zhang, Malik Peiris, Zhenghong Yuan

Interpretation: Reduction of viral load following antiviral treatment correlated with improved outcome. Emergence of  NA Arg292Lys mutation in two patients who also received corticosteroid treatment led to treatment failure and a poor  clinical outcome.

 

The emergence of antiviral resistance in A/H7N9 viruses, especially in patients receiving corticosteroid therapy, is concerning, needs to be closely monitored, and considered in pandemic preparedness planning.

 

 

While most of the H7N9 patients we’ve had information about appear to have benefited from oseltamivir treatment, we have seen a worrying number of failures.

 

Helen Branswell has more on this in her article:

 

Study warns drug resistance develops easily with new H7N9 bird flu

By: Helen Branswell, The Canadian Press

Tuesday, May. 28, 2013 at 8:01 AM |

TORONTO - A new study warns that resistance to the main flu drug Tamiflu seems to develop easily in infections with the new H7N9 bird flu.

 

The authors say early treatment with Tamiflu or other drugs in that class is still the best approach for treating these cases when they arise.

(Continue . . . )

 

 

 

Of note, both patients received relatively low-dose corticosteroid treatment (40mg/day) during part of their hospitalization, and researchers question whether this might have contributed to their development of resistance.

 

Higher dose steroid treatment (250-500+ mg/day) has been tried for both H5N1 and SARS in the past. While patients often showed showed short-term improvement, long-term survival rates were less than encouraging. 

 

The good news here is we are getting patient treatment and outcome data on these H7N9 infections from China with remarkable speed, and in far greater detail, than we ever did for H5N1 or SARS.

 

Which means that if this virus does manage to spread beyond the Chinese mainland, doctors around the world will have a much better idea of what they will be dealing with.

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.

Research: Antiviral Resistance In 2009 H1N1 Influenza A Strain

 

 

# 7014

 

 

Readers with good memories will recall that in December of 2011, in NEJM: Oseltamivir Resistant H1N1 in Australia, we looked at a cluster of oseltamivir (Tamiflu ®) resistant H1N1 viruses in and around the Newcastle area of New South Wales.

 

The lead author of that NEJM correspondence was Aeron C. Hurt, Ph.D. from the World Health Organization (WHO) Collaborating Centre for Reference and Research on Influenza, North Melbourne, VIC, Australia.  

 

What Hurt and his colleagues found was evidence for the sustained community transmission of a resistant strain of the H1N1pdm09 virus.

 

After analyzing viral samples pulled from 182 patients seen in emergency departments, intensive care units, and doctor’s offices in New South Wales between May and August of 2011, they found 29 (16%) carried the H275Y resistance mutation.

 

H275Y is 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)).

Most of the patients lived within 50km of Newcastle, and while 10 of the cases could be epidemiologically linked (2 in 4 households, 2 in a shared car trip), the rest could not.

 

Only one had been treated with oseltamivir prior to testing.

 

 

While globally the percentage of Tamiflu resistant H1N1 viruses remains low (about 2%), it does appear to be increasing.

 

Today, Dr. Hurt will present his research at ASID (Annual Scientific Meeting of the Australasian Society for Infectious Diseases) in Canberra, where he will warn of the dangers of growing resistance (see MedPage Today article Tamiflu Resistance May Be Rising).

Should the incidence of resistant H1N1 increase, it would not be without precedent.

 

Not too many years ago Amantadine (an M2 ion channel blocker) was the preferred influenza antiviral.  It was cheap, plentiful, and effective. But by the mid 2000s Amantadine began to lose its ability to combat the H3N2 seasonal flu virus along with some strains of the H5N1 bird flu.

 

It has been suggested that the prophylactic use of Amantadine by Chinese poultry farmers (who supposedly included it in their chicken feed for several years) may have contributed to this sudden resistance.

 

But whatever the cause, by January of 2006 the CDC had issued a warning to doctors not to rely on Amantadine (or Rimantadine) to treat influenza.

