There have been recent reports about a novel avian-origin influenza virus subtype (A/H7N9) in patients with severe and fatal respiratory disease in eastern China. To date, it has caused disease in 132 human beings in nine provinces and municipalities in China, leading to 33 deaths. Poultry seem to be the source of human infections. Although other avian influenza viruses (eg, subtypes H5N1, H9N2, H7N7, and H7N3) have infected man before, such transmission has remained exceedingly inefficient whilst the novel A/H7N9 virus, which has mammalian adaptation mutations in the receptor binding site of certain genes of the virus seems to cross species from poultry to man more easily, raising concern about its pandemic potential.
Since A/H7N9 is resistant to the M2-ion channel blockers amantadine and rimantadine, the neuraminidase inhibitors oseltamivir, zanamivir, and peramivir have been the main drugs used for antiviral treatment of patients with A/H7N9. The viral and host factors associated with the unusual severity of this disease are poorly understood. In this study, researchers quantified the viral load in sequentially obtained throat swabs, serum, urine, and stool specimens from A/H7N9 patients, as well as looking for mutations associated with resistance to neuraminidase inhibitors.
The study included 14 patients admitted to the Shanghai Public Health Clinical Centre, who were given antiviral treatment (oseltamivir or peramivir) for less than 2 days before admission.
All patients developed pneumonia, seven of them required mechanical ventilation, and three of them further deteriorated to become dependent on ECMO, two of whom died. Antiviral treatment was associated with a reduction of viral load in throat swab specimens in 11 surviving patients. Three patients with persistently high viral load in the throat in spite of antiviral therapy became ECMO dependent.
An Arg292Lys mutation in the virus neuraminidase (NA) gene known to confer resistance to both zanamivir and oseltamivir was identified in two of these patients, who had both also received corticosteroid treatment, and led to treatment failure and a poor clinical outcome. In one of them, wild-type sequence Arg292 was noted 2 days after start of antiviral treatment, and the resistant mutant Lys292 dominated 9 days after start of treatment.
The researchers question whether the role of corticosteroids in facilitating the emergence of the NA Arg292Lys mutation or even directly affecting viral load and adverse clinical outcome deserves consideration. They call for investigation of the fitness and stability of the Arg292Lys mutation in A/H7N9. They conclude that the apparent ease with which antiviral resistance emerges in A/H7N9 viruses is concerning; this needs to be closely monitored and considered in future pandemic response plans.
Following intensive pressure from the Cochrane Colloboration and other groups over the past few years, regarding access to all 74 Roche-sponsored trials involving oseltamivir (Tamiflu), after discrepancies between different regulatory bodies' views on the drug’s effectiveness, Roche has recently agreed to release the trial data to the Cochrane Collaboration but a recent letter in the BMJ suggests that this has not happened.