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According to a recent report on influenza in the Journal of Virology, 'Although vaccination is the ideal way to reduce the interspecies spread of influenza viruses, the preparation of a new vaccine takes six months or more. In the interim, antiviral drugs are the only option.'

Antiviral drugs can be used for both treatment and prevention of H5N1 bird flu, but have significant limitations. These drugs are expensive, supplies of them are limited, they have to be given within a short time period to be effective, and resistance either has already developed or can develop at any time. Even under optimal circumstances, none of them are 100 percent effective.

There are four antivirals that are approved by the U.S. Food and Drug Administration (FDA) for use against influenza'two older and inexpensive drugs, amantadine and rimantadine, to which the bird-flu virus has developed significant resistance'and two newer, more expensive and more effective drugs, Roche's oseltamivir (brand name: Tamiflu), and GlaxoSmithKline's zanamivir (brand name: Relenza; must be inhaled). The two new drugs belong to a class of antiviral agents called neuraminidase inhibitors. Tamiflu works by blocking the action of a specific enzyme, known as neuraminidase, on the surface of the influenza virus to prevent it from spreading and infecting other cells in the body.

Amantadine was once effective against H5N1, but its effectiveness has diminished drastically because the virus has developed resistance against it. There is some indication, however, that a combination of Tamiflu and amantadine might be more effective than Tamiflu alone. Information about Tamiflu and Relenza is summarized below:

Tamiflu (oseltamivir; the first choice for prevention or treatment of bird flu)

1. Prescription antiviral medication approved for treatment of seasonal influenza by the Food and Drug Administration (FDA). Note that use of Tamiflu for treatment or prevention of avian influenza (bird flu) is an 'off-label' use of the medication, that is, a use that has not been officially approved by the FDA. However, Tamiflu is widely recognized as the best available medication for prevention or treatment of bird flu, and its use in this situation is recommended by the Centers for Disease Control (CDC) and the World Health Organization (WHO).

2. Mechanism of action: neuraminidase inhibitor (active against all nine influenza A neuraminidase subtypes recognized in nature, including recent pathogenic avian viruses [H5N1, H7N7, N9N2], as well as a virus containing the neuraminidase from the 1918 pandemic strain).

3. Available forms: 75 mg capsules and 12 mg/ml suspension.

4. Effective only if given within 48 hours of onset of symptoms.

5. FDA-approved for treatment for those one year and older.

a. Dose for treatment of influenza for those 12 and older: 75 mg twice daily for five days.

b. Dose for treatment of influenza for those under twelve: 2 mg/kg up to a maximum of 75 mg twice daily for five days.

c. Side effects occurring in five percent or more of patients taking Tamiflu for treatment were nausea, vomiting, and diarrhea. These symptoms generally do not persist with ongoing treatment. Rare instances of serious side effects have been reported, but they are of uncertain relationship to Tamiflu.

6. FDA-approved for prophylaxis (prevention) of influenza for those 13 and older:

a. Dose for prophylaxis of influenza for those 12 and older: 75 mg daily for 10 days.

b. Not approved for prophylaxis of influenza for those younger than 12. However, use of Tamiflu in this situation is probably safe and effective. By deduction, dose should be 1 mg/kg up to a maximum of 75 mg daily for 10 days.

c. Side effects occurring in five percent or more of patients taking Tamiflu for prophylaxis were headache, nausea, and fatigue.

7. Use in pregnancy: Category C (meaning no scientific studies have been done to prove that it is safe in pregnancy'because of liability, no such studies are ever undertaken'but available evidence indicates that it is probably safe to use during pregnancy).

8. Significant drug interactions: none (although probenecid doubles the level of oseltamivir)

How effective is Tamiflu for prevention or treatment of seasonal influenza? Clinical studies have shown the following:

Oral oseltamivir is highly protective against experimental human influenza, and early treatment is associated with reductions in viral titers, symptoms, nasal cytokines [inflammatory agents], and middle-ear pressure abnormalities. Early oseltamivir treatment of acute influenza in otherwise healthy adults and children aged one to 12 years reduces the time to illness alleviation by one to 1.5 days, fever duration, and viral titers in the upper respiratory tract. Early treatment reduces time to functional recovery by three days or more.

Treatment of children also reduces the risk for otitis media [inner-ear infection] and decreases overall antibiotic use. In healthy and high-risk adults, early treatment decreased the risk for lower respiratory tract complications leading to antibiotics and to hospitalization. In is unknown whether treatment reduces the risk for transmission [of the virus from the infected person to someone else].

