ECDC Influenza Season Risk Assessment

Credit ECDC – Week 3

 

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While North America’s flu season is already well underway (and in some regions has already peaked), seasonal flu is getting a later - but no less strenuous start - in Europe this year.  And as we’ve seen here in the United States, the predominant flu strain in Europe this season is a `drifted’ H3N2 virus, one which has reduced the effectiveness of this year’s vaccine.

This morning ECDC released an updated Rapid Risk Assessment and summary on this year’s flu season, and  Director Dr. Marc Sprenger  tweeted:

 

First a press release summary, with links to the Rapid Risk Assessment, and then I’ll be back with a few words on the CDC & ECDC’s strong recommendations for the use of antiviral medications.

 

More severe influenza season to be expected in Europe

28 Jan 2015

Medium or high rates of influenza intensity are likely to be observed in the vast majority of EU and EEA countries, concludes ECDC annual risk assessment on influenza for the remainder of the season. The number of severe cases of influenza as well as fatal outcomes especially among older people and other risk groups can be expected to rise.

Strenuous start of this influenza season

• Influenza activity in Europe started in week 50/2014 without a particular geographic progression, affecting the Netherlands, Sweden and England first, and then followed by Iceland, Malta and Portugal.
• Children between 0 and four years of age have been the most affected age group according to primary healthcare data in almost all reporting countries, similarly as in other seasons.
• Influenza-like illness and acute respiratory infections have been increasing in adults and older people in almost all countries.
• Most of the first affected countries report greater pressure on primary healthcare services during this season compared to the peak activity in previous season.
• Among the countries reporting hospitalised influenza cases, 34 fatal outcomes were reported, two thirds of these in the elderly.

Drifted A(H3N2) viruses dominant

• Subtype A(H3N2) viruses, known to cause more severe disease, are dominant in almost all reporting European countries.
• Majority of A(H3N2) viruses analysed are antigenically distinct from the A(H3N2) virus included in the vaccine for this season.
• Reduced vaccine effectiveness is expected as a result of this mismatch between the vaccine and the circulating influenza strains.

ECDC Director, Dr Marc Sprenger, said:
“We face an influenza season that could be more severe and exert bigger pressure on health care systems than in the last few years. As each year, ECDC undertakes a risk assessment early in the season, combining a multitude of data sources and aiming to inform and strengthen EU and EEA countries in their response to the influenza epidemics.”

How to protect oneself and others from the flu

• Self-isolation when sick, hand-washing and good respiratory hygiene as well as cough etiquette remain simple yet effective measures to protect from catching or passing on influenza.
• A lower overall vaccine effectiveness due to the circulation of drifted A(H3N2) viruses is expected, however, the vaccine may still reduce complications and severe outcomes associated with this subtype of influenza viruses.
• Influenza vaccine offers good protection against the circulating A(H1N1)pdm09 viruses.

Antivirals particularly important this season

• Treatment and post-exposure prophylaxis with antivirals protects the elderly and people in other risk groups against severe influenza illness.
• The circulating viruses are susceptible to antiviral drugs oseltamivir and zanamivir.

Dr Marc Sprenger emphasizes:

“In a season dominated by a drifted A(H3N2) strain of influenza viruses, more severe illness can be expected especially among older people and those in medical risk groups. It is therefore paramount that physicians across Europe consider treatment and post-exposure prophylaxis with antivirals especially for these patients.”

The annual ECDC risk assessment of seasonal influenza aims to provide an early description of seasonal influenza in the first affected countries and to inform public health decisions to be taken to reduce the burden of seasonal influenza in 2015 in Europe.

Read full risk assessment of seasonal influenza in the EU/EEA countries, 2014-2015

More information:

Flu News Europe: weekly influenza updates
Seasonal influenza on ECDC website
Influenza maps and graphs
Follow us on Twitter: @ECDC_Flu

 

 

In Europe, even more so than in the US, antiviral drugs have been excoriated in the press; often referred to as an expensive scam on the part of the government, purportedly in cahoots with `Big Pharma’.  In the past we’ve seen Tamiflu’s ®  value questioned by Cochrane meta-studies, some prestigious medical journals, conspiracy theorists, pundits, but most often, the tabloid press.

 

Admittedly, it hasn’t helped that for many years Tamiflu’s maker -  Roche Pharmaceuticals - has refused to release all of the testing data on their best selling antiviral drug, and we’ve seen some scare articles in the popular press suggesting adverse side effects to the drug.

