Effectiveness of neuraminidase inhibitors in treatment and prevention of influenza A and B: systematic review and meta-analyses of randomised controlled trials
BMJ 2003; 326 doi: https://doi.org/10.1136/bmj.326.7401.1235 (Published 05 June 2003) Cite this as: BMJ 2003;326:1235
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In a recent issue of BMJ, Cooper et al [1] succinctly
outlined the role of neurominadase inhibitors in prophylaxis and treatment
of influenza. Certainly, they would be very important as chemoprophylactic
agents during the early phase of any outbreak of influenza. Nevertheless,
their efficacy might not be perfect had they not been primed to resist
adverse environment encountered in the field.
Like vaccines, the potency
of antiviral medicines is as well maintained at the stipulated level only
if they were to be stored at controlled temperatures. They require storage
at temperature not exceeding 25-30oC [2]. An inadvertent exposure to
temperatures outside the specified range was possible everywhere. In
refrigerators at the pediatric offices and clinics in Los Angeles, the
inside temperature exceeded 8oC in 22% of offices and clinics [3].
Right
at the beginning of the century, the January 2001 power shut down in
California was alarming. Similar episodes were not unlikely in other parts
of the globe. They would be inimical to an effective outcome of
chemotherapeutic intervention.
Designers of prospective influenza vaccines and chemotherapeutics [1]
should ensure that such products adequately resisted environmental rigors.
In face of a pandemic, they would be transported to different continents
at a very short notice.
Addition of pirodavir and deuterium oxide to the
most labile of the childhood vaccine, the live poliovirus vaccine has been
remarkable. Their pre-addition in experimental vaccine lots, resulted in
maintenance of vaccine immunogenicity after 10-hour exposure to 42oC[4].
Innovative stabilization strategies should be important in prospective
influenza vaccines as well as neurominidase inhibitors [1]. During the
interim period, both the practitioners of clinical medicine and public
health should appreciate the value of storage of influenza therapeutics or
prophylactics in accordance with the recommendations by the manufacturers.
The clinicians might recommend their patients for storage of therapeutic
recipes inside the domestic refrigerators.
ARYA, Subhash C
AGARWAL, Nirmala
Sant Parmanand Hospital
18 Alipore Road
Delhi- 110054, India
Email subhashji@hotmail.com
REFERENCES
1. Cooper NJ, Sutton AJ, Abrams KR et al. Effectiveness of
neuraminidase inhibitors in treatment and prevention of influenza A and B:
systematic review and meta-analyses of randomised controlled trials
BMJ 2003; 326: 1235
2. Physicians’ Desk Reference. 2002. Medical Economics Company, Montvale:
56th edition.
3. Bidshai DM, Bhatt S, Miller LT, Hayden GF. Vaccine storage practices in
pediatric offices. Pediatrics 1992; 89: 193-196
4. Verheyden B, Andrus K, Rombart B. Capsid and viral RNA stabilization of
the poliovirus. Vaccine 2001; 19: 1899-1905
Competing interests:
None declared
Competing interests: No competing interests
I have found that the best way to deal with infectious diseases like
flu is not to resort to expensive drugs after the event, but to prevent
them. This is done, in my experience, simply by reducing people’s intake
of carbohydrate-rich foods, particularly fruit, sugar (sucrose) and honey,
in that order.
In a 1973 study, after an overnight fast and after their leucocytes
had been tested for phagocytic activity and their leukocytic index (LI)
had been recorded, subjects were fed 100 grams of a specific carbohydrate
(a sugar or starch). Sugars reduced the neutrophils' effectiveness at
destroying bacteria and other micro-organisms by up to 45%.(1) The worst
was fructose (fruit sugar). All other sugars tested also reduced
leukocytic phagocytosis by more than 40%. Starches were not so bad,
reducing phagocytosis by around 13%. The effects in all cases lasted for
more than 5 hours.
This study was confirmed in 1976.(2) A similar study tested the
effect of sucrose by giving subjects 24 ounces of sugar sweetened Cola. In
this test the leucocytic index of all their subjects was reduced by 50%.
To prevent the huge toll on health caused by infectious diseases, all
we have to do is NOT eat “5 portions of fruit a day”. Not only is it
healthier, it is also a great deal cheaper both for the potential patient
and the NHS.
Barry Groves, PhD
Author: Eat Fat, Get Thin!
References:
1. Sanchez A, et al. Role of sugars in human neutrophilic
phagocytosis. Am J Clin Nutr 1973; 26: 1180-84
2. Ringsdorf WM jr, Cheraskin E and Ramsey RR jr. Sucrose,
Neutrophilic Phagocytosis, and Resistance to Disease. Dent Surv 1976; 52
(12): 46-48
Competing interests:
None declared
Competing interests: No competing interests
In the introduction to the BMJ of 6th June you state, regarding
neuraminidase inhibitors for influenza, “The treatment also lowers the
risk of complications that require antibiotics by 29-43% when it is given
within 48 hours of onset of symptoms.”
