Modeling Drug Resistant Influenza
By Amesh A. Adalja, M.D., November 21, 2008
In a mathematical modeling study published in Virology Journal, Brockmann and colleagues report that drug resistant influenza was capable of increasing hospitalization rates by up to 233% in a hypothetical Swiss town of 100,000 inhabitants. Coupled with increased reports of drug-resistant virus, these findings have implications for hospital planning, infection control activities, and chemoprophylaxis strategies.1
Given the increasing prevalence of oseltamavir resistant influenza strains and the stockpiling of these agents for use in a future pandemic, the authors developed a mathematical model to assess the impact of this resistance. Parameters culled from prior studies and incorporated into their model include: a reproductive number (Ro) of 2.5; equivalent viral fitness of resistant and wild type virus; and the assumption that 1/3 of infected individuals are asymptomatic, 1/3 moderately sick, and 1/3 require medical help. The authors also incorporate the effects of antiviral treatment (for drug sensitive virus) and social distancing measures. Infection was introduced at day 0 and day 21 of the simulated outbreak.1
Addressing both de novo resistance development (occurring in 4.1% of children and 0.32% of adults, based on results from prior studies illustrating higher replication in rates in children) and importation of drug resistant virus, the authors find that resistant strains could not only increase hospitalization rates but also outpatient sickness rates, which increased by 129% in their model. The importation of a resistant virus into an area without prior resistance was found to have a much greater effect on these rates than de novo resistance, with a 121% vs. 233% increase in hospitalization rates based on de novo resistance occurring late in a treatment course and rendering the virus unable to be transmitted efficiently.1
Given that the benefits of anti-viral treatment—ameliorating the course of illness, decreasing the likelihood of hospitalization, and attenuating viral spread—would not be realized in those infected with a drug-resistant virus, higher hospitalization rates could be anticipated given no available pharmaceutical recourse.1
Neuraminidase Inhibitor Resistance Increasing with No Cost in Fitness
As previously reported in the CBN, H1N1 influenza viruses increasingly have been identified as harboring a resistance mutation, H274Y, that confers non-susceptibility to the neuraminidase inhibitor oseltamavir by altering the neuraminidase binding site. In certain regions of the world, drug resistant virus accounts for 100% of the isolates, completely displacing wild-type virus.2,4 Strikingly, these viruses are propagated without the selection pressure engendered by utilization of oseltamavir—a sign that the accumulation of these mutations does not hamper, and may in fact enhance, the ability of the virus to replicate and infect fresh hosts.3
Implications for Hospital infection Control
The authors elaborate on the implications of their study by drawing attention to the fact that current H1N1 oseltamavir-resistant strains have already shown the ability to spread efficiently person-to-person, and their importation into a previously uninfected area where oseltamavir is the main countermeasure may create a substantial increase in hospital utilization. Physicians and hospital policy makers should account for these contingencies when undertaking planning for seasonal influenza and making decisions regarding resource allocation, infection control, and chemoprophylaxis/treatment. Additionally, H5N1 avian influenza viruses have exhibited various degrees of oseltamavir resistance without reduced fitness, and, if adaptation to humans occurs, its high propensity for severe disease could have a catastrophic effect on the healthcare system.1 More ominous still would be genetic reassortment between co-circulating seasonal and H5N1 viruses resulting in widespread oseltamavir resistance in H5N1.
Brockmann SO, Schwehm M, Duerr H, et al. Modeling the effects of drug resistant influenza virus in a pandemic. Virology Journal. 2008, 5:133; http://www.virologyj.com/content/pdf/1743-422X-5-133.pdf. Accessed November 6, 2008.
Sheu TG et al. Surveillance for neuraminidase inhibitor resistance among human influenza A and B viruses circulating worldwide in 2004-2008. Antimicrob Agents Chemother 2008;doi:10.1128/AAC.00555-08. http://aac.asm.org/cgi/reprint/AAC.00555-08v1?view=long&pmid=18625765. Accessed November 6, 2008.
Deyde VM, Okomo-Adhiambo M, Sheu TG, et al. Pyrosequencing as a tool to detect molecular markers of resistance to neuraminidase inhibitors in seasonal influenza A viruses. Antiviral Research. 2008. http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T2H-4TMC2BR-&_user=88470&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_version=1&_urlVersion=0&_userid=88470&md5=7040b699c8a94ef8ad8443190ff9ebc1. Accessed November 6, 2008.
World Health Organization. Influenza A(H1N1) virus resistance to oseltamivir–2008 influenza season, southern hemisphere. August 20, 2008. http://www.who.int/csr/disease/influenza/H1N1webupdate20082008_kf.pdf. Accessed November 13, 2008.