neuraminidase inhibitor resistance in influenza assessing the danger of its generation and spread神经氨酸酶抑制剂抵抗流感评估其生成和传播的危险.pdfVIP

Neuraminidase Inhibitor Resistance in Influenza: Assessing the Danger of Its Generation and Spread Andreas Handel1*, Ira M. Longini Jr.2,3, Rustom Antia1 1 Department of Biology, Emory University, Atlanta, Georgia, United States of America, 2 Program of Biostatistics and Biomathematics, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America, 3 Department of Biostatistics and School of Public Health and Community Medicine, University of Washington, Seattle, Washington, United States of America Neuraminidase Inhibitors (NI) are currently the most effective drugs against influenza. Recent cases of NI resistance are a cause for concern. To assess the danger of NI resistance, a number of studies have reported the fraction of treated patients from which resistant strains could be isolated. Unfortunately, those results strongly depend on the details of the experimental protocol. Additionally, knowing the fraction of patients harboring resistance is not too useful by itself. Instead, we want to know how likely it is that an infected patient can generate a resistant infection in a secondary host, and how likely it is that the resistant strain subsequently spreads. While estimates for these parameters can often be obtained from epidemiological data, such data is lacking for NI resistance in influenza. Here, we use an approach that does not rely on epidemiological data. Instead, we combine data from influenza infections of human volunteers with a mathematical framework that allows estimation of the parameters that govern the initial generation and subsequent spread of resistance. We show how these parameters are influenced by changes in drug efficacy, timing of treatment, fitness of the resistant strain, and details of virus and immune system dynamics. Our study provides estimates for parameters that can be directly used in mathemati