Sunday, April 30, 2006

Bird Flu in America and the truth about the much touted Tamiflu....

I saw a promo for ABC's "Fatal Contact: Bird Flu in America" airing Tuesday, May 9. Touted as a "meticulously researched" two-hour film of an avian flu outbreak in the United States, the people affected by it and those trying to stop it and the possible consequences. The entertainment industry and the conventional thinking on antivirals(neuraminidase inhibitors) as a treatment which is being discussed on Talk Radio and Legacy Media is that these medicines(which are inhibitors of the H5N1 viral enzyme neuraminidase) are one of the best solutions for protection against and treatment of the Avian Flu influenza is deeply flawed( see"Doubts raised about avian flu drug Tamiflu"):

Two new antiviral drugs known as

  • Neuraminidase inhibitors

    Two drugs were approved in 2000 Canada for treatments of influenza A(The Avian Flu) and B. Both selectively inhibit neuraminidase, a surface enzyme of the influenza virus. Oral oseltamivir (Tamiflu®) is indicated for patients aged 18 and over and inhaled zanamivir (Relenza®) for patients aged 12 and over. Begin treatment within 36 hours of first symptoms. Both drugs are indicated for influenza A and B, but clinical evidence of efficacy for B is limited.

are currently available that have been shown in laboratory settings to be effective against avian flu like but:

  1. Tamiflu (oseltamivir) is less effective due to the some strains of H5N1 virus developing resistance :
    • From NEJM 12-22-2005: "The neuraminidase inhibitors provide valuable defenses against pandemic and seasonal influenza, and physicians have been flooded with requests from patients for personal supplies of oseltamivir (Tamiflu). A benefit of having oseltamivir at home is that the sooner the drug is taken after the onset of symptoms, the better its clinical efficacy.1 And certainly, enabling ill people to stay home and out of waiting rooms and pharmacies should limit the spread of influenza. So it is not surprising that many believe there should be a supply of oseltamivir in every medicine cabinet. This scenario, however, is potentially dangerous. Misuse of the drug could rob us of the advantages that neuraminidase inhibitors provide, by favoring the emergence of oseltamivir-resistant influenza virus. The potentially serious consequences of oseltamivir resistance in patients with influenza A (H5N1) virus infections is alarmingly underscored by the report by de Jong and colleagues in this issue of the Journal (pages 2667-2672)".see below
  2. Relenza (zanamivir). Their possible effectiveness against the deadly H5N1 strain of avian flu is currently being studied."
The truth of whether we should rely on these reports from "New" and "Old" Media prompted me to do a Medical Literature update available by doing a literature at the National Library of Medicine:
News Flash:
My review of the latest Medical Literature reveals that a genetic mutation has occurred in the H5N1 virus known as H274Y mutation that confers resistance to oseltamivir(TamiFlu) in patients with H5N1 infection causing two two patients to die in Vietnam!
From New England Journal Medicine 12/2005:

  • Influenza A (H5N1) virus with an amino acid substitution in neuraminidase conferring high-level resistance to oseltamivir was isolated from two of eight Vietnamese patients during oseltamivir treatment. Both patients died of influenza A (H5N1) virus infection, despite early initiation of treatment in one patient. Surviving patients had rapid declines in the viral load to undetectable levels during treatment. These observations suggest that resistance can emerge during the currently recommended regimen of oseltamivir therapy and may be associated with clinical deterioration and that the strategy for the treatment of influenza A (H5N1) virus infection should include additional antiviral agents.
Too further underscore these points here are importand quotes from my Avian Flu Expert and Minnesota's Gov. Pawlenty's, Dr. Michael Osterhom

  • "Pandemics are like hurricanes, tsunamis and earthquakes," Michael Osterholm, director of the Center for Disease Research and Policy explained on "Good Morning America" today. "We had 10 of them in the last 300 years, and we're due for another one sometime soon."

  • "The flu is one of the most infectious agents to humans, so readily transmitted person-to-person," he said. "In the case of our population today, we have no immunity throughout the world to this particular strain of virus in Southeast Asia and because of the large bird population and human population now together over there, this virus has an opportunity to continue to be transmitted among birds, occasionally hitting humans, and each one might become a human agent."

  • "It's the perfect setup," Osterholm said. "Then you put air travel in and it could be around the world overnight."

  • "You have to take a look at the 1918 experience and realize if 50 [million] to 100 million people died and those numbers come from a recent study from a group of historians that went country by country to determine that number," said Osterholm.

  • "Today we have three times the number in the world -those numbers are roughly at 180 [million] to 360 million could die. The bottom line is the way these people die. Our medical care delivery system in the modern world isn't any better prepared than in 1918."
Is there possible Solution to this dilemma of "Resistance" to Tamiflu? Yes it is combination therapy with Zanamivir (Relenza schroll to bottom). The good news is that the mutation described above does not confer "cross-resistance" to this particular antiviral a, most fortunate break with Physicians. This phenomenon is attributable to differences in binding properties between Tamiflu and Relenza(NEJM). A treatment regimen combining these two neuraminidase inhibitors would be expected to reduce the opportunity for the selection of resistant mutants, in a manner akin to the use of dual nucleoside analogues in antiretroviral therapy.

