Flu antivirals: the good news (they work), the bad news (not very well), the good news in the bad news (we're not likely to lose much)

Yesterday (today as I am writing this) the British Medical Journal published another Cochrane meta-analysis on the efficacy of neurimminidase inhibitor antivirals (the only two in use now, being oseltamivir [Tamiflu] and zanimivir [Relenza]). Their conclusions have made the news, so I guess I should cast my baleful eye on their handiwork. I think there is less here than meets the eye, but first let's look at what meets the eye.

This is a meta-analysis, that is, an analysis of other analyses, the other analyses in this case being drug trials of Tamiflu or Relanza in children. So it's an observational study of experimental studies, if you follow me. "Experimental" in this context means studies on children where the investigators control the treatment assignment (an antiviral or a placebo or no treatment). In essence, it is a review article of other studies where the authors employ various qualitative and quantitative techniques to combine results to come up with a summary of the studies, taken together. It's more complicated than that, but that's the general idea. It's potentially better than the kind of reviews of the literature commonly done because it is very explicit about what kinds of analyses will be included and the methods of weighting the results are also explicit and often quite sophisticated. I say potentially better because it takes a very narrow view of the subject, only allowing data from scientific studies of a particular kind. The Cochrane consortium last looked at this question in 2005 and this article looks at what has been learned in the interim, clearly with an eye on the swine flu pandemic now underway. All of the analyses they looked at were for seasonal flu, not pandemic flu. How generalizable this is to pandemic flu is unclear, but it is reasonable to think it has relevance.

There were only four studies meeting their strict eligibility criteria in this time period using antivirals to treat flu in children, two for each antiviral. The total number of children in the treatment studies was just under 1800, about two thirds of whom had virologically confirmed flu. Two thirds of those had influenza A. The rest had flu B. There was no differentiation of flu A subtypes. Three more studies used antivirals (two Relenza, one Tamiflu) as post exposure prophylaxis (just under 900 children). The studies were randomized trials involving children less than 12 who had flu (either clinically suspected or virologically confirmed) but not sick enough to be hospitalized. Thus the conclusions say nothing about the efficacy of these drugs for really sick children, although this is not clear from the news reports (example from the BBC: "The antiviral drugs being used to treat swine flu do not appear to work well in children, say UK researchers." This also fails to mention this was not a study of the use of these drugs for swine flu.)

I've never been much of a fan of antivirals as a way to deal with pandemic flu, but that's because I'm a public health person, not a clinician. My interest is in things that work on the population level, not applied at the level of the individual. In addition I was never impressed by how well these drugs worked. At times I even wondered if they worked at all were we to take a hard look at them (many of the studies were financed by the drug companies and we now know this is often a tainted source). Antivirals aren't like antibiotics, where you can sometimes work almost miraculous cures. If they work, they work at the margins. With those prejudices of mine as background, I can state that one clear message of the 2005 review and this one is that both of these drugs work to some extent. You wouldn't get that idea at all if all you read was the news headlines (the BBC again: Flu drugs 'unhelpful' in children). They not only work, but they work on every single measure examined: reduction of time with symptoms (.5 days to 1.5 days); time of illness (.4 days to 1.5 days), where this was defined as resolution of all symptoms and resolution of fever and return to school or normal activities; reduction in cough or fever (1.3 days for Tamiflu, "reduced incidence of moderate or severe cough" at day five with Relenza); reduction in asthma exacerbation; improvement in pulmonary function; reduction in antibiotic use; reduction in otitis media (middle ear infection) at day 10; and in confirmed secondary cases with an infected index case (reduction in transmission of about 8%).

In some of these outcomes the differences were not statistically significant, but in no instance -- not a single one I was able to see in this paper -- was there an outcome that wasn't consistent with the drugs working. Remember that the authors were surveying less than 3000 children divided up into seven studies, each of varying quality and different outcomes. The most plausible explanation for a lack of statistical significance given the consistent pattern and the biology is that there was insufficient statistical power. It is certainly false and absolutely incorrect to say that the outcomes that were not statistically significant showed no effect. In every instance they showed an effect of the drug in the right direction. In some instances the alternative explanation of random variation remained on the table along with a real effect.

