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. 

»» Read More

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.

»» Read More

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.

»» Read More

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.

 

»» Read More

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.

»» Read More