Health Technology Review

Cost-Effectiveness of Antiviral Drugs to Prevent or Treat Influenza A, Influenza B, or Zoonotic Influenza

Authors: Ilke Akpinar, Dagmara Chojecki

This rapid review was conducted by the Alberta Drug and Therapeutic Evaluation Consortium (ADTEC) through the Post-Market Drug Evaluation CoLab Network.

What Is the Issue?

• Influenza is a major public health concern, causing significant illness, death, economic challenges, and pandemic potential. This underscores the need for effective prevention (also known as prophylaxis), treatment, and pandemic preparedness strategies.

• Antiviral medications such as baloxavir marboxil, oseltamivir, peramivir, zanamivir are recommended for the treatment of influenza; however, their economic value remains unclear.

What Did We Do?

• We conducted a rapid review to identify and summarize evidence on the cost-effectiveness of antivirals for preventing and treating influenza A, influenza B, and zoonotic influenza, as well as the cost-effectiveness of antiviral stockpiling.

• We searched electronic databases and key online sources for economic evaluation studies published in English from January 1, 2019, to December 13, 2024. Additionally, we examined the cost-effectiveness of stockpiling from studies published from January 1, 2020, to April 4, 2025.

• One researcher screened citations, selected studies, and narratively summarized the study findings.

What Did We Find?

• We identified 9 economic evaluations: 8 examining the treatment of influenza and 1 examining both post-exposure prophylaxis and treatment.

• We did not identify any studies on the cost-effectiveness of antivirals for the prophylaxis or treatment of zoonotic influenza or any studies that evaluated the cost-effectiveness of stockpiling antiviral drugs.

• Economic studies suggest that certain antivirals may be cost-effective for treating influenza compared to standard of care, particularly in high-risk populations. However, it is unclear how cost-effective antivirals are for post-exposure prophylaxis, as there is limited evidence from just 1 study.

What Does It Mean?

• Economic evaluations suggest that oseltamivir or baloxavir marboxil are cost-effective treatments for influenza, particularly in high-risk populations.

• Baloxavir marboxil may be a valuable alternative in cases of oseltamivir resistance to ensure optimal resource allocation and long-term sustainability of antiviral treatments. However, its higher cost requires careful consideration.

• The generalizability of existing economic evaluations may be limited due to variability in influenza strains, health care systems, and cost structures that differ from Canada.

Introduction and Rationale

Background

Influenza is a viral infection of the respiratory system that carries a significant risk of morbidity and mortality. It is among the top 10 leading causes of death in Canada.¹ The severity of the disease can vary, from asymptomatic cases to severe complications. Common symptoms of influenza usually start suddenly and include fever, cough, and myalgias. Other frequently reported symptoms include chills, fatigue, headache, sore throat, loss of appetite, and nasal congestion.¹ Uncomplicated influenza typically resolves within 3 to 8 days.² However, influenza infection can lead to severe complications, particularly among high-risk groups. These include individuals over 65 years of age, pregnant people, children under 6 years old, and people with underlying health conditions such as heart, kidney, or liver disease; obesity; diabetes; or weakened immune systems.^1,2 The 3 primary types of influenza viruses that infect humans are A, B, and C. Among these, influenza A has the broadest host range, affecting humans, swine, equines, and birds. Its high susceptibility to antigenic variations makes it the leading cause of pandemics.¹ Influenza B primarily infects humans and can lead to seasonal influenza outbreaks.¹ Influenza C causes mild respiratory illness and is generally not associated with epidemics or pandemics.² Zoonotic influenza refers to strains of the virus that are transmitted from animals to humans, which can result in severe illness and even death, especially when the virus undergoes mutations that allow efficient human-to-human transmission.²

In Canada, influenza represents a major economic burden, affecting both the health care system and broader economic productivity. Before the COVID-19 pandemic, influenza caused an estimated 12,200 hospitalizations and 3,500 deaths annually.³ Each hospitalization was estimated to cost between CA$14,000 and CA$20,000, contributing to an annual economic burden of CA$168 million to CA$240 million.^3,4 Beyond health care, influenza also has a significant impact on workplace productivity. For example, during the H1N1 pandemic in November 2009, approximately 1.5 million employed people living in Canada who were aged 15 to 69 reported absences from work due to influenza, resulting in a loss of 29.5 million work hours.⁵ These figures underscore the widespread economic consequences of influenza, highlighting the critical need for effective prevention and control measures to mitigate its impact on both public health and the economy.⁶

Prevention and Treatment of Influenza

The National Advisory Committee on Immunization of the Public Health Agency of Canada recommends annual seasonal influenza vaccination for all individuals aged 6 months and older, unless contraindicated, regardless of prior vaccination history.⁶ Antiviral drug prophylaxis is recommended for both pre-exposure and post-exposure in various scenarios by the Association for Medical Microbiology and Infectious Disease Canada.⁷

As of January 2025, 3 antiviral drugs are available in Canada for the prophylaxis and treatment of influenza: oseltamivir (Tamiflu), zanamivir (Relenza), and peramivir (Rapivab).^8,9 Additionally, baloxavir marboxil (Xofluza) was approved by Health Canada in 2020 for the treatment of uncomplicated influenza in individuals aged 12 years and older.⁹ Only Health Canada–approved antivirals are considered in this review.

When given before or shortly after exposure, oseltamivir and zanamivir have been reported to be 68% to 92% and 69% to 81% effective, respectively, in preventing influenza in general adult populations.¹⁰ Early antiviral treatment, especially within 24 to 36 hours of symptom onset, can reduce the severity and duration of influenza. Neuraminidase inhibitors (NAIs), like oseltamivir, zanamivir, and peramivir, can shorten symptom duration by 30% to 40% and reduce the severity of the illness.¹¹ These treatments also help reduce the risk of complications such as pneumonia and sinusitis.¹¹ Additionally, antiviral treatments can decrease viral transmission within households, contributing to controlling the spread of influenza.¹²

The cost-effectiveness of antiviral drugs for outpatient influenza, including prophylaxis and treatment of seasonal, pandemic, and zoonotic strains, remains unclear.

Policy Issue

This rapid review is part of a broader project examining antiviral drugs for influenza. Evidence from this review, along with other components, including safety, effectiveness, and cost-effectiveness, will inform multijurisdictional decisions on the appropriate use of these drugs for the prophylaxis and treatment of influenza A, influenza B, and zoonotic influenza for pandemic preparedness.

Policy Questions

1. Is there a need to stockpile antiviral drugs for prepandemic or pandemic preparedness for treatment and prophylaxis of influenza A or B or zoonotic influenza strains?

1.1 Which influenza antivirals should be stockpiled for prepandemic or pandemic preparedness for treatment and prophylaxis?

1.2 What does each influenza antiviral offer in the prepandemic or pandemic context, considering relevant outcomes for specific populations?

2. What are the priorities for use of influenza antivirals by risk group, and high-risk setting including treatment and for pre-exposure and post-exposure prophylaxis?

Purpose

The purpose of this report is to summarize the evidence on the cost-effectiveness of antiviral drugs for the pre-exposure prophylaxis, post-exposure prophylaxis, and treatment of influenza A, B, and zoonotic influenza in individuals who are not hospitalized.

The scope of this project does not include evaluating the availability of antiviral drugs for influenza A and B, specifically addressing potential shortages that may require stockpiling. It also excludes the assessment of the accessibility and feasibility of these drugs for Canadians, including the availability of medications and the timeliness of health care access for diagnosis and prescription during a pandemic. Additionally, this project does not examine primary health care providers’ hesitancy to prescribe antiviral drugs for the prophylaxis and treatment of influenza or exploring the underlying reasons for such hesitancy. Lastly, the creation of a mathematical model and conducting a pharmacoeconomic analysis to assist decision-making on stockpiling strategies for both prepandemic and pandemic preparedness fall outside the scope of this work.