 

With all of this baggage, you may be wondering why the ECDC, CDC , the UK’s PHE, and many other public health agencies continue to recommend the use of influenza antivirals for influenza. 

 

Last April, 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.

 

A few days later, the CDC 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.

(Continue . . .)

 

Recommendations that were echoed a few months ago by Public Health England (see UK PHE: Revisiting Influenza Antiviral Recommendations), and that are supported by many studies I’ve written about previously, including:

 

Study: Antivirals Saved Lives Of Pregnant Women

BMJ: Efficacy of Oseltamivir In Mild H1N1

Study: The Benefits Of Antiviral Therapy During the 2009 Pandemic

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

CID Journal: Under Utilization Of Antivirals For At Risk Flu Patients

 

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

 

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

 

While not a cure, the preponderance of evidence shows that taking antivirals early can limit the severity and duration of symptoms – and for those patients  – that could help keep them out of the hospital, and even prove life saving.

CDC HAN Advisory On `Drifted’ H3N2 Seasonal Flu Virus

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Late yesterday the CDC issued a HAN Advisory for clinicians on the possibility of seeing `drifted’ H3N2 virus infections during this year’s flu season, along with a reminder on the appropriate and timely use of antivirals. 

 

If this sounds familiar, we looked at this possibility at some length a little over a month ago in A `Drift’ In A Sea Of Influenza Viruses.

 

But briefly, over the summer – and since this year’s flu vaccine components were selected last February – a new, antigenically drifted H3N2 virus has begun to circulate more widely.

 

The rise of this new strain has already prompted  WHO to recommend a strain change for next year’s Southern Hemisphere vaccine formulation from the current A/Texas/50/2012 (H3N2)-like virus to a new A/Switzerland/9715293/2013 (H3N2)-like virus.

 

The most recent FluView report (week 47) shows that of the 85 H3N2 viruses tested since October 1st, 41 (48%) are a good match to the vaccine strain, while 52% were not.  This `mismatch’ is expected to reduce the vaccine’s effectiveness against this drifted strain, although some protection or a reduction in the severity of illness may still result.

 

With this year shaping up to be an H3N2-dominant year, and a possible vaccine `mismatch’ in the works, the CDC is reminding clinicians of value of prescribing neuraminidase inhibitor antiviral medications for severe influenza, or for patients with co-morbidities that raise their risk of seeing serious complications.

 

Despite the constant excoriation of Tamiflu ® and other NI antiviral medications in the press – based primarily on a series of Cochrane reports (see Revisiting Tamiflu Efficacy (Again)) – there are demonstrable benefits to using these medications, particularly when given early and for severe influenza (see The CDC Responds To The Cochrane Tamiflu Study).

Earlier this summer we saw a review in the journal Clinical Infectious Disease that suggested a serious Under Utilization Of Antivirals For At Risk Flu Patients, and a month ago we saw the UK’s PHE reiterate their Influenza Antiviral Recommendations.

 

Although you can never be sure what kind of flu season we will have until it is over, years in which H3N2 viruses have dominated tend to be rougher for the elderly, and the very young,  than years when H1N1 or influenza B dominate. 

 

Despite the expected reduced effectiveness of this year’s flu shot, there are still benefits to getting the vaccine if you haven’t done so already. 

• There are two other strains (H1N1 & Influenza B) covered by the shot,
• Half the H3N2 viruses tested so far are still a `match’  to the vaccine strain
• There may still be some degree of cross-protection afforded against this new strain.

I’ve only posted the summary, so follow the link below to read the full HAN advisory, and the recommendations of antiviral use.

 

CDC Health Advisory Regarding the Potential for Circulation of Drifted Influenza A (H3N2) Viruses

 

CDC HEALTH ADVISORY

Distributed via the CDC Health Alert Network
December 3, 2014, 16:00 ET (4:00PM ET)
CDCHAN-00374

CDC is reminding clinicians of the benefits of influenza antiviral medications and urging continued influenza vaccination of unvaccinated patients this influenza season.

Summary

Influenza activity is currently low in the United States as a whole, but is increasing in some parts of the country. This season, influenza A (H3N2) viruses have been reported most frequently and have been detected in almost all states.

During past seasons when influenza A (H3N2) viruses have predominated, higher overall and age-specific hospitalization rates and more mortality have been observed, especially among older people, very young children, and persons with certain chronic medical conditions compared with seasons during which influenza A (H1N1) or influenza B viruses have predominated.