In trying to make the jump from this review to the current swine flu situation there are other issues to contend with. Anywhere from 2% to 20% of the children in these trials had gotten seasonal flu vaccination, which could well have modulated the severity of their illness and the response to antivirals. This is especially pertinent in trying to extrapolate to populations of children in the initial stages of this pandemic, where none of them will have been vaccinated. Second, as already noted, none of these children were sick enough to be hospitalized. The marginal improvement in these community residing patients may look very different in very sick children who are on the margin between needing vents or no vents or even a fatal outcome. Nor do we know much about children with serious underlying medical conditions. That is work that remains to be done and some of it is happening now. Third, we know little about the efficacy of these drugs across flu A and flu B or between subtypes of flu A. Are there significant differences? We know that the neuriminidase protein on the virus looks different in different subtypes (there are at least two main NA subgroups) but we don't know much about the effect of those differences on antiviral efficacy. Moreover it is likely that many of these children were infected with viruses resistant to Tamiflu. So far the swine flu virus remains sensitive.

While we fear this paper will lead to misinterpretation and we think it has been oversold, it does raise some very important questions. It presents clear evidence these drugs work, but do they work well enough? In the Big Picture, for most patients the improvement is not very significant (although for individuals a day or more gained without symptoms is not just a tunafish sandwich). Tamiflu has some adverse effects, most commonly nausea and vomiting. That's not fun, either. When told of this, my daughter declined the Tamiflu she was offered when she came down with the virus.

Finally, there is the prospect that unwise use will promote resistance and deprive us of one of the few therapies we have for swine flu. This is not a simple issue. To have the greatest chance of success these drugs should be used relatively early in the course of the illness, often before anyone knows which direction it is headed. If we wait to use them only when the patient goes sour, they will have lost much of their potential efficacy. On the other hand, suppose we do lose their use because the virus develops resistance. The current seasonal H1N1 is almost entirely resistant to Tamiflu (but not Relenza) and we have managed quite well without it. That's the silver lining to the fact these are not miracle drugs. If you lose them, you aren't losing the ability to work a miracle. It's the good news in the bad news.

The real take home lesson in the BMJ paper is that for seasonal flu these drugs work for children but not well enough to rely on them for much. We don't know whether this is also true for swine flu and for very sick children, but studies now underway which will likely provide some data. How much of what this paper provides will turn out to be of any use remains to be seen.

Meanwhile, caveat lector.


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This paper in Pediatrics was missing from the BMJ analysis.

For kids with underlying conditions (ie the kids most vulnerable to flu) oseltamivir can be helpful. Usual caveats - retrospective data, etc - but the point needs to be clarified that the BMJ paper was talking about healthy kids.


Pediatrics. 2009 Jul;124(1):170-8.

Effects of oseltamivir on influenza-related complications in children with chronic medical conditions.

Piedra PA, Schulman KL, Blumentals WA.

Departments of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas 77030, USA. ppiedra@bcm.tmc.edu

OBJECTIVE: This study investigated the influence of oseltamivir on influenza-related complications and hospitalizations for children and adolescents, 1 to 17 years of age, with chronic medical conditions or neurologic or neuromuscular disease. METHODS: In a retrospective study, outcomes for patients who were given oseltamivir within 1 day after influenza diagnosis were compared with those for patients who received no antiviral therapy. Anonymous data from MarketScan databases (Thomson Reuters, Cambridge, MA) were used to identify patients from 6 influenza seasons between 2000 and 2006. The study outcomes were frequencies of pneumonia, respiratory illnesses other than pneumonia, otitis media, and hospitalization. RESULTS: Oseltamivir was prescribed for 1634 patients according to the study criteria, and 3721 patients received no antiviral therapy for their influenza. After adjustment for demographic and medical history variables, oseltamivir was associated with significant reductions in the risks of respiratory illnesses other than pneumonia, otitis media and its complications, and all-cause hospitalization in the 14 days after influenza diagnosis. Analyses for 30 days after influenza diagnosis also showed significant risk reductions for respiratory illnesses other than pneumonia, otitis media and its complications, and all-cause hospitalization with oseltamivir. CONCLUSION: When it was prescribed at influenza diagnosis, oseltamivir was associated with reduced risks of influenza-related complications and hospitalizations for children and adolescents at high risk of influenza complications.

