Xofluza Prophylaxis Mostly Stopped Flu in Japanese Families

Baloxavir marboxil (Xofluza) appeared effective in preventing household contacts of flu patients from developing infections themselves, a randomized trial in Japan showed.

Only 1.9% of contacts developed laboratory-confirmed clinical influenza after post-exposure prophylaxis with baloxavir compared to 13.6% of those assigned to placebo (adjusted RR 0.14, 95% CI 0.06-0.30, P<0.001), reported Frederick Hayden, MD, of the University of Virginia in Charlottesville, and colleagues.

Moreover, risk of influenza infection was lower in the baloxavir group, regardless of symptoms (adjusted RR 0.43, 95% CI 0.32-0.58), the authors wrote in the New England Journal of Medicine.

Xofluza was approved by the FDA in 2018, with studies showing it shortened duration of illness by approximately 1 day versus placebo and had "superior antiviral efficacy" to both placebo and oseltamivir (Tamiflu). They noted "variant viruses" have been observed following treatment with baloxavir, which have been associated with "prolongation of infectious virus replication and potential transmissibility, including one instance of household transmission."

Researchers decided then to look at post-exposure prophylaxis with baloxavir among contacts in households where the index patients with flu were mostly children, who had either been treated with baloxavir or a neuraminidase inhibitor. They also aimed to assess the risks of both emergence and transmission of viruses with "reduced susceptibility to baloxavir."

This multicenter trial examined contacts who were healthy and in the same household as the index patient for at least 48 hours before enrollment during the 2018-2019 influenza season. They were assigned to receive an oral dose of either baloxavir or placebo, and participants age 12 and older assessed themselves for influenza symptoms, including cough, sore throat, and fever, on a 4-point scale. They had their axillary temperature taken twice daily from screening until day 10.

Nasopharyngeal swabs were administered before the dose of baloxavir or placebo on day 1, day 5, and day 11. Hemagglutination inhibition (HAI) antibody titers were measured on day 1 and between days 15 and 22. The primary efficacy endpoint was laboratory-confirmed influenza via real-time polymerase chain reaction (RT-PCR) assay over a period of 10 days, presence of fever of at least 37.5º C, and at least one other respiratory symptom of moderate to greater severity during days 1-10.

Overall, there were 752 contacts randomized of 545 index patients. Nearly three-quarters of index patients were younger than age 12; 53% were treated with baloxavir and 31% with oseltamivir.

A modified intention-to-treat analysis included 749 contacts, with a mean age of about 34; 71% to 75% were ages 20-64, and 67% to 71% were parents. Interestingly, two-thirds of contacts were unvaccinated against influenza.

There were 51 contacts in the placebo group who developed the flu, which occurred by day 5 in nearly all participants. All seven contacts who got the flu in the baloxavir group had illness after day 5.

Notably, baloxavir efficacy was lower among contacts younger than age 12 versus older contacts, although risk of influenza was lower in children younger than age 12 in the baloxavir group versus placebo (adjusted RR 0.27, 95% CI 0.08-0.90).

But an accompanying editorial by Timothy Uyeki, MD, of the CDC, raised some important caveats to the findings, including that almost three-quarters of contacts received baloxavir or placebo within 24 hours after the index patient developed symptoms.

"Unlike in Japan, where patients typically seek medical care for influenza testing and treatment soon after the onset of illness, in the United States, even high-risk patients with influenza may not present within 2 days after the onset of illness or may not receive early antiviral treatment," he wrote.

Uyeki addressed the issue of variant viruses with certain mutations associated with reduced susceptibility to baloxavir. These variant viruses were detected in 15 participants in the baloxavir group, and in seven patients in this group, transmission of a virus with reduced susceptibility to baloxavir from a baloxavir-treated index patient "could not be ruled out."

"Public health concerns are that viruses with reduced susceptibility to baloxavir can emerge more frequently in baloxavir-treated children and may be associated with prolonged illness, longer viral shedding and rebound in influenza virus levels in the upper respiratory tract," he wrote, saying global surveillance is necessary to monitor these types of viruses with reduced susceptibility to baloxavir.

The authors noted that an important limitation was that follow-up samples were not obtained, so they could not determine how frequently the resistant variant viruses emerged. In addition, they could not assess efficacy against influenza B, due to limited circulation.

Given its success in reducing influenza among households, they recommended studying baloxavir as prophylaxis in other non-household settings.

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