The New York Times
September 21, 2005
By ELISABETH ROSENTHAL
Rome, Sept. 21 - Just as governments around the world are stockpiling millions of doses of flu vaccine and antiviral drugs in anticipation of a potential influenza pandemic, two new research papers published today have found that such treatments are far less effective than previously thought.
"The studies published today reinforce the shortcomings of our efforts to control influenza," wrote Dr. Guan Yi, a virologist at the University of Hong Kong, in an editorial that accompanied the papers. The two studies were published early online by the British medical journal, the Lancet, because of their implications for the upcoming flu season.
In one paper, international researchers analyzed all the data from patient studies on the flu vaccine performed worldwide in the past 37 years and discovered that vaccines showed at best a "modest" ability to prevent influenza or its complications in elderly people.
"The runaway 100 percent effectiveness that's touted by proponents was nowhere to be seen," said Tom Jefferson, a Rome-based researcher with the Cochrane Vaccine Fields project, an international consortium of scientists who perform systematic reviews of research data.
"There is a wild overestimation of the impact of these vaccines in the community," Dr. Jefferson said. "In the case of a pandemic, we are unsure from the data whether these vaccines would work on the elderly."
In the second paper, researchers from the Centers for Disease Control found that influenza viruses, particularly those from the dreaded bird flu strain, had developed high rates of resistance to older and cheaper antiviral drugs - rates that have escalated rapidly since 2003, particularly in Asia.
"We were alarmed to find such a dramatic increase in drug resistance in circulating human influenza viruses in recent years," said Dr. Rick Bright of the Centers for Disease Control, in Atlanta. "Our report has broad implications for agencies and governments planning to stockpile these drugs for epidemic and pandemic strains of influenza."
Before 2000, almost no virus was resistant to the drug Amantadine. By 2004, 15 percent of influenza A viruses collected in South Korea, 70 percent in Hong Kong and 74 percent in China were impervious. During the first six months of 2005, 15 percent of the influenza A viruses in the United States were resistant, up from 2 percent the year before. All human cases of the bird flu (H5N1) strain - which is still extremely rare in humans - have been resistant, the researchers said.
The immediate implications of these finding are most ominous for the developing world, because wealthier nations have been stockpiling newer and vastly more expensive antiviral medicines, like Tamiflu, which are effective against the disease but still on patent.
Even so, the research is alarming because it demonstrates how quickly and unexpectedly flu viruses can become impervious to medicines once they are put into common use, as they would be in the case of a pandemic. Also, at their best, antiviral medicines do not cure influenza. They cut down on transmission of the disease and reduce somewhat the symptoms and complications in those already infected, including the high rate of associated pneumonias.
Called for comment, a spokesman for the World Health Organization, Dick Thompson, said that the group could neither support nor deny the findings of the analysis of vaccine studies at this point, noting only that some experts criticized the researchers for "not including some important past studies" in their sample.
But the problem of resistance "is a finding that is being discussed widely within the flu world and will bear careful monitoring," Mr. Thompson said, noting that he was not aware of any country in the developing world that had been able to stockpile the newer drugs.
Anticipating a possible flu pandemic caused by a variant of the bird flu virus - which belongs to the influenza A group - countries have been aggressively buying up antiviral medicines and contracting to purchase a flu vaccine against that strain, even though it is still under development.
The United States has ordered $100 million worth of vaccine and Italy $43 million worth, for example.
The current bird flu virus does not spread easily - if at all - from human to human, and so has little potential to become a worldwide human scourge. But the World Health Organization has warned that it could acquire that potential through a couple of common biological processes, and that countries should prepare for a possible wave of serious influenza.
The fact that the current study showed that flu vaccines have had only a modest effect in the elderly is particularly worrisome, since this a group that tends to suffer high rates of complications and deaths from the disease and vaccination is currently standard practice. In people over 65, the vaccines "are apparently ineffective" in the prevention of influenza, pneumonia and hospital admissions, although they did reduce deaths from pneumonia by "up to 30 per cent."
"What you see is that marketing rules the response to influenza, and scientific evidence comes fourth or fifth," Dr. Jefferson said. "Vaccines may have a role, but they appear to have a modest effect. The best strategy to prevent the illness is to wash your hands."
The research showed, however, that vaccines offered better protection in nursing home patients, who suffered significantly lower rates of complications like pneumonia if inoculated.
In terms of antiviral drugs, 30 countries have placed huge orders for Tamiflu, the most popular, newer, more expensive antiviral medicine, a spokesman for Roche Martina Rupp, said. The company is offering it at a "substantial discount" for public health purchases. The Dutch Health Ministry has ordered 5 million doses, enough to treat one-third of the population. The British Department of Health has ordered supplies to treat 15 million.
Ms. Rupp would not give either the retail or the discounted price, although pharmacists said a full course of the drug costs more than $100.
Researchers speculate that one reason why resistance rates to the older, cheaper antiviral drugs in Asia jumped so much starting in 2000 - and skyrocketed after 2002 - is that doctors there started prescribing the drugs far more widely after the advent of bird flu in 1997 and of sudden acute respiratory syndrome, or SARS, in 2002.
Although actual human cases of these two diseases have always been rare, they are also quite deadly, so patients are sometimes started on antiviral drugs when they develop a respiratory illness, even though in most cases they will prove to have nothing more than a common cold.
This is because all antiviral medicines work only if they are started within 48 hours of the onset of symptoms and, in that period, it is generally impossible to tell if patients have a deadly strain of flu or
merely a mild virus.