 

Oseltamivir (Tamiflu) – a newer neuraminidase (NA) inhibitor drug  introduced in 1999 - while far more expensive, became the new treatment standard. But by 2008 seasonal H1N1 began to show growing resistance to Oseltamivir as well (although H3N2 remained sensitive).

 

By the spring of 2009, - in the space of just about a  year – seasonal H1N1 had gone from almost 100% sensitive to the drug to nearly 100% resistant.

The arrival of the novel 2009 H1N1 pandemic virus was a game changer, in that it – unlike seasonal H1N1 – was still sensitive to oseltamivir. Since then, we’ve been watching to see if – like its predecessor – learns to evade oseltamivir as well.

 

So far, the news is good; resistance in the (formerly pandemic) 2009 H1N1 strain remains rare. 

 

But pharmacological victories over constantly evolving viruses (and bacteria) tend to be fleeting, and so the need for new classes of antivirals and antibiotics is great.

Study: The Benefits Of Antiviral Therapy During the 2009 Pandemic

 

Photo Credit – Wikipedia

 

# 6758

 

While the British press continues to excoriate Roche Pharmaceuticals for their refusal to release all of the testing data on their antiviral drug Tamiflu © – and through innuendo, suggest that the drug is ineffective, or worse, even dangerous – we continue to get third party confirmation that oseltamivir does, in fact, have beneficial effects for severe influenza.

 

A quote from an article yesterday in the Daily Mail reads:

 

“And yet for all we know, Tamiflu might be no better than paracetamol: because Roche, the company making it, still withholds vital information on the risks and benefits from researchers, doctors and patients.”

 

Compelling rhetoric, I suppose. And not wrong in its stated goal, which is the full release of all drug testing data.

 

But then again, not precisely true. 

 

We’ve seen many observational studies conducted over the past few years that show pretty clear evidence that the use of oseltamivir in severe influenza reduces morbidity and mortality.

 

The evidence for its benefits for mild, seasonal flu in healthy patients  . . . well, not so much.

 

Although falling short of the `gold standard’ Randomized Controlled Trials (RCTs) preferred by most scientists, we’ve seen a number of observational studies that suggest significant benefits from the drug.

 

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.

 

And in Study: Antiviral Therapy For H5N1, we saw the largest study to date on the outcomes of H5N1 patients. 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.

 

On the safety side of the equation, while all drugs can have adverse effects (AEs), a recent study (see Study: Adverse Events Associated With Oseltamivir Outpatient Treatment) found `no evidence was identified for an increased risk of neuropsychiatric or other AEs following oseltamivir treatment.’

 

We’ve another study published last week in the Journal of Infectious Diseases that conducted a meta-analysis of 90 observational studies during the 2009 H1N1 flu pandemic. Included were nearly 35,000 patients, 85% of whom has laboratory confirmed H1N1.

 

Impact of neuraminidase inhibitor treatment on outcomes of public health importance during the 2009-10 influenza A(H1N1) pandemic: a systematic review and meta-analysis in hospitalized patients

Stella G. Muthuri*, Puja R. Myles*,Sudhir Venkatesan, Jo Leonardi-Bee and Jonathan S. Nguyen-Van-Tam1

Abstract

Background. The impact of neuraminidase inhibitors (NAI) treatment on clinical outcomes of public health importance during the 2009-10 pandemic has not been firmly established.

<SNIP>

Results. Regarding mortality we observed a non-significant reduction associated with NAI treatment (at any time) vs none (OR, 0.72 [95% CI, 0.51 - 1.01]). However we observed significant reductions for early treatment (≤48h after symptom onset) vs late (OR, 0.38 [95% CI, 0.27 - 0.53]); and for early treatment vs none (OR, 0.35 [95% CI, 0.18 - 0.71]). NAI treatment (at any time) vs none was associated with an elevated risk of severe outcome (OR, 1.76 [95% CI, 1.22 - 2.54]); but early treatment vs. late reduced the likelihood (OR, 0.41 [95% CI, 0.30 - 0.56]).

