Monitoring the fitness of transmissible antiviral resistant influenza strains

Abstract

BACKGROUND: Antivirals, such as oseltamivir, are an important pharmaceutical intervention for mitigating influenza epidemics and pandemics. In 2007, an oseltamivir-resistant seasonal A(H1N1) strain emerged and spread to global fixation within one year. This shows that antiviral-resistant (AVR) strains can be intrinsically more transmissible than its contemporaneous antiviral-sensitive (AVS) counterpart. Real-time surveillance of AVR fitness is therefore essential, especially in the context of influenza pandemics because many countries have stockpiled large amounts of antivirals for pandemic mitigation. METHOD: We developed a novel and simple method for estimating the fitness of AVR strains (defined as their transmissibility relative to co-circulating AVS strains) using data from contemporary influenza AVR surveillance systems. This method requires only information on generation time but not other specific details regarding transmission dynamics. We first used simulations to show that this method yields unbiased and robust fitness estimates. We then applied this method in three case studies: (i) We estimated that the oseltamivir-resistant seasonal A(H1N1) strain that emerged in 2007 and subsequently spread to fixation was 4.1% (3.3-5.0%) more transmissible than its oseltamivir-sensitive predecessor; (ii) We estimated that the oseltamivir-resistant pandemic A(H1N1) strain that emerged and circulated in Japan during 2013-2014 was 22% (17-30%) less transmissible than its oseltamivir-sensitive counterpart; (iii) We showed that in the event of large-scale antiviral interventions during an influenza pandemic with co-circulation of AVS and AVR strains, our method can be used to inform optimal use of antivirals in real-time by monitoring intrinsic fitness of the AVR strain and drug pressure on the AVS strain. CONCLUSION: Our method can be easily implemented in contemporary influenza surveillance systems for real-time surveillance of AVR fitness. Timely and accurate estimates of AVR fitness is particularly important in the context of large-scale antiviral intervention during a pandemic because the spread of AVR can substantially attenuate the effectiveness of antivirals in treating severe pandemic infections.