How H1N1 flu escaped Tamiflu

A recent Hutchinson Center study on drug-resistant flu makes fact more compelling than fiction. In the new movie "Contagion," health experts scramble to get ahead of a flu-like pandemic as a drug-resistant virus quickly spreads, killing millions of people within days after they contract the illness.

In reality, "certain strains of influenza are becoming resistant to common treatments," said Dr. Ira Longini, who conducted the study with lead author Dr. Dennis Chao, of the Vaccine and Infectious Disease Division, and Dr. Jesse Bloom, of the Basic Sciences and Public Health Sciences divisions. "We’ve been able to map out globally how this phenomenon is happening."

The study, which appeared in September in Journal of the Royal Society Interface, explains how seasonal H1N1 influenza became resistant to oseltamivir, known as Tamiflu, the most widely used antiviral agent for treating and preventing flu. The study shows that a combination of genetic mutations and human migration through air travel can lead to the rapid global spread of drug-resistant strains.

"If you see resistant strains in parts of the world where no one is taking antiviral drugs, that's the smoking gun that the resistant strain must be transmitting," said Longini, now professor of biostatistics in the University of Florida College of Public Health and Health Professions and the UF Emerging Pathogens Institute.

A theory and mathematical model

In some situations, drug-resistant bacteria and viruses can spread when drugs are overused. The scientists explored this theory using a mathematical model that simulates the spread of influenza across 321 cities connected by air travel. Using this model, they found that oseltamivir use had not been nearly widespread enough to promote the spread of antiviral resistance after it arose. However, the resistant strain probably originated in one person taking the drug.

"Oseltamivir is an important prophylactic, or preventative agent, against future flu viruses, including a potential H5N1, or 'bird flu,' pandemic," said Chao, a staff scientist in VIDD's Center for Statistics and Quantitative Infectious Diseases.

However, influenza can mutate, making the drug less effective. It had been believed that this mutation would not spread because it makes the flu less transmissible in people not taking the drug. "The fact that it spread so quickly in seasonal H1N1 between 2006 and 2008 took everyone by surprise," Chao said.

"This type of study is important because computer simulations are the best tool that we have to understand how mutations would have to affect viral fitness in order to lead to the observed epidemiological patterns," said Bloom, whose research focuses on various aspects of the molecular evolution of proteins and viruses, particularly influenza.

How the mutation may have migrated

The researchers report the mutation may have "hitchhiked" on one or more other mutations that made the drug-resistant influenza strain more transmissible. They suggest that because strains of influenza turn over so rapidly, there are many opportunities for these types of mutations to arise in an otherwise highly transmissible strain and become widespread, and it can become the dominant strain within a couple of years, making the drug useless.

"For the next pandemic, we should have all the available drugs at our disposal as a first line of defense to both prevent infection and to treat the most vulnerable," Longini said. "Or else, the chance that the next pandemic influenza strain is resistant goes up."

Study co-authors include Beth Kochin and Dr. Rustom Antia of Emory University. 

[Adapted from University of Florida News]