RIDER OF THE PALE HORSE
Avian Flu Deaths Linked to Tamiflu Resistance
By Michael Smith, MedPage Today Staff Writer
Reviewed by Zalman S. Agus, MD; Emeritus Professor at the University of Pennsylvania School of Medicine.
December 21, 2005
MedPage Today Action Points
* Advise patients who ask that the H5N1 strain of avian flu - while seen as having the potential to spark a human pandemic - is so far mostly confined to birds and shows little sign of being able to cause widespread disease in humans.
* Note that this study shows that the H5N1 virus, when it does infect humans, can develop resistance to the antiviral drug Tamiflu (oseltamivir) with fatal consequences.
* Advise patients that this study suggests stockpiling Tamiflu may not be appropriate, and inappropriate or inadequate use of the drug may lead to resistance; such improper use is likely without medical guidance.
* Note that accompanying editorials to this study suggest that the public health perspective clearly indicates that a physician has an obligation not to prescribe Tamiflu for stockpiling- a position that is tantamount to a prohibition against prescribing it.
Review
So far, avian flu is mostly confined to birds.
HO CHI MINH CITY, VIETNAM, Dec. 21 - Researchers here have reported that the H5N1 avian influenza that killed two patients earlier this year was resistant to Tamiflu (oseltamivir). One authority calls this frightening.
In one of the cases -- a 13-year-old girl -- it appears that the development of resistance to Tamiflu "contributed to the failure of therapy and, ultimately, the death of this patient," said Menno de Jong, M.D., Ph.D., of the Oxford University Clinical Research Unit's Hospital for Tropical Diseases here.
In the other case, an 18-year-old woman, the link between resistance and death was less clear, but replicating virus was isolated from her after 14 days of treatment with Tamiflu, Dr. de Jong and colleagues reported in the Dec. 22 issue of the New England Journal of Medicine.
The report raises troubling questions about how to preserve the usefulness of Tamiflu, one of two drugs that inhibit neuraminidase, an enzyme that allows the release of newly formed viral particles. (The other is Relenza (zanamivir), which is currently available only in inhaled form.)
The availability of Tamiflu, which shortens the course of the disease and alleviates symptoms, has heartened "physicians and patients alike" in face of a potential influenza pandemic, said Anne Moscona, M.D., of Weill Cornell Medical College in New York.
But if the drug becomes ineffective, "we have no backup," Dr. Moscona said in an audio interview with the NEJM.
"This frightening report should inspire us to devise pandemic strategies that do not favor the development of oseltamivir-resistant strains," she argued in an accompanying Perspective article in the journal.
The "really scary thing" is that one of the patients -- the 13-year-old girl -- was given a full therapeutic dose of the drug early in the course of the disease and yet the virus still developed resistance, Dr. Moscona said.
Because an H5N1 infection was suspected when the child presented, Dr. de Jong and colleagues said, she was immediately given 75 mg of Tamiflu and transferred to a pediatric hospital. She weighed 62 pounds and had been previously healthy.
Over the 24 hours after presentation, she was given two more 75-mg doses of the drug, and then physicians moved to the standard twice-daily administration. The child's condition was stable for the next three days and she did not require supplemental oxygen, although chest x-rays showed a small focal pulmonary infiltrate in the right middle lobe.
On day four of Tamiflu treatment, however, she required supplemental high-dose oxygen and x-rays showed her pneumonia had worsened. On day six, she was intubated and ventilated. On day seven, x-rays showed the pneumonia had completely involved the right lung and extended to the left; she died the same day.
The case is the "most worrisome," Dr. Moscona said, because the girl was treated quickly and appropriately, appeared to respond, and then died.
She and other experts, writing in Perspective articles in the journal, call for restraint in prescribing Tamiflu, which has been stockpiled by some people in hopes of warding off a possible pandemic strain of the H5N1 avian flu.
When patients ask for a Tamiflu prescription in order to create a personal stockpile, doctors should simply say no, wrote Allan Brett, M.D., of the University of South Carolina School of Medicine in Columbia, SC, and Abigail Zuger, M.D., of St. Luke's-Roosevelt Hospital Center in New York.
"Physicians have no obligation to prescribe oseltamivir to patients who request it for a hypothetical outbreak of avian influenza," they said, and doing so is likely to be counterproductive in any case.
"Patients would probably use their stockpiles in a chaotic fashion, rather than optimally," they argued. "Indeed, some or most of it would no doubt be wasted on viral illnesses other than influenza.
"In the absence of formal guidelines from the government, some
professional societies and private medical groups have stepped in to issue statements that are consistent with our conclusion: physicians should decline any request for a prescription for the purpose of stockpiling oseltamivir, optimally with an explanation that reflects the reasoning here."
So far, an avian flu pandemic remains hypothetical, and the H5N1 strain has not shown itself able to pass easily from human to human despite isolated cases. More commonly, people infected with the strain have acquired it from contact with infected birds.
As of Dec. 15, according to the World Health Organization, 139 people have been infected with the virus and 71 have died.
But Tamiflu resistance has also been reported in seasonal flu strains, although usually at low levels, Dr. Moscona said. However, there is evidence that under-treatment with the drug can lead to resistance rates of nearly 20%, she said.
Such under-treatment is likely to arise if patients treat themselves and family members from personal stockpiles, she argues.
The other neuraminidase inhibitor, Relenza, has not been shown to produce resistance, Dr. Moscona said, because its chemical structure is different from that of Tamiflu. The neuraminidase active site actually changes shape to allow Tamiflu to bind to it; any of several viral variations can prevent the alteration.
On the other hand, the active site accommodates Relenza without a morphological change, making resistance less likely, she said.
