ノイラミニダーゼ抑制剤(oseltamivirまたはzanamivir)が、2009H1N1パンデミックにおいて入院患者の合併症や死亡を減らすと、ＮＥＪＭでＣＤＣのDr. Tim Uyeki は書いている。多くの専門家はコクランレビューが、インフルエンザ患者全てに当てはまると思われるべきでないと警告している。
Researchers Questions Tamiflu's Effectiveness
Doctors Say Popular Drug May Not Be Very Effective in Cutting Flu Severityhttp://abcnews.go.com/Health/SwineFluNews/tamiflus-flu-fighting-effectiveness-questioned/story?id=9283865
By MICHAEL SMITH
MedPage Today North American Correspondent
Dec. 8, 2009
There's not enough evidence to conclude that the antiviral drug oseltamivir (Tamiflu) has any benefit for the complications of influenza in otherwise healthy patients.
Photo: Tamiflu-Resistant Swine Flu Cluster Reported in NC: CDC: 4 people in NC test positive for Tamiflu-resistant swine flu, first such US cluster
A new report suggests the influenza drug Tamiflu may not be as effective as many believe.
That's the straightforward conclusion of an updated Cochrane review of the drug, appearing online in the British Medical Journal -- and many experts say it's not surprising.
"The currently available antiviral medications for treating influenza in otherwise healthy adults have never been shown to have much impact," said Dr. Richard Besser, ABC News senior health and medical editor.
But the path that led to that conclusion is anything but clear-cut, according to the journal's editors.
In a series of articles, including the review, the journal says that what began as a "straightforward exercise to confirm the evidence base for current policy and practice became instead a complex investigation."
The journal's editors raised a series of issues aside from the narrow clinical question, including who had access to data from Roche-funded trials, whether ghost writers were used to prepare journal manuscripts, and why some authors were not listed while -- in at least one case -- an author was cited who later said he can't recall performing the study.
A key concern was a meta-analysis of 10 studies that formed part of an earlier review -- a report whose conclusions could not be validated, in part because the drug's manufacturer, Roche, was slow in releasing the raw data, according to Fiona Godlee, the journal's editor.
"This is a long way from being the only time in which Roche and other drug companies have declined to share necessary data with legitimate authorities," Godlee said in an email.
The Cochrane group reviewed the evidence on antiflu drugs and concluded in early 2006 that -- among other things -- oseltamivir was effective in reducing the complications of flu among healthy adults.
At 150 milligrams a day, oseltamivir was effective in preventing lower respiratory tract complications in influenza cases, with an odds ratio of 0.32, the reviewers, led by Tom Jefferson, concluded at the time.
But earlier this year Jefferson and his colleagues at the Italy-based Cochrane Vaccines Field, a collaborative evaluation group, were asked by the British National Health Service to update the analysis.
At roughly the same time, they reported in BMJ, they got a letter from a Japanese pediatrician who criticized the earlier review for relying on unpublished, manufacturer-funded data contained in the 10-study meta-analysis.
Best and Worst States for H1N1 Info
The Cochrane reviewers reported that they asked Roche for the raw data in order to see if the earlier conclusions could stand, but did not get the information in time.
That meant, Jefferson and colleagues wrote, that they had to throw the whole study out, leaving only three studies ― not enough to cast light on the value of the drug in preventing complications.
"Paucity of good data has undermined previous findings for oseltamivir's prevention of complications from influenza," they said in the review.
In a prepared statement, a Roche spokesman said the company "stands behind" its research.
"The Cochrane Group was wrong to exclude the data," said David Reddy, head of the company's global pandemic taskforce.
Still, many doctors say the Cochrane reviewers' findings are no surprise.
"It's generally known that the evidence for prevention of flu complications is weak," said Dr. Marvin Bittner of Creighton University in Omaha.
Dr. Amy Kaji of the University of California Los Angeles said she and her colleagues don't recommend the drug for otherwise healthy adults.
"I think we have all known this data that Tamiflu reduces symptomatology, at best, by one day," she said in an email. "The news is therefore not very new."
On the other hand, she said, in severely ill patients admitted for pneumonia and an influenza-like-illness, "there is some evidence demonstrating benefit."
Dr. Kristi Koenig of the University of California Irvine said she's seeing many otherwise healthy adults with flu-like symptoms who are worried about the H1N1 pandemic flu.
"They should understand that Tamiflu may not be indicated for them," Koenig said. "The vast majority of young healthy adults will do well with rest, fluids and ibuprofen/Tylenol, without tamiflu."
But it's a question of perspective, said Dr. William Schaffner of Vanderbilt University. "The drug is not perfect," he said in a telephone interview, but it offers at least some benefit for some people.
He said the Cochrane reviewers, while ethical and well-meaning, can sometimes be "extraordinarily prissy" about what kinds of data they'll accept.
"They're a lot more critical of some of the data than I would be," he said.
The U.S. Centers for Disease Control and Prevention doesn't comment on papers before they're published, a CDC spokesman said. But the spokesman said the agency's position has not changed from last month when Dr. Tim Uyeki of the agency's influenza division, wrote that observations suggested a benefit for the drug in reducing complications at least in some patients.
"Evidence from observational studies supports the benefit of neuraminidase inhibitors (oseltamivir or zanamivir) in reducing complications, including deaths, among hospitalized patients with 2009 pandemic influenza A (H1N1)," Uyeki wrote in the New England Journal of Medicine.
