Tamiflu-resistant H1N1 Varients Has Experts Worried by Anthony...

Tamiflu-resistant H1N1 Varients Has Experts Worried
by Anthony L. Kimery
Tuesday, 24 November 2009

'Argues for vaccination as the one sure way to combat this disease before it strikes'
Four patients at Duke University Medical Center in Durham, NC, at least five persons in a hospital in Wales, and a father in Quebec, Canada have become infected with an apparently mutated strain of H1N1 that is resistant to Tamiflu (oseltamivir), the leading antiviral of choice to treat influenza in lieu of having a vaccine.

Meanwhile, Norwegian health authorities reported a potentially significant mutation in H1N1 that could be responsible for the severest symptoms in those infected by the strain - especially persons most at risk to the virus - which authorities are monitoring carefully because of concerns that it, too, might become resistant to Tamiflu, and, possibly, other antivirals if they become as widely administered as oseltamivir.

Similar mutations have been reported elsewhere, but haven’t necessarily provoked a more virulent virus or proven to be less resistant to Tamiflu or other antivirals. Nevertheless, authorities are concerned.

There have been growing concerns on the part of virologists for some time that antiviral-resistant influenza could be a serious problem during a pandemic, as antivirals are the primary defense against a pandemic until an effective vaccine is developed and distributed.

The World Health Organization (WHO) reported that it has confirmed more than 40 cases of Tamiflu-resistant pandemic H1N1 viruses globally since it declared a pandemic in June.

The Centers for Disease Control and Prevention (CDC) said there have been 57 US cases of Tamiflu resistance since the pandemic H1N1 virus was identified in April, and “sporadic” reports of mutations similar to those in Norway.

Seasonal H1N1 viruses had already developed resistance to Tamiflu several years ago, and experts are concerned that the same thing could occur with the pandemic strain of H1N1 given that Tamiflu is now in widespread use.

According to the recent study, Morbidity and Mortality Associated With Nosocomial Transmission of Oseltamivir-Resistant Influenza A (H1N1) Virus, published in the March 2 Journal of the American Medical Association (JAMA), and authorities at CDC, a natural genetic mutation in A-H1N1 rather than the virus’s adaptation to survive treatment with antivirals, has made it resistant to Tamiflu. This poses an extraordinarily serious health threat to patients hospitalized with the flu virus who are being treated with the antiviral.

“I think the seminal message [of this study] is a valuable key to our understanding of the presumed efficacy of antiviral treatment, and again argues for vaccination as the one sure way to combat this disease before it strikes,” a top public health official told HSToday.us on background because of the politically sensitive nature of his position.

While Tamiflu-resistant influenza increasingly has been found around the world since January 2008, it had been presumed that strains carrying the mutation were of lower risk and less likely to be transmitted.

"However, current widespread circulation of oseltamivir-resistant influenza A-H1N1 viruses associated with typical influenza illnesses and viral pneumonia suggest that these viruses retain significant transmissibility and pathogenicity," the authors of the JAMA report wrote.

Because flu viruses are among the most mutable viruses, they interchange genes swiftly and routinely, meaning antiviral-resistant viruses could quickly spread worldwide.

CDC officials stated that nearly all cases of the most common seasonal flu strain in the United States are resistant to Tamiflu.
"As of February 19, resistance to oseltamivir had been identified among 264 of 268 (98.5 percent) US influenza A-H1N1 viruses tested,” researchers noted.

The problem of antiviral-resistant strains of a pandemic influenza virus has long worried public health authorities. As HSToday.us has reported, resistance to Tamiflu in particular has been growing among some strains, including highly virulent H5N1 strains and seasonal influenza. Authorities say evidence indicates antiviral-resistant influenza occurs in settings of overuse of the medications.

Experts worry that over-prescribing Tamiflu for what remains a relatively mild illness for the majority of people who are infected by A-H1N1 could make antivirals useless over the long term.

Brit Oiulfstad, the pandemic influenza coordinator for the County of Los Angeles, had earlier told HSToday.us that heavy reliance on antivirals is “even more troubling when we are currently dealing with the effects of overuse/misuse of antibiotics.”

Despite these concerns, though, prescriptions for Tamiflu, Relenza, and other antivirals totaled 587,960 for the week ending Oct. 30, a 5.9 percent increase from the week before, according to Wolters Kluwer Pharma Solutions, which provides information on prescriptions for the antivirals to the Food and Drug Administration (FDA), which uses the data to track the treatment of H1N1 and other influenza viruses.

In late September, CDC cautioned that the spread of H1N1 would "likely impact the nation’s pharmacies as a greater number of people than usual seek to fill prescriptions for influenza antiviral drugs."