However the paper by Cooper et al itself states “Complications
requiring antibiotics — Only one study (WV15670) in otherwise healthy
adults reported a non-significant relative reduction (oseltamivir v
placebo, 43%) in the odds of complications requiring antibiotics in the
ITT population and a significant relative reduction (87%) in the flu
positive population. Among children, a 35% relative reduction in the odds
of complications requiring antibiotics was observed in one study
(WV15758).The authors looked at 17 studies in total. In the summary of
results in the abstract the effect on antibiotic requirements is not
commented on by the authors, presumably because of the limited evidence
available.
As a GP I read your summary with interest thinking a new and dramatic
benefit had emerged,but the evidence for the statement that antibiotic
requirements are reduced appears far from compelling on reading the paper.
That together with only a half to one days reduction in symptoms with
early treatment still makes me very sceptical about the promotion of these
costly drugs to a cash strapped NHS.
Competing interests:
None declared
Competing interests: No competing interests
I'm a jobbing GP with no great love of stats, but I thought relative
risk had been superceded by use of absolute risk reduction and NNT/NNH
calculations.
Is there any reason the complication rates and prevention rates are not
reported in this way? Better still, can someone do the sums & post
them, as I don't trust my arithmetic?
Competing interests:
None declared
Competing interests: No competing interests
NICE guidlines on the use of neuraminidase inhibitors in children are not supported by evidence
EDITOR – Current guidance from the National Institute for Clinical
Excellence (NICE) on the use of the neuraminidase inhibitors recommends
oseltamivir for the treatment of ‘at risk’ children with influenza-like
illness of fewer than 48 hours duration (1). Oseltamivir is not
recommended for otherwise healthy children, and zanamivir, the other
neuraminidase inhibitor, is not currently licensed for patients aged less
than 12 years. Because children with an underlying chronic medical
condition are at a higher risk of complications of influenza infection,
one might assume that the benefits of neuraminidase inhibitors in these
'at risk' children are greater than in the general paediatric population.
In our recent systematic review of the use of neuraminidase
inhibitors in children with influenza, we found no published studies on
the effectiveness of oseltamivir in reducing the time to resolution of
illness or time to return to normal activity in ‘at-risk’ children (2).
However, as we discovered by searching the website of the European Agency
for the Evaluation of Medicinal Products, it is evident that data from ‘at
risk’ children do exist, and that these were made available by Roche, the
manufacturers of oseltamivir, during their application for Marketing
Authorisation for the drug. In the ensuing European Public Assessment
Report, limited results are documented from 178 children with chronic
asthma and confirmed influenza infection enrolled in study
WV15759/WV158713. The stated difference in ‘time to freedom from illness’
between children receiving placebo and children receiving oseltamivir is
statistically non-significant, at only 10.3 hours (a reduction of 8%;
p=0.54). Indeed, the report comments that Roche have ‘committed to perform
a new study in asthmatic children in order to further clarify the
potential clinical benefits’.
The failure to publish study WV15759/WV15871 is an example of
publication bias. Furthermore, it appears that this result, although
distributed to the European Agency for the Evaluation of Medicinal
Products, was not made available to NICE. Certainly, the systematic review
commissioned by NICE to inform their guidance, recently abbreviated in the
BMJ, excluded the study because there were ‘no data’ (4,5).
We believe that significant doubt persists about the efficacy of
oseltamivir in ‘at risk’ children. Although the efficacy of oseltamivir in
healthy children has been demonstrated, and this apparently non-
significant result may represent a Type II error, we do think that it is a
mistake for our national prescribing policy to focus use of the drug on
this very population of children in whom there remains a dearth of
evidence.
References:
1. National Institute for Clinical Excellence. Technology Appraisal
Guidance No. 58. London: NICE, 2003.
http://www.nice.org.uk/pdf/58_Flu_fullguidance.pdf
2. Matheson NJ, Symmonds-Abrahams M, Sheikh A, Shepperd S, Harnden A.
Neuraminidase inhibitors for preventing and treating influenza in children
(Cochrane Review). In: The Cochrane Library, Issue 3, 2003. Oxford: Update
Software.
3. European Agency for the Evaluation of Medicinal Products. Tamiflu.
European Public Assessment Report 2002.
http://www.eudra.org/humandocs/humans/epar/tamiflu/tamiflu.htm
4. Turner D, Wailoo A, Nicholson K, Cooper N, Sutton A, Abrams K.
Systematic review and economic decision modelling for the prevention and
treatment of influenza A and B. Health Technology Assessment 2002.
http://www.nice.org.uk/docref.asp?d=35650
5. Cooper NJ, Sutton AJ, Abrams KR, Wailoo A, Turner DA, Nicholson
KG. Effectiveness of neuraminidase inhibitors in treatment and prevention
of influenza A and B: systematic review and meta-analyses of randomised
controlled trials. BMJ 2003;326:1235-40.
Competing interests:
None declared
Competing interests: No competing interests