Some strains of H7N9 viruses have mutations that make them resistant to the main antiviral drugs, tamiflu and zanamivir. As there is currently no vaccine for H7N9 and the virus is on the verge of achieving stable human-to-human transmission, the likelihood of the fall flu pandemic is high. The disease is severe, and the mortality rate among experimental animals was high throughout the study.
A team of scientists led by Dr. Robert Webster from St. Jude Children’s Research Hospital in Memphis, conducted research on the resistance of the latest strains of the H7N9 virus – a mutant avian flu virus that can already infect humans.
As the researchers found, as much as 35 percent. of the virus population has a mutation that causes resistance to the most important and currently used as the only antiviral drugs – oseltamivir (commercially known as tamiflu) and zanamivir (known under various names, including relenza). Worse still, the tests used so far have not shown that the viruses are immune, so the entire testing technique has proved ineffective.
If H7N9 has the possibility of stable human-to-human transmission, and not only in certain cases, what will we have at our disposal until we get a vaccine? Only oseltamivir. And this one, as you can see, does not always work. It seems we will have a big problem, Dr. Webster told Science.
The virus activity test is not working
Scientists obtained virus samples isolated from the first confirmed case of H7N9 flu. They tested the virus by the traditional method for neuraminidase activity. It is an enzyme specific to influenza viruses that allows them to leave the affected cell by breaking down the cell membrane. The new viruses thus infect other cells in the body. The test showed that the viruses are sensitive to neuraminidase inhibitors like oseltamivir. These drugs block the enzyme, preventing new viruses from leaving the infected cell. Meanwhile, it turned out after the administration of oseltamivir and zanamivir that viruses exist and, contrary to the test, infect new cells.
Two treatments with antiviral drugs carried out in China on patients suffering from H7N9 influenza, probably caused by strains with the R292K mutation, may be a warning against the treatment methods used so far. Therapies have failed and the prognosis for patients is severe and they are now in a severe condition.
As scientists from Sweden have previously stated, the H7N9 virus is generally resistant to another type of antiviral therapy – blocking the ion channel with the drug with the active substance amantadine (known, among others, as symmetrel) or its variant with a similar active compound with an attached methyl group – rimatandin ( (e.g. known as flumadine). As a result, we have virtually no antiviral therapies for H7N9 strains, and it is imperative to determine how quickly resistant strains spread spread, say researchers at St. Jude Children’s Research Hospital.
It started with chickens
If we follow the history of the H5N1 virus, it can be expected that soon the H7N9 virus will become fully human-to-human. If this happens this fall, the situation will be serious as oseltamivir and zanamivir are the main medications for antiviral therapies for influenza.
However, scientists say there is some hope that this will not happen, as the R292K mutation puts some strain on the virus and the strains carrying it may be eliminated from the genetic pool. However, should that be the case, agents based on neuraminidase inhibitors would not be allowed in anti-influenza therapy. There is a great need for new drug-based therapies employing viral elimination techniques that have not been used so far. There are several new types of drugs, but so far they are being tested. So a ready-to-use vaccine would be better, because the anti-virus option in controlling the spread of H7N9 doesn’t look very good, says Dr. Webster.
The H7N9 virus is the newest viral strain belonging to the so-called bird flu, which has so far been a minor threat to humans. It was first detected in April 2013 in China. According to the National Health Committee of China, the virus was usually detected in chickens or in large poultry markets in nearly all Chinese cities (one of the largest markets of this type is in Hong Kong). The sick are mainly people associated with poultry farming and poultry traders or their families. As of July 12, there were 132 confirmed cases of the disease, 43 of which were fatal.
An international team of scientists, consisting of specialists from France, Sweden, Germany and the United Kingdom, was investigating the virus. Great Britain, USA, China and Japan under the supervision of prof. Yoshihiro Kawaoka from the University of Tokyo. Researchers found that the virus is on the verge of a mutation that will allow it to spread among humans, similar to known strains of influenza viruses. Currently, it infects monkeys and ferrets by airborne disease, in the latter case direct transmission is already possible. The H7N9 virus has properties typical of human influenza viruses and poses a potential pandemic threat, hence its constant monitoring is necessary – said Prof. Kawaoka who is an expert on avian flu.
H7N9 like spanish
Until now, strains of the H5N1 virus, or avian influenza, very rarely infect humans and spread between animals. The researchers showed that the possibility of infection and multiplication in human cells in the case of H7N9 was caused by several changes in the genetic material of the virus. According to prof. Kawaoka, these changes are necessary for the virus because it depends on the host cell to produce its progeny and thus to form the infection chain. Already in monkeys H7N9 can infect cells of both the upper and lower respiratory tract. This is a very dangerous signal because the influenza viruses known so far infected only the cells of the upper respiratory tract in non-human primates. The only virus that survived research reports claimed to have had this ability was the highly lethal Spanish flu virus of 1918-1919. Its pandemic swept in three separate waves through Europe, the Americas and Asia, killing 50 to 100 million people worldwide, and the number of cases reached 500 million (1/3 of the world’s population then).
If H7N9 is able to transmit effectively from person to person, a pandemic is very likely because people have insufficient immune defense against these types of viruses, Kawaoka says.
In studies of the virus, scientists used ferrets for which the respiratory tract infection mechanism and immune system most closely resembled humans. They constitute the basic research model in the work on influenza viruses. The good news is that despite the virulence of the virus, its transmission between animals has so far been worse than that of known strains of human influenza. The bad news is the high rate of mortality and infected animals and the fact that successful animals were very weakened and recovered for a long time, which means that this strain of influenza drains the body very much.
The real problem is that H7N9 does not kill chickens, which makes monitoring their flocks very difficult. We can’t just search for sick or dead chickens. If necessary, tests will have to be conducted to determine whether the chickens are infected or not. Given the huge number of poultry, this will be a very difficult task, the researchers say.
The National Health Committee of China, however, has no doubts that in such cases there will be no waiting for a decision from doctors and diagnosticians. The epidemic in China alone will mean the killing of hundreds of thousands of chickens, as was the case with two other flu epidemics at the beginning of the decade.
The good news is the successful study of a group of scientists from the University of Hong Kong, led by Dr. Chloe KS Wong. Her team managed to create a real-time PCR test that will detect the presence of the H7N9 virus. Sample processing now takes 3 hours, but this time is likely to be reduced by 1/3 or even half. The test already detects H7 viruses of types very similar to H7N9. It is sensitive enough to identify a replicating virus in humans, which means that it will be possible to diagnose the disease early on, which will greatly facilitate treatment.
Text: Marek Mejssner
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