Research Question

What is the cost-effectiveness of antiviral drugs administered to individuals who are not hospitalized for the prophylaxis and treatment of influenza A or B or zoonotic influenza?

Methods

Literature Search Methods

An information specialist conducted searches in the electronic databases Ovid MEDLINE, Ovid Embase, and Web of Science for English-language literature published from January 1, 2019, to December 13, 2024. Articles were identified using a combination of controlled vocabulary, for example, MeSH and Embase subject heading terms, and relevant keywords surrounding the topics of antivirals and influenza. A cost analysis filter developed by Canada’s Drug Agency was also used to limit the search to economic analyses. Grey literature searching was conducted in ChatGPT, Perplexity AI, Google Scholar, Google Advanced, The National Institute for Health and Care Research website, the International Network of Agencies for Health Technology Assessment database, and Research Papers in Economics (RePEc). Reference lists of included articles were scanned, to help identify additional relevant evidence. An additional search was conducted on April 5, 2025, within the same databases to gather studies published from January 1, 2020, to April 4, 2025, focusing on the cost-effectiveness of stockpiling antivirals for influenza. This search employed MeSH terms and keywords related to stockpiles and stockpiling, as well as antivirals and influenza.

Selection Criteria and Methods

One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the selection criteria presented in Table 1.

Table 1: Selection Criteria

PEP = post-exposure prophylaxis; PrEP = pre-exposure prophylaxis; QALY = quality-adjusted life-year.

Notes: PrEP is an antiviral drug taken before any exposure to virus or pathogen (likely in the context of at-risk workers e.g., occupational exposure, high-risk individuals) to reduce or prevent the risk of developing an infection. PEP is an antiviral drug given after exposure to virus or pathogen (e.g., after exposure to an infectious case) before the presence of symptoms and/or a positive test result to prevent or control the spread of disease. Treatment is with an antiviral drug to treat signs and symptoms. Prepandemic is the period before a widespread outbreak and seasonal flu is categorized within the prepandemic context.

^aIncluding comparing different doses of the same intervention.

^bCombination treatment includes a neuraminidase inhibitor with another neuraminidase inhibitor or a neuraminidase inhibitor with baloxavir marboxil.

^cFor example, unvaccinated population (i.e., before a vaccine is available).

Exclusion Criteria

Studies were excluded if they did not meet Table 1 criteria, they were duplicate publications, or they were published before 2019. Costing studies, which focus solely on the costs associated with a particular intervention or program without considering the outcomes or effectiveness, are often categorized as partial economic evaluations. As they do not involve a full comparison of both costs and outcomes, they were excluded. Additionally, studies on the cost-effectiveness of drugs not approved in Canada (e.g., laninamivir) were excluded.

Critical Appraisal of Individual Studies

The included publications were critically appraised by 1 reviewer using the Drummond checklist.¹³ Summary scores were not calculated for the included studies; rather, the strengths and limitations of each included publication were described narratively.

Data Extraction

One reviewer extracted information from each article using a standardized data extraction form. During data extraction, the following were collected: author, publication year, country, source of funding, study design, modelling approach, study perspective, population characteristics, intervention(s), and comparator(s), discounting, time horizon, outcomes, source of clinical efficacy, cost and utility data, and results.

Summary of Evidence

Quantity of Research Available

Of the 590 citations identified in the economic evaluation literature search, 14 were potentially relevant based on title and abstract screening and were retrieved for full-text review. The full-text articles of an additional 10 potentially relevant publications identified through the grey literature search were similarly retrieved. Of these 24 articles, 15 were excluded, and 8 peer-reviewed articles and 1 paper identified through grey literature met the inclusion criteria and were included in this report. These comprised 9 economic evaluations.^14-22 An additional search on economic evaluation of stockpiling antiviral drugs identified 88 citations. After removing duplicates, 56 citations from databases and 8 from the grey literature were included for the title and abstract screening. One study was potentially relevant based on title and abstract, it was retrieved for full-text review but was not included. While this study incorporates cost considerations, it does not constitute a full economic evaluation. Rather, it provides insights into the trade-offs between antiviral effectiveness and cost, making it a cost-effectiveness–informed modelling study rather than a comprehensive economic analysis. Appendix 2 presents the PRISMA²³ flow chart of the study selection. A list of the excluded studies with reasons for exclusion are available in Appendix 3.

Study Characteristics

Nine economic evaluations^14-22 were identified and included in this rapid review, all of which were peer-reviewed except 1.¹³ Of the 9 studies identified, 8 focused on the treatment of influenza,^14-18,20-22 while 1 examined post-exposure prophylaxis and treatment.¹⁹ No economic evaluations were found for zoonotic influenza. The settings of the included studies were as follows: 7 focused on seasonal influenza,^14,16,18-22 1 on pandemic influenza,¹⁵ and 1 addressed both seasonal and pandemic influenza.¹⁷ Table 2 presents the studies on the post-exposure prophylaxis and treatment of influenza, organized by interventions, comparators, and respective settings, including both seasonal and pandemic influenza contexts, along with the number of studies under each category. Additional details regarding the characteristics of included publications are provided in Appendix 4.

Table 2: Studies on Post-Exposure Prophylaxis and the Treatment of Influenza

NOS = not otherwise specified; vs. = versus.

^aLaninamivir is not approved in Canada.

^bIn the study, the first drug was used for prophylaxis, followed by the second drug for treatment.

Study Design

All economic evaluations identified^14-22 were cost-utility analysis (CUA).

Six economic evaluations adopted a health care payer’s perspective.^{14,15,17-19,22} One study¹⁶ used a US commercial payer perspective. van der Pol et al.²⁰ employed a societal perspective for the CUA. Similarly, Li et al.²¹ adopted both societal and health care payer perspectives to provide a comprehensive evaluation of the economic impact of interventions.

Six studies^{14,16,18-20,22} employed decision-tree models. The assumptions included in the reviewed studies are as follows: fixed infection rates,¹⁵ one-time infection scenarios,¹⁵ and the exclusion of long-term health consequences of influenza.^18,19,21,22 Additionally, it was assumed that patients tested positive for influenza before receiving antiviral therapy,¹⁴ with an antiviral drug uptake rate of 35% among infected patients, and only 1 complication was considered in the analysis.¹⁵ A zero-mortality rate was assumed for exposed and infected individuals before becoming infectious.¹⁷ Furthermore, baloxavir marboxil was assumed to be effective only for the “true influenza” group, and outcomes were assumed to be the same for both baloxavir marboxil and the current standard of care arms.²⁰ Two studies^15,17 used linked dynamic transmission-economic models.²¹ All decision-tree models incorporated key health states such as infection onset, treatment, complications, and recovery, while dynamic models captured population-level transmission and mitigation effects. Sensitivity analyses, including probabilistic and scenario-based approaches, were conducted in all studies to evaluate the robustness of results.

The time horizons varied across the included studies, reflecting differences in the scope and objectives of the analyses. Eight studies employed relatively short time frames, with 4 studies using a 14-day horizon^18,19,21,22 and 2 studies adopting a 1-year horizon.^14,15 In contrast, 3 studies used a lifetime horizon.^16,17,20 These variations highlight the diversity in methodological approaches tailored to specific research questions and health care contexts.

