Estimating the global demand and potential public health impact of oral antiviral treatment stockpile for influenza pandemics: a mathematical modelling study
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Background
Oral influenza antiviral drugs could potentially minimize the disease burden of a nascent influenza pandemic prior to the availability of vaccines. Mathematical modelling is useful for designing antiviral stockpiling options but previous studies have yielded conflicting results, using outdated assumptions on health-seeking behavior and transmission risk reduction effects of antivirals.
Methods
We developed a novel multiscale model that accounts for heterogeneous transmission dynamics which depend on when individuals are treated with after infection, using recent clinical estimates of transmission risk reduction by antivirals. We estimated the antiviral demand of oseltamivir and baloxavir marboxil (BXM), and their corresponding reduction on pandemic deaths in 186 countries during the first epidemic wave of the 1918 A/H1N1, 1968 A/H3N2, 2009 A/H1N1 and COVID-19-like influenza pandemics.
Findings
Across all simulated pandemic scenarios and countries, provided that drug distribution and treatment delays are minimized, BXM doubles the median percentage of mean pandemic deaths averted relative to oseltamivir, ranging between 37% and 68%, with ∼5%–10% less mean treatment demand at 7%–34% per-capita. Drug rationing by age group does not meaningfully lower antiviral demand but instead diminishes the impact of the drug stockpile. Under limited drug availability, antivirals should be prioritized for treatment over provision of post-exposure prophylaxis to household contacts.
Interpretation
BXM stockpile for treatment of symptomatic individuals can substantially lower the disease burden of future influenza pandemics but only if robust public health infrastructure is in place to swiftly test and distribute treatment.
Funding
Dutch Research Council (NWO) and European Research Council.
Research in context
Evidence before this study
We searched PubMed and Google Scholar for peer-reviewed articles and preprints, published up to 31 December 2024, that relate to the use of modelling to design oral influenza antiviral stockpile sizing options for pandemic preparedness and their corresponding health and/or economic impact, using search terms “modelling”, “influenza”, “pandemic”, “oral antiviral”, “antiviral”, “antiviral stockpile”, “oseltamivir”, and “baloxavir marboxil”. Due to differences in modelling frameworks and study objectives that focus either on one or a handful of countries (i.e. no more than ten), existing studies have yielded inconsistent results, making it difficult to synthesize current findings for meaningful public health guidance. These studies proposed a wide range of antiviral stockpile size recommendations from covering as little as 15% of the population in the country to >140% of the population. Previous studies have also differently concluded on the effectiveness of distributing post-exposure prophylaxis to uninfected and/or asymptomatic individuals, from finding little benefit at reducing transmissions to the ability to contain a nascent influenza pandemic at its source. Most studies also liberally assumed that symptomatic individuals largely have similar health-seeking behaviors that prompt them to seek treatment swiftly after infection, within two days of symptom onset, which has now been shown to be far more heterogenous since the COVID-19 pandemic. Additionally, they assumed indirectly inferred and outsized effects of antivirals in lowering transmission risk based on post-hoc analyses of past clinical trial data.
Added value of this study
Based on a recent randomized clinical trial, baloxavir marboxil, a polymerase inhibitor that blocks influenza viral replication and was approved for medical use in 2018, was found to reduce transmission risk of treated index patients by 29%. Baloxavir marboxil is therefore the first oral influenza antiviral drug to demonstrate reduction of transmission, which is typically achieved by prophylactic use of drugs of close contacts, by treatment of the index infected patient. We developed a novel mathematical modelling framework, parameterized by the new clinical data alongside more grounded assumptions on health-seeking behavior and simulated pandemic scenarios, accounting for country-specific demography and age-structured contact rates. This is the first study to estimate the maximum oral influenza antiviral treatment demand and the corresponding reduction in disease burden achievable with oral antivirals in the event of a nascent influenza pandemic in 186 countries.
Implications of all the available evidence
This study suggests that baloxavir marboxil, owing to its demonstrated effectiveness in lowering transmission risk, can be considered by governments for stockpiling to mitigate disease burden during an influenza pandemic. If antiviral distribution is the sole intervention measure, the maximum baloxavir marboxil demand during the first wave of an influenza pandemic would amount to no more than 40% per-capita and can potentially averted >37% of expected pandemic deaths. However, its impact depends on the prompt and effective implementation of test-and-treat programs in the country upon pandemic initiation.