Influenza viral characterization data indicates that 48% of the influenza A (H3N2) viruses collected and analyzed in the United States from October 1 through November 22, 2014 were antigenically "like" the 2014-2015 influenza A (H3N2) vaccine component, but that 52% were antigenically different (drifted) from the H3N2 vaccine virus. In past seasons during which predominant circulating influenza viruses have been antigenically drifted, decreased vaccine effectiveness has been observed. However, vaccination has been found to provide some protection against drifted viruses. Though reduced, this cross-protection might reduce the likelihood of severe outcomes such as hospitalization and death. In addition, vaccination will offer protection against circulating influenza strains that have not undergone significant antigenic drift from the vaccine viruses (such as influenza A (H1N1) and B viruses).

Because of the detection of these drifted influenza A (H3N2) viruses, this CDC Health Advisory is being issued to re-emphasize the importance of the use of neuraminidase inhibitor antiviral medications when indicated for treatment and prevention of influenza, as an adjunct to vaccination.

The two prescription antiviral medications recommended for treatment or prevention of influenza are oseltamivir (Tamiflu®) and zanamivir (Relenza®). Evidence from past influenza seasons and the 2009 H1N1 pandemic has shown that treatment with neuraminidase inhibitors has clinical and public health benefit in reducing severe outcomes of influenza and, when indicated, should be initiated as soon as possible after illness onset. Clinical trials and observational data show that early antiviral treatment can:

• shorten the duration of fever and illness symptoms;
• reduce the risk of complications from influenza (e.g., otitis media in young children and pneumonia requiring antibiotics in adults); and
• reduce the risk of death among hospitalized patients.

(Continue . . .)

 

UK PHE: Revisiting Influenza Antiviral Recommendations

Credit UK PHE

 

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Last spring the Cochrane group made headlines (again) for their less-than-sparkling review of the influenza antiviral drug oseltamivir (Tamiflu ®), which cast doubts on its efficacy and on the wisdom of governments around the world stockpiling the drug. (see Revisiting Tamiflu Efficacy (Again)).  

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

These results were then picked up by tabloid (and other) media sources, tortured to within an inch of its life, and then splashed across the media as `proof’ that the governments of the world were nothing but shills for Big Pharma (see Ministers blew £650MILLION on useless anti-flu drugs.).

Much of this ire has been garnered 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.

 

As a result, many people have come away with the erroneous impression that these drugs are worthless – or worse.   And that could dissuade some from seeking early medical treatment during this year’s flu season, costing lives in the process. 

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 much too high as to what studies they would consider, excluding many observational studies. 

 

They also were looking at the effects of Tamiflu on healthy children and adults – those least likely to see benefits from taking antivirals.

 

Despite its critics, there are studies that show that Tamiflu can significantly reduce morbidity and mortality associated with influenza – particularly with severe infection, or those with comorbidities. 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 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.

 

While it is true that antivirals are of limited value for those who are healthy, and suffering from uncomplicated seasonal influenza, the preponderance of evidence shows significant benefits from the early administration in cases of severe infection, co-morbidities, or infection with novel influenza strains.

One of the most dramatic avian flu studies (see Study: Antiviral Therapy For H5N1) looked at 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.

 

Last April we saw the The CDC Responds To The Cochrane Tamiflu Study, where they provided their rationale for continuing to recommend its use. You can visit the CDC’s current advice on antiviral administration (which is unchanged) at this site:

 

Recommendations of the Advisory Committee on Immunization Practices (ACIP): Information for Health Care Professionals

The information on this page should be considered current for the 2014-2015 influenza season for clinical practice regarding the use of influenza antiviral medications. Also see the current summary of recommendations available at Influenza Antiviral Medications: Summary for Clinicians and a list of related references at Antiviral Guide References.

 

Today the UK’s Public Health England has released the following recommendations, which also restates their position on the use of antivirals: Influenza: treatment and prophylaxis using anti-viral agents  4 November 2014. 

In addition to their recommendations, you’ll also find a push-back against the Cochrane study.

Update following the 2014 Cochrane Review Public Health England (PHE) has produced a summary of the current guidance and evidence and a position statement on the use of antivirals for the treatment and prophylaxis of influenza. (2). The PHE summary and position statement has been published following the 2014 Cochrane Review on the efficacy of antivirals (3). The findings of the 2014 Cochrane review were not substantially different to the previous (2010 and 2012) reviews. Overall the 2014 review adds to the evidence base for the treatment of influenza in some settings, however the conclusions made are limited due to the variation in outcomes, patient groups, and settings studied.

