TORONTO — Can cheap and readily available treatments like steroids and cholesterol-lowering statin drugs help save the sickest of H1N1 patients? New efforts by researchers in Canada, the United States and France could help answer this pressing question.
Randomized controlled studies looking at whether corticosteroids, statins or a combination of the two could contribute to improved survival rates in gravely ill pandemic flu patients are being organized in the three countries by linked networks of intensive care specialists, according to Dr. John Marshall, chair of the Canadian Critical Care Trials Group.
The aim is to try to gather data fast enough to answer the questions in real time, a goal that eluded researchers during SARS.
Toronto physicians treating SARS cases tried to mount a clinical trial to see whether the antiviral drug ribavirin - which was routinely given to SARS patients for lack of other options - was actually helping. But before the trial could be approved, the disease disappeared.
The same could happen with this effort, admits Marshall, a trauma surgeon and critical-care specialist at Toronto's St. Michael's Hospital, who says it will take quick work and international collaborations to generate enough data to clarify the role steroids and statins might play in treating H1N1 cases.
"What are the chances that we will have 1,400 Canadian patients enrolled in the study by the middle of January? Pretty small. But what are the chances that we will have made a good inroad into being able to run the study and pool some data with France and the United States? I think the chances are relatively good that we can do that," he says.
"And what are the chances that we're going to have an extraordinarily rich understanding of how one optimally does these studies under pandemic conditions? I think the chances are 100 per cent of that."
In recent years as the influenza world prepared for a feared pandemic, the scarcity of weapons with which to fight flu weighed heavily on the minds of planners.
Vaccine would take months to make. And because of the limited global production capacity, it would be in short supply and available mostly in wealthy countries. Antiviral drugs might be more readily available, but the best ones aren't cheap and all are vulnerable to the development of drug resistance. (As it turns out, the cheap flu drugs don't work against this virus, which has been resistant to them from the start.)
So were there drugs already in existence, preferably off-patent, that might help?
Spurred in large measure by the relentless commentary writing of retired American virologist Dr. David Fedson - who believes statins could play a major role in combating pandemic influenza - others have started to look at the question.
A study presented at the recent meeting of the Infectious Diseases Society of America suggested that people on statins for cholesterol control who were hospitalized with seasonal flu were half as likely to die as hospitalized flu patients who were not on the drugs.
While tantalizing, that doesn't prove statins - which reduce inflammation and may have mild antiviral properties - are useful as treatment for severe H1N1 infection.
For one thing the two groups of patients were not randomized, so there could have been key differences between them that contributed to the different outcomes. And for another, the people who are hospitalized for seasonal flu are generally a lot older than the severely ill H1N1 patients. The way the drugs act in people with waning immune systems might not be the same as they would act in younger adults who were reasonably healthy before contracting H1N1.
Marshall says the trials to be done will compare patients who got a statin versus a placebo (the United States) or corticosteroids versus a placebo (France). The Canadian team hopes to run a four-armed study randomly assigning patients to get neither of these drugs, one of the drugs or the drugs in combination.
The World Health Organization recommended against use of corticosteroids in care of patients with H5N1 avian flu virus, and the experience in SARS was that patients who received heavy doses of steroids suffered a number of side-effects, including bone loss.
"There's no questions that steroids can have real downsides," says Dr. Frederick Hayden, an antiviral expert who splits his time between the University of Virginia and Britain's Wellcome Trust.
Hayden notes a recent study from Hong Kong suggested steroid use in the treatment of seasonal flu prolonged the period in which the virus replicated. Still, he suggested there is evidence that low-dose steroids might be beneficial, but said much depends on when they are used and for how long.
Marshall says the steroid question is an open one and the reality is that a substantial portion of severely ill H1N1 patients are probably getting steroid therapy, as their doctors struggle to find anything that might help.
The statins and steroids would be used in addition to standard treatment for severe H1N1 patients, which includes the antivirals Tamiflu or Relenza and use of mechanical breathing techniques if needed.
Because the drugs will be used in addition to standard care, these trials won't tell researchers whether statins and steroids on their own would help H1N1 patients in resource-poor countries survive severe infection, Hayden says. "I don't think one can generalize those findings to other patient populations or other settings."
Still, he says it would be good to have some data based on randomized controlled trials, the gold standard of medical evidence.
"Given the uncertainty in these circumstances, having controlled data from a prospective trial will be very useful," Hayden says. "And they will hopefully make us smarter in terms of our management of seriously ill patients in the future."
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