PMID: 19564297

I'm not familiar with zanimivir... I would like to know more about it so I can suggest to stock it in our hospital. What is it's pharmacological action? Is it same with oseltamivir?

Anyone interested in science-based prevention measures one can take against any flu virus should read the article, Defending Yourself Against Virus Infections

The authors state: "We decided to evaluate the peer-reviewed scientific literature indexed by the National Library of Medicine on natural products for those that have useful antiviral effects at safe dosages."

Rae: zanimivir's trade name is Relenza. Same mechanism as Tamiflu but it must be inhaled in a dry powder. It has been on the market for years.

I just read on Pro-Med that tamiflu should not be given to children. Here's a quote from the post:
"Children should not be given the antiviral drug Tamiflu [oseltamivir] for swine flu [influenza pandemic (H1N1) 2009 virus infection] because its harms outweigh any benefits, and the government should review its policy on dealing with the pandemic, researchers have said."
The actual link is pretty long but the post can be found on August 11, 2009's listing of posts. The title is INFLUENZA PANDEMIC (H1N1) 2009 (28): CHILD TREATMENT

On the 28th July 'The Guardian' newspaper (UK) had a cut-out-and-keep advice in partnership with the British Medical Journal.

Under the headline 'What if my child has swine flu?' the advice is 'Children can take antiviral medicines, on the advice of a doctor. Even babies under one year old can take anitviral medicines if a doctor thinks it is necessary.'

Elswhere in the article, under the heading 'What anitviral drugs are there?', the following information is given. 'Oseltamivir {Tamiflu} is a tablet, and zanamivir {Relenza} comes as a spray you breathe in. Both may have side-effects. Some people taking oseltamivir feel sick or vomit. Zanamivir can cause diarrhoea.'

{my inclusions}

Gindy: There is an ongoing controversy. I think truffle points to the usual advice, which is follow the advice of your health care provider. Each patient is different and for many things there isn't a one size fits all recommendation. Almost all medical care involves untested or uncertain advice and therapy. As always, it is a balancing act and sometimes we don't get it right. In this case there remains uncertainty. If my daughter had asked me about Tamiflu I would have said to take it (she didn't ask and didn't take it) and if my grandchildren were down with what I knew was flu I'd probably recommend it for them, too. But I don't know for sure. You have to make choices and it's easy to second guess.

We are going to find out soon enough-- and I may add for the very first time in human history--just how useful antivirals are in a pandemic setting. The concerning thing is that they are strongly incorporated into pandemic plans but with little research or experience to substantiate such a prominent postion in the pandemic strategy of the US govt. and its overseas counterparts. Modelling says ya they work but I dont believe the 30% or so reduction in R0 as a consequece of there use the models claim. I have gotten enormous grief from pts who have presented to me demanding tamiflu even though they have had ILI symptoms for over 4 days--again a shortcoming of the lack of risk communication that is pervasive in medicine and public health of not educating the public on their use.

The other problem is that 13 states still have not purchased at least 50 % of their half of the federally subsidized strategic stockpile (my state MA and its neighbors CT and RI are 3 of the 13). Sound economic politics on their behalf or stupidity--time will tell.

Is anyone stocking up on elderberry extract which is touted (several peer review journals--and dont ask I didnt keep a file on this) as mother nature's influenza antiviral?

By BostonERdoc (not verified) on 11 Aug 2009 #permalink

Comments from some physicians who have treated mostly young patients with H5 disease in Asia and South Asia suggest that, at least in some, upping the dose of oseltamivir from 75 to 150 mgm BID was helpful, but who knows? Larry Altman's piece in this morning's NYT about novel H1N1 patients who are afebrile could add more complexity to the making of a timely diagnosis and initiating treatment. Can anyone provide details to Altman's piece?

Here's the conventional medicine view on elderberry:



and the traditional medicine view:

King's Dispensatory

Dr. Scudder (Eclectic, 1870)

and a comment about toxicity from today's herbalists:


and my two cents: red elderberries are made into jelly in Alaska (i.e., cooked berries are not toxic)

By phytosleuth (not verified) on 11 Aug 2009 #permalink

The thing that I don't understand - is there not an argument for "reserving" the antivirals for cases bad enough to need hospitalization, people with other underlying health probs, high-risk groups etc? Surely chucking it at anyone who reports ILI - which is what is reputedly happening here in the UK via Govt phonelines - is simply going to generate resistance and ultimately make the drugs less useful for those that might really need them (and who are also presumably the people where the risk / benefit for antiviral treatment is likely to be more towards benefit?)

