Attached, article published last week on "Medscape" to USA...

Attached, article published last week on "Medscape" to USA Emergency Docs - (Docs in many other countries also subscribe to it.) [free login]

Main points continue the party line to date...
- "Zanamivir has retained its effectiveness against all recent flu viruses."

BUT... still no outright recommendation of if in preference for therapy...
- "Treatment should be with neuraminidase inhibitors alone. At this point, resistance to either oseltamivir or zanamivir is negligible, so both are good choices for therapy."


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How Should Antivirals Be Used This Flu Season?
James Wilde, MD

Posted: 12/16/2010
What are the recommendations for the use of antiviral medications during the upcoming influenza season?
Response from James Wilde, MD
Associate Professor of Emergency Medicine & Pediatrics, Department of Emergency Medicine; Faculty, Pediatric Emergency Medicine, Medical College of Georgia, Augusta, Georgia

Influenza season is here, and with the arrival of flu comes confusion over how and when to use antiviral therapy. Unfortunately, the subject of antiviral therapy for influenza has become more complicated over the past 4-5 years because of a complex combination of resistance patterns that have emerged in various influenza A subtypes. Currently, medications from 2 categories have been approved by the Food and Drug Administration (FDA) for use in influenza infections: the adamantanes, including amantadine and rimantadine, and the neuraminidase inhibitors, represented by oseltamivir and zanamivir. Several newer neuraminidase inhibitors are in development, most notably peramivir, a medication available only for intravenous use that was granted an Emergency Use Authorization during the 2009 influenza A (H1N1) pandemic of 2009-2010. However, neither peramivir nor the other medications in development have been approved for use by the FDA.

All viruses are parasites that must use living cells to reproduce. In the case of the influenza virus, the target cells are those lining the respiratory epithelium. After gaining access to the interior of the cell, the virus sheds its shell and releases its nucleic acid into the cytoplasm. The organelles within the cell are then used to replicate the nucleic acid and repackage the genetic material into hundreds or even thousands of new virions. After the new virions are released from the cell, they are free to infect many more nearby cells. When a sufficient number of cells are infected, symptoms begin to appear.

The adamantanes were approved for treatment of influenza decades ago, and they have been used for the treatment of only influenza A for many years. The adamantanes have no effectiveness against influenza B. Their mechanism of action is unclear, but they seem to interfere with the early stages of infection, possibly by inhibiting the uncoating of the virus in the infected cell.

FDA approval for the use of oseltamivir and zanamivir in influenza infections was granted in 1999. These medications are effective against both influenza A and influenza B. The mechanism of action is inhibition of neuraminidase, the viral surface glycoprotein that facilitates the egress of replicated virions from infected cells.

All of the antiviral medications share a common limitation: They must be started within 48 hours of the onset of symptoms in order to have a significant effect on the course of the illness. An analogy can help to illustrate this point. Imagine a fire in the backyard of a property that abuts a national forest. If the fire can be controlled before it crosses the fence into the forest, damage is limited to the yard. Once the fire hops the fence and ignites the forest, it becomes a raging inferno. Similarly, if an influenza infection can be treated in the "backyard stage" early in the course of the illness, control is possible. Once it "hops the fence" and spreads to the rest of the respiratory tract, therapy is largely ineffective, and the infection will continue its natural course.

Antiviral medications for influenza have limited benefits. They have been shown to reduce the symptoms of influenza by 12-36 hours in both children and adults if started within the first 48 hours of symptom onset.[1,2] This means that a 3- to 5-day illness can be reduced to a 2 to 4 days. Antiviral medications have not been shown to reduce mortality from flu in children or in young, healthy adults. Two studies in high-risk, older patients have shown a modest reduction in mortality.[3,4] Largely because of their limited effectiveness, antiviral medications for flu are recommended primarily for high-risk patients or those with severe symptoms.

Treatment of influenza became much more complicated after 2005. Until that year, flu had been fairly predictable for decades. Each year saw the seasonal return of influenza A (H3N2), influenza A (H1N1), and influenza B, in varying proportions. The adamantanes were effective only against influenza A, and the neuraminidase inhibitors were effective against both influenza A and B. In 2005, resistance to the adamantanes was detected among strains of influenza A (H3N2), and resistance levels reached close to 100% within 1 year.[5] Two years later, resistance to oseltamivir (but not zanamivir) was detected among strains of seasonal A (H1N1), and again virtually all isolates of this subtype were resistant to this medication within 1 year.[6] The complexity increased last year, when 2009 influenza A (H1N1) caused our first influenza pandemic since 1968. This virus is completely resistant to the adamantanes but remains susceptible to both oseltamivir and zanamivir. Zanamivir has retained its effectiveness against all recent flu viruses.

Treatment decisions are further complicated by the fact that in most cases, physicians do not know what type or subtype is causing the infection in their patients or even if their patient has a definite influenza infection. Rapid flu tests are 60%-90% sensitive in detecting seasonal influenza viruses, but the sensitivity of the rapid tests is much lower for 2009 influenza A (H1N1).[7] For this reason, during the 2009-2010 pandemic, when virtually all circulating isolates were the novel virus, the Centers for Disease Control and Prevention (CDC) discouraged the use of rapid tests. CDC recommended treatment for patients who had symptoms of a flu-like illness (fever plus either cough or sore throat) for 48 hours or less when influenza was known to be in the community and who had recognized risk factors for complications due to influenza infection. High-risk conditions include:

* Children younger than 2 years, especially those younger than 6 months;
* Adults aged 65 years or older;
* Immunosuppression;
* Pregnant females;
* Persons who are morbidly obese;
* American Indians/Alaska natives;
* Residents of nursing homes or chronic medical care facilities; and
* Persons with chronic medical problems, including pulmonary, cardiovascular (except hypertension), renal, hepatic, hematologic (including sickle-cell disease), neurologic and neurodevelopmental disorders, or metabolic disorders (including diabetes mellitus).

A change in circulating influenza viruses has helped to simplify the choice of medications for 2010-2011. Seasonal influenza A now seems to have been displaced by 2009 influenza A (H1N1). As of November 2010, 2009 influenza A (H1N1) has been identified in 12% of proven influenza infections in the United States, influenza A (H3N2) in 28%, and influenza B in 60%.[8] Because seasonal A (H1N1) is no longer in circulation, there is no longer a reason to use the adamantanes. Treatment should be with neuraminidase inhibitors alone. At this point, resistance to either oseltamivir or zanamivir is negligible, so both are good choices for therapy. Oseltamivir is an oral medication that has not been approved by the FDA for use in children younger than 1 year. Zanamivir is an inhaled powder that is approved for patients aged 7 years or older.

Given the significant mortality that we observed from influenza A (H1N1) last year, it would be prudent to treat all high-risk patients with a neuraminidase inhibitor if influenza is known to be circulating in the community and if symptoms of an influenza-like illness have been present for less than 48 hours.[9] Treating inpatients with flu should be considered even beyond the 48-hour window because several recent studies have shown some benefit.[10] Treatment is not recommended for outpatients who have had symptoms for more than 48 hours. Treatment of low-risk patients whose symptoms have been present for less than 48 hours is optional.