The key messages from the summary are:

• there is evidence that antivirals can reduce the risk of death in patients hospitalised with influenza
• in the light of this evidence, it is important that doctors treating severely unwell patients continue to prescribe these drugs where appropriate
• PHE continues to support the early use of antivirals for patients with proven or suspected seasonal influenza who are in high risk groups, or who are considerably unwell (even if not in a high risk group)

This position is consistent with that taken by the World Health Organisation (WHO) and other national public health organisations such as the USA’s Centers for Disease Control and Prevention (CDC). Although there is no evidence to support any change to the recommended use of neuraminidase inhibitor, media reporting around the Cochrane Review 2014 publication suggested that antivirals are not effective for influenza. This may impact the prescribing of these important drugs. It is essential that physicians treating severely unwell patients in any setting are not deterred from prescribing what may be lifesaving drugs as a result of confusion over efficacy in this situation; this is especially true for patients hospitalised with proven or suspected influenza.

Download the full 22 page PDF file

CID Journal: Under Utilization Of Antivirals For At Risk Flu Patients

 

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Between the frequent hyperbolic demonization of  influenza antivirals (see Daily Mail: Ministers blew £650MILLION on useless anti-flu drugs) by media critics of `Big Pharma’,  spurred on by repeated Cochrane group analyses that have found insufficient evidence that the drug reduces influenza complications, it probably comes as little surprise that many doctors – particularly in outpatient settings – tend to underutilize antiviral drugs, even for patients at the greatest risk for complications.

 

While well-respected, the Cochrane Group uses a very narrow (and some would say misguided) criteria for evaluating the effectiveness of antiviral drugs.  One that discards all but a handful of studies.

 

Last April, 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.

 

A few days later, the CDC 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.

(Continue . . .)

 

The CDC considers those a higher risk of influenza complications, and for whom they recommend antiviral treatment for suspected or confirmed influenza , to include:

• children aged younger than 2 years;
• adults aged 65 years and older;
• persons with chronic pulmonary (including asthma), cardiovascular (except hypertension alone), renal, hepatic, hematological (including sickle cell disease), metabolic disorders (including diabetes mellitus) or neurologic and neurodevelopment conditions (including disorders of the brain, spinal cord, peripheral nerve, and muscle such as cerebral palsy, epilepsy [seizure disorders], stroke, intellectual disability [mental retardation], moderate to severe developmental delay, muscular dystrophy, or spinal cord injury);
• persons with immunosuppression, including that caused by medications or by HIV infection;
• women who are pregnant or postpartum (within 2 weeks after delivery);
• persons aged younger than 19 years who are receiving long-term aspirin therapy;
• American Indians/Alaska Natives;
• persons who are morbidly obese (i.e., BMI is 40 or greater); and
• residents of nursing homes and other chronic-care facilities.

But based on a new study, published this week in Clinical Infectious Diseases, antiviral drugs for these cohorts appear to be underutilized. Worse, patients were twice as likely to be prescribed antibiotics than antivirals for influenza.

Use of Influenza Antiviral Agents by Ambulatory Care Clinicians During the 2012–2013 Influenza Season

Fiona Havers1, Swathi Thaker2, Jessie R. Clippard2, Michael Jackson3, Huong Q. McLean4, Manjusha Gaglani5, Arnold S. Monto6, Richard K. Zimmerman7, Lisa Jackson3, Josh G. Petrie6, Mary Patricia Nowalk7, Krissy K. Moehling7, Brendan Flannery2, Mark G. Thompson2, and Alicia M. Fry2

Abstract

Background. Early antiviral treatment (≤2 days since illness onset) of influenza reduces the probability of influenza-associated complications. Early empiric antiviral treatment is recommended for those with suspected influenza at higher risk for influenza complications regardless of their illness severity. We describe antiviral receipt among outpatients with acute respiratory illness (ARI) and antibiotic receipt among patients with influenza.

Methods. We analyzed data from 5 sites in the US Influenza Vaccine Effectiveness Network Study during the 2012–2013 influenza season. Subjects were outpatients aged ≥6 months with ARI defined by cough of ≤7 days’ duration; all were tested for influenza by polymerase chain reaction (PCR). Medical history and prescription information were collected by medical and pharmacy records. Four sites collected prescribing data on 3 common antibiotics (amoxicillin-clavulanate, amoxicillin, and azithromycin).

