Researchers find easy development of H7N9 Tamiflu resistance

May 28, 2013 (CIDRAP News) – Antiviral drugs such as oseltamivir (Tamiflu) are useful for treating H7N9 influenza infections, but there are worrisome signs that resistance can easily develop when patients take the drug, which can lead to a poor prognosis, researchers from China and Hong Kong reported today.

Their analysis, which includes 14 patients who were hospitalized in Shanghai within 2 days of starting therapy with Tamiflu, appears in an early online edition of The Lancet.

Meanwhile, Chinese health officials reported one more infection and one more death, pushing the overall number of people infected in the H7N9 outbreak to 132, including 37 deaths.

Beijing reports second case
The new case, the first to be reported since May 8, is that of a 6-year-old Beijing boy whose infection was detected during flu surveillance activities, according to a translated statement today from the Beijing Municipal Health Bureau that appeared on the FluTrackers infectious disease message board.

He was hospitalized in Beijing on May 21 for symptoms such as fever and sore throat, but he recovered and was released 2 days later and has since returned to nursery school, according to the report.

The Beijing Center for Disease Control confirmed H7N9 in the boy's respiratory samples today. The test result prompted health officials to hospitalize the boy again for observation, and health officials started monitoring his close contacts.

The boy is Beijing's second H7N9 case. The city's first patient was a 7-year-old girl whose case was announced on Apr 13. The daughter of a poultry trader, the girl was hospitalized but has since recovered.

China's latest death appears to be in a previously announced case, though it's not clear which one. News of the most recent death came today in an announcement from China's National Health and Family Planning Commission, according to a report today from Xinhua, China's state news agency.

The report also said that four more H7N9 patients have recovered from their infections. Case reports in the medical literature have said several H7N9 patients are still hospitalized, some requiring mechanical ventilation and extracorporeal membrane oxygenation (ECMO).

Antiviral resistance study
The goals of the Lancet study were to gauge viral loads in patients' throat, stool, blood, and urine specimens during their hospitalizations and to look for antiviral resistance mutations and their impact on clinical outcomes. The patients were hospitalized from Apr 4 to Apr 27. Their median age was 71, and 10 of the patients were men.

All patients had pneumonia, four had acute respiratory distress syndrome and needed mechanical ventilation, and the conditions of three deteriorated further despite neuraminidase inhibitor treatment and ECMO. Two of the three ECMO patients died.

The researchers found that duration of illness before hospitalization or viral load in admission throat swabs didn't predict the patients' response to antivirals or clinical outcome. Those with falling viral load in throat swabs during treatment were more likely to survive, but viral loads stayed high in the three who got worse and needed ECMO.

Pandemic 2009 H1N1 influenza viral loads typically decline a few days after disease onset, but the H7N9 patients had high loads the first week of infection, similar to the pattern with H5N1 avian influenza, the investigators observed.

They noted that the more persistent level could reflect the lack of earlier exposure to H7N9. "By contrast with seasonal influenza, antiviral treatment of A/H7N9 initiated many days after disease onset may still provide some clinical benefit," they wrote. 

The sequencing part of the study revealed that the Arg292Lys mutation, previously linked to zanamivir (Relenza) and oseltamivir resistance, in the neuraminidase was linked to treatment failures and poor patient outcomes. In one of the patients, resistance was detected 2 days after antiviral treatment began.

How easily antiviral resistance developed in some of the patients is worrisome and needs to be closely watched, the group emphasized.

Resistance markers were seen in two patients who received corticosteroid treatment, which the team said is also worrisome and needs to be monitored, especially for pandemic planning purposes.

Lab partnership, H7N9 tests for birds
In related developments, the Center for Infection and Immunity (CII), based at Columbia University's Mailman School of Public Health, announced today that it and a virus research institute in the Chinese Center for Disease Control and Prevention will open a joint pathogen research laboratory within China CDC, the first international team to do so, according to a CII blog post.

Scientists from the two groups will conduct surveillance, identify new pathogens, develop new diagnostic test platforms, and develop drugs and vaccines to treat human and animal diseases, CII said.

W. Ian Lipkin, MD, CII's director, said in the blog post that the agreement took years to develop and was finalized on May 9, according to CII. It will "enable CII and Chinese CDC investigators to work side-by-side developing solutions for pandemic threats to global health."

The lab is expected to begin operating this summer. Lipkin is the lab's scientific director along with two researchers from China's National Institute for Viral Disease Control and Prevention (NIVDC): Xiao-ping Dong, MD, and Zhao-jun Duan, PhD. The 5-year agreement between the two groups is funded by the NIVDC, according to CII.

Elsewhere, Australian researchers have played a key role in developing a blood test for detecting H7N9 in poultry and ducks, Western Australia Today (WA Today) reported yesterday. Scientists from the country's Commonwealth Scientific and Industrial Research Organization, working with international labs, used live samples of the virus shared by China to make irradiated virus as a component of a test kit.

The kits have already been sent to labs in 11 countries, most of them in Asia, according to the report.

See also:

May 28 Lancet report

May 27 Xinhua story

May 28 FluTrackers thread

Apr 13 CIDRAP News story "Beijing reports first H7N9 infection"

May 28 CII blog post

May 27 WA Today story

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