Conclusions. During the 2009-10 influenza A(H1N1) pandemic, early initiation of NAI treatment reduced the likelihood of severe outcomes compared with late or no treatment.

 

The full text of the article is available online.

 

For those adverse to navigating the 23-page study, a summary can be found in an accompanying commentary by Fred Y. Aoki, MD, and Frederick G. Hayden, MD.  Although based on observational, often retrospective, studies - Aoki and Hayden praised the large number of studies and patients, and the `methodologic rigor’ of their analysis.

The bottom line?

 

. . . 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%.

 

They did find that patients who received oseltamivir were more likely to develop pneumonia, but this is a bit of a red herring, as the most seriously ill patients are more apt to receive antiviral therapy.

 

No, oseltamivir isn’t a panacea against influenza.  It isn’t perfect by any means.

 

But once again we get pretty good data to suggest that it does have significant therapeutic value.  Particularly when administered within the first 48 hours of illness.

 

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

Several weeks later in The CDC Responds To The Cochrane Group’s Tamiflu Study we saw that agency’s reaffirmation of their support for the drug.

 

Hopefully, in time we’ll see better antivirals developed.

 

Whether we approve of the data release policy of the parent company or not, oseltamivir remains one of the few pharmacological options we have available to treat severe influenza. 

Study: Adverse Events Associated With Oseltamivir Outpatient Treatment

 

Photo Credit – Wikipedia

 

# 6709

 

 

Oseltamivir (aka Tamiflu ©) is an oral antiviral that was heavily stockpiled by many nations between 2005 and 2088 in anticipation of a  feared `bird flu’ pandemic. 

 

While that particular pathogen remains in the wings (sorry . . . I couldn’t help myself), a pandemic of porcine origin did emerged in 2009 (H1N1), and so these antivirals saw heavy use, particularly in Japan, Great Britain, and in the United States.

 

That said . . . the  stockpiling, and use, of Tamiflu has not been without some controversy.

 

Critics have pointed out a lack of Randomized Controlled Trials (RCTs) to gauge the effectiveness of the drug, and the BMJ has been working along with the Cochrane group to get the manufacturer, Hoffmann-La Roche, to release unpublished trial data.

 

Although falling short of the `gold standard’ RCTs preferred by the Cochrane group for inclusion in their analyses, we’ve seen a number of observational studies that suggest significant benefits from the drug.

 

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.

 

And lastly, in Study: Antiviral Therapy For H5N1, we saw the largest study to date on the 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.

 

Efficacy arguments aside, there have also been concerns raised over possible side effects from the drug.

 

It is axiomatic that all drugs have side effects. In fact, in trials with placebos, test subjects have reported adverse reactions (nocebo effect) even though they were taking pills with no active ingredient.

 

Even the most widely used over-the-counter medications can – and sometimes do – cause serious adverse effects.

 

So the mere existence of adverse effects aren’t enough to counsel against a drug’s use. The risks of adverse effects must be weighed against the benefits the drug may provide.

 

Often these AEs are mild, and transitory, and of little concern.

 

 

But in 2006 we began to see reports out of Japan suggesting that a small number of adolescents taking Tamiflu had experienced serious neuropsychiatric symptoms, including delirium, hallucinations, and convulsions.

 

Whether these symptoms were produced by the drug, or by their viral infection, wasn’t known (see Study: Pediatric Neurological Complications With H1N1). But in November of 2006, the FDA posted this safety warning:

 

Tamiflu (oseltamivir phosphate)

Audience: Pediatric and primary care healthcare professionals and patients

[Posted 11/13/2006] Roche and FDA notified healthcare professionals of revisions to the PRECAUTIONS/Neuropsychiatric Events and Patient Information sections of the prescribing information for Tamiflu, indicated for the treatment of uncomplicated acute illness due to influenza infection in patients 1 year and older who have been symptomatic for no more than 2 days and for the prophylaxis of influenza in patients 1 year and older.

