WASHINGTON: At first it looked like the 13-year-old girl was lucky. She only had a little pneumonia in one lung and doctors had treated her early with Tamiflu, a drug known to be effective against avian influenza.
She “presented to a hospital in Dong Thap Province on January 22, 2005, with a one-day history of fever and cough,” wrote Dr. Menno de Jong of the Hospital for Tropical Diseases in Ho Chi Minh city and colleagues.
And for several days, the drug seemed to be working. But then the girl began struggling to breathe and needed more and more oxygen.
The pneumonia worsened and she died six days after being admitted.
Tests done in Hong Kong showed the virus infecting her had mutated in a way known to make it immune to Tamiflu. She had a “H274Y substitution in the neuraminidase gene, which confers high-level resistance to oseltamivir (Tamiflu),” the researchers wrote in a report published in the New England Journal of Medicine.
The same thing happened with another patient treated by the same group. And four of eight patients they treated with Tamiflu, made by Roche AG under the generic name oseltamivir, died despite treatment with the drug.
No one is surprised — viruses often develop resistance to drugs. For this reason, AIDS infections are treated with a cocktail of drugs.
“The best prevention of resistance is to suppress replication as completely and as early in the infection as possible. The paradigm ‘Hit hard and Hit early’ which has been used in the past for HIV/AIDS therapy is most likely true for influenza and undoubtedly many other viral infections,” De Jong said in a statement.
“Anything that you throw at a virus, a virus can evolve to evade it,” said Dr. Anne Moscona, an expert in pediatric viral diseases at Weill Medical College of Cornell University, New York, in a telephone interview. “You can’t attack a virus with just one compound.”
Tamiflu is one of two influenza drugs in a class called neuraminidase inhibitors. These drugs target a protein on the surface of cells called sialic acid. Influenza viruses use an enzyme called neuraminidase — the “N” in H5N1 — to attach to the cells it infects.
Tamiflu and the other neuraminidase inhibitor, Relenza, block the neuraminidase enzyme used by the virus and keep the virus from hooking onto the sialic acid “doorway” on the cell.
But influenza viruses are mistake-prone — they constantly evolve and change, and the neuraminidase structure can change, too.
Tamiflu does not block neuraminidase perfectly and has to make it stretch a little, Moscona said. “The structure of Tamiflu is such that several mutations are possible that allow for the neuraminidase molecule to still work and the virus to remain viable,” Moscona said.
“The structure of Relenza is somewhat different, so that it seems to be somewhat less likely to allow for the development of resistance.” But Relenza, known generically as zanamivir, has its own drawbacks — it must be inhaled, making it inappropriate for some patients, and it may only treat the lungs.
Moscona said the report clearly illustrates why governments but not individuals should stockpile Tamiflu.
“One thing about stockpiling — people are going to tend to share. They’ll try to make a small amount go farther because there is a shortage,” she said.
That will make resistance evolve even more quickly.—Reuters
