The antiviral drug baloxavir (Xofluza) prevented influenza in household contacts of infected patients, according to a study yesterday in the New England Journal of Medicine, but a US expert outlined several caveats about the findings.
The multicenter randomized controlled trial assessed the prophylactic effectiveness of baloxavir over 10 days in 749 household members of index patients with flu during the 2018-19 season in Japan. Participants were given a single dose of either baloxavir or a placebo.
Baloxavir, an endonuclease inhibitor developed by study sponsor Shionogi Co. of Japan and Roche AG of Switzerland, was approved in the United States and Japan as a single-dose oral treatment for uncomplicated influenza A and B in 2018, and the United States recently also approved it for the treatment of flu in patients at high risk for complications. It is the newest approved antiviral, joining other antivirals such as the neuraminidase inhibitors oseltamivir (Tamiflu) and zanamivir (Relenza).
Effective across age-groups
The percentage of the 374 participants who received baloxavir and developed the flu was much lower than that in the 375 who received a placebo (2% vs 14%), but the effectiveness of baloxavir was slightly lower in participants younger than 12 years (adjusted risk ratio [ARR], 0.27; 95% confidence interval [CI], 0.08 to 0.90) than in older participants (ARR, 0.10; 95% CI, 0.04 to 0.28).
The antiviral was also effective in at-risk, pediatric, and unvaccinated participants. Regardless of symptoms, the risk of flu was lower in the baloxavir group than in the placebo group (ARR, 0.43; 95% CI, 0.32 to 0.58).
Adverse events occurred at similar rates in both groups (22% with baloxavir and 21% with placebo). The most common adverse events included headache, blood in the urine, sore throat, and increased alanine aminotransferase level (indicating liver inflammation).
Among 545 index patients, 96% had influenza A, 74% were younger than 12 years, 53% received baloxavir, 31% received oseltamivir, and 16% received another neuraminidase inhibitor. Of all participants, 19% were younger than 12 years, 3% were at least 65 years old, 66% hadn't received a flu shot in the current season, and 13% had at least one risk factor for flu complications.
Most subjects (73%) received baloxavir or a placebo within 24 hours after the index patient became ill. Twenty-six subjects (7%) who received baloxavir and 36 (10%) who received a placebo tested positive for flu at baseline on polymerase chain reaction (PCR) assay.
Amino acid changes indicating a possible emerging reduction in susceptibility were identified in 10 patients (3%) who received baloxavir and 5 (1%) of those who received a placebo; no changes had been observed at baseline.
Although no transmission of these variants could be traced from baloxavir-treated index patients to those who received a placebo, the authors noted that several cases of flu transmission to participants who received baloxavir could not be ruled out.
"The positive findings with baloxavir prophylaxis in reducing the spread of influenza virus within households suggest the need for studying its prophylactic efficacy in other nonhousehold settings," they wrote.
Differences in use in US, Japan
In an editorial in the same journal, Timothy Uyeki, MD, MPH, a flu expert with the US Centers for Disease Control and Prevention, pointed out that 74% of index patients were younger than 12 years, and all received antiviral therapy (53% of them with baloxavir), per standard protocol in Japan, and 73% of household contacts received baloxavir or placebo within 24 hours after the index patient became ill.
But baloxavir isn't approved by the US Food and Drug Administration for the treatment of flu in patients younger than 12 years or for prophylaxis at any age, Uyeki said. And in the United States, even at-risk patients typically avoid seeking treatment for as long as 2 days after flu symptom onset.
Also, Uyeki noted concerns that viruses with reduced susceptibility to baloxavir may emerge more often in children treated with baloxavir and that the drug may lead to prolonged illness and viral shedding as well as a rebound in flu virus levels in the upper respiratory tract that can spread to others.
He said that while the best way to prevent flu is through annual vaccination, further studies should determine whether more doses of baloxavir for treatment and prophylaxis could reduce the emergence and spread of flu viruses with reduced susceptibility to the antiviral "and whether the combination of baloxavir for early treatment in symptomatic patients and oseltamivir for prompt postexposure prophylaxis in their close contacts might be useful for controlling institutional outbreaks."
