Efficacy of oseltamivir treatment in influenza virus-infected obese mice

Abstract

Obesity has been epidemiologically and empirically linked with more severe diseases upon influenza infection. To ameliorate severe disease, treatment with antivirals, such as the neuraminidase inhibitor oseltamivir, is suggested to begin within days of infection especially in high-risk hosts. However, this treatment can be poorly effective and may generate resistance variants within the treated host. Here, we hypothesized that obesity would reduce oseltamivir treatment effectiveness in the genetically obese mouse model. We demonstrated that oseltamivir treatment does not improve viral clearance in obese mice. While no traditional variants associated with oseltamivir resistance emerged, we did note that drug treatment failed to quench the viral population and did lead to phenotypic drug resistance in vitro . Together, these studies suggest that the unique pathogenesis and immune responses in obese mice could have implications for pharmaceutical interventions and the within-host dynamics of the influenza virus population. IMPORTANCE Influenza virus infections, while typically resolving within days to weeks, can turn critical, especially in high-risk populations. Prompt antiviral administration is crucial to mitigating these severe sequalae, yet concerns remain if antiviral treatment is effective in hosts with obesity. Here, we show that oseltamivir does not improve viral clearance in genetically obese or type I interferon receptor-deficient mice. This suggests a blunted immune response may impair oseltamivir efficacy and render a host more susceptible to severe disease. This study furthers our understanding of oseltamivir treatment dynamics both systemically and in the lungs of obese mice, as well as the consequences of oseltamivir treatment for the within-host emergence of drug-resistant variants.

The Impact of Obesity on the Host–Pathogen Interaction with Influenza Viruses – Novel Insights: Narrative Review

“…However, it led to phenotypic resistance in vitro. 63 This suggests the need for careful surveillance of pharmaceutical interventions in obese patients with influenza, as well as monitoring for possible resistance mutations in the neuraminidase gene.…”

Comparative Pathology of Animal Models for Influenza A Virus Infection

“…Mice are an efficient and low-cost influenza model that has been indispensable for the discovery of new vaccines (reviewed in ref [146]) and therapeutics [147][148][149] and gaining insight into disease pathogenesis (Table 2) [80,84,87,141]. A major drawback of this model is that mice are not naturally susceptible to many strains of human IAV.…”

Oseltamivir (Tamiflu), a Commonly Prescribed Antiviral Drug, Mitigates Hearing Loss in Mice

“…The prodrug oseltamivir phosphate has the advantage of being highly orally bioavailable, at least 75% of the orally administered drug reaches the systemic circulation in humans and mice in the form of the active metabolite oseltamivir carboxylate (Davies, 2010; Dutkowski et al, 2003; He et al, 1999). The half-life of oseltamivir phosphate after oral administration is 2 to 3 hours in mice and humans, and the half-life of oseltamivir carboxylate is 2 to 3 hours in mice and 6 to 10 hours in humans (He et al, 1999; Honce et al, 2023. ; Pillai et al, 2015; Shin et al, 2017).…”