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Avian Flu: Threat of Pandemic Leads to Shortage of Antiviral Drugs

By Jeff Norris

Predictions vary as to when - or if - the ongoing spread of new avian influenza virus, H5N1, will result in a human pandemic. H5N1, which has recently become widespread in Southeast Asia and China, already has killed roughly half of the more than 120 people who have been diagnosed - mostly those who work with poultry - and has triggered the death or slaughter of millions of birds. Influenza pandemics - such as the 1968 Hong Kong flu and the great 1918-1919 so-called Spanish flu that killed perhaps 40 million globally - seem to arise and travel around the world every two to three decades. H5N1 is now widely regarded as the latest candidate for possible evolution into a more infectious, still deadly pathogen that could be transmitted directly from human to human. Many experts fear that a human plague may emerge if the virus acquires the ability to spread directly from person to person. In response to the risk, wealthy nations are ordering large supplies of the antiviral drug oseltamivir. Oseltamivir is made by the Swiss drug giant Roche Laboratories and sold under the brand name Tamiflu. Tamiflu to the Rescue? Roche is backed up for years on Tamiflu orders. So far, the US has ordered a quantity of antiviral drugs sufficient to treat only a tiny fraction of the populace. A US Department of Health and Human Services planning blueprint, released in early November, calls for stockpiling enough to provide a course of treatment for about one-third of Americans. Oseltamivir targets a component of the virus - an enzyme called neuraminidase. The virus needs this protein to escape from infected cells and spread. Another, less popular neuraminidase inhibitor called zanamivir also is available. It is taken via an inhaler and sold as Relenza by GlaxoSmithKline. "Neuraminidase inhibitors can shorten the duration and severity of conventional, seasonal flu," says Joseph Guglielmo, a professor of clinical pharmacy at UCSF with a research interest in infectious disease prevention. Clinical trials indicate that neuraminidase inhibitors may shorten the duration of flu, on average, by about a day in generally healthy adults, and perhaps by two days or more in persons at risk due to old age or chronic disease. The drugs also lessen the severity of flu symptoms. Collectively, clinical trials indicate that Relenza results in less need to use antibiotics to treat bacterial pneumonia - a complication of severe, seasonal flu that kills many older adults each year. Side effects of treatment, such as nausea and diarrhea, are not unusual. Neuraminidase inhibitors must be taken early in the course of a seasonal flu infection to shorten illness. Some flu-fighting strategies emphasize the use of neuraminidase inhibitors as a preventive to stop the spread of the virus to those who are uninfected. Studies of flu outbreaks in nursing homes indicate that antivirals may be very effective in preventing the spread of infection, at least for seasonal flu, Guglielmo notes. At least one US research study has shown that people who take courses of Tamiflu treatment for several weeks at the beginning of seasonal flu season are several times less likely to catch flu. But the strategy of using the drugs to contain a larger outbreak has never been tested in any controlled clinical trial. Tamiflu is approved by the Food and Drug Administration as a treatment to increase the chances that young children ages 2 to 3 years will not come down with flu. Tamiflu can lessen the duration of flu symptoms and the need for antibacterial treatment in children who already have the flu. Zanamivir (Relenza) is not approved for any pediatric use, although it has been studied in children and shown to reduce the duration of flu symptoms. Drug Resistance There is an entirely separate class of antivirals for flu - the M2 inhibitors amantadine and rimantadine. These drugs stop a key step in viral replication. The M2 inhibitors have been used to treat type A influenza - the type to which the H5N1 subtype belongs - for years. Drug resistance was negligible a decade ago - but now more than 10 percent of circulating influenza strains are resistant to the M2 inhibitors. Most resistant strains were isolated from people in Asia. H5N1 demonstrates resistance to this class of drugs, which is why all the talk today is about oseltamivir - Tamiflu. The influenza virus is less capable of mutating into forms that are resistant to oseltamivir, Guglielmo says. Among all flu patients, children with weakened immune systems are most likely to harbor an oseltamivir-resistant virus. But at least one Tamiflu-resistant flu strain already has been discovered in a Hanoi patient who died from H5N1 infection after treatment with Tamiflu. "The good news," according to Guglielmo, "is that resistant influenza viruses have less fitness, resulting in less replication, less intensity of symptoms and less likelihood of the virus being passed from person to person." Poor Nations Balk Poorer countries that cannot pay the going market price are looking into the possibility of making their own copycat versions of Tamiflu. After first resisting, Roche declared its willingness in mid-October to sublicense production of oseltamivir to other companies. This was after the Indian firm Cipla - a large generic drugmaker - already claimed to have figured out how to make the drug on its own. If Roche approvals are not forthcoming, some poor countries may issue compulsory licenses to produce antiviral supplies locally in anticipation of a health emergency. Recently, Thailand has announced that it will make its own version of Tamiflu, and Roche and Vietnam have reached an agreement that will enable Vietnam - where most human deaths attributed to H5N1 have occurred - to make oseltamivir with ingredients supplied by Roche. Roche also has granted permission to Indonesia to make oseltamivir, because Tamiflu is not patented there. The inventor of the drug is the Bay Area biotech firm Gilead Sciences, which licensed the drug to Roche. In mid-November, Roche agreed to settle a contract dispute with Gilead by sharing control of production and sales of oseltamivir. More companies may end up making the drug. Taiwan now is negotiating with Gilead for a license to make its own oseltamivir. Roche has said it will ramp up its own production capacity to 300 million treatments per year by 2007. Even so, there is no way the company can meet current demand. But, according to Guglielmo, "We are talking about a matter of years before even developed countries will have sufficient numbers of doses of Tamiflu to protect the populace." "The shortage of seasonal flu vaccine in recent years has gotten people accustomed to thinking of priorities." "It's no different than when we didn't have enough seasonal flu vaccine last year," Guglielmo says. "We established priorities for health care workers and people at risk." UCSF will host a symposium on pandemic flu for the scientific community on Monday, Dec.12, from 1 to 5 p.m. in the School of Nursing room N 225 on the Parnassus campus. For more details, see this story. Source: Jeff Norris