This is, not, note, a terribly informed argument - I'm basing it on an idiot PhD's (i.e. my) vague analogy to antibiotic overuse. I'd be interested to hear from the public health / ER / infectious disease specialists on here whether they think there is anything to the argument.

Dr. Aust: It's a complicated situation. You want to get the drug to people early in the illness or it isn't very effective. But you don't want people overwhelming the Emergency Room or GP's office for things that can be handled by phone. So this is a compromise, which, like all compromises or balancing acts, may turn out to need modification. Identifying those "who most need it" is the hard part. We don't know how to do that, now. If you wait until they are on vents, it's probably too late. But using them for folks with co-morbidities or specific risk factors probably makes sense and I expect that is a modification that is coming.

Is anyone stocking up on elderberry extract which is touted (several peer review journals--and dont ask I didnt keep a file on this) as mother nature's influenza antiviral?

I seem to recall there being some concern that elderberry could be dangerous in certain flu cases because it increases TNF and other cytokines....

I wonder if the timely application of the antivirals immediately at the time of symptom onset is the most crucial factor determining their efficiency.

This is because antivirals (unlike to the way antibiotics work) can not destroy existing virus particles but only work by preventing/slowing their further replication.

So considering the explosive exponential growth of the number of virus particles in a newly infected individual's body with the number of particles doubling, say, every hour and reaching peak viral load levels within only 48 hours, then it becomes clear that the antiviral looses power exponentially with every hour of delay in treatment.

Starting treatment within the conventionally recommeded "48 hour window" may very well be much too late to prevent the bulk of the damage done to the body cells because after 48 hours the largest part of the virus growth phase is already over and the symptoms of the disease ("viral inflammation") are now largely due to the body's cleanup efforts to repair the damage already done from the previous virus replication phase. It is like a steep and short "pandemic wave" sweeping the body cells and the antiviral can only be effective if it is already present in the cells at the time of arrival of the "infection wave".

By h1n1_watcher (not verified) on 11 Aug 2009 #permalink

Tamiflu does work but in varying capacity and with dangerous side effects in teens apparently.

I have noted the dosages suggested to be use increasing for it to produce an outcome. But there never is any way to determine if it was the body or the drug against the bug that fixed it.

It was shown to work pretty damned good in Pakistan when H5N1 was getting ready to run amok there. The WHO shipped that stuff in and passed it out like candy and the sudden surge stopped. So thats an acceptable assumption that it stopped it. Remember slow it down, stamp it out and if all else fails throw the antiviral blanket...

Everything that this administration and Mexico failed to do.

Revere is right though... if this shit takes a big turn for the worse I would try everything from elderberries to Tamiflu/Relenza. Vax trials started yesterday on 2000 by the way and that may be all the testing this stuff gets.

By M. Randolph Kruger (not verified) on 11 Aug 2009 #permalink

Hmm, I skimmed the paper yesterday and my feeling was that if the manufacturers can only obtain marginal or non-significant benefit in laboratory-confirmed cases, then the efficacy of the treatment in pragmatic use is going to be negligible.

BTW, according to Tom Nolan's blog on the BMJ website, the UK Department of Health has extended the prescription time for Tamiflu to patients who have been symptomatic for up to 7 days: http://blogs.bmj.com/bmj/2009/07/22/tom-nolan-prescribing-antivirals-is…

Revere, I'm curious as to what you think of the usage of pneumococcal vaccinations as prophylaxis for complications due to influenza (if I'm phrasing this correctly) from a public health standpoint. Mightn't mass pneumococcal vaccinations stave off some of the complications - and thereby reduce mortality among those who don't typically experience said complications during a normal flu season (but might in a pandemic situation)?

By VassarLiberal (not verified) on 11 Aug 2009 #permalink

Stoker: I did see that about extending the time. The truth is there isn't good data on how long before there is no or negligible efficacy and it undoubtedly varies with the patient and perhaps the virus. But it is also pretty clear that the earlier the better. With respect to the "non significant benefit" that is something you have to be careful about. The "significance" doesn't refer to the importance of the clinical benefit but has to do with statistical issues regarding the estimate. Things can be statistically significant and not have any clinical or public health significance and vice versa.

