Study urges against regular use of flu drugsUpdated Wed. Jan. 18...

Study urges against regular use of flu drugs
Updated Wed. Jan. 18 2006 11:23 PM ET

Canadian Press

TORONTO — A newly published re-analysis of existing studies is questioning the merits of the only four flu drugs on the market, saying use of two should be discouraged and the remaining two should only be used in the event of a serious flu season or an influenza pandemic.

Antiviral experts and infectious disease specialists viewed the study with dismay and annoyance, saying the conclusions will feed confusion among the public and policy-makers over what role the drugs can and should play in minimizing the toll of seasonal -- and potentially pandemic -- influenza.

"It's also going to confuse (medical) practitioners, in my view,'' said Dr. Frederick Hayden, a leading antiviral expert from the University of Virginia whose studies are among those the authors draw upon to reach their conclusions.

"And the fact that it's appearing in a widely disseminated journal like the Lancet may provide it with credibility that is undeserved.''

The lead author, meanwhile, argued Wednesday that the work is a solid piece of analysis aimed not at the public but at the scientific community. And Dr. Tom Jefferson said anyone taking from the review the message that neuraminidase inhibitors -- the better known of which is oseltamivir or Tamiflu -- do not work against H5N1 avian influenza would be misreading the article.

"That's not what the review says. That is wrong,'' Jefferson said from Rome, where he works with the Cochrane Vaccines Field, a division of the Cochrane Collaboration, an international not-for-profit network aimed at promoting evidence-based health care.

The study, published Thursday by The Lancet, said the authors could find "no credible data on the effects of oseltamivir on avian influenza.''

Jefferson explained the only data the authors included in their analysis were those drawn from randomized controlled trials or prospective clinical trials.

Scientists who took issue with the review readily admitted the world needs more data on how well oseltamivir and the other neuraminidase inhibitor, zanamivir (Relenza) work in human cases of H5N1 flu. Public health authorities have been anxious to conduct the needed studies, but have faced significant logistical challenges.

Some affected countries have been slow to green light the projects. Human cases have popped up sporadically, across a diverse geographic range spanning six countries. In many cases, drug treatment has started a number of days after the onset of illness.

Treatment with neuraminidase inhibitors is meant to be started within 48 hours of the start of symptoms and little is known about how useful the drugs are when started outside that window.

Hayden and others working under the auspices of the World Health Organization are in the process of getting up and running a prospective trial of Tamiflu as therapy for H5N1 flu in humans. Prospective trials follow patients forward from the start of treatment, gathering consistent data from each patient.

But it is impossible at this point to perform a randomized controlled trial comparing Tamiflu to a placebo in H5N1 cases. Given the severity of H5N1 disease in people, and the fact that there are no other treatment options, providing a patient with a placebo instead of the drug would be unethical and would not be allowed.

"You can't deny people who are unwell licensed treatments,'' agreed Jefferson, a public health epidemiologist.

Jefferson and his co-authors wrote what is known as a Cochrane review -- a highly specialized type of meta-analysis in which authors scour the entire published medical literature for specific types of trials and studies on a particular treatment or issue and then re-analyze the combined data.

The review examined studies looking at the performance and safety of the two classes of flu drugs, the adamantanes (amantadine and rimantadine) and the neuraminidase inhibitors (oseltamivir and zanamivir, sold under the brand name Relenza).

The authors concluded that because neuraminidase inhibitors don't work against what are called influenza-like illnesses -- the myriad bugs that circulate in winter and cause flu-like symptoms but which are not influenza -- they should not be prescribed during regular flu seasons, when doctors rarely know if the patient has actual influenza or some other ailment.

During severe flu seasons and pandemics, when the likelihood is great that patients who complain of flu-like symptoms actually have influenza, the drugs should be used along with other public health measures such as isolation of sick people, they said.

Dr. Anne Moscona, a virologist at Cornell University's Weill Medical College, disagreed with the authors' interpretation of how useful neuraminidase inhibitors are against seasonal flu.

"I don't think anyone's arguing that these drugs are going to protect everyone, even from (regular) influenza,'' she said from New York. "Based on the very same data that these authors use to claim that they should not be used, I would argue that they will protect people who deserve protection....They're one of our useful tools.''

A number of experts questioned why the manufacturers of the existing flu drugs would continue to make them -- or why competitors would go through the expensive process of developing new flu drugs -- if there is no sustained market for them.

Jefferson said the authors could only deal with the data on the drugs and would leave discussion of markets forces to others. "That's outside my brief,'' he said.

In their closing arguments, the authors warned that over-estimation of the role drugs can play in containing and treating influenza may deter the development and use of other public health strategies aimed at dealing with the disease. The comment left infectious disease expert Dr. Allison McGeer shaking her head.

"Like all the things that have been failing with influenza for the last 150 years? This is dreaming in technicolour,'' said McGeer, head of infection control at Toronto's Mount Sinai Hospital.

"The reason we use drugs is because we haven't found anything else that works.''

While many authorities bristled over the review's findings and the timing of its publication, the Public Health Agency of Canada's lead flu expert took a more moderate approach to the work.

Dr. Arlene King, director of the respiratory diseases branch, said the review underscores the agency's longstanding position on the role antiviral drugs could play in the context of a flu pandemic.

"We have said all along that antivirals are not a panacea for pandemic influenza,'' King said.

"And they have to be used in conjunction with a whole armamentarium of strategies to deal with and combat a pandemic. And the cornerstone -- both in preventing seasonal flu and pandemic flu -- is vaccination.''

Of the older adamantane drugs, which are rarely prescribed outside of hospitals and nursing homes, the authors said use should be discouraged. They noted the drugs have serious side-effects -- nausea, insomnia and hallucinations -- and their use quickly gives rise to drug-resistant strains of virus.

Drug resistance has long been known to be a problem with the adamantane drugs. In fact, both the Public Health Agency of Canada and the U.S. Centers for Disease Control last weekend instructed doctors not to prescribe the drugs for prevention or treatment of flu this year after finding 91 per cent of samples of the dominant circulating strain of human flu are resistant to amantadine and rimantadine.