Prophylactic administration of once-daily oral oseltamivir (75 mg) is highly effective in reducing the risk for developing febrile illness during influenza season in unimmunized adults. Prevention of influenza reduces secondary complications in institutionalized older adults. Once-daily oseltamivir for seven to 10 days is also effective for post-exposure prophylaxis in household contacts, including children, and when ill index cases receive concurrent treatment.

Relenza (zanamivir; the second choice for treatment of bird flu)

1. Prescription antiviral medication approved for treatment of seasonal influenza by the FDA.

2. Mechanism of action: neuraminidase inhibitor. (It is a potent and specific inhibitor of the neuraminidase activity of influenza A and B viruses. Compared to oseltamivir, zanamivir is more active against influenza B but less active against influenza A/N2 neuraminidases of clinical isolates, although the clinical importance of such differences is uncertain. Zanamivir is inhibitory for certain influenza A neuraminidase variants that are resistant to oseltamivir.) [Emphasis added.]

3. Available forms: Not available in tablet or pill form; available only for oral inhalation with a proprietary Diskhaler device.

NOTE: The proprietary inhaler device for delivering zanamivir is breath-activated and requires a cooperative, trained patient. The use of the Diskhaler device is not reliable in young children, very infirm or elderly persons, or those cognitively impaired. Although the inhaler has been used effectively in older adults, over half of hospitalized older adults could not correctly use the device after instruction.

4. Effective only if given within 48 hours of onset of symptoms.

5. FDA-approved for treatment for those seven years and older.

 10 mg (two inhalations) twice daily for five days.

6. Not FDA-approved for prophylaxis (prevention) of seasonal influenza (but may be effective).

7. Side effects: Inhaled zanamivir is generally well tolerated, and the frequency of complaints is not significantly different from those in placebo [sugar pill] recipients among adults and children aged five years and older.

However, post-marketing reports indicate a potential risk for acute bronchospasm, respiratory arrest, or worsening of COPD [chronic obstructive pulmonary disease] accompanied by pulmonary edema [water in the lungs], after zanamivir inhalation, particularly in persons with underlying airway disease [such as asthma]. Apparent declines in respiratory function have also been rarely reported in those without recognized airway disease.

Consequently, use in patients with underlying airway disease is not generally recommended in the United States, although treatment in at-risk patients is used in other countries. If used in patients with obstructive airway disease, zanamivir should be administered cautiously under close observation and with availability of fast-acting bronchodilators.

8. Use in pregnancy: Category C (meaning no scientific studies have been done to prove that it is safe in pregnancy'because of liability, no such studies are ever undertaken'but available evidence indicates that it is probably safe to use during pregnancy).

9. Significant drug interactions: none.

How effective is Relenza for prevention or treatment of seasonal influenza? Clinical studies have shown the following:

Early inhaled zanamivir (10 mg twice daily for five days) treatment of uncomplicated influenza in previously healthy adults and children aged five to 12 years shortens the time to illness resolution and return to usual activities by one to three days. Treatment benefits appear to be greater in those with severe symptoms at entry, in those older than 50 years, and in higher-risk patients.

Inhaled zanamivir treatment in adults is associated with a 40 percent reduction in lower respiratory tract events leading to antibiotic use and a 28 percent overall reduction in antibiotic prescriptions. In high-risk patients with primarily mild-to-moderate asthma or other chronic cardiopulmonary conditions, zanamivir treatment reduces illness duration and the incidence of complications leading to antibiotic use.

Prophylactic administration of once-daily inhaled zanamivir (10 mg) is protective against febrile influenza illness during influenza season (84 percent efficacy) or when used for post-exposure prophylaxis in households with or without treatment of the ill index case (82 percent efficacy).

One study found that two weeks of inhaled zanamivir was superior to oral rimantadine [another antiviral drug] in preventing influenza A infection in nursing home residents, in part because of a high frequency of rimantadine resistance, and inhaled zanamivir has been used to curtail transmission of amantadine-resistant influenza A in nursing homes. However, inhaled zanamivir is not approved for chemoprophylaxis (prevention) in the United States or most other countries.

Finally, it is important to be aware of the fact that the effectiveness of Tamiflu and Relenza has been studied against circulating strains of human influenza, not against the bird flu virus. In a study reported in the August issue of the Journal of Infectious Diseases, Yen and others from St. Jude Children's Research Hospital in Memphis, Tennessee found that eight-day regimens of Tamiflu were more effective than the suggested five-day regimen for treating infections with the H5N1 bird-flu virus. The authors concluded that a prolonged and higher-dose oseltamivir regimen may be required for the most beneficial antiviral effect.

Bradford Frank, M.D., M.P.H., M.B.A.
The Frank Group
P.O. Box 138
Lakewood, NY 14750
www.AvoidBirdFlu.com