Phyto and others: the 'to cook or not to cook' sambucus niger controversy rages. Since extraction can be hot or cold depending on the method and complexity of the extrator, does anyone know what method is used in OTC versions, such as Sambucol? How much cooking is enough? For example, a tincture of raw niger introduced into boiling tea and allowed to cool...would that be 'cooked'?

I read with interest that the fully ripe berries supposedly don't have the bad gastro effect. Does anyone know definitively? As kids we made jelly (cooked) wine (not cooked) and ate off the bush, but as they are pretty tart we didn't eat many. All old cooking recipes say to use 'ripe fruit' and 'be sure to pull all those little berries off the stems' because of cyanide in the stems. I have trusted old cookbooks for years because the writers actually used the ingredients and often depended on wild fruit. Until construction in the area made the berries harder to find, elderberry jelly was a staple in our house and my Dad made wine, too (it tasted awful). No one got sick in my remembrance, though.

Sambucus Niger is ripening now here in New England, and since it's been a good berry year there might be plenty to find in wetlands and rural areas for those who want to be herbally prepared. I've even seen it by the side of the road, but obviously you don't pick there but away from the polluted bushes.


By Columbkille (not verified) on 11 Aug 2009 #permalink

It's not appropriate to draw out a discussion on herbal remedies here. So here's a key paper, cited over a dozen times by newer papers which might clarify:

Zakay-Rones Z, Thorn E, Wollan T, Wadstein J. Randomized study of the efficacy and safety of oral elderberry extract in the treatment of influenza A and B virus infections. J Int Med Res 2004;32:132-140).

The initial hypothesis was that the lectins in the berries may bind to and neutralize hemagglutin spikes on the surface of some kinds of viruses. But other compounds such as polyphenols suggest some bioactivity as well.

It's prudent to go to someone who is appropriately educated for clarity on this product and to avoid marketing schemes that make promises sounding too good to be true. I'll be making elderberry syrup later next month, but I'm not putting all my hopes in elderberry. Life is never that simple. Neither is illness.

By phytosleuth (not verified) on 11 Aug 2009 #permalink

I am not familiar with anti-virals or influenze literature, but your summary of the review article struck me as being similar to summaries of homeopathic meta-analyses.

Industry-sponsored small trials, on individuals where the disease is self-limiting, with multiple outcomes that achieve non-significant improvements on average.

When I was reading your article I found myself agreeing with your cautious approval, but afterwards I thought that if I'd substituted "anti-virals" for "homeopathy" I would have been scandalised about over-interpretation of the data.

Dear Rae

I find it appalling that an administrator / doctor of a hospital doesnt know what zanimivir is. That kind of ignorance is truely scary. Hope I don't end in your hospital with swine or any other type of flu.

Time to crawl out from under that rock my friend and read a few medical or news papers. Unbelievable.

dmcw: What we find here is not dissimilar to many therapies, including conventional ones. There is both biology here (lots of it) and the question of statistical non-significance is most plausibly a result of populations that aren't big enough. This is not a multiple comparison issue. Every outcome, without exception, was in the direction of the drug having an effect, and the outcomes were chosen in advance. There are really only a handful of them. Again, I think you are in danger of confusing statistical significance with treatment effect size. They are not the same. You can have very large effects that are not statistically significant and statistically significant effects whose size is inconsequential.

Annoyed that the media reporting tends to lump Tamiflu and Relenza together, when the main issue of vomiting / dehydration in kids was limited to the Tamiflu, and not the Relenza. I know which of the two drugs I'd rather go with, especially if you're just aiming at a placebo and calming effect as the late prescriptions seem to be.

...speaking of which, did Miso get banned? I thought (s)he'd be all over this thread like stink on a monkey.

Magpie: No, didn't ban Miso. I hardly ever ban anyone. However the Cochrane review wasn't especially favorable to zanamivir with most outcomes so I'm not sure there was a lot to grab on to. I think zanamivir is a viable option and it works, too. But neither work very well and each has its drawbacks. I've never put much stock in antivirals, but as I said, I'm a public health person and not a clinician (although I have a license to practice, my career has been in research and teaching and public health practice). The antiviral connection is more relevant to clinicians.