There have been postmarketing reports (mostly from Japan) of self-injury and delirium with the use of Tamiflu in patients with influenza. People with the flu, particularly children, may be at an increased risk of self-injury and confusion shortly after taking Tamiflu and should be closely monitored for signs of unusual behavior. A healthcare professional should be contacted immediately if the patient taking Tamiflu shows any signs of unusual behavior.

 

During the 2009 pandemic millions of doses of Tamiflu were prescribed, often to children. While we heard reports of some adverse effects (primarily vomiting & nausea), serious reactions were rare. 

 

In 2010 we saw a review in the journal Eurosurveillance: Adverse Effects of Oseltamivir in Children, that 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.

 

Today we’ve a new, much larger study, that appears in the journal Pharmacoepidemiology and Drug Safety. It examines the risk of AEs (primarily psychiatric in nature) among more than 27,000 matched pairs (by sex, age, week of illness, and location - where half took the drug & half did not).

 

Encouragingly, they research concludes that `no evidence was identified for an increased risk of neuropsychiatric or other AEs following oseltamivir treatment.’

Original Report

Risk of adverse events following oseltamivir treatment in influenza outpatients, Vaccine Safety Datalink Project, 2007–2010†

Sharon K. Greene^,, Lingling Li, David K. Shay, Alicia M. Fry, Grace M. Lee, Steven J. Jacobsen, Roger Baxter, Stephanie A. Irving, Michael L. Jackson, Allison L. Naleway, James D. Nordin, Komal J. Narwaney, Tracy A. Lieu

Article first published online: 5 NOV 2012

 

While comforting, this study doesn’t mean that oseltamivir is completely without side effects. Only that their research didn’t turn up an statistically significant increases in the AEs they were tracking among those taking the drug.

 

There are other concerns when it comes to use of oseltamivir, including the possibility that overuse will help generate resistant strains of the influenza virus.

 

But for now, oseltamivir remains one of the few pharmacological options we have available to treat severe influenza.

The CDC Responds To The Cochrane Group’s Tamiflu Study

 

Photo Credit – Wikipedia

 

# 6127

 

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

 

Robert Roos of CIDRAP provided a good summation of that Cochrane group analysis in:

 

Review renews questions about oseltamivir benefits

Robert Roos News Editor

Jan 19, 2012 (CIDRAP News) – A lengthy new analysis of unpublished clinical trial data is renewing questions about the effectiveness of the influenza drug oseltamivir (Tamiflu), saying that although the drug shortens flu symptoms by about a day, there is no evidence that it reduces hospital admissions.

(Continue . . .)

 

 

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, and effectively ignored any observational studies.  

 

As few studies met their criteria, they were unable to determine one way or the other, the overall effectiveness of the drug.

 

Despite the fact that their analysis was inconclusive, some aspects of the media immediately latched onto this as `proof’ that Tamiflu was ineffective. 

 

No doubt spurred by this media buzz, yesterday the CDC on their Have You Heard? website 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.

 

The Cochrane review assessed unpublished and published data from randomized controlled trials (RCTs) of oral oseltamivir or inhaled zanamivir versus placebo for early treatment (within 48 hours after illness onset) or chemoprophylaxis of uncomplicated seasonal influenza in otherwise healthy adults and children. The review concluded that in adults and children with influenza-like illness, early oseltamivir treatment shortens the duration of symptoms by approximately 21 hours compared to placebo. This finding is similar to results in published RCTs which reported a reduction of approximately one day of laboratory-confirmed influenza illness by early oseltamivir treatment. One RCT in children aged 1 to 3 years with influenza found a reduction of 3.5 days when oseltamivir treatment was started within 24 hours after illness onset. The Cochrane review was unable to reach conclusions about the efficacy of oral oseltamivir or inhaled zanamivir treatment to reduce health complications, including those which might result in hospitalization. The review authors reported that they did not have full access to all unpublished data for oseltamivir RCTs as requested from the manufacturer.

