PRO/AH/EDR> Influenza pandemic (H1N1) 2009 (132): Tamiflu efficacy INFLUENZA PANDEMIC (H1N1) 2009 (132): TAMIFLU EFFICACY
A ProMED-mail post
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International Society for Infectious Diseases
Date: Thu 10 Dec 2009
Source: nature.com blogs [edited]
Robo-doc: RobSci-Fi Surgery at the Royal College of Surgeons [edited]
The BMJ [British Medical Journal] has just published a whole slew of papers
about Tamiflu (oseltamivir) -- a key drug in the public health response
against swine flu [influenza pandemic (H1N1) 2009 virus infection].
The linchpin is a Cochrane review on the efficacy of neuraminidase
inhibitors -- namely zanamivir (Relenza; Glaxo Wellcome) and oseltamivir
(Tamiflu; Roche) -- for preventing and treating influenza in healthy
adults. The review found that these 2 drugs were only partly effective
against laboratory confirmed symptomatic influenza
(oseltamivir 61 per cent
effective; zanamivir 62 per cent effective), and no good at all against
asymptomatic flu or flu-like illness.
In addition, Tamiflu did not reduce the risk of influenza-related lower
respiratory tract complications -- bad news for the Department of Health,
which recommends using the drug to prevent secondary complications in
The authors conclude: "Neuraminidase inhibitors might be
regarded as optional for reducing the symptoms of seasonal influenza.
Paucity of good data has undermined previous findings for oseltamivir's
prevention of complications from influenza." [The abstract of this
publication is reproduced at  below. - Mod.CP]
In an accompanying feature, Deborah Cohen retraces the steps leading to the
publication of the Cochrane review and highlights all the difficulties the
authors had extracting data from Roche, the makers of Tamiflu. The review
"exposed a complex interplay between politics, public health planning,
availability of trial data, publishing, and drug regulation."
Turns out that Roche's claims that Tamiflu reduces hospital admissions and
secondary complications of influenza were based on a 2003 meta-analysis
that only included 2 proper randomised controlled trials
and was authored
by several Roche employees. When the authors of the Cochrane review tried
to get their hands on the data in this paper to include them in their own
analysis, they came up against all sorts of obstacles thrown up by Roche.
Peter Doshi, an author of the new Cochrane review, writes in the BMJ of his
struggle to get hold of the elusive data and offers a damning verdict on
the use of the drug in the swine flu epidemic. "Since August 2009, our
Cochrane review team has tried to obtain the data needed to verify claims
that oseltamivir (Tamiflu) lowers serious complications of influenza such
as pneumonia. We failed, but in failing discovered that the public evidence
base for this global public health drug is fragmented, inconsistent, and
contradictory. We are no longer sure that oseltamivir offers a therapeutic
and public health policy advantage over cheap, over the counter drugs such
In an analysis article, Nick Freemantle and Mel Calvert look over the
observational studies of Tamiflu that Roche cited in defense of their
claims for the drug and found that they also do not support the use of
Tamiflu to treat influenza in healthy adults. In their discussion they
write: "oseltamivir may reduce the risk of pneumonia in otherwise healthy
people who contract flu. However, the absolute benefit is small, and side
effects and safety should also be considered. None of the studies examined
the role of oseltamivir in patients with H1N1 influenza, which may be
associated with higher rates of pneumonitis than seasonal influenza."
Finally, in a linked editorial, Fiona Godlee, editor of the BMJ, and Mike
Clarke, director of the UK Cochrane Centre in Oxford, rail against the
obstructive techniques used by Roche and call for full data from clinical
trials to be made available to the scientific community. "Why should the
public have to rely on detective work by academics and journalists to patch
together the evidence on such a potentially important drug?" they ask.
All this is bad news for public health planning against swine flu -- the
Department of Health has already stockpiled more than 30 million doses of
potentially useless Tamiflu -- and even worse news for Roche.
Date: Tue 8 Dec 2009
Source: BMJ 2009; 339: b5106 [edited]
Neuraminidase inhibitors for preventing and treating influenza in healthy
adults: systematic review and meta-analysis
[authors: Tom Jefferson, Mark Jones, Peter Doshi, Chris Del Mar]
Objectives: to update a 2005 Cochrane review that assessed the effects of
neuraminidase inhibitors in preventing or ameliorating the symptoms of
influenza, the transmission of influenza, and complications from influenza
in healthy adults, and to estimate the frequency of adverse effects.