Setting

Three economic evaluations were conducted based on country-specific data and costs from Japan,^18,19,22 and 1 study each for the following jurisdictions: Hong Kong,¹⁴ China,¹⁵ the US,¹⁶ the UK,¹⁷ and the Netherlands.²⁰ One economic evaluation used country-specific costs and drug prices for 15 different European countries.²¹

Patient Population

The studies investigated diverse populations that varied by age, risk profile, time since exposure or symptom onset (within 48 hours of symptom onset¹⁴ or at least 24 hours after onset¹⁵) and influenza symptoms. Nakagawa et al.^18,22 examined adults aged 18 and older diagnosed with influenza. Symptomatic individuals aged 12 and older were evaluated by Kommandantvold et al. in both the US¹⁶ and the UK,¹⁷ including a mix of healthy and high-risk groups. Nakagawa et al.¹⁹ focused on prophylaxis and treatment strategies in healthy adults while Li et al.²¹ investigated influenza-like illness among adults/adolescents (aged 13 and over), and children (≥ 1 year and < 13 years), including subgroups with and without comorbidities. van der Pol et al.²⁰ examined at-risk groups, such as older individuals and those with comorbidities.

Interventions and Comparators

The included studies evaluated cost-effectiveness of various antiviral interventions for influenza management, addressing both post-exposure prophylaxis and treatment. Nakagawa et al.¹⁹ focused on the cost-effectiveness of 8 antiviral post-exposure prophylaxis and treatment combinations, with the first drug administered for prophylaxis and the second for treatment.

For treatment, Chen et al.¹⁴ examined baloxavir marboxil for oseltamivir-resistant seasonal influenza and compared baloxavir marboxil to oseltamivir or baseline. Kommandantvold et al.^16,17 compared baloxavir marboxil to oseltamivir or no antiviral treatment in both seasonal^16,17and pandemic influenza.¹⁷ Jiang et al.¹⁵ compared baloxavir marboxil to oseltamivir for influenza pandemics.

Additionally, van der Pol et al.²⁰ evaluated baloxavir marboxil against the current standard of care, which included symptomatic treatment with paracetamol. Li et al.²¹ focused on comparing oseltamivir to standard care, specifically examining the addition of oseltamivir to usual care. Finally, Nakagawa et al.^18,22 compared oseltamivir, zanamivir, laninamivir, and peramivir for the treatment of seasonal influenza.

As laninamivir is not available in Canada, the results of from the laninamivir arms will not be discussed further.^18,19,22

Outcomes

The included studies^14-22 evaluated the cost-effectiveness of antiviral treatments for influenza using a variety of clinical and economic outcomes. Common economic outcomes included incremental cost-effectiveness ratios (ICERs) and net monetary benefit (NMB) at specified willingness-to-pay (WTP) thresholds. QALYs were derived from clinical trial data, network meta-analyses, and utility instruments like EQ-5D, a standardized instrument used to measure and assess the health-related quality of life (QoL) of individuals. Cost data encompassed drug acquisition costs, health care resource utilization (e.g., outpatient visits, hospitalization), and, where applicable, indirect costs, including productivity loss for studies adopting a societal perspective.

Funding

Industry funding played a dominant role in supporting economic evaluations of influenza interventions, with additional contributions from government and academic sources. Four studies reported industry funding,^15-17,20 while 2 studies received support from government funding,^14,21 and 1 received funding from a university.¹⁸ Two studies reported receiving no funding.^19,22

Characteristics of Individual Studies

None of the studies included in this report were conducted in Canada, which makes it uncertain how well their findings apply to context in Canada. Differences in population demographics, disease prevalence, and WTP thresholds can affect the relevance of these results. However, 2 studies^17,21 provide the most directly applicable insights for policy in Canada. While studies from Japan and China are of high quality, their direct relevance to cost structures in Canada is limited due to significant differences in health care financing systems. Given these considerations regarding the applicability of the findings to the context in Canada, the studies in this report are listed in order of recency and are organized based on the specific interventions (e.g., antiviral drugs) they compare. This structure allows for a clear comparison of the studies, while acknowledging the varying degrees of relevance to Canadian policy.

Cost-Effectiveness of Influenza Post-Exposure Prophylaxis and Treatment

Nakagawa et al.¹⁹ conducted a CUA in Japan to evaluate the cost-effectiveness of post-exposure prophylaxis followed by treatment strategies for seasonal influenza. The study focused on healthy adults aged 18 and older and employed a decision-tree model with a 14-day time horizon from a health care payer's perspective. The following 8 prophylaxis-treatment antiviral combination strategies (the first drug was used for prophylaxis, followed by the second drug for treatment) were examined in the study: oseltamivir with zanamivir, oseltamivir with laninamivir, oseltamivir with baloxavir marboxil, zanamivir with baloxavir marboxil, laninamivir with baloxavir marboxil, baloxavir marboxil with oseltamivir, baloxavir marboxil with zanamivir, and baloxavir marboxil with laninamivir. Effectiveness probabilities were obtained from clinical trials, while cost data were sourced from the 2020 Japanese Medical Fee Index. Utility values were derived from EQ-5D-5L questionnaires. The decision tree categorized patients into 8 health statuses based on prophylaxis effectiveness, treatment outcomes, side effects, and pneumonia-related hospitalizations. The study defined antiviral dosages for post-exposure prophylaxis as follows: oseltamivir was administered orally at a dose of 75 mg once daily for 10 days, while zanamivir was given as an inhaled dose of 10 mg once daily for the same duration. Laninamivir was prescribed as a 20 mg inhaled dose once daily for 2 days. Baloxavir marboxil was dosed based on body weight, with patients weighing less than 80 kg receiving 40 mg and those weighing 80 kg or more receiving 80 mg once orally. If post-exposure prophylaxis failed, patients were assumed to receive an alternative influenza treatment with 1 of these drugs, with its effectiveness incorporated into the analysis.

Cost-Effectiveness of Influenza Treatment

Cost-Effectiveness of Baloxavir Marboxil Versus Oseltamivir Versus Baseline

Chen et al.¹⁴ conducted a CUA comparing baloxavir marboxil, oseltamivir, or no treatment for treating seasonal influenza in adult outpatients in Hong Kong. The study used a decision-tree model with a 1-year time horizon from a health care payer’s perspective. The analysis accounted for key clinical events among patients with confirmed influenza receiving antiviral treatment, including treatment-related adverse events, the development of antiviral resistance, influenza-related complications, hospitalization due to complications, and mortality from complications or other causes. Both otherwise healthy and high-risk adult populations were considered. Clinical data were sourced from 2 Phase III clinical trials, while cost estimates were derived from Hong Kong-specific health care data, including outpatient consultations, diagnostic tests, medications, hospitalizations, and intensive care unit (ICU) costs. Utility values were adjusted to reflect the impact of treatment-related adverse events, the duration of influenza symptoms, and influenza-related complications, based on data from health technology assessments. A key assumption in the model was that all patients were tested for influenza before treatment initiation.

Cost-Effectiveness of Baloxavir Marboxil Versus Oseltamivir

Jiang et al.¹⁵ evaluated the public health and economic impacts of adding baloxavir marboxil as a treatment option, in addition to oseltamivir for influenza pandemic control in China. The study employed a linked dynamic transmission-economic evaluation model over a one-year time horizon from the perspective of the Chinese health care system. Health state utilities for the baseline healthy state, influenza-infected state, and complication-related states were sourced from the literature, while clinical data were drawn from existing studies. Cost estimates, including treatment costs, were derived from 2021 CN¥ values and economic evaluations specific to China. The decision-tree model compared 2 strategies— access to only oseltamivir and - access to baloxavir marboxil or oseltamivir—with patient numbers estimated based on cumulative infection incidence from the Susceptible-Exposed-Infected-Recovered model (SEIR) model. Outpatients were categorized into 5 groups according to complication status: uncomplicated influenza, pneumonia, bronchitis, middle ear infection, and sinus infection. Treatment pathways included outpatient care or hospitalization, with hospital cases further classified into general ward or ICU admissions. The model assumed that each patient could only experience 1 influenza infection per year and develop a single complication. Sensitivity analyses confirmed the robustness of the results across a range of parameter variations.