  • From NEJM 3-30-2006 "Zanamivir is an attractive antiviral drug for combined treatment of influenza A (H5N1) because of nonoverlapping resistance patterns in this drug and oseltamivir. However, the licensed preparation of zanamivir may be less appealing since it is administered by inhalation, which provides drugs predominantly to the upper respiratory tract. Since human infection with current strains of influenza H5N1 can be associated with disseminated infection and replication in the lower respiratory tract and extrapulmonary sites,1,2,3 combined treatment with nebulized zanamivir and oral oseltamivir would be likely to result in monotherapy in the lower respiratory tract and nonrespiratory sites. Although it would be important to evaluate the effects of combined treatment with zanamivir in influenza H5N1, the route of administration will need to be carefully considered. "
Sorry to say but the scenario for an H5N1 outbreak is a ture Brothers Grimm fable that can not be tweaked ala Walt Disney into a Happy ever after story.....that is until we develop new age Bio-Tech vaccine production replacing the 1950's chicken egg approach (post forthcoming)

Thanks for reading and Dominus Vobiscum(Lord be with You) especially given this situation.
Francis Xavier Yubero, M.D.


Blogger Micky said...

Experts say that human-to-human transmission of the virus is required for the avian flu to become an epidemic, and there have been few documented cases of human-to-human transmission of the avian flu virus worldwide.

9:47 PM, May 02, 2006  
Blogger Powder Tracks and Fever said...

True as far as I know their have been no human to human transfers. However if an individual who has the a garden variety flu(Type A The most serious type with the most acute symptoms. It is also the most common form, usually breaking out every two or three years; Type B: Similar symptoms to type A, but not as serious. The outbreaks happen every four to five years; Type C: The mildest type, with symptoms similar to a cold.)gets exposed to an animal or animal products with H5N1 gene swapping can occur. If the correct combination of genes are swapped then H5N1 can be transmitted human to human. Genetic scrambling. (A) H5N1 mutates quickly and is notorious for grabbing large blocks of genetic code from viruses that infect other species, a process called reassortment. For that reason, it has particular potential to combine with a human flu virus, creating a new viral strain that spreads rapidly from person to person. The emergence of such a virus would mark the beginning of a potentially devastating pandemic. (CNN)
"Birds & Bird Flu graphics showing avian influenza (H5N1) mixing with other 'flu strains; image of bird flu viruses and human flu viruses entering the same cell and pandemic influenza emerging, diagram of replication of viruses showing reassortment of viral RNA genome segments (genetic mixing or recombination) creating a new viral strain (reassortant) with the potential to create a catastrophic new flu pandemic."
The virus can improve its transmissibility among humans via two principal mechanisms. The first is a “reassortment” event, in which genetic material is exchanged between human and avian viruses during co-infection of a human or pig. Reassortment could result in a fully transmissible pandemic virus, announced by a sudden surge of cases with explosive spread.
The second mechanism is a more gradual process of adaptive mutation, whereby the capability of the virus to bind to human cells increases during subsequent infections of humans. Adaptive mutation, expressed initially as small clusters of human cases with some evidence of human-to-human transmission, would probably give the world some time to take defensive action, if detected sufficiently early.

These reassortants could result when a single host bird is simultaneously infected with both the vaccine and another AI virus. Owing to the segmented nature of the influenza virus genome, a reassortment of genetic material can readily occur, creating new influenza viruses. The basic drawback to any vaccine approach for the control of HPAI is the large number of HA subtypes that can cause the disease. Because there is no cross-protection among the 15 known HA subtypes, either a multivalent vaccine will be needed or vaccination postponed until the prevalent disease-causing subtype in the area is identified. A recombinant fowl pox virus vaccine containing the gene that codes for the production of the H5 antigen has recently been licensed. The use of a recombinant insect virus containing the gene for either the H5 or H7 antigen has been used to make these vaccine proteins in insect cell cultures.

Antigenic shift refers to an abrupt, major change to produce a novel influenza A virus subtype in humans that was not currently circulating among people (see more information below under Influenza Type A and Its Subtypes). Antigenic shift can occur either through direct animal (poultry)-to-human transmission or through mixing of human influenza A and animal influenza A virus genes to create a new human influenza A subtype virus through a process called genetic reassortment. Antigenic shift results in a new human influenza A subtype. A global influenza pandemic (worldwide spread) may occur if three conditions are met:

A new subtype of influenza A virus is introduced into the human population.
The virus causes serious illness in humans.
The virus can spread easily from person to person in a sustained manner.
Reassortment occurs when genetic material is exchanged between human and avian viruses during co-infection (infection with both viruses at the same time) of a human or pig. The result could be a fully transmissible pandemic virus—that is, a virus that can spread easily and directly to humans. A more gradual process is adaptive mutation, where the capability of a virus to bind to human cells increases during infections of humans.( (

2:26 AM, May 03, 2006  

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