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1 Appendix 2 Methods 3 Strategies 4 We compared no intervention with 16 single and combination strategies (table 1). 5 Prophylactic strategies included prevaccination before the outbreak of the pandemic, 6 antiviral post-exposure prophylaxis, and school closure. Antiviral targeted prophylaxis 7 (TAP) strategies included household-only prophylaxis (household targeted antiviral 8 prophylaxis [HTAP]), and prophylaxis in the full set of contact groups for an index case 9 (full targeted antiviral prophylaxis [FTAP]). It was assumed that oseltamivir stockpiles of 10 varying quantity are available from the start of a pandemic, ranging from covering 25% 11 of the population (i.e. one pack with 10 capsules per capita for 25% of population) to 12 “unlimited” stockpile (i.e. as much as needed). TAP is carried out by treating identified 13 index cases (the first symptomatic illness in a contact group) and offering prophylaxis 14 only to the contacts of these index cases in close contact groups, namely: households, 15 neighbourhood clusters, large daycare centres, small playgroups, schools, and 16 workgroups. Index cases are therapeutically treated the day after the onset of illness, and 17 prophylaxis of contacts begins at the same time; both are given a single course of 18 oseltamivir. A susceptible individual may receive subsequent courses if exposed to 19 further index cases. We assumed that 60% of symptomatic index cases (i.e. 67% of all 20 infections develop symptoms and 60% of those are ascertained) in households, 21 neighbourhood clusters, day care centres, small play groups and workgroups could be 22 ascertained (1), and that all the other members of those groups would receive 23 prophylaxis. For an index case in a school, a random sample of 60% of the close contacts 1 1 of the ill child in the school would receive prophylaxis. (1, 2) We also evaluated a 2 treatment only strategy. Treatment means individuals are adequately treated with 3 oseltamivir, i.e. they start treatment within 48 hours of symptom onset and are compliant. 4 Prevaccination means that 70% of the population is successfully vaccinated with a 5 low-efficacy vaccine before the outbreak of a pandemic. This assumes that prepandemic, 6 low-efficacy vaccine has been stockpiled. Vaccination after the outbreak of the pandemic 7 (or later) was not considered, as it is not a useful strategy if R0 is high. (2) 8 9 We also considered school closure as a measure of social distancing alone, or in combination with pharmaceutical interventions (prevaccination, TAP). We modelled the 10 impact of closing schools for the duration of the pandemic, or until a well-matched 11 vaccine is available (26 weeks). 12 13 Mathematical model 14 An overview of the disease transmission simulator is shown in Figure A1. The 15 discrete-time stochastic simulator, coded in ANSI C, models influenza natural history, 16 daily infection transmission dynamics (based on an infection probability function) within 17 a structured population, and the effect of the intervention strategies described above, 18 during the first 180 days of an influenza pandemic. 19 The population represents a 1.632 million person city, divided into communities 20 of approximately 2000 people, each of which is further subdivided into four smaller 21 neighbourhoods (Figure A2). The model tracks the number of close contacts that a typical 22 person makes in the course of a day within specified contact groups. Each person is 23 assumed to have daily contacts with household members and with people in the three 24 closest households (neighbourhood cluster), as well as with people in the larger 2 1 neighbourhood and community. The age and approximate household size distributions 2 are matched to those of the US Census 2000 (3). Preschool children attend either small 3 play groups or larger daycare centres, and school-age children attend elementary, middle, 4 or high school, as appropriate. Small play groups have four children each, and there are 5 between 4 and 6 small play groups per neighbourhood. Large daycare centers have, on 6 average, 14 children. School-age children are assigned to either an elementary school, 7 middle school, or high school based on their age. Two neighbourhoods share one 8 elementary school, and all four neighborhoods share a middle and high school. 9 Elementary schools have, on average, 79 children per school, middle schools have an 10 average of 141 students, and high schools have an average of 110 students. Ten percent 11 of high school students attend a high school in a neighboring community. This 12 community structure is similar to that described in previously published reports (1, 2, 4). 13 In addition, sixty-three percent of adults are in workgroups (4) of average size 25. 14 Workgroups are made up of adults from different communities, allowing for transmission 15 of infection from one community to another. 16 Each run of the simulator is seeded with twelve randomly chosen, unvaccinated, 17 initial infectives. Within each contact group, people make contacts sufficient for infection 18 to be transmitted from an infectious to a susceptible person according to the contact 19 probabilities shown in Table A1. These probabilities are based on community 20 transmission parameters discussed by Longini et al. (5), with adjustments made during 21 the calibration of the simulator to achieve a representative basic reproductive number 22 (R0, defined below) for pandemic flu. The probabilities vary by contact group and, in 23 some cases, by the ages of the infectious and susceptible persons. For example, for an 3 1 elementary school child, the relevant contact probabilities are: household contact with a 2 child chcc = 0.2, household contact with an adult chac = 0.3, contact in an elementary 3 school ce = 0.07, contact in the neighborhood cn = 0.00046, and the community, cc = 4 0.00011. The probabilities do not vary over time in our model. 