Cost-Effectiveness of Baloxavir Marboxil Versus Oseltamivir Versus no Treatment

Kommandantvold et al.¹⁶ conducted a cost-effectiveness analysis (CEA) comparing baloxavir marboxil, oseltamivir, and no antiviral treatment for seasonal influenza management in the US. The study employed a decision-tree model with a lifetime horizon from the perspective of a US payer. The analysis included individuals aged 12 and older with influenza, with 56% classified as otherwise healthy and 44% as high risk, based on a real-world study with a mean age of 32 years. The decision-tree model incorporated mutually exclusive pathways, where each individual could experience infection, receive treatment, develop complications, and either recover or die. In cases of complications, individuals could receive outpatient or inpatient care, including ICU admission. Clinical and cost data were obtained from the Merative™ MarketScan® Research Databases. The study applied a 3.0% annual discount rate and conducted sensitivity analyses, including scenarios assessing the impact of transmission reduction.

Kommandantvold et al.¹⁷ evaluated the cost-effectiveness of baloxavir marboxil for managing seasonal and pandemic influenza in the UK. The study employed a SEIR model alongside a cost-effectiveness model from the perspective of the UK National Health Service. It compared baloxavir marboxil to oseltamivir or to no antiviral treatment in individuals aged 12 and older, categorized as otherwise healthy or high-risk. The analysis used a lifetime horizon with a 3.5% annual discount rate, assessing key outcomes such as attack rates (proportions of the population infected), QALYs, and ICERs. Utility values for various health states, including healthy, influenza-infected, and complication-related states, were derived from the literature. Cost data were obtained from the NHS 2021/2022 National Cost Collection, while information on influenza-related complications and their likelihood in the otherwise healthy and high-risk populations was obtained from existing studies. The cost-effectiveness model analyzed the otherwise healthy and high-risk populations separately, incorporating data from the SEIR model under seasonal, pandemic, and high-treatment pandemic scenarios. The decision-tree model structured disease progression through mutually exclusive pathways: individuals could be infected or not, receive antiviral treatment or not, experience 1 complication at a time or none, and either recover or die. Those with complications could receive outpatient care, general inpatient care, or ICU admission.

Cost-Effectiveness of Baloxavir Marboxil Versus Standard of Care

van der Pol et al.²⁰ conducted a CUA to evaluate the cost-effectiveness of baloxavir marboxil for treating seasonal influenza in the Netherlands. The CUA employed a lifetime horizon. The study adopted a societal perspective for the CUA. The base-case CUA included a cohort of 1,000 individuals aged 52 and at risk for influenza-related complications. Scenario analysis considered other age groups. The study applied a 4% discount rate to costs and 1.5% to outcomes. A decision-tree model was used, with clinical data sourced from the CAPSTONE-2 trial and cost data obtained from Dutch reference prices and existing literature. Sensitivity analyses, including deterministic sensitivity analysis, probabilistic sensitivity analysis (PSA), and scenario analysis, were conducted to assess the robustness of the findings. Baloxavir marboxil was compared to the current standard of care, which consists of symptomatic treatment with paracetamol.

Cost-Effectiveness of Oseltamivir Plus Standard of Care Versus Standard of Care

Li et al.²¹ conducted a CUA to evaluate the economic impact of adding oseltamivir to the usual care for managing influenza-like illness across 15 European countries. This study, part of the European Commission’s Seventh Framework Programme, adopted both health care payer and societal perspectives. The analysis used data from the ALIC⁴E randomized controlled trial (RCT) and assessed outcomes in terms of QALYs and associated health care costs. The study population included adults/adolescents (aged 13 years and older), and children (≥ 1 year and < 13 years) diagnosed with influenza-like illness. A 14-day time horizon was applied, and cost estimates were derived from patient-reported resource use and country-specific unit costs. The analysis did not capture long-term health consequences from influenza-like illness.

Cost-Effectiveness of Oseltamivir Versus Zanamivir Versus Peramivir Versus Laninamivir

Nakagawa et al.¹⁸ conducted a CEA of anti-influenza drugs for adult patients in outpatient settings in Japan. The study employed a decision-tree model with 7 disease states, which were evaluated under both the base-case scenario and various sensitivity analyses. The model utilized a 14-day time horizon, and the cost-effectiveness evaluation focused on multiple NAIs, including oseltamivir, zanamivir, laninamivir, and peramivir. The study population comprised patients aged 18 and older, all diagnosed with seasonal influenza virus infection in Japan. Sensitivity analyses were performed using deterministic sensitivity analysis, Monte Carlo simulations, and PSA with 10,000 iterations to evaluate the results robustness. Cost data were sourced from the 2020 Japanese Medical Fee Index, and utility values were derived from EQ-5D-5L questionnaires.

Nakagawa et al.²² conducted a CEA to assess the economic value of NAIs for treating seasonal influenza virus infections in adult outpatients in Japan. The analysis adopted a health care payer perspective and employed a decision-tree model with a 14-day time horizon. Clinical inputs were derived from RCTs, while cost data were sourced from the 2016 Japanese medical fee schedule. Utility values were obtained using EQ-5D-3L questionnaires. The study compared 4 NAIs: oseltamivir, zanamivir, laninamivir, and peramivir. The decision-tree model categorized disease progression into 3 states: effective treatment within 5 days using NAIs, ineffective treatment leading to hospitalization and pneumonia, and ineffective treatment requiring more than 5 days of therapy with persistent fever. Medical costs, including physician fees, hospital admission costs, and drug prices, were evaluated from the health care payer's perspective. Community pharmacy costs, covering dispensing fees, pharmaceutical management fees, and drug costs were also considered. One-way sensitivity analyses were conducted to assess the impact of variations in factors such as treatment duration, QoL values, drug prices, and the costs associated with physician and community pharmacy visits, as well as hospital admission.

Critical Appraisal

The included economic evaluations had several strengths as assessed using the Drummond checklist.^14-22 The objectives and economic importance of the studies were described, the interventions and comparators of interest were clearly reported, and the form of analysis and perspectives were described. The sources of input parameters in the analysis were mentioned,^14-22 and currency, conversion rates, and price data were described. One of the studies²¹ used a trial-based analysis, and other 8 studies^14-20,22 used modelling with parameters obtained from other sources to conduct analysis. All studies conducted sensitivity analyses and incremental effectiveness results were reported. Conclusions were consistent with the data reported and were accompanied by the appropriate caveats.^14-22

In the study by Chen et al.¹⁴ the input parameters were sourced from local data (Hong Kong-specific costs, and epidemiological inputs) enhancing the validity of the results. Subgroup analyses (healthy versus high-risk adults) improved the generalizability of the findings. A decision-tree model was employed, and the rates were not discounted, given the shorter time horizon of 1 year. Sensitivity analyses (both one-way and probabilistic) confirmed the cost-effectiveness of baloxavir marboxil across plausible scenarios. While the funding sources were disclosed, a conflict of interest (author ties to Roche) introduces potential bias. Overall, the analysis is robust for short-term decision-making.

The Jiang et al.¹⁵ study adopted a Chinese health care system perspective and employed a linked SEIR and decision-tree model, incorporating both transmission dynamics and individual patient outcomes. Local data from China, including data from the 2009 H1N1 pandemic, inform key parameters. The one-year time horizon limits the ability to assess long-term consequences. Sensitivity analyses confirm the robustness of the findings. However, uncertainties remain regarding key parameters, particularly the transmission coefficient and vaccination assumptions, and the model does not explicitly account for viral evolution. The study clearly articulates its assumptions and limitations. Additionally, funding from Hoffmann-La Roche introduces a potential source of bias. Overall, while the analysis provides valuable insights for short-term pandemic planning, it warrants cautious interpretation due to the limitations of scope and parameter uncertainty.