 

A systematic review of RCTs should include unpublished and published data, and researchers should have full access to these data. However, such a review may not fully inform the question of whether antiviral treatment reduces severe influenza complications such as those resulting in hospitalization in generally healthy persons because enormous numbers of participants are needed. The burden of influenza disease is greatest among the elderly, persons with underlying medical conditions such as chronic obstructive pulmonary disease, asthma, congestive heart failure, diabetes, pregnant women, and young children. These groups are at highest risk for developing severe complications from influenza resulting in hospitalization or death, and generally have not been studied in RCTs.

 

The Cochrane review did not consider any data from uncontrolled observational studies of oseltamivir treatment. While such studies have inherent design limitations, they can inform clinical practice and public health, especially when data from RCTs are unavailable or have not been conducted among high-risk groups or hospitalized influenza patients, or because having a placebo group would be unethical since antiviral treatment is recommended for these groups. Indeed, many observational studies of antiviral treatment of seasonal influenza or influenza A (H1N1) pdm09 (2009 pandemic H1N1) have been conducted among hospitalized patients, including critically ill children and adults. These observational studies from many countries have consistently found that early oseltamivir treatment of influenza patients reduces the duration of hospitalization and risk of severe outcomes such as intensive care unit admission or death. These studies have reported that clinical benefit is greatest when oseltamivir treatment is started within 48 hours of illness onset; however clinical benefit has still been observed when oseltamivir treatment is started up to less than 5 days after illness onset.

(Continue . . .)

 

 

While falling short of the `gold standard’ employed by the Cochrane group for inclusion into their analysis, we’ve a number of compelling observational studies to look at, including:

 

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.

 

And lastly, in Study: Antiviral Therapy For H5N1, we saw the largest study to date on the 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.

 

 

There are other concerns when it comes to use of oseltamivir, of course. Including the possibility inducing side effects and the possibility of generating resistant strains of the influenza virus.

 

But for now, it remains one of the few pharmacological options we have available to treat severe influenza.

Indonesia: MOH Suspects H5N1 May Be Gaining Antiviral Resistance

 

 

 

# 6086

 

 

In Indonesia the antiviral Tamiflu ® (Oseltamivir) has been distributed fairly liberally over the past 6 years whenever there has been a suspected case of H5N1.

 

Households, whole neighborhoods - sometimes entire villages - have been placed on prophylactic antivirals in what is  commonly called a `Tamiflu Blanket’. The idea is to stop or prevent household or community transmission of the virus.

 

And the fact that we’ve seen only a few clusters of the H5N1 virus over the years is suggestive that this policy may have been at least partially successful.

 

But the fear when you use antivirals is that over time, the targeted virus will develop resistance.

 

That happened in 2008 with the old seasonal H1N1 virus (which was supplanted by pandemic H1N1 in 2009), and in recent months we’ve seen small indications that it may be occurring in some strains of the new H1N1 virus (see NEJM: Oseltamivir Resistant H1N1 in Australia).

 

So far, most of the H5N1 cases we’ve seen have appeared to be sensitive to oseltamivir, although a few resistant cases have been documented in Indonesia and Egypt.

 

See CIDRAP’s  2007 article Tamiflu-resistant H5N1 strain surfaces in Egypt and 2005 article Tamiflu resistance in avian flu victims sparks concern.

 

 

One of the striking features about Indonesia’s H5N1 cases is the  high CFR (Case fatality rate) of 82% – even with antiviral treatment – which is more than double that seen in Egypt (35%).

 

Today, Indonesia’s Health Minister Endang Rahayu Sedyaningsi is quoted in the media as worrying that oseltamivir may be losing effectiveness against the Indonesian strains of bird flu.

 

A hat tip to Diane Morin on FluTrackers for finding the following article which appears in Media Indonesia. The original link to the Indonesia (Bahasa) language version is HERE.

 

The following is a machine translation.