Results. Of 6766 enrolled ARI patients, 509 (7.5%) received an antiviral prescription. Overall, 2366 (35%) had PCR-confirmed influenza; 355 (15%) of those received an antiviral prescription. Among 1021 ARI patients at high risk for influenza complications (eg, aged <2 years or ≥65 years or with ≥1 chronic medical condition) presenting to care ≤2 days from symptom onset, 195 (19%) were prescribed an antiviral medication. Among participants with PCR-confirmed influenza and antibiotic data, 540 of 1825 (30%) were prescribed 1 of 3 antibiotics; 297 of 1825 (16%) were prescribed antiviral medications.

Conclusions. Antiviral treatment was prescribed infrequently among outpatients with influenza for whom therapy would be most beneficial; in contrast, antibiotic prescribing was more frequent. Continued efforts to educate clinicians on appropriate antibiotic and antiviral use are essential to improve healthcare quality.

 

In an accompanying press release from the Infectious Diseases Society of America we get the following summary:

 

 

Findings suggest antivirals underprescribed for patients at risk for flu complications

Study also shows that antibiotics may have been prescribed unnecessarily

(EXCERPT)

Overall, only 19 percent of the patients at high risk for influenza-associated complications who saw a primary-care provider within two days of the onset of their symptoms received antiviral treatment. Among patients with laboratory-confirmed influenza, just 16 percent were prescribed antivirals. In contrast, 30 percent of these patients received one of the three antibiotics.

"Our results suggest that during 2012-'13, antiviral medications were underprescribed and antibiotics may have been inappropriately prescribed to a large proportion of outpatients with influenza," the authors wrote. "Continuing education on appropriate antibiotic and antiviral use is essential to improve health care quality."

While some of the antibiotics may have been appropriate for bacterial infections secondary to influenza, which is caused by a virus, it is likely most were unnecessary, potentially contributing to the growing problem of antibiotic resistance, the authors noted.

(Continue . . . )

 

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.

(Continue. . . )

Revisiting Tamiflu Efficacy (Again)

 

 

 

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

 

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

 

CDC Recommendations for Influenza Antiviral Medications Remain Unchanged

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

(Continue . . . )

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

 

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

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

 

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

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

Cite this as: BMJ 2014;348:g2545

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

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

The Cochrane Summary is available at:

 

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

Editorial Group: Cochrane Acute Respiratory Infections Group

Published Online: 10 APR 2014

 

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

 

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

 

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

 

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

 

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

 

Flu Experts Line Up to Defend Tamiflu Against New Study

By Maggie Fox

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

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

(Continue . . . )

 

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

 

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

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

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

 

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

 

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

 

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

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

PLoS Pathogens: Fitness Advantage From Permissive NA Mutations In Oseltamivir Resistant pH1N1

 

 

# 8429

 

Hopefully today’s blog won’t be as tedious as the title might first suggest.

 

Oseltamivir (aka Tamiflu ®) – an NAI (Neuraminidase Inhibiting) antiviral drug – is our primary pharmaceutical weapon against influenza.   While it doesn’t `cure’  the flu - when started early enough (preferentially within 48 hrs of onset of symptoms) - it can reduce both the severity and duration of infection (see Effectiveness Of NAI Antivirals In Reducing Mortality In Hospitalized H1N1pdm09 Cases).

Up until the middle of the last decade, we had another class of antiviral drugs - M2 ion channel blockers (e.g. Amantadine, Rimantadine) –  which were first developed in the late 1950s. But excessive use over the years (including in agricultural settings) eventually led to widespread resistance.

 

The replacement antivirals introduced during the last decade include Oseltamivir (Tamiflu), Zanamivir (Relenza), and Peramivir. Of these, Oseltamivir is by far the most widely used, and has been stockpiled by many governments for use in the event of a pandemic.

 

While occasional instances of Oseltamivir resistance was recorded prior to 2007, in nearly every case, it developed after a person was placed on the drug (`spontaneous mutations’).  While of concern to the patient being treated, it occurred in only about 1% of treated cases, and studies suggested that these resistant strains were `less biologically fit’, and were therefore believed to be unlikely to spread.

 

Which of course, is exactly what they did do.  Between 2007 and 2008, the incidence of resistant seasonal H1N1 viruses literally exploded around the globe. 