In the study by Kommandantvold et al.¹⁶ use of a decision-tree model is appropriate for the clinical pathway being examined, and a lifetime time horizon with discounting is employed to capture long-term effects. US administrative claims data inform key model parameters, enhancing the validity and relevance to the US health care setting. Scenario analysis explores the potential impact of baloxavir marboxil on viral transmission. The study includes sensitivity analysis, examining a range of transmission reduction scenarios. The authors disclosed funding from Hoffmann-La Roche and Genentech, manufacturers of baloxavir marboxil, which introduces a potential for bias. Overall, the study provides useful information for decision-makers in the US health care system, although the generalizability of the findings may be limited to Canada.

In the study by Kommandantvold et al.,¹⁷ the use of a linked SEIR and decision-tree model is a strength as it captures both the transmission dynamics and individual patient outcomes. UK-specific data are used, including population size, health care costs, and estimates of influenza burden. The SEIR model allows for estimating the population attack rates under different treatment strategies, while the decision-tree model captures short-term costs and outcomes. Scenario analyses explored different settings (seasonal, pandemic, high-treatment pandemic) and the impact of asymptomatic patients and self-isolation. However, the study has limitations. The time horizon for the SEIR model is limited to 1 influenza season, potentially missing longer-term effects. The study discloses funding from Hoffmann-La Roche, which introduces a potential bias. Overall, the study provides useful information for decision-makers in the UK, particularly regarding the potential benefits of baloxavir marboxil in reducing influenza transmission, but the limitations related to model assumptions and potential bias should be considered.

In the study by Nakagawa et al.,¹⁸ the objective is clearly defined: to re-evaluate the cost-effectiveness of NAIs (oseltamivir, laninamivir, zanamivir, and peramivir) for influenza treatment in Japan from a health care payer perspective. This study addresses limitations in a prior study²² by incorporating network meta-analysis (NMA) data, a more detailed decision tree, and EQ-5D-5L-derived QoL scores. Both studies use Japanese medical costs. Deterministic and probabilistic sensitivity analyses were performed. However, the study has limitations. The time horizon is limited to 14 days, which may not capture all relevant long-term outcomes. The QoL scores are based on a relatively small sample (n = 50). While the study uses NMA data, the validity of the overall analysis depends on the quality and assumptions within that NMA. The reliance on the EQ-5D-5L, although an improvement over the EQ-5D-3L, introduces potential biases inherent in utility elicitation methods. Additionally, the study does not evaluate baloxavir marboxil, which could be a relevant comparator. Finally, the study was publicly funded, and none of the authors disclosed any financial relationship with drug manufacturers. Overall, the study provides useful information for decision-makers in Japan, but the limitations related to the short time horizon, sample size for QoL scores, and the exclusion of baloxavir marboxil may be a consideration.

In the study by Nakagawa et al.,¹⁹ a decision-tree model is employed to simulate 8 combination treatment strategies for prophylaxis, with a time horizon of 14 days, which may limit the capture of long-term effects. The study uses Japanese cost data from the 2020 Medical Fee Index and utility values derived from EQ-5D-5L questionnaires administered to healthy university students. Deterministic and probabilistic sensitivity analyses are conducted to assess the robustness of the results. A key limitation is that utility values from healthy individuals may not accurately reflect the QoL impact on those who develop influenza. The study identifies and values all relevant inputs, but the reliance on a short time horizon for influenza treatment warrants caution. Overall, the study provides useful information for formulary management in Japan, suggesting the potential cost-effectiveness of baloxavir marboxil and oseltamivir as prophylactic drugs. However, its limitations related to the short time horizon and the use of utility values from healthy individuals should be considered when interpreting the results.

In the study by van der Pol et al.,²⁰ a decision-tree model is used for the CUA, and a lifetime horizon allows for capturing long-term QALY effects, with appropriate discounting. The study incorporates Dutch-specific data, and productivity losses are included. However, the study has limitations: the modelled results are uncertain due to variability in key outcomes, particularly the hospitalization rate. The reliance on data from the CAPSTONE-2 trial may not fully reflect real-world effectiveness in the Netherlands. Although baloxavir marboxil has been shown to reduce the viral load of influenza and shorten the time to cessation of viral shedding, which may impact transmission, these effects were not included in the CEA. Additionally, the study discloses funding from Roche Netherlands B.V. which introduces the potential for bias. Overall, the study provides useful information for health care decision-makers in the Netherlands, but limitations related to model structure, data sources, and sensitivity analysis should be considered.

In the study by Li et al.,²¹ the analysis is conducted from both health care payers’ and societal perspectives. The study leverages patient-level data on resource use, costs, and health-related QoL, collected prospectively in the ALIC⁴E trial, which enhances validity and reduces reliance on modelling assumptions. Country-specific unit costs and purchasing power parity conversions are used, increasing the relevance and comparability of the findings. However, the 14-day time horizon is a limitation, potentially missing the longer-term sequelae of influenza-like illness. The study appropriately addresses uncertainty through PSA and also conducts an expected value for perfect information analysis. Nonetheless, important methodological details are lacking, such as the translation of EQ-5D-Y (a generic self-report instrument designed to measure health-related QoL in children and adolescents aged 8 to 15) results. Finally, the study was publicly funded, and none of the authors disclosed any financial relationships with drug manufacturers. It provides valuable evidence on the cost-effectiveness of oseltamivir for influenza-like illness in Europe. The limitations related to the short time horizon and methodological transparency should be considered when interpreting the results.

In the study by Nakagawa et al.,²² a decision-tree model used is appropriate for this clinical context. The study employs Japanese cost data from the 2016 medical fee schedule as well as effectiveness probabilities derived from RCTs. QoL values are elicited using EQ-5D-3L questionnaires administered to patients who had previously experienced influenza. One-way sensitivity analyses are conducted. The study identifies and values most relevant inputs, but there are several limitations. The time horizon is limited to 14 days, which may not capture all relevant costs or long-term effects. The reliance on the EQ-5D-3L for QoL assessment may introduce biases, and the sample of patients used to derive the EQ-5D-3L values is not described in detail beyond being collected from a community pharmacy. Additionally, the study does not appear to conduct PSA. The base-case analysis found oseltamivir to be the most cost-effective NAI. Overall, the study provides useful information for decision-makers in Japan, but the limitations related to the short time horizon, the QoL data collection, and the lack of PSA should be considered when interpreting the results.

Although the included studies discussed the results and acknowledged limitations, several assumptions made it difficult to assess the reliability of the results and the model’s robustness to changes. Finally, none of the studies were conducted in Canada, making the generalizability of the findings to settings in Canada uncertain due to differences in population, differences in health care financing systems, and WTP thresholds.

Additional details regarding the strengths and limitations of included publications are provided in Appendix 4.

Findings

Nine economic evaluations were included in this rapid review. The cost-effectiveness of antivirals for post-exposure prophylaxis and treatment was examined in 1 study,¹⁹ and the cost-effectiveness of antivirals for the treatment of influenza was examined in all 9 studies.^14-22

No relevant evidence was identified on the cost-effectiveness of antivirals for pre-exposure prophylaxis, zoonotic influenza post-exposure prophylaxis, or treatment of zoonotic influenza; therefore, a summary of the evidence could not be provided.

Cost-Effectiveness of Influenza Post-Exposure Prophylaxis and Treatment

Nakagawa et al.¹⁹ conducted a pharmacoeconomic study in Japan to assess the cost-effectiveness of 8 prophylaxis-treatment antiviral combination strategies (the first drug was used for prophylaxis, followed by the second drug for treatment) for seasonal influenza: oseltamivir with zanamivir, oseltamivir with laninamivir, oseltamivir with baloxavir marboxil, zanamivir with baloxavir marboxil, laninamivir with baloxavir marboxil, baloxavir marboxil with oseltamivir, baloxavir marboxil with zanamivir, and baloxavir marboxil with laninamivir.