Search strategy: an updated search of the Cochrane central register of
controlled trials (Cochrane Library 2009, issue 2), which contains the
Acute Respiratory Infections Group's specialised register, Medline
(1950-Aug 2009), Embase (1980-Aug 2009), and post-marketing
pharmacovigilance data and comparative safety cohorts.
Selection criteria: randomised placebo controlled studies of neuraminidase
inhibitors in otherwise healthy adults exposed to naturally occurring
Main outcome measures: duration and incidence of symptoms; incidence of
lower respiratory tract infections, or their proxies; and adverse events.
Data extraction: 2 reviewers applied inclusion criteria, assessed trial
quality, and extracted data.
Data analysis: comparisons were structured into prophylaxis, treatment, and
adverse events, with further subdivision by outcome and dose.
Results: 20 trials were included: 4 on prophylaxis, 12 on treatment, and 4
on postexposure prophylaxis. For prophylaxis, neuraminidase inhibitors had
no effect against influenza-like illness or asymptomatic influenza. The
efficacy of oral oseltamivir against symptomatic laboratory confirmed
influenza was 61 per cent (risk ratio 0.39, 95 per cent confidence interval
0.18 to 0.85) at 75 mg daily and 73 per cent (0.27, 0.11 to 0.67) at 150 mg
daily. Inhaled zanamivir 10 mg daily was 62 per cent efficacious (0.38,
0.17 to 0.85). Oseltamivir for postexposure prophylaxis had an efficacy of
58 per cent (95 per cent confidence interval 15 per cent to 79 per cent)
and 84 per cent (49 per cent to 95 per cent) in 2 trials of households.
Zanamivir performed similarly. The hazard ratios for time to alleviation of
influenza-like illness symptoms were in favour of treatment: 1.20 (95 per
cent confidence interval 1.06 to 1.35) for oseltamivir and 1.24 (1.13 to
1.36) for zanamivir. 8 unpublished studies on complications were ineligible
and therefore excluded. The remaining evidence suggests oseltamivir did not
reduce influenza related lower respiratory tract complications (risk ratio
0.55, 95 per cent confidence interval 0.22 to 1.35). From trial evidence,
oseltamivir induced nausea (odds ratio 1.79, 95 per cent confidence
interval 1.10 to 2.93). Evidence of rarer adverse events from
pharmacovigilance was of poor quality or possibly under-reported.
The data suggest that neuraminidase inhibitors are effective at reducing
the symptoms of influenza. The evidence is of modest benefit -- reduction
of illness by about one day. This benefit has been generalised to assume
benefits for very ill people in hospital. This seems reasonable, although
it is worth remembering that we have no data to support this, and it is
unlikely that ethics committees would allow a trial of no treatment for
people with influenza who have life threatening disease.
One important caveat to these results arises from concerns about the
difference between efficacy (treatment response to pure influenza virus
infection) and effectiveness (the real life response to influenza-like
illness, when real cases of influenza are indistinguishable from other
causative agents not responsive to neuraminidase inhibitors. Understanding
the proportion of influenza-like illness caused by both seasonal and
epidemic influenza is critical to generalising the results of this review
to clinical practice. The finding of treatment effectiveness for the
neuraminidase inhibitors may have been enhanced by the high percentage of
influenza-like illness caused by influenza in most of the included trials
-- for example, up to 80 per cent.
Data on the effectiveness of oseltamivir against the complications of
influenza are confusing. Hayashi pointed out that the original data, which
led to the 2005 version of this original Cochrane review reporting benefits
for oseltamivir on reduction of complications from lower respiratory tract
infection, principally came from one meta-analysis that summarised 10
trials containing a mixture of published and unpublished data. Only 2 of
the trials it contains are published (and are reported in this Cochrane
review update), the remainder were offered to us under conditions we
thought unacceptable, and what was offered to us was insufficient to
analyse properly. (Comments on the Kaiser et al paper are in the web
extra). This means we are now obliged to exclude the meta-analysis. The
remaining published evidence is insufficient to answer the question about
the effectiveness of either neuraminidase inhibitor on reducing the
complications of lower respiratory tract infection, antibiotic use, or
admissions to hospital. It is possible that there is a publication bias,
especially as we know of 8 trials that are unpublished and inaccessible. We
have not undertaken a funnel plot because there are only 3 trials (fig 6 --
available at the source URL above), and so the issue of publication bias
remains unresolved. Its direction might be in favour of exaggerating the
treatment effect. Hayashi's comments point out a serious problem with our
original review, which we now address.
