New research published in The Lancet documents the first clinical cases of resistance to treatment with Tamiflu (oseltamivir) and similar drugs in people infected with the H7N9 influenza virus.

 

The study, led by Dr Zhenghong Yuang of the Shanghai Public Health Clinical Centre and School of Basic Medical Sciences, Shanghai Medical College of Fudan University, China, and Dr Malik Peiris, of the University of Hong Kong, China, provides one of the most detailed virological studies of the H7N9 virus to date.  The researchers studied 14 patients who were admitted to the Shanghai Public Health Clinical Centre with confirmed H7N9 infection in April this year, measuring their viral load (the quantity of virus in their throats, blood, stools and urine, used as an indicator of virus severity) throughout the course of their illness and treatment.

Following the expected course of H7N9 infection, all of the patients developed pneumonia.  Seven of the patients became ill enough to require mechanical ventilation, and three further patients became so severely ill that they required extracorporeal membrane oxygenation (ECMO), which provides oxygen to the blood from outside the body when the lungs are not able to.  Two of these patients died, and the third was still dependent on ECMO for survival at the time the paper was submitted.

By analysing each of the 14 patients’ viral loads throughout the course of their illness, the researchers found that, for most of the patients, treatment with a class of antiviral drugs called neuraminidase inhibitors – a group which includes Tamiflu, and currently offers the only known treatment option for H7N9 – resulted in a reduction in the viral load found on throat swabs and was associated with clinical recovery.  

However, for the three patients who became severely ill, antiviral treatment did not reduce their viral load, leading the researchers to suspect that the H7N9 virus had become resistant to the antiviral drugs in these cases.  This was confirmed by genetic testing of the viruses taken from these patients, where the researchers found a genetic mutation characteristic of resistance to neuraminidase inhibitors.  This mutation had been noted in one other virus strain in an earlier study of H7N9, but its clinical relevance remained unclear. The new paper contains the first research to link clinical cases of resistance to neuraminidase inhibitors with this genetic mutation in H7N9 virus to poor clinical outcome.

Moreover, in one patient, the gene mutation responsible for conferring resistance to neuraminidase inhibitors appears to have arisen after the initial infection took hold, probably as a result of treatment with Tamiflu, leading to concerns that resistance might arise in response to treatment with neuraminidase inhibitors.

From analysing the viral load in all of the patients’ throats, blood, stools and urine, the researchers found traces of viral RNA in all of these areas for some patients.  While the viral RNA detected is not necessarily infectious, and might have found its way into the digestive system via swallowed respiratory secretions, the researchers caution that further investigation is needed into whether H7N9 is able to disseminate beyond the respiratory tract.

According to the authors, early treatment with antivirals, including Tamiflu (oseltamivir), currently provides the best option for recovery. However, they note that “The apparent ease with which antiviral resistance emerges in A/H7N9 viruses is concerning; it needs to be closely monitored and considered in future pandemic response plans.”

The Lancet