To our knowledge, this was the first comparative, real-world study describing patient-reported outcomes on the effect of baloxavir vs oseltamivir on influenza transmission and healthcare utilization in the USA. Numerically, smaller proportions of baloxavir-treated participants reported household transmission, irrespective of household size. Participants treated with baloxavir reported fewer outpatient and emergency department visits compared with participants treated with oseltamivir.

The data from this study are consistent with previously reported data from Japan, suggesting that baloxavir may be more effective than oseltamivir at preventing household transmission of influenza [10, 11]. However, the Japanese data were limited in that their results were based on claims data, which required infected individuals to have had a formal interaction with a healthcare system, including disease coding or billing procedures, which may differ between Japan and the USA. Individuals who are infected by household members may not visit healthcare professionals for various reasons, including reduced incentive to seek care after one household member was diagnosed, and their data will not be captured in claims. This, and other claims data studies, may have underestimated actual household composition and subsequent influenza transmission [10, 11, 23]. In addition, claims data does not account for date of infection or symptom onset and can be less accurate. Despite these limitations, our study using patient-reported outcomes substantiates and expands those results by describing patient-reported transmission from households of a confirmed size and are in line with observational studies suggesting that treatment with antivirals is associated with lower infectivity [24,25,26]. Additional studies comparing the direct effect of baloxavir on transmission are warranted. A worldwide, phase 3 clinical trial assessing baloxavir for the reduction of direct transmission of influenza is in progress (NCT03969212) [27].

Household cohort studies have been a reliable tool in assessing the epidemiological impact of influenza and provide decisive data on estimating the transmission dynamics in households and the broader community [28,29,30,31,32,33,34,35,36]. Indeed, a substantial portion of viral transmission occurs in households [28, 29]; a prospective study estimated that as many as 50% of household contacts of patients with influenza were infected during the 2021–2022 influenza season [30]. However, until the 2009 H1N1 pandemic, direct information about seasonal influenza in the USA was based mostly on cohort studies conducted between 1948 and 1981 [31,32,33]. Cohort studies assessing influenza in the USA from 2009 on have focused on the transmission of the disease with little emphasis on the nonprophylactic role that antivirals may play in reducing transmission [34, 35]; one study that directly assessed the use of oseltamivir during the 2009 influenza pandemic suggested that early use of the antiviral was associated with reduced transmission [36]. Our study addresses these knowledge gaps by excluding participants who sought treatment for prophylactic use and comparing the effects of baloxavir and oseltamivir on secondary household transmission.

Limiting household transmission is a key goal of influenza prevention, as the health and wellness of residents can widely differ from member to member. Patients with severe influenza infections have more active and prolonged virus shedding, increasing the transmission risk and healthcare utilization [37]. Influenza often leads to severe infection in patients with comorbidities and can often exacerbate them, causing and complicating severe illness [1]. Our study included a population in which almost half of participants reported comorbidities; nonetheless, household transmission between the two treatment groups was less than 30%, demonstrating real-world effectiveness of antiviral therapies in reducing the impact of influenza on those with comorbidities. Controlling household transmission is a valuable tool in reducing the spread of influenza to vulnerable populations and overall healthcare utilization. Further real-world studies in high-risk populations are needed to fully understand the effects of antivirals on household transmission.

A unique strength of our study was the methodology and use of CVS Pharmacy in gathering participant survey information. CVS Pharmacy is among the largest pharmacies in the USA, with approximately 10,000 stores across all 50 states and territories. This large national reach allows researchers to connect with a wide variety of patients and other household members who may provide a more representative view of the population in the USA on how infectious diseases are managed in the public domain. Although the methodology of our study was payer agnostic, it was in line with a retrospective cohort study that used insurance claims to directly compare the healthcare utilization and costs between treatment with baloxavir and oseltamivir [38]. Both results suggested that treatment with baloxavir was generally associated with less healthcare resource utilization than treatment with oseltamivir.

Baloxavir is a novel anti-influenza molecule that inhibits viral cap-dependent endonuclease activity and is the first in this new antiviral class that inhibits the viral cycle at a very early stage [39]. Data from CAPSTONE-1 and CAPSTONE-2 showed baloxavir reduced viral titers and stopped the shedding of infectious virus from the body more rapidly than oseltamivir [15, 16]. Also, baloxavir is a single dose compared with oseltamivir, which is administered for 5 days. Patients are likely to be more adherent to a therapy that requires one dose than to a therapy that requires multiple doses over several days; higher adherence may potentially increase effectiveness. For the US 2019–2020 flu season, a real-world study observed 27% of patients did not complete their antiviral treatment, which was primarily neuraminidase inhibitors, including oseltamivir [40].

The findings of this study may provide guidance on future clinical implications surrounding influenza and its treatment. Our study suggests that baloxavir treatment reduces household transmission and healthcare utilization, which may decrease rates of additional hospitalizations and transmissions outside of the home. As baloxavir currently requires a prescription prior to use, the development and distribution of readily available, over-the-counter diagnostic tests for influenza may streamline and increase the use of antiviral treatment and have the potential to further reduce the transmission and healthcare use observed in this study.

Our study has several limitations. Participation in the survey was voluntary, and survey information was self-reported. Our study was limited in its sample size, partly from a low response rate, which may have been due to the short period that patients had to respond to the survey. There is potential for follow-up bias, e.g., the effectiveness estimate to be biased because of eligible patients not completing the survey. For example, if the proportion of those eligible patients differed in response (outcome) the relative risk for household transmission for baloxavir versus oseltamivir could either increase or decrease. Although most transmission and healthcare resource utilization outcomes favored treatment with baloxavir over oseltamivir, the comparisons were not statistically significant. Patients were not explicitly asked if the healthcare resource utilization they reported was influenza related, so it is possible that some of it was not influenza related; however, results are consistent with a published claims analysis that reported lower resource use and costs of treatment with baloxavir compared with oseltamivir [38]. Also, influenza-like illness was self-reported and, without testing, it was not confirmed that the additional family member(s) had influenza and whether they got it before or after the index patient began treatment; it is reasonable to assume that a family member had influenza if they became ill within the window of time allowed after the index patient picked up an antiviral prescription. Sensitivity analyses (data not shown) indicated that potential bias may have minimal or no effect on study findings. A power analysis revealed that approximately 750 survey participants would be needed to highlight significant differences in household transmission. As a result of the size of the study cohort, sensitivity analyses and other subgroup analyses were not conducted and, in general, larger studies are needed to confirm these findings.