New Tamiflu-Resistant Bird Flu Cases Stir Fears

Fears have been raised over more evidence suggesting that the deadly H5N1 avian influenza can mutate into strains resistant to the frontline flu drug Tamiflu.

Two more patients with drug-resistant bird flu have been documented by researchers in Vietnam. The two patients, of eight studied, died from H5N1 influenza A, despite treatment with Tamiflu (oseltamivir) having been started early in one of them. The first case of Tamiflu-resistant bird flu was reported in October 2005 .

Although the case raised alarm, some scientists noted at the time that in becoming resistant to Tamiflu, the H5N1 virus also seemed to become less virulent. In addition, ordinary human flu with such a mutation rarely goes on to cause a new infection in another person.

“Becoming resistant to this class of drugs seems to impose a fitness penalty on the virus,” Frederick Hayden of the University of Virginia, US, an expert in antiviral drugs, told New Scientist at the time.

But the first case was only partially resistant, whereas the new cases show high-level resistance to Tamiflu. And the first case had also received the drug for preventative purposes, once daily. The two new cases received the full therapeutic, twice-daily dose.

“Furthermore, although the patient with partially resistant virus ultimately received oseltamivir at therapeutic doses and survived, both of our patients died,” writes the team led by Menno de Jong and Jeremy Farrar at the Oxford University Clinical Research Unit in Ho Chi Minh City, Vietnam.

“This frightening report should inspire us to devise pandemic strategies that do not favour the development of oseltamivir-resistant flu strains,” says Anne Moscona at Weill Medical College of Cornell University, New York, US, in a perspective accompanying the new study published in the New England Journal of Medicine.

She warns that individual stockpiling of Tamiflu by people at home could be “potentially dangerous” as this is more likely to lead to people taking insufficient doses or stopping their course of drugs prematurely, which can allow the surviving flu virus to develop drug resistance.

The researchers in Vietnam found that in the two patients with resistant strains of H5N1, the virus had undergone a change in a gene which codes for a protein called neuraminidase. This change means that it is much harder for oseltamivir to bind to the virus and block neuraminidase's function. Neuraminidase enables the virus to release copies of itself from an infected cell.

The team also found that in patients who went on to survive bird flu, the viral load became undetectable during treatment – this was not the case in the patients who died. This suggests that the emergence of Tamiflu drug-resistance “may be associated with clinical deterioration”, say the researchers.

However, the emergence of drug resistance is unsurprising. The team notes that up to 18% of children who receive Tamiflu for human flu develop drug-resistant flu strains.

“When a virus becomes resistant to oseltamivir, in theory that virus will be less virulent. It won't be as fit,” Farrar told the BBC television programme Panorama on 18 October. “I don't share that optimism. These organisms are fantastically able to adapt."

He added: “I think as soon as we apply widespread use of oseltamivir, we will start to see resistance developing inevitably, and I think we do have to pay attention to drugs other than oseltamivir.”

Other scientists have cautioned against alarm. "Whenever you use any kind of drugs, antivirals or antibiotics, you expect to see resistance develop. Finding some resistance is not necessarily alarming," said Keiji Fukuda, an expert at the World Health Organization’s global influenza programme, speaking to Reuters.

Bird flu drug 'should work', says DoH

James Sturcke
Thursday December 22, 2005
The Guradian (UK)

The government today insisted that the antiviral drug Tamiflu "should work" against a pandemic disease outbreak as it was confirmed that two more people had died from H5N1 bird flu.

The Department of Health said it had ordered Tamilflu on the basis of international expert advice but added that it was "looking carefully" at other drugs as a backup.

Health officials' attempts to calm fears about the effectiveness of Tamiflu came as the Indonesian health ministry confirmed that a 39-year-old security guard and an eight-year-old boy had died from bird flu.

The latest deaths mean 11 people have died from the disease in Indonesia and takes the global toll to 73. Worries about Tamiflu have increased after doctors from the Oxford University clinical research unit working at the hospital for tropical diseases in Ho Chi Minh City, Vietnam, revealed that the H5N1 virus in the bloodstream of two patients rapidly developed resistance to the drug.

The deaths are reported today in the respected New England Journal of Medicine by doctors funded by the British Wellcome Trust working in Vietnam.

They urge changes to the global plans for fighting a flu pandemic. Other antiviral drugs are needed alongside Tamiflu, they say.

But the government, which has ordered 14.6m courses of Tamiflu, today insisted it was still the first line of defence against any flu pandemic.

"Whilst there is some anecdotal evidence of the build-up of resistance to antiviral drugs such as Tamiflu, at present the experience is that these drugs do work and that they should work against a pandemic strain," a Department of Health spokeswoman said.

"They need to be used carefully and appropriately to minimise the risk of resistance. Tamiflu was chosen on the basis of independent expert advice that reflected its efficacy and ease of administration. Internationally, this is agreed as the product of choice.

"Our antiviral strategy is kept under constant review and we are looking carefully at [another antiviral drug] Relenza as a possible backup to Tamiflu."

The manufacturers of Tamiflu, Roche, said that the drug had been shown to be effective against the H5N1 virus.

"The potential exists for an influenza virus to emerge with decreased sensitivity to any antiviral treatment, and Roche has both internal and external mechanisms in place to monitor for emerging reports of resistance," the company said in a statement.

"The vast majority of data, collected from thousands of patients worldwide who were treated with Tamiflu for seasonal influenza, indicate that incidence of resistant viruses is rare."

The Department of Health's chief scientist, David Harper, last month told a House of Lords committee that there could be no guarantee until the [pandemic] virus actually emerges as to "the efficacy of Tamiflu".

He told the science and technology committee that the government was taking scientific advice about alternatives to Tamiflu, such as Relenza.

"So we are keeping a very close eye on any emergence of antiviral resistance to oseltamivir [Tamiflu], and that alone would mean that we might need to reconsider our antiviral strategy."

In the subsequent report, published last week, peers said they were "extremely concerned" at the lack of clarity over the government's policy for using antiviral drugs.

"We recommend that the government develop backup plans in case resistance to oseltamivir [Tamiflu] emerges," the report stated. "These should encompass possible combination therapies or the acquisition of reserve stocks of zanamivir [Relenza]."

Last month, it emerged that safety regulators in the US and Europe were reviewing the safety of Tamiflu among children and adolescents after reports of 12 deaths and psychiatric symptoms among users in Japan.

Most governments and the World Health Organisation have opted for Tamiflu as the first line of defence against pandemic flu as evidence suggests it could slow the spread of the disease and lessen its effects.

Since it is produced in pill form, it is seen as easier to administer than Relenza, which has to be inhaled.

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