Durham, N.C. — North Carolina public health officials said Friday that three of four patients at Duke University Hospital with a drug-resistant form of the H1N1 flu virus have died.

The adult patients, treated in an isolated unit of the hospital over the last six weeks, tested positive for a mutation of the virus that was resistant to the drug Tamiflu, one of two medicines that help against H1N1.

Health officials said the cases were rare and the patients were very ill with underlying compromised immune systems and multiple other complex medical conditions. It is not clear whether their deaths were related to the flu infections.

The patients that died were identified as two men and a woman. The fourth patient is a woman. The patients were from different parts of the state. Doctors are investigating to see if there is any link between the cases.

Tamiflu is still the most effective treatment for the virus, and a vaccination is the best prevention for contracting the virus, they emphasized Friday. No resistance has been found to Relenza, also known as zanamivir, the other drug approved to treat H1N1, they said.

Health officials have been closely watching for signs to see if the virus is mutating and making the drugs ineffective.

Duke is looking into the cases, along with the U.S. Centers for Disease Control and Prevention, the state Division of Public Health and the Durham County Health Department.

"The mutation is not expected to have any effect on the vaccine at all," said Dr. Cameron Wolfe, an infectious disease specialist at Duke University Medical Center. "So, the vaccine will still be very effective in protecting patients against this form of H1N1. If anything, it re-encourages us to encourage everyone to get vaccinated."

 The only other reported U.S. instance of Tamiflu-resistant swine flu spreading from one person to another occurred about four months ago at a summer camp in western North Carolina, where two teenage girls – cabin mates – were diagnosed with the same drug-resistant strain. Health officials said at the time that the virus may have spread from one girl to the other, or it's possible that the girls got it from another camper.

Why did both Tamiflu-resistant clusters occur in North Carolina? It could be coincidence, or perhaps North Carolina's disease surveillance is unusually good, said Megan Davies, the state's epidemiologist.

About 52 resistant cases have been reported in the world since April, including 15 in the U.S. Last summer, health officials said two people in western North Carolina also had a drug-resistant form of the virus.

CDC officials have said that almost all the U.S. cases have been isolated.

Since the H1N1 pandemic began, 58 people in North Carolina have died as a result of the virus, health officials said. That number is based on reports from local health departments to the state as of last Monday.