The downside is that Relenza is only available in inhaled form, making it unsuitable for patients whose respiration is compromised.
By Michael Smith, MedPage Today Staff Writer
Reviewed by Zalman S. Agus, MD; Emeritus Professor at the University of Pennsylvania School of Medicine.
December 21, 2005
MedPage Today Action Points
* Advise patients who ask that the H5N1 strain of avian flu - while seen as having the potential to spark a human pandemic - is so far mostly confined to birds and shows little sign of being able to cause widespread disease in humans.
* Note that this study shows that the H5N1 virus, when it does infect humans, can develop resistance to the antiviral drug Tamiflu (oseltamivir) with fatal consequences.
* Advise patients that this study suggests stockpiling Tamiflu may not be appropriate, and inappropriate or inadequate use of the drug may lead to resistance; such improper use is likely without medical guidance.
* Note that accompanying editorials to this study suggest that the public health perspective clearly indicates that a physician has an obligation not to prescribe Tamiflu for stockpiling- a position that is tantamount to a prohibition against prescribing it.
Review
So far, avian flu is mostly confined to birds.
HO CHI MINH CITY, VIETNAM, Dec. 21 - Researchers here have reported that the H5N1 avian influenza that killed two patients earlier this year was resistant to Tamiflu (oseltamivir). One authority calls this frightening.
In one of the cases -- a 13-year-old girl -- it appears that the development of resistance to Tamiflu "contributed to the failure of therapy and, ultimately, the death of this patient," said Menno de Jong, M.D., Ph.D., of the Oxford University Clinical Research Unit's Hospital for Tropical Diseases here.
In the other case, an 18-year-old woman, the link between resistance and death was less clear, but replicating virus was isolated from her after 14 days of treatment with Tamiflu, Dr. de Jong and colleagues reported in the Dec. 22 issue of the New England Journal of Medicine.
The report raises troubling questions about how to preserve the usefulness of Tamiflu, one of two drugs that inhibit neuraminidase, an enzyme that allows the release of newly formed viral particles. (The other is Relenza (zanamivir), which is currently available only in inhaled form.)
The availability of Tamiflu, which shortens the course of the disease and alleviates symptoms, has heartened "physicians and patients alike" in face of a potential influenza pandemic, said Anne Moscona, M.D., of Weill Cornell Medical College in New York.
But if the drug becomes ineffective, "we have no backup," Dr. Moscona said in an audio interview with the NEJM.
"This frightening report should inspire us to devise pandemic strategies that do not favor the development of oseltamivir-resistant strains," she argued in an accompanying Perspective article in the journal.
The "really scary thing" is that one of the patients -- the 13-year-old girl -- was given a full therapeutic dose of the drug early in the course of the disease and yet the virus still developed resistance, Dr. Moscona said.
Because an H5N1 infection was suspected when the child presented, Dr. de Jong and colleagues said, she was immediately given 75 mg of Tamiflu and transferred to a pediatric hospital. She weighed 62 pounds and had been previously healthy.
Over the 24 hours after presentation, she was given two more 75-mg doses of the drug, and then physicians moved to the standard twice-daily administration. The child's condition was stable for the next three days and she did not require supplemental oxygen, although chest x-rays showed a small focal pulmonary infiltrate in the right middle lobe.
On day four of Tamiflu treatment, however, she required supplemental high-dose oxygen and x-rays showed her pneumonia had worsened. On day six, she was intubated and ventilated. On day seven, x-rays showed the pneumonia had completely involved the right lung and extended to the left; she died the same day.
The case is the "most worrisome," Dr. Moscona said, because the girl was treated quickly and appropriately, appeared to respond, and then died.
She and other experts, writing in Perspective articles in the journal, call for restraint in prescribing Tamiflu, which has been stockpiled by some people in hopes of warding off a possible pandemic strain of the H5N1 avian flu.
When patients ask for a Tamiflu prescription in order to create a personal stockpile, doctors should simply say no, wrote Allan Brett, M.D., of the University of South Carolina School of Medicine in Columbia, SC, and Abigail Zuger, M.D., of St. Luke's-Roosevelt Hospital Center in New York.
"Physicians have no obligation to prescribe oseltamivir to patients who request it for a hypothetical outbreak of avian influenza," they said, and doing so is likely to be counterproductive in any case.
"Patients would probably use their stockpiles in a chaotic fashion, rather than optimally," they argued. "Indeed, some or most of it would no doubt be wasted on viral illnesses other than influenza.
"In the absence of formal guidelines from the government, some
professional societies and private medical groups have stepped in to issue statements that are consistent with our conclusion: physicians should decline any request for a prescription for the purpose of stockpiling oseltamivir, optimally with an explanation that reflects the reasoning here."
So far, an avian flu pandemic remains hypothetical, and the H5N1 strain has not shown itself able to pass easily from human to human despite isolated cases. More commonly, people infected with the strain have acquired it from contact with infected birds.
As of Dec. 15, according to the World Health Organization, 139 people have been infected with the virus and 71 have died.
But Tamiflu resistance has also been reported in seasonal flu strains, although usually at low levels, Dr. Moscona said. However, there is evidence that under-treatment with the drug can lead to resistance rates of nearly 20%, she said.
Such under-treatment is likely to arise if patients treat themselves and family members from personal stockpiles, she argues.
The other neuraminidase inhibitor, Relenza, has not been shown to produce resistance, Dr. Moscona said, because its chemical structure is different from that of Tamiflu. The neuraminidase active site actually changes shape to allow Tamiflu to bind to it; any of several viral variations can prevent the alteration.
On the other hand, the active site accommodates Relenza without a morphological change, making resistance less likely, she said.
The downside is that Relenza is only available in inhaled form, making it unsuitable for patients whose respiration is compromised.
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