Lisa Schnirring  Staff Writer

Jan 18, 2007 (CIDRAP News) – Two patients who recently died of H5N1 avian influenza in Egypt had a strain of the virus that was moderately resistant to oseltamivir (Tamiflu), the World Health Organization (WHO) announced today, but the finding has not prompted new health advisories.

News of the drug-resistant strain came as Egypt"e;s health ministry announced a new human H5N1 case, involving a 27-year-old woman from the town of Beni Suef, about 62 miles south of Cairo. The report was carried today by IRIN, a United Nations news and information service.

Oseltamivir is recommended by the WHO as the first-line drug for H5N1 patients. The patients who had resistant infections were a 16-year-old girl and her 26-year-old uncle, who lived in the same house in Egypt"e;s Gharbiyah province, in the Nile delta 50 miles northwest of Cairo. They got sick in December; the man was hospitalized on the 17th, followed by his niece 2 days later, the WHO said. Both received 2 tablets of oseltamivir on Dec 21 and were transferred to a referral hospital on Dec 23, the same day samples were taken.

The girl died Dec 25 and her uncle died Dec 28. They were part of a possible family cluster; H5N1 avian influenza was also confirmed in a 30-year-old woman in the household, said to be the man"e;s sister, who died, though few details are available about her. The WHO said the patients reportedly had contact with sick ducks. The two cases boosted Egypt"e;s avian flu total to 18 cases and 10 fatalities, all of which occurred in 2006.

Genetic sequencing was done at US Naval Medical Research Unit 3 in Cairo and at WHO collaborating centers in Atlanta and London, the WHO said. Tests suggested that the virus had "moderately reduced susceptibility" to osteltamivir. The same type of mutation was previously identified in a Vietnamese case in 2005, the WHO said.

But in contrast to the Egyptian cases, the virus in the Vietnamese case appeared to be highly resistant to oseltamivir. The case, reported in December 2005 in the New England Journal of Medicine (NEJM), involved a 13-year-old girl who was started on oseltamivir the day she was hospitalized, receiving the recommended dose of 75 mg twice a day for 5 days.

The girl was one of 8 patients whose cases were analyzed after they were treated for H5N1 infection in Ho Chi Minh City in 2004 and 2005. Researchers sequenced the H5N1 virus"e;s neuraminidase gene to look for resistance, signaled by the substitution of tyrosine for histidine at amino acid position 274. The mutation was found in the 13-year-old girl, who died of severe pneumonia on her seventh day in the hospital.

The viral load in her throat was higher by the time of her death than it was earlier, which, with other laboratory evidence, suggested that drug resistance contributed to treatment failure and ultimately death, the NEJM report noted.

The mutation was also found in an 18-year-old girl, but the researchers said the relationship between the viral resistance and her death was less clear.

Fred Hayden, a WHO avian flu and antiviral expert, told the Associated Press (AP) today the drug-resistant strains in the Egyptian patients likely developed after they were treated with oseltamivir. He said a more worrying scenario would be if oseltamivir-resistant strains were circulating in birds.

The mutations in Egypt are different from the ones in Vietnam, Hayden told the AP. The Vietnamese strains were definitely resistant to oseltamivir, but the Egyptian ones were only shown to be less susceptible to the drug.

There is no evidence that oseltamivir-resistant strains are spreading in Egypt or elsewhere, the WHO said. The agency said it is not changing its antiviral treatment recommendations, because the clinical level of resistance of the mutations is not yet well established.

Public health implications of the findings are limited because the mutation is not associated with any known changes in transmissibility of the virus between humans, the WHO said, adding that it would not be raising the pandemic alert level.

Because of concerns about drug-resistant strains, avian flu experts have suggested that a higher dosage, longer treatment course, or combination therapy with other antiviral drugs may be needed to ensure the effectiveness of oseltamivir.

Terence Hurley, a US spokesperson for Roche, the maker of Tamiflu, told CIDRAP News by e-mail that studies are being conducted to gauge the optimal oseltamivir regimens for use in H5N1 flu cases. "These activities are based upon laboratory data and from information from patients infected with H5N1 who have been treated with Tamiflu," he said.

Roche is collaborating with the US National Institutes of Health on clinical studies to determine the efficacy of oseltamivir in the treatment of severe influenza, including H5N1, Hurley reported. "The NIH study is comparing standard doses of Tamiflu versus double doses for the treatment of people infected with avian influenza and other severe influenza infections in the Far East," he wrote. "Results of the study will be reported as soon as they are available."

The Egyptian woman reported today as a new H5N1 patient was admitted to a hospital Jan 11 after having given birth on Jan 2, IRIN reported. She initially denied contact with poultry, but WHO spokesman Hassan el-Bushra told IRIN that ducks and pigeons were found in her home and chickens had died nearby.

If her case is confirmed by the WHO, it will be Egypt"e;s 19th.