 

So much so, that by the end of 2008, nearly all of the H1N1 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).

This resistance was primarily due to an 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)). 

 

While this mutation had been seen before, obviously something had changed between 2006 and 2008 to allow the resistant form of the virus to spread so quickly.

 

In 2010  Bloom, Gong & Baltimore discussed these `enabling’ changes in the Journal Science in  a report called Permissive Secondary Mutations Enable the Evolution of Influenza Oseltamivir Resistance.

ABSTACT

The His²⁷⁴→Tyr²⁷⁴ (H274Y) mutation confers oseltamivir resistance on N1 influenza neuraminidase but had long been thought to compromise viral fitness. However, beginning in 2007–2008, viruses containing H274Y rapidly became predominant among human seasonal H1N1 isolates. We show that H274Y decreases the amount of neuraminidase that reaches the cell surface and that this defect can be counteracted by secondary mutations that also restore viral fitness.

Two such mutations occurred in seasonal H1N1 shortly before the widespread appearance of H274Y. The evolution of oseltamivir resistance was therefore enabled by “permissive” mutations that allowed the virus to tolerate subsequent occurrences of H274Y. An understanding of this process may provide a basis for predicting the evolution of oseltamivir resistance in other influenza strains.

 

In 2011 Abed,  Pizzorno,  Bouhy &  Boivin identified several `permissive’ neuraminidase mutations that occurred just prior to the spread of resistant H1N1 - that when combined with H275Y -  `enabled’ its efficient transmission (see PLoS Pathogens Role of Permissive Neuraminidase Mutations in Influenza A/Brisbane/59/2007-like (H1N1) Viruses).

 

This pervasive spread of resistant H1N1 would have been a much bigger deal had it not been for the arrival of the 2009 H1N1 pandemic virus, which effectively supplanted the old (resistant) H1N1, and replaced it with a new – but fortunately, still susceptible to NAIs – H1N1 virus.

 

Fast forward five years, and the (now seasonal, formerly pandemic) pH1N1 virus remains overwhelmingly susceptible to Oseltamivir and other NAI antiviral drugs, although we have seen a few signs of `creeping resistance’. 

 

Reassuringly, the latest FluView report (week 12) indicated that of 4524 viruses tested this flu season in the United States, only 54 (1.2%) showed signs of NA Inhibitor resistance.

 

But we have seen a few worrisome clusters of NAI resistant flu (see Eurosurveillance: Community Cluster Of Antiviral Resistant pH1N1 in Japan & NEJM: Oseltamivir Resistant H1N1 in Australia), which has raised concerns that we could see a repeat of the 2007-2008 rise in antiviral resistance in our current H1N1 strain.

 

All of which serves as prelude to a new study that appears in PloS Pathogens, that looks at the potential of pH1N1 following the same course as its predecessor.  Their assessment is not particularly rosy.

 

Estimating the Fitness Advantage Conferred by Permissive Neuraminidase Mutations in Recent Oseltamivir-Resistant A(H1N1)pdm09 Influenza Viruses

Jeff Butler, Kathryn A. Hooper, Stephen Petrie, Raphael Lee, Sebastian Maurer-Stroh, Lucia Reh, Teagan Guarnaccia, Chantal Baas, Lumin Xue, Sophie Vitesnik, Sook-Kwan Leang, Jodie McVernon, Anne Kelso, Ian G. Barr, James M. McCaw, Jesse D. Bloom, Aeron C. Hurt mail

Published: April 03, 2014  DOI: 10.1371/journal.ppat.1004065

Abstract

Oseltamivir is relied upon worldwide as the drug of choice for the treatment of human influenza infection. Surveillance for oseltamivir resistance is routinely performed to ensure the ongoing efficacy of oseltamivir against circulating viruses.

Since the emergence of the pandemic 2009 A(H1N1) influenza virus (A(H1N1)pdm09), the proportion of A(H1N1)pdm09 viruses that are oseltamivir resistant (OR) has generally been low. However, a cluster of OR A(H1N1)pdm09 viruses, encoding the neuraminidase (NA) H275Y oseltamivir resistance mutation, was detected in Australia in 2011 amongst community patients that had not been treated with oseltamivir. Here we combine a competitive mixtures ferret model of influenza infection with a mathematical model to assess the fitness, both within and between hosts, of recent OR A(H1N1)pdm09 viruses.

