By Richard R. Watkins, MD, MS, FACP, FIDSA, FISAC
Synopsis: Treatment with a single dose of baloxavir led to an adjusted relative risk reduction of 29% in household transmission of influenza compared to placebo. There was no significant difference in safety signals between baloxavir and placebo.
Source: Monto AS, Kuhlbusch K, Bernasconi C, et al. Efficacy of baloxavir treatment in preventing transmission of influenza. N Engl J Med. 2025;392:1582-1593.
Seasonal influenza is an ongoing serious threat to public health. Although vaccination is an important means of prevention, it is not sufficient to achieve community control because many people remain unvaccinated. Using antiviral drugs to complement vaccination could be an effective strategy to reduce the spread of influenza in the community, in addition to benefiting the infected individual. Baloxavir is an influenza virus cap-dependent endonuclease inhibitor given orally as a single dose for treatment and prophylaxis. Monto and colleagues aimed to determine whether baloxavir would prevent transmission of influenza from index patients to household contacts.
The study was a phase 3b, double-blind, randomized, placebo-controlled trial (CENTERSTONE) conducted in 15 countries in Asia, Europe, and North America. Patients included were between 5 and 64 years of age, were positive for influenza by polymerase chain reaction (PCR) or rapid antigen testing, had a negative test for SARS-CoV-2, underwent screening within 48 hours after the onset of symptoms, and lived in a household with at least one other person. Index patients were excluded if they were at high risk for influenza-related complications. Household contacts underwent screening within 24 hours from the index patient and were eligible for inclusion if they tested negative for influenza and SARS-CoV-2 and at least one household contact had not received the influenza vaccine within the past six months. Furthermore, the household contacts needed to be not younger than 2 years of age, immunocompromised, or pregnant.
Index patients were randomized 1:1 to receive either a single oral dose of baloxavir or placebo. Respiratory swab samples were obtained from index patients and household contacts at screening and on days 5 and 9. An additional sample was obtained from index patients on day 3. The primary endpoint was transmission of influenza from an index patient to a household contact by day 5 after randomization. Safety endpoints were the frequency, severity, and timing of adverse events in index patients.
There were 1,457 index patients enrolled in the study: 726 received baloxavir and 731 received placebo. There were 2,681 household contacts of the index patients enrolled, of whom 1,345 were associated with an index patient who received baloxavir and 1,336 were associated with one who received placebo. Eighty percent of index patients had influenza A (H1N1 or H3N2) while 20% had influenza B. The adjusted incidence of transmission of influenza to household contacts by day 5 was 9.5% in the baloxavir group and 13.4% in the placebo group (P = 0.01). This translated to an adjusted relative risk reduction of 29% (95% confidence interval [CI], 12 to 45). The emergence of drug-resistant viruses occurred in 7.2% of index patients in the baloxavir group and none in their household contacts. At day 9, the adjusted incidence of transmission of influenza was 10.8% with baloxavir and 15.4% with placebo.
Regarding safety, 33 index patients who received baloxavir (4.6%) and 51 index patients who received placebo (7.0%) reported one or more adverse events. Most of these were grade 1 or 2 in severity. There were four serious adverse events reported: one spontaneous abortion in the baloxavir group and hyponatremia, pneumonia, and bronchitis in the placebo group. No patients in the baloxavir group withdrew from the study because of an adverse event.
Commentary
The incidence of influenza in household contacts was significantly reduced when the index patient received a dose of baloxavir. This difference remained in favor of baloxavir over placebo across age groups, seasons, influenza types, time from symptom onset to receipt of baloxavir, and geographic areas. The investigators astutely matched the influenza subtypes with the timing of trial assessments to eliminate the small chance that transmission of influenza occurred because of a non-household source of infection.
The emergence of baloxavir resistance in the study is concerning. However, although 7.2% of index patients who received baloxavir developed a drug-resistant virus, it is reassuring that none of their household contacts acquired the resistant strain. Why this happened is not clear. One possibility is that the resistant variants became less fit and/or transmissible than the original strains. This hypothesis warrants further investigation.
The study has some important real-world applications. When the next influenza pandemic occurs, vaccination will be the mainstay for mitigation. However, vaccine development takes time, and many people likely will choose to remain unvaccinated. Thus, antiviral drugs like baloxavir with a dual effect on illness and community transmission might play an important adjunctive role in influenza control.
Richard R. Watkins, MD, MS, FACP, FIDSA, FISAC, is Professor of Medicine, Division of Infectious Diseases, Northeast Ohio Medical University, Rootstown, OH.
Treatment with a single dose of baloxavir led to an adjusted relative risk reduction of 29% in household transmission of influenza compared to placebo. There was no significant difference in safety signals between baloxavir and placebo.
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