The results indicated that the most cost-effective approach was using baloxavir marboxil for post-exposure prophylaxis and laninamivir for treatment, yielding a NMB of ¥179,952 at the WTP level of ¥5,000,000 per QALY. The second most cost-effective strategy involved oseltamivir for post-exposure prophylaxis and zanamivir for treatment, with an NMB of ¥180,148 at the WTP level of ¥5,000,000 per QALY. The authors concluded that baloxavir marboxil and oseltamivir are the most cost-effective treatments for post-exposure prophylaxis in Japan from the perspective of health care payers.

Cost-Effectiveness of Influenza Treatment

Cost-Effectiveness of Baloxavir Marboxil Versus Oseltamivir Versus Baseline

Chen et al.¹⁴ conducted a CUA comparing baloxavir marboxil to oseltamivir or to no treatment for the treatment of seasonal influenza in adult outpatients in Hong Kong. In the general population, baloxavir marboxil demonstrated an ICER of US$66,856 per QALY gained compared to no treatment and US$29,660 per QALY gained compared to oseltamivir, both of which were lower than the WTP threshold of US$152,667. In otherwise healthy adults, the ICERs were US$122,767 compared to baseline and US$75,800 compared to oseltamivir. In the high-risk population, baloxavir marboxil was dominant (more effective and less costly), with ICERs of US$20,222 compared to baseline and US$–1,813 compared to oseltamivir. At the baseline, sensitivity analysis indicated a 78% probability of baloxavir marboxil being cost-effective at the specified WTP threshold ($152,667 per QALY). In the otherwise healthy subpopulation, baloxavir marboxil is cost-effective in 72% of scenarios, while in the high-risk population, it is cost-effective in 99% of scenarios. The study concluded that baloxavir marboxil is a cost-effective alternative to oseltamivir and effective against resistant strains with a single-dose regimen.

Cost-Effectiveness of Baloxavir Marboxil Versus Oseltamivir

Jiang et al.¹⁵ evaluated the public health and economic impacts of adding baloxavir marboxil to oseltamivir for influenza pandemic control in China. The addition of baloxavir marboxil reduced the cumulative infection incidence from 49.5% to 43.3% and increased QALYs by 0.00021 per person. At a WTP threshold of CN¥80,976 per QALY, the NMB was CN¥77.85 per person. The authors concluded that, in the context of an influenza pandemic, adding baloxavir marboxil to oseltamivir is a cost-effective strategy in China.

Cost-Effectiveness of Baloxavir Marboxil Versus Oseltamivir Versus No Treatment

Kommandantvold et al.¹⁶ evaluated the cost-effectiveness of baloxavir marboxil compared to oseltamivir or no treatment for seasonal influenza management in the US. The study found that baloxavir marboxil was cost-effective in all scenarios. In the base-case analysis, the ICER for baloxavir marboxil was US$6,813 per QALY gained compared to oseltamivir and US$669 per QALY gained compared to no treatment, both well lower than the WTP (US$100,000 per QALY) threshold. In the high-risk subpopulation, baloxavir marboxil was dominant compared to no treatment, and had an ICER of US$8,597 per QALY compared to oseltamivir. In the otherwise healthy subpopulation, the ICER for baloxavir marboxil was US$5,861 per QALY gained compared to oseltamivir and US$2,037 per QALY gained compared to no treatment. The NMB of baloxavir marboxil in the base case was US$1,180 compared to oseltamivir and US$6,208 compared to no treatment. A scenario analysis showed that a 5% reduction in viral transmission increased baloxavir marboxil’s NMB compared to oseltamivir from US$1,180 in the base case to US$2,592. Each additional 5% reduction further increased baloxavir marboxil’s incremental NMB by approximately US$1,413 relative to oseltamivir or no treatment. Baloxavir marboxil became cost-dominant when it decreased viral transmission by 12% compared to oseltamivir and by 6% compared to no treatment. The authors concluded that baloxavir marboxil is a cost-effective alternative to oseltamivir or no treatment, with its potential to reduce viral transmission providing economic benefits from a US payer perspective.

Kommandantvold et al.¹⁷ evaluated the cost-effectiveness of baloxavir marboxil for treating seasonal and pandemic influenza in the UK. The SEIR model predicted greater reductions in infections with baloxavir marboxil compared to oseltamivir or no treatment. In the seasonal influenza setting, the ICER for baloxavir marboxil compared to oseltamivir was £1,884 per QALY gained, and baloxavir marboxil was dominant (more effective and less costly) compared to no treatment. Among high-risk individuals in the seasonal influenza setting, baloxavir marboxil had an ICER of £2,574 per QALY gained compared to oseltamivir and £128 per QALY gained compared to no treatment. In the pandemic influenza setting, the ICER for baloxavir marboxil compared to oseltamivir was £11,693 per QALY gained, and in a high-treatment scenario, this decreased slightly to £10,186 per QALY gained. For high-risk individuals during a pandemic, baloxavir marboxil had an ICER of £12,802 per QALY gained compared to oseltamivir and £1,401 per QALY gained compared to no treatment. Overall, the study highlighted baloxavir marboxil as a cost-effective treatment option at the WTP threshold of £20,000 per QALY for both seasonal and pandemic influenza from the UK National Health Service perspective.

Cost-Effectiveness of Baloxavir Marboxil Versus Standard of Care

van der Pol et al.²⁰ conducted a CUA to assess the cost-effectiveness of baloxavir marboxil for treating seasonal influenza in the Netherlands. The economic evaluation showed that the base-case ICER for baloxavir marboxil was €8,300 per QALY gained compared to the current standard of care. At a WTP threshold of €20,000 per QALY, baloxavir marboxil had a 58% probability of being cost-effective. Baloxavir marboxil remained cost-effective across various scenarios, particularly for older adults and individuals at high risk of influenza-related complications. The primary drivers of cost-effectiveness were reduced illness duration and productivity gains in the working population. Overall, the study concluded that baloxavir marboxil is a cost-effective treatment for seasonal influenza in the Netherlands, particularly for individuals aged 60 years and older or those at high-risk for severe influenza outcomes.

Cost-Effectiveness of Oseltamivir Plus Standard of Care Versus Standard of Care

Li et al.²¹ conducted a CUA to evaluate the economic value of adding oseltamivir to usual care for managing influenza-like illness across 15 European countries. From a health care payer perspective, the ICER for oseltamivir was €22,445 per QALY gained for adults and adolescents and €13,006 per QALY gained for children. From a societal perspective that accounted for productivity losses, oseltamivir was cost-saving for adults and adolescents and had an ICER of €8,347 per QALY for children. The cost-effectiveness of oseltamivir varied by country. Sensitivity analyses confirmed the robustness of the findings across various parameters, though uncertainties remained in subgroups with comorbidities, particularly among children. These uncertainties were primarily due to the small sample sizes, greater variability in treatment outcomes and costs, and the impact of hospitalization events in the usual care group, which introduced additional variability in cost-effectiveness estimates. At a WTP threshold of €20,000 per QALY, oseltamivir had a 45% probability of being cost-effective. The expected value of perfect information (the value of conducting additional research to reduce uncertainty in estimating incremental costs and effects of oseltamivir vs. usual care) ranged from €1 to €35 per patient. The study concluded that adding oseltamivir to usual care is likely cost-effective for the treatment of influenza-like illness in Europe from a health care payer perspective when the WTP exceeds €22,445 per QALY and cost-saving (WTP > €8,347) from a societal perspective for adults and adolescents. These findings support oseltamivir as a feasible treatment option in primary care settings across Europe, particularly during seasonal influenza epidemics.