The results from the meta-analyses involving hazard ratios should be viewed
with caution because of the approximate methods used to extract estimates
for each study. Hazard ratios were rarely reported directly, so we had to
use the ratio of the observed median duration of symptoms in each group as
an approximation to the hazard ratio. This approach may be overly
simplistic, as it makes a comparison at only one time point and assumes a
constant survival difference over time, and thus may produce different
meta-analysis results than if the actual hazard ratio estimates were available.
Role of neuraminidase inhibitors in seasonal influenza: neuraminidase
inhibitors had low effectiveness and high efficacy against symptoms
(shortening the illness by half to one day, a crude estimate made by
applying a hazard ratio of 1.2 on the control length of illness of 4 days
to about 3.3 days, a reduction of less than one day, and preventing
symptoms from appearing), and initially seemed to be well tolerated (with
the possible exception of oseltamivir induced nausea and vomiting).
A surprising finding was the high percentage (57-80 per cent) of influenza
in the trial populations receiving neuraminidase inhibitors. We remain at a
loss to explain this because most other data suggest much lower rates.
Role of neuraminidase inhibitors in pandemic influenza: we identified no
direct comparative evidence of the role of neuraminidase inhibitors in
avian influenza A/H5N1 or in the current novel influenza A/H1N1 pandemic.
This means that we have to generalise from the trials, and this seems
reasonable given that the pandemic influenza A/H1N1 virus will likely be
acted on in the same biological manner as previously circulating influenza
viruses, such as seasonal A/H1N1.
Neuraminidase inhibitors do not, however, prevent infection or stop nasal
viral excretion, so they may be a suboptimal means of interrupting viral
spread in a pandemic. If used to contain a severe pandemic outbreak,
neuraminidase inhibitors should be considered only part of a package of
measures to interrupt spread, including physical measures.
Possible harms of neuraminidase inhibitors: we focused on oseltamivir
because of the considerably greater global experience with this drug.
Post-marketing pharmacovigilance data about oseltamivir obtained from the
FDA are of limited use because of likely under-representation of reports
generated from outside the United States. The entire AERS database
(containing adverse event reports of all types) between 1999 and 15 Sep
2007 contains only 1805 reports. However, the Roche global safety database
contains reports of 2466 neuropsychiatric adverse events during this time,
of which 562 (22.8 per cent) were classified as "serious."
Another important limitation of the AERS database is the practice by the
FDA of not registering non-electronically submitted reports of non-serious
adverse events 3 years after a drug's initial approval (personal
correspondence with FDA, 14 Oct 2009).
Our findings of a possible association with neuraminidase inhibitors and
the onset of rare harms coming from the US AERS data accord with a review
of phase IV evidence from 8 cases (adolescents and adults), suggesting
oseltamivir may induce sudden behavioural changes in recipients, including
hallucination, suicidal tendencies, and sudden death while asleep. This
evidence came soon after a review ordered by the Japanese government, in
part triggered by the 567 serious neuropsychiatric cases received since the
2001 launch of the drug and May 2007. It is, however, estimated that more
than 36 million doses have been prescribed since 2001, making such harms
(even if confirmed) rare.
We therefore found under-reported evidence of varied quality, which could
not answer concerns about the toxicity of neuraminidase inhibitors,
especially oseltamivir. Governments should set up studies to monitor the
safety of neuraminidase inhibitors.
Conclusion: neuraminidase inhibitors have modest effectiveness against the
symptoms of influenza in otherwise healthy adults. The drugs are effective
postexposure against laboratory confirmed influenza, but this is a small
component of influenza-like illness, so for this outcome neuraminidase
inhibitors are not effective. Neuraminidase inhibitors might be regarded as
optional for reducing the symptoms of seasonal influenza. Paucity of good
data has undermined previous findings for oseltamivir's prevention of
complications from influenza. Independent randomised trials to resolve
these uncertainties are needed.
[For further information readers are advised to consult the full text of
this paper, which includes responses from F Hoffmann-La Roche and related
This moderator's opinion is that clinicians have expected too much of the
neuraminidase inhibitors Tamiflu and Relenza. The mode of action of
neuraminidase inhibitors is to bind to the influenza virus neuraminidase
protein and interfere with attachment and adsorption of the virus. Once
adsorbed there is no inhibitory effect of the drugs. Maximum efficacy
depends on treatment immediately prior to or very soon after exposure to
the virus. Any effect of treatment at later stages of influenza virus
infection is an (unexpected) bonus. Anecdotal evidence, however, suggests
that the Egyptian health care authorities have had considerable success in
reducing fatalities from avian H5N1 virus infection of children by prompt
initiation of Tamiflu treatment. - Mod.CP] http://www.promedmail.org/pls/otn/f?..._ID:1000,80499