RALEIGH, N.C. -- A cluster of four Tamiflu-resistant cases of H1N1 flu at Duke University Medical Center have raised concerns that changes in the virus may make severe infections more difficult to treat.Three of the Duke patients died. All were adults, including two women and one man, and they had other major diseases, said Dr. Cameron Wolfe, a Duke infectious disease specialist. He said a fourth patient remains hospitalized.

Doctors use Tamiflu as the front-line defense to ease the symptoms and duration of flu infection, and international health authorities have been watching the H1N1 virus closely for signs that it has mutated to overpower the therapy.

Another anti-viral drug, Relenza, remains potent, but it generally can't be taken by preschool-aged children or people with asthma and other respiratory diseases.

The Duke cluster comes at the same time a hospital in Wales reported five Tamiflu-resistant cases, and the World Health Organization began investigating a more virulent strain of H1N1 virus that appeared in Norway.

But North Carolina officials yesterday said there is no evidence that a drug-resistant H1N1 strain is becoming dominant. In fact, they said, 99 percent of H1N1 flu cases remain treatable with Tamiflu.

"Reports of resistance have been very few," said Dr. Zack Moore, a medical epidemiologist with North Carolina's Division of Public Health. He said the U.S. Centers for Disease Control and Prevention has reported about 21 instances of resistant flu in the United States -- not counting the Duke cluster or any others that might have come to light this week.

The Duke patients were housed in the same unit of the hospital over the past six weeks. "It was pretty astute, in hindsight," Dr. Wolfe said of the hospital raising the alert when the patients did not respond to treatment.

The CDC, which has headed the nation's response to pandemic flu, was called to investigate. Lab tests this week confirmed that the patients all had the resistant strain.

Dr. Wolfe said it remains unknown how and where the patients contracted the virus. "We're trying to work back to see when their symptoms started to manifest, and when it looks like they may have come into contact with influenza," he said.

North Carolina has reported three prior instances of people coming down with Tamiflu-resistant flu, including the infection of two summer campers.

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