Cost-Effectiveness Comparing Oseltamivir, Zanamivir, Peramivir, and Laninamivir

Nakagawa et al.¹⁸ performed a CEA of anti-influenza drugs for adult patients in outpatient settings in Japan and found oseltamivir to be the most cost-effective NAI for treating seasonal influenza in Japan. In the initial analysis, the authors re-examined the most cost-effective anti-influenza drug by using a decision tree from the previously referenced study,²² while also incorporating data from the NMA. The analysis found that oseltamivir outperformed zanamivir, laninamivir, and peramivir. Sensitivity analyses revealed that zanamivir had a negative INMB of ¥−38,470 (US$ −384) compared to oseltamivir, while laninamivir and peramivir had INMBs of ¥−1,836 (US$ −18) and ¥−6,178 (US$ −61) compared to oseltamivir, respectively. PSA showed that oseltamivir was the most cost-effective option in 32.3% of iterations at a WTP threshold of ¥5,000,000 per QALY. In the second analysis, the authors used a more detailed decision tree (comprising 7 disease states) along with the NMA data. Oseltamivir consistently yielded the highest INMB, while laninamivir and peramivir remained less cost-effective. Two-way sensitivity analyses focused on comparing the probability of effectiveness of laninamivir and oseltamivir indicated that oseltamivir covered the largest cost-effectiveness area, with acceptability curves reinforcing its preferred status across a broad range of WTP thresholds (¥ 0 to ¥10,000,000 per QALY). The authors concluded that oseltamivir is the most cost-effective NAI for treating influenza in Japan.

Nakagawa et al.²² conducted a CEA to evaluate the economic value of NAIs for treating seasonal influenza in adult outpatients in Japan. The analysis identified oseltamivir as the most cost-effective NAI, with an incremental cost-effectiveness ratio of ¥393,674 per QALY (US$3,883.41 per QALY) at a WTP threshold of ¥5,000,000 per QALY. In comparison, the cost-effectiveness ratios for zanamivir, laninamivir, and peramivir were ¥ 408,241 per QALY (US$4,027.10 per QALY), 407,980 yen per QALY (US$4,024.53 per QALY), and 444,264 yen per QALY (US$4,382.45 per QALY), respectively. Zanamivir was dominated, as it was both less effective and more costly than oseltamivir. Compared to oseltamivir, laninamivir and peramivir were less cost-effective, with ICERs of 1,129,459 yen per QALY (US$11,141.58 per QALY) and 1,287,118 yen per QALY (US$12,696.81 per QALY), respectively. One-way sensitivity analyses on various parameters (duration of treatment, QoL values, drug prices, costs of physician visits, costs of community pharmacy visits, costs of hospital admission and effectiveness to high-risk patients) confirmed the robustness of the results, with laninamivir showing a minimum ICER of −596,850 yen per QALY (US$ −5,887.64 per QALY) and peramivir a maximum ICER of 14,717,518 yen per QALY (US$145,181.32 per QALY). The study concluded that oseltamivir is the most cost-effective NAI for treating influenza in adult outpatients in Japan.

Cost-Effectiveness of Stockpiling

A comprehensive economic evaluation of antiviral stockpiling is lacking in the literature. The study “Estimation of Optimal Antiviral Stockpile for a Novel Influenza Pandemic”²⁴ employs epidemiological modelling to assess antiviral stockpile composition, comparing NAIs and cap-dependent endonuclease inhibitors using data from South Korea’s 2009 H1N1 pandemic. The results show that cap-dependent endonuclease inhibitors, despite their higher cost, could reduce infections from 30% to 25% when administered to 10% of cases. When the cost of cap-dependent endonuclease inhibitors is 3 times that of NAIs, no additional expenditures beyond the current budget are needed; however, if the cost of cap-dependent endonuclease inhibitors is 5 times that of NAIs, expenditures increase by 17%. The authors concluded that stockpiling cap-dependent endonuclease inhibitors reduces patient numbers by shortening the infectious period, but the government must consider the cost-effectiveness of the stockpile, factoring in the drug’s cost, virus transmissibility, vaccine development time, and the potential for resistance. While this study incorporates cost considerations, it does not provide a full economic evaluation but offers insights into the trade-offs between antiviral effectiveness and cost, making it a cost-effectiveness–informed modelling study rather than a comprehensive economic analysis.

Appendix 5 presents the main study findings, antiviral drug costs reported in included studies, and opportunity cost information.

Limitations

No pharmacoeconomic studies evaluating the cost-effectiveness of antivirals for pre-exposure prophylaxis, zoonotic influenza post-exposure prophylaxis, or treatment for zoonotic influenza were identified. Additionally, there is no evidence on the cost-effectiveness of stockpiling antiviral drugs.

The cost-effectiveness of post-exposure prophylaxis remains uncertain, as only 1 study was identified.¹⁹ This study primarily focused on Japanese populations and used utility values derived from a young, healthy cohort, which may limit its generalizability to broader age populations and to the population in Canada.

The cost-effectiveness of antiviral treatments for influenza varies depending on the drug, population, and implementation strategy. While antiviral drugs can be cost-effective, particularly for high-risk groups and during severe seasons, the generalizability of the identified studies to Canada is limited due to differences across jurisdictions and study settings. These include variations in health care systems, population characteristics, epidemiological contexts, and treatment costs, all of which can have an impact on the cost-effectiveness of antiviral treatments.

While the 5 studies^14-17,20 offer valuable insights into the potential cost-effectiveness of baloxavir marboxil, the direct industry funding and authors’ affiliations with the industry raise significant concerns regarding potential bias. Therefore, the findings should be interpreted with caution.

Conclusions and Implications for Decision- or Policy-Making

Economic Findings

• Oseltamivir was most consistently reported to be a cost-effective option, especially when considering broader health care system and societal costs.

• Baloxavir marboxil was also reported to be a cost-effective treatment, particularly for high-risk populations, for reducing viral transmission or in cases of oseltamivir resistance.

• The cost-effectiveness of antiviral treatments depends on factors such as drug choice, target population, and implementation strategies. While newer treatments like baloxavir marboxil may be more expensive, their cost-effectiveness in high-risk groups may justify the investment, particularly when considering potential savings from reduced transmission, hospitalizations, and complications.

Implications for the Health Care Systems in Canada

• The use of antiviral treatments for post-exposure prophylaxis and influenza treatment may reduce overall health care costs by preventing transmission, hospitalizations, and alleviating the economic burden associated with severe influenza cases.

• Given the potential for oseltamivir resistance, evaluating the cost-effectiveness of alternative antivirals like baloxavir marboxil is crucial to ensure optimal resource allocation and the long-term sustainability of antiviral strategies.

• While thresholds like £30,000 per QALY (UK) and $100,000 per QALY (US) reflect the health system’s opportunity cost of care, few studies explicitly discussed antiviral use in the context of constrained health care resources. Although many studies applied WTP thresholds or NMB frameworks, most did not examine the trade-offs between antiviral investment and other potentially cost-effective interventions.

Limitations of the Assessment or Evidence

• Economic analyses were based on modelled data and assumptions, which may not fully capture the complexities of real-world implementation and costs.

• Not all studies considered the transmission dynamics of influenza.

• A key limitation across the existing economic evaluations is the use of region-specific data, such as country-specific costs, utility values, and WTP thresholds, combined with assumptions (e.g, treatment adherence, transmission dynamics) that may not reflect the context in Canada.

Conclusions

• The available evidence suggests that antiviral drugs are cost-effective for both post-exposure prophylaxis and the treatment of influenza, particularly in high-risk groups. However, cost-effectiveness of specific antivirals could vary based on population characteristics, differences in influenza strain, health care delivery systems, and resource availability. It is important to note that much of the current evidence is not based on settings in Canada, which may limit its direct applicability to the health care systems in Canada.

• Given the higher cost of newer treatments such as baloxavir marboxil, careful consideration is warranted related to their potential cost-effectiveness to better understand how overall population health is improved through efficient use of resources.