"I want to stress that people who are not from the at risk group ... need not take antivirals," Dr. Nikki Shindo of WHO’s global influenza program stated. "We are not recommending taking antivirals if otherwise healthy people are experiencing only mild illness, or as a preventive in healthy people."

"Tamiflu prophylaxis given to the wrong people can increase your risk of a resistant strain developing - and that's the last thing we need," Dr. Marc Siegel, an associate professor of medicine at New York University Langone Medical Center, told Health Day News.

Dr. Joel Lexchin, a professor at York University's School of Health Policy and Management in Canada, told Health Canada that "If we prescribe [antivirals] for people with relatively mild flu, and the virus develops resistance, then they wouldn't be of very much use for people with severe cases of H1N1."

"We are encouraging prudent use and warning against abuse of these medications as we want to make sure we have medications that work for these people who really need it," New Brunswick, Canada's chief medical officer of health, Dr. Eilish Cleary, told the Times & Transcript.

Because of the widespread demand for Tamiflu to protect those most at risk to A-H1NI, coupled to some physicians writing prescriptions for the drug to any patient who asks for it, there have been spot shortages of the drug nationwide, especially in the form that is given to children.

Before his untimely death, renowned virologist, Dr. Graeme Laver – who was instrumental in developing Tamiflu and Relenza - told HSToday.us during many lengthy interviews with him that pandemic preparedness authorities needed to begin stockpiling all flu antivirals in the event that one or more strains of influenza – in particular especially virulent strains - began to show marked resistance to the most prescribed antivirals like Tamiflu.

Currently, “we have no evidence as yet of resistance to Relenza - in part this may be due to lesser use of this drug as a first line treatment modality,” said the public official who spoke on background.

Laver warned that widespread use of Tamiflu and other antivirals as a prophylaxis to prevent infection by a pandemic strain of influenza is simply wrongheaded.

Laver, who studied influenza viruses for nearly 40 years and with Dr. Robert Webster (another world-renowned virologist at St. Jude Children’s Research Hospital) discovered the link between human flu and bird flu and in the 1960's received world acclaim when they developed a new and innovative generation of vaccines for flu viruses, told HSToday.us that “prophylaxis with Tamiflu in a pandemic is wrong. Early treatment is the only way to go.”

In Canada, authorities there report that about one-third of the cases of Tamiflu resistance has been found in people who had been given the drug prophylactically.

"Because of that we need to limit as much as possible the use of Tamiflu prophylaxis and instead focus on early treatment," said Dr. Guy Boivin of Laval University in Quebec City.

Responding to the disclosure that a Tamiflu-resistant strain of H1N1 had spread between five patients at the University Hospital of Wales, Cardiff, in a unit treating people with severe underlying health conditions, the public health official who spoke to HSToday.us on background said, “as you know, there have been sporadic reports around the world of isolated cases of Tamiflu resistance, [but] transmission can occur irrespective of whether resistance is present. These two viral functions are separate and unrelated … Given the hundreds of thousands of courses [of antivirals] prescribed it is inevitable that direct transmission of such a mutation would eventually be found. It's true for all infectious agents: viral, bacterial, protozoan, etc. All of us have been on the alert for such occurrences. It is our hope that vaccination, coupled with standard non-pharmaceutical prevention practices, will diminish the need for anitivirals and thus diminish events of this nature.”

“We do not know the effects of long-term antiviral use in a prophylactic setting. Therefore, we always consider that we must do no harm, and until we have some more answers, we proceed on those recommendations for prophylaxis with great caution," Oiulfstad said. "Until the science is in that shows that these drugs prevent illness, this seems to be the only reasonable way to approach the problem.”

Because of the evidence of growing Tamiflu resistance, British researchers have warned that governments need to stockpile other antivirals besides Tamiflu in the event that a mutated pandemic strain resistant to Tamiflu becomes widespread.

"We have been extremely foolish on our policies of stockpiling drugs. We have been stockpiling two varieties of the same drug," stated virologist Robert Webster at St Jude Children's Hospital at a medical conference in Hong Kong.

Discussing with reporters the problem of H5N1 and antivirals, Webster said “the likely scenario is that the [H5N1] virus will become resistant when you start using more and more [of one] drug; you get resistant [H5N1] mutants.”

Because authorities are beginning to see this scenario playing out with varients of H1N1, they are concerned about the widespread use of Tamiflu among people who are not considered to be at risk to complications from the bug. Similarly, they are concerned about generalized prophylactic use of the antiviral among at risk populations whether they've contracted the H1N1 pandemic flu or not.

http://www.hstoday.us/content/view/11197/149/