Many experts cautioned that the Cochrane review should not be taken to apply to all people with flu.
"It is important not to extend these findings to high-risk individuals or people with severe illness for whom antiviral drugs are recommended," said Besser.
"In these people, even a small benefit may be worth it," he said.
The truth about Tamiflu?
This Cochrane group's update of a 2005 review of oseltamivir in pandemic influenza concludes: "Neuraminidase inhibitors have modest effectiveness against the symptoms of influenza in otherwise healthy adults. The drugs are effective postexposure against laboratory confirmed influenza, but this is a small component of influenza-like illness, so for this outcome neuraminidase inhibitors are not effective. Neuraminidase inhibitors might be regarded as optional for reducing the symptoms of seasonal influenza. Paucity of good data has undermined previous findings for oseltamivir's prevention of complications from influenza. Independent randomised trials to resolve these uncertainties are needed."
A cluster of articles on bmj.com seeks to elucidate problems with the data that have underpinned the use of oseltamivir in healthy adults with pandemic influenza. Deborah Cohen retraces the steps of the Cochrane reviewers as they tried to obtain all the relevant data and finds that commitments to transparency are still in doubt. Peter Doshi explains that the public evidence base for this global public health drug is fragmented and inconsistent. And Nick Freemantle and Mel Calvert find that observational studies of oseltamivir's efficacy show minimal benefit. In an accompanying editorial, Fiona Godlee and Mike Clarke say that the full data from drug trials must be available for scrutiny by the scientific community.
Published 8 December 2009, doi:10.1136/bmj.b5106
Cite this as: BMJ 2009;339:b5106
Neuraminidase inhibitors for preventing and treating influenza in healthy adults: systematic review and meta-analysis
Tom Jefferson, researcher1, Mark Jones, statistician2, Peter Doshi, doctoral student3, Chris Del Mar, dean; coordinating editor of Cochrane Acute Respiratory Infections Group4
1 Acute Respiratory Infections Group, Cochrane Collaboration, Rome, Italy, 2 University of Queensland, School of Population Health, Brisbane, Australia, 3 Program in History, Anthropology, Science, Technology and Society, Massachusetts Institute of Technology, Cambridge, MA, USA, 4 Faculty of Health Sciences and Medicine, Bond University, Gold Coast, Australia
Correspondence to: C Del Mar firstname.lastname@example.org
Objectives To update a 2005 Cochrane review that assessed the effects of neuraminidase inhibitors in preventing or ameliorating the symptoms of influenza, the transmission of influenza, and complications from influenza in healthy adults, and to estimate the frequency of adverse effects.
Search strategy An updated search of the Cochrane central register of controlled trials (Cochrane Library 2009, issue 2), which contains the Acute Respiratory Infections Group’s specialised register, Medline (1950-Aug 2009), Embase (1980-Aug 2009), and post-marketing pharmacovigilance data and comparative safety cohorts.
Selection criteria Randomised placebo controlled studies of neuraminidase inhibitors in otherwise healthy adults exposed to naturally occurring influenza.
Main outcome measures Duration and incidence of symptoms; incidence of lower respiratory tract infections, or their proxies; and adverse events.
Data extraction Two reviewers applied inclusion criteria, assessed trial quality, and extracted data.
Data analysis Comparisons were structured into prophylaxis, treatment, and adverse events, with further subdivision by outcome and dose.
Results 20 trials were included: four on prophylaxis, 12 on treatment, and four on postexposure prophylaxis. For prophylaxis, neuraminidase inhibitors had no effect against influenza-like illness or asymptomatic influenza. The efficacy of oral oseltamivir against symptomatic laboratory confirmed influenza was 61% (risk ratio 0.39, 95% confidence interval 0.18 to 0.85) at 75 mg daily and 73% (0.27, 0.11 to 0.67) at 150 mg daily. Inhaled zanamivir 10 mg daily was 62% efficacious (0.38, 0.17 to 0.85). Oseltamivir for postexposure prophylaxis had an efficacy of 58% (95% confidence interval 15% to 79%) and 84% (49% to 95%) in two trials of households. Zanamivir performed similarly. The hazard ratios for time to alleviation of influenza-like illness symptoms were in favour of treatment: 1.20 (95% confidence interval 1.06 to 1.35) for oseltamivir and 1.24 (1.13 to 1.36) for zanamivir. Eight unpublished studies on complications were ineligible and therefore excluded. The remaining evidence suggests oseltamivir did not reduce influenza related lower respiratory tract complications (risk ratio 0.55, 95% confidence interval 0.22 to 1.35). From trial evidence, oseltamivir induced nausea (odds ratio 1.79, 95% confidence interval 1.10 to 2.93). Evidence of rarer adverse events from pharmacovigilance was of poor quality or possibly under-reported.
Conclusion Neuraminidase inhibitors have modest effectiveness against the symptoms of influenza in otherwise healthy adults. The drugs are effective postexposure against laboratory confirmed influenza, but this is a small component of influenza-like illness, so for this outcome neuraminidase inhibitors are not effective. Neuraminidase inhibitors might be regarded as optional for reducing the symptoms of seasonal influenza. Paucity of good data has undermined previous findings for oseltamivir’s prevention of complications from influenza. Independent randomised trials to resolve these uncertainties are needed.
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