• There is no evidence on the cost-effectiveness of antivirals for pre-exposure prophylaxis of seasonal influenza, and pre-exposure prophylaxis of zoonotic influenza, post-exposure prophylaxis, or the treatment for zoonotic influenza. Additionally, there is no evidence on the cost-effectiveness of antiviral stockpiling.

• The generalizability of these findings to the population in Canada is limited due to differences in study settings.

Authors

Ilke Akpinar led the rapid review, conducted title and abstract screening, study selection, and data extraction, and authored the report.

Dagmara Chojecki developed search strategies and conducted the literature searches.

Conflicts of Interest

No conflicts of interest were declared.

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Appendix 1: Selection of Included Studies

Please note that this appendix has not been copy-edited.

Figure 1: PRISMA Flow Chart of Selected Reports on Cost-Effectiveness of Antiviral Drugs

Figure 2: PRISMA Flow Chart of Selected Reports on Cost-Effectiveness of Stockpiling

Appendix 2: List of Excluded Studies by Reason for Exclusion

Please note that this appendix has not been copy-edited.

Cost-Effectiveness of Antivirals

Irrelevant Population (n = 4)

Benlloch J-M, Cortés J-C, Martínez-Rodríguez D, Julián R-S, Villanueva R-J. Effect of the early use of antivirals on the COVID-19 pandemic. A computational network modeling approach. Chaos, Solitons & Fractals. 2020;140:110168. PubMed

Jo Y, Kim SB, Radnaabaatar M, et al. Model-based cost-effectiveness analysis of oral antivirals against SARS-CoV-2 in Korea. Epidemiol Health. 2022;44:e2022034. PubMed

Le Rutte EA, Shattock AJ, Marcelino I, Goldenberg S, Penny MA. Efficacy thresholds and target populations for antiviral COVID-19 treatments to save lives and costs: a modelling study. eClinicalMedicine. 2024;73. PubMed

Metry A, Pandor A, Ren S, et al. Cost-effectiveness of therapeutics for COVID-19 patients: a rapid review and economic analysis. Health Technol Assess. 2023;27(14):1-92. PubMed

Irrelevant Intervention (n = 3)

Dawoud DM, Soliman KY. Cost-Effectiveness of Antiviral Treatments for Pandemics and Outbreaks of Respiratory Illnesses, Including COVID-19: A Systematic Review of Published Economic Evaluations. Value Health. 2020;23(11):1409-1422. PubMed

Newall AT, Wood JG, Oudin N, MacIntyre CR. Cost-effectiveness of pharmaceutical-based pandemic influenza mitigation strategies. Emerg Infect Dis. 2010;16(2):224-230. PubMed

Rasmussen MK, Kronborg C, Fasterholdt I, Kidholm K. Economic evaluations of interventions against viral pandemics: a scoping review. Public Health. 2022;208:72-79. PubMed

Irrelevant Comparator (n = 3)

Dronova M, Ikeoka H, Itsumura N, et al. Cost-effectiveness of baloxavir marboxil compared with laninamivir for the treatment of influenza in patients at high-risk for complications in Japan. Curr Med Res Opin. 2021;37(7):1135-1148. PubMed

Huang G, Tian Y, Cui W, Zhang X, Zhao Y, Liu X. Rapid health technology assessment of the novel endonuclease inhibitor baloxavir for the treatment of influenza. J Chemother. 2024;36(4):267-282. PubMed

Skrzeczek A, Ikeoka H, Hirotsu N, et al. Cost-effectiveness of baloxavir marboxil compared to laninamivir for the treatment of influenza in Japan. J Infect Chemother. 2021;27(2):296-305. PubMed

Irrelevant Outcome(s) (n = 1)

Panovska-Griffiths J, Grieco L, van Leeuwen E, Grove P, Utley M. A method for evaluating the cost-benefit of different preparedness planning policies against pandemic influenza. MethodsX. 2020;7(no pagination). PubMed

Ineligible Study Design (n = 4)

National Institute for Health and Care Excellence (NICE). Baloxavir marboxil for treating acute uncomplicated influenza (terminated appraisal). 2021; https://www.nice.org.uk/guidance/ta732/.Accessed January 20, 2025.

Suslo R, Pobrotyn P, Brydak L, Rypicz L, Grata-Borkowska U, Drobnik J. Seasonal Influenza and Low Flu Vaccination Coverage as Important Factors Modifying the Costs and Availability of Hospital Services in Poland: A Retrospective Comparative Study. Int J Environ Res Public Health. 2021;18(10). PubMed

van der Pol S, Postma MJ, Boersma C. Cost-effectiveness and Budget Impact of Baloxavir Marboxil in the Netherlands based on Post-COVID Seasonal Influenza Scenario. Poster presented at ISPOR 2022; 2022 Nov 6-9, 2022; Vienna, Austria. https://www.ispor.org/docs/default-source/euro2022/isporxofluzadef-pdf.pdf?sfvrsn=799e0269. Accessed January 20, 2025.

Yechezkel M, Ndeffo Mbah ML, Yamin D. Optimizing antiviral treatment for seasonal influenza in the USA: a mathematical modeling analysis. BMC Med. 2021;19(1):54. PubMed

Cost-Effectiveness of Stockpiling

Ineligible Study Design (n = 1)

Kim S, Bin Seo Y, Lee J, Kim YS, Jung E. Estimation of optimal antiviral stockpile for a novel influenza pandemic. J Infect Public Health. 2022;15(7):720-725. PubMed

Appendix 3: Characteristics of Included Publications

Table 3: Characteristics of Included Economic Evaluations

BIA = budget impact analysis; CUA = cost-utility analysis; DSA = deterministic sensitivity analysis; EVIP = expected value for perfect information; GP = general practitioner; HTA = health technology assessment; ICU = intensive care unit; ILI = influenza-like illness; NA = not applicable; NR = not reported; NMA = network meta-analysis; PSA = probabilistic sensitivity analysis; QALY = quality-adjusted life-year; RCT = randomized controlled trial; SEIR = Susceptible-Exposed-Infected-Recovered model.

Note: This table has not been copy-edited.

Appendix 4: Critical Appraisal of Included Publications

Please note that this appendix has not been copy-edited.

Table 4: Strengths and Limitations of Economic Evaluations Using the Drummond Checklist¹³

DSA = deterministic sensitivity analysis; EVPI = expected value of perfect information; HR = high risk; HRQoL = health-related quality of life; ILI = influenza-like illness; NAIs = neuraminidase inhibitors; NMA = network meta-analysis; OwH = otherwise healthy; PEP = post-exposure prophylaxis; PPP = purchasing power parity; PSA = probabilistic sensitivity analysis; QALY = quality-adjusted-life-year; QoL = quality of life.

Appendix 5: Main Study Findings

Please note that this appendix has not been copy-edited.

Table 5: Summary of Findings of Included Economic Evaluations

BIA = budget impact analysis; CEA = cost-effectiveness analysis; CN¥: Chinese yuan; EQ-5D: EuroQol – 5 Dimension; EVPI = expected value of perfect information; ICER = incremental cost-effectiveness ratio; ILI = influenza like illness; INMB = incremental net monetary benefit; NAI = neuraminidase inhibitor; NHS = National Health Service; NMB = net monetary benefit; SEIR = Susceptible-Exposed-Infected-Recovered model; QALY = quality-adjusted life-year; QoL = quality of life; WTP = willingness to pay.

^aConsidering various potential level.

Table 6: Antiviral Drug Costs Reported in Included Studies

NR = not reported; PPP = purchasing power parity.

Table 7: Consideration of Opportunity Cost Across Included Studies

NMB = net monetary benefit; NHS = National Health Service; QALY = quality-adjusted life-year; WTP = willingness to pay.