 

Indonesia Health Minister Suspected Bird Flu Immune Drug

Authors: Cornelius Eko Susanto

Friday, January 20, 2012 22:47 pm

JAKARTA - MICOM: Health Minister Endang Rahayu Sedyaningsih suspect in Indonesia has occurred the possibility of resistance (drug resistance) to the drug oseltamivir.

 

The hypothesis was made ​​based on the presence of some positive victims of bird flu in Indonesia are still died despite oseltamivir have been given early on.

 

"I suspect resistance to oseltamivir has been happening in Indonesia. That is why the death rate of bird flu patients here reaches more than 80% when oseltamivir was given, "said Minister of Health at a press conference after the ministerial coordination meeting to discuss bird flu on Friday (20 / 1), in Jakarta.

 

Himself said, there may exist specific genes in the H5N1 virus in Indonesia that caused the H5N1 virus in Indonesia is more virulent than the H5N1 viruses that exist in other countries.

 

"Honestly, I was curious as a former researcher with the possibility of the existence of this gene," he said.

 

If there is resistance to oseltamivir, Indonesia no longer has a drug to counteract the spread of the H5N1 virus. Because, oseltamivir is the only drug that can kill the flu virus, although with certain prerequisites and conditions.

 

In the market, oseltamivir sold under the brand Tamiflu. (Tlc/OL-5)

 

Based on this article, this theory appears predicated on anecdotal observations; mostly the high CFR. What is needed now is genetic sequencing of these isolates to look for known resistance markers.

 

One of the big concerns over Indonesia’s prolonged refusal to share samples of the H5N1 virus was that the virus would mutate or change without the world being aware what was happening.

With new virus sharing agreements put into place last year, hopefully the world will get a good look at the viral evolution in Indonesia and be able to document if any serious changes have occurred.

 

Stay tuned.

 

The Tamiflu Controversy Continues

 

 

Photo Credit – Wikipedia  

# 6085

 

 

The debate over the effectiveness of oseltamivir (Tamiflu ®) is back in the news once more with the release of a new Cochrane group analysis that finds insufficient evidence to prove that the drug reduces flu complications and transmission.

 

If it seems we’ve been here before, you are right (see Effect Measure’s The Tamiflu doesn't work non-story from 2009).

 

Many researchers point out anecdotal and observational data showing that early administration of oseltamivir does reduce complications from influenza, and can be lifesaving.

 

As an example, 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.

 

And lastly, in Study: Antiviral Therapy For H5N1, we saw the largest study to date on the 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.

 

 

Alas, these are observational studies, which are not considered the `best evidence’ by most scientists.

 

Ideally what researchers want are a series of well mounted Randomized controlled trials (RCTs) – long considered the `gold standard’ for drug research. But these are expensive, and difficult to conduct ethically when trying to evaluate a potentially life saving drug.

 

So we are left with is a choice that reminds one of the one offered by Chico Marx in the 1933 classic Duck Soup (“Who you gonna believe, me or your own eyes?”).

 

Choosing between observational data that suggests a clinical benefit verses a lack of well mounted studies that actually prove a benefit.

 

Complicating matters, there are ongoing charges that Roche Laboratories has not been forthcoming with all of the data that has been requested by the Cochrane group.

 

Admittedly, there are other concerns when it comes to use of oseltamivir, including the possibility of incurring side effects and the (potential, at least) of generating resistant strains of the influenza virus.

 

Robert Roos of CIDRAP News takes us on a detailed journey down this rabbit hole, with as good a summary of the issues as you are apt to find anywhere.

 

Review renews questions about oseltamivir benefits

Robert Roos News Editor

Jan 19, 2012 (CIDRAP News) – A lengthy new analysis of unpublished clinical trial data is renewing questions about the effectiveness of the influenza drug oseltamivir (Tamiflu), saying that although the drug shortens flu symptoms by about a day, there is no evidence that it reduces hospital admissions.

(Continue . . .)

 

Despite a lot of unanswered questions, for now at least, oseltamivir remains one of the few pharmacological options likely to be available during a pandemic.