An antiflu medication first approved in Japan in 2018 and given the green light later that year in the US may be fostering the emergence of drug-resistant strains of influenza. A study published yesterday (November 25) in Nature Microbiology finds that nearly one-fourth of patients who took baloxavir (Xofluza) harbored flu viruses with mutations in their genomes that made them less vulnerable to the drug. The mutations were not present before the treatment.
“In a worst case scenario, these mutations could render the drug entirely useless,” Andrew Pekosz, a molecular biologist at Johns Hopkins who was not involved in the study, tells Endpoints News. “They haven’t yet, and it’s not clear why that’s been the case.”
In prior cell culture studies and clinical trials, scientists had observed mutant influenza sometimes occurring after Xofluza exposure. Each of the mutant viruses carried the same change, in a gene encoding a polymerase subunit. The variant weakened the drug’s effect because Xofluza ordinarily disrupts the polymerase complex.
In this latest work, Yoshihiro Kawaoka of the University of Wisconsin–Madison and his colleagues collected viral samples from 38 patients with influenza infections before and after Xofluza treatment. Before the study participants took the drug, none of the viruses had the polymerase variant, but afterward, samples from nine patients had mutated.
To see if the treatment-associated variant made a difference to the drug’s efficacy, the researchers conducted experiments in hamsters, ferrets, and cells, finding the mutant virus was pathogenic, transmissible, and more drug-resistant.
Kawaoka’s team also sequenced the influenza virus from a boy before he took Xofluza and from his sister, who caught the flu a couple of days later. The genome was entirely the same between their samples, except for one mutation—in the gene for the polymerase subunit. “It tells you the virus acquired resistance during treatment and transmitted from brother to sister,” Kawaoka says in a press release.
He adds that while this drug-resistant strain is a threat to those in close proximity to the person harboring it, it will not likely become a widespread problem. “The drug resistant virus does transmit but there are so many influenza viruses worldwide and only a small population will be treated with this drug,” Kawaoka says in the press statement. “The vast majority remain drug sensitive.”