In conjunction with data from in vitro analyses of NA expression and activity we demonstrate that contemporary A(H1N1)pdm09 viruses are now more capable of acquiring H275Y without compromising their fitness, than earlier A(H1N1)pdm09 viruses circulating in 2009. Furthermore, using reverse engineered viruses we demonstrate that a pair of permissive secondary NA mutations, V241I and N369K, confers robust fitness on recent H275Y A(H1N1)pdm09 viruses, which correlated with enhanced surface expression and enzymatic activity of the A(H1N1)pdm09 NA protein.

These permissive mutations first emerged in 2010 and are now present in almost all circulating A(H1N1)pdm09 viruses. Our findings suggest that recent A(H1N1)pdm09 viruses are now more permissive to the acquisition of H275Y than earlier A(H1N1)pdm09 viruses, increasing the risk that OR A(H1N1)pdm09 will emerge and spread worldwide.

 

Fair warning: the methods and materials section is lengthy, complex, and pretty tough sledding for those without a solid background in virology.  Those interested in the details (or with a masochistic bent) will want to read this report in its entirety.

 

The bottom line, however, is that since the 2009 H1N1 virus emerged five years ago, it has managed to pick up a series of `permissive’ mutations that are believed to increase its ability to replicate when it carries the H275Y resistance mutation.

 

Which in theory, should promote its spread.

 

Given that these mutations are already entrenched, it is a bit surprising we haven’t already seen an expansion in resistant pH1N1, beyond a couple of documented clusters in Australia and Japan.  The authors write:

One explanation is that a high level of circulating A(H1N1)pdm09 viruses may be required for a A(H1N1)pdm09 OR virus to become established and spread. The Australian HNE2011 virus cluster emerged [25], [26] during a season when A(H1N1)pdm09 viruses accounted for almost 40% of all influenza A and B viruses detected globally but, in 2012 and 2013, the proportion of A(H1N1)pdm09 viruses circulating has been considerably lower (9% and 25% respectively) [52].

In the most recent 2013/14 Northern Hemisphere influenza season, a cluster of A(H1N1)pdm09 H275Y OR viruses that contained both the V241I and N369K PPMs plus an additional N386K NA mutation, was detected in Sapporo, Japan [53], during a period of the season where A(H1N1)pdm09 viruses contributed approximately 50% of the circulating influenza strains [54].

We’ve just come through an H1N1 dominated flu season in North America, and the incidence of H274Y has remained low, so other factors may be involved. The authors suggest:

Apart from NA PPMs, it may be that other properties, such as antigenic novelty, are also necessary for an OR virus to spread widely. In 2007–2008, the H275Y NA mutation became fixed in a new seasonal A(H1N1) antigenic variant (A/Brisbane/59/2007-like), suggesting that the antigenic novelty of the OR virus assisted its prolific spread.

In this vein, the authors warn:

A(H1N1)pdm09 viruses have now been circulating in humans for over four years, but are yet to undergo a significant antigenic change (as evidenced by the continued inclusion of A/California/7/2009 in the human seasonal influenza vaccine since 2009).

As the H1 component of the vaccine has been updated, on average, every 2.8 years (range 1 to 8 years), and the H3 component every 1.8 years (range 1 to 4 years) since 1980, it is reasonable to anticipate that A(H1N1)pdm09 viruses will undergo antigenic change in the near future.

The significance being that an antigenic change in the virus might be the spark needed to spread the resistant mutation, and at the same time would reduce the effectiveness of the current vaccine (and evade herd immunity), and therefore increase our need for effective antiviral medications.

 

Viruses and bacteria evolve and adapt very quickly. The sobering truth is pharmacological victories over them tend to be fleeting. New classes of drugs are going to be needed, along with prudent stewardship of the drugs currently in our arsenal.

 

The authors of this study wrap up by saying:

 

Here we demonstrate that contemporary A(H1N1)pdm09 viruses have acquired NA mutations which permit the acquisition of NA H275Y without compromising viral fitness. These mutations, which are now present in virtually all circulating A(H1N1)pdm09 viruses, enhance the surface expression and enzymatic activity of the A(H1N1)pdm09 H275Y NA protein in vitro and result in enhanced viral fitness in vivo.

Hence, the risk that H275Y A(H1N1)pdm09 viruses will spread globally, in a similar manner to OR seasonal A(H1N1) viruses in 2007–2008, now appears greater than at any time since the A(H1N1)pdm09 lineage emerged in 2009.

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