5 Each day, infection of a susceptible person depends on the number of infectious 6 people in the susceptible’s contact groups, on the contact probabilities, and on the 7 probability of transmission given contact, pt, a single probability which can be scaled to 8 represent viruses with different levels of contagiousness or transmissibility. As an 9 example, consider the simplest case that no one is vaccinated. An elementary school child 10 is exposed to the number of child and adult infectives in his household, Ihc and Iha, the 11 infectives in his elementary school, Ie, his neighborhood In, and the community, Ic, with 12 corresponding per-contact infection probabilities for each contact of phcc = chcc∙pt (child to 13 child), phac = chac∙pt (adult to child), pe = ce∙pt, pn = cn∙pt, and pc = cc∙pt, respectively. The 14 probability, P, for that child to become infected on that day is 15 16 17 18 P 1 [(1 phcc ) I hc (1 phac ) I ha (1 pe ) Ie 1 pn n (1 pc ) Ic ] I A uniform [0,1] random number is selected. If the number is less than P, the child becomes infected. If exposed people have been given antiviral agents, the per-contact infection 19 probabilities are multiplied by θ, the relative susceptibility, where protective efficacy 20 AVES=1-θ. If an infected person is using an antiviral, then the probability of infection 21 being transmitted from that infected person to a susceptible not using an antiviral is 22 multiplied by φ, the relative infectiousness of infectives. The antiviral efficacy for 23 infectiousness is AVEI=1-φ. If a person using an antiviral agent is infected, then the 4 1 probability that he will become ill is multiplied by ψ, the relative probability of illness 2 given infection. Thus, the antiviral efficacy for illness given infection is AVED=1-ψ. In 3 addition, if a person on antiviral agents does become ill, then his duration of illness is one 4 day less than if he had not taken an antiviral agent. If a person takes an antiviral agent 5 after he is infected, then the AVEI and AVED apply as above, from the time such use 6 begins. For vaccination, we use arguments similar to those above to define vaccine 7 efficacy for susceptibility, VES, and vaccine efficacy for infectiousness, VEI. 8 9 People infected with influenza first pass through a latent and incubation period. During this period, they do not have influenza symptoms, and they are not infectious until 10 the last day of the period, during which they are half as infectious as they are in the 11 subsequent period, the infectious period. During the infectious period they may develop 12 influenza symptoms. Additionally, the model allows for people to withdraw from all of 13 their mixing groups, except the household, if they become infected. We have set many of 14 the influenza natural history and other transmission parameters of the model according to 15 literature on influenza (6-8), estimates from field studies, and randomized influenza 16 vaccine and antiviral agent trials (11-14). Rather than use fixed values for many of these 17 parameters, we could put prior distributions on them and then use Monte Carlo 18 techniques to add uncertainty about parameters to the simulation output. However, such 19 an approach is prohibitive given the current speed of our simulations. 20 The simulator tracks the infection status of each person in the population each day 21 during each run, and the final infection and illness status of each person is recorded, as 22 are the overall- and age-group-specific illness attack rates. One hundred runs are 23 performed for each scenario, and the results averaged. Larger numbers of runs are not 5 1 feasible, given the complexity of the simulator, the large size of the modeled population 2 and the resulting simulator run-time. However, the authors’ experience with similar 3 simulation models (1, 2, 4, 19) indicates that 100 runs are sufficient to arrive at stable 4 results. 5 Once infected, people follow the clinical pathway as shown in figure 1. If 6 infected, the person may receive treatment, which modifies health outcome (probability 7 of complications, mortality) and resource use (probability of healthcare contact). The 8 epidemiological influenza transmission model determines the proportion of individuals 9 infected with influenza. Stratification of the population by age and risk status is not 10 shown in the simplified clinical pathway, but is accounted for in the model. The age 11 groups were: children 0-4 years, children 5-18 years, younger adults (19-64 years), and 12 older adults (≥65 years). Younger adults are further stratified into high and low risk of 13 complications. High risk adults have underlying chronic conditions (e.g. cardiovascular 14 disease, diabetes, renal disease), which increases their risk for influenza complications 15 and mortality. The option “prophylaxis” denotes a range of prophylactic interventions, including 16 17 prevaccination before onset of the pandemic, post-exposure TAP with oseltamivir, and 18 school closure. ‘Treatment’ means individuals are effectively treated with oseltamivir, i.e. 19 they start treatment within 48 hours of symptom onset and are compliant. 20 21 Data 22 Basic reproductive number 23 R0 is defined as the average number of secondary infections produced by a typical 24 infected person in a fully susceptible population. (10) To calculate R0, we assumed a 6 1 scenario in which one randomly chosen, unvaccinated, infected person was seeded into a 2 population where everyone else’s ability to transmit was 0. We then counted the number 3 of secondary infections. This was repeated 1000 times. In this way, we generated the 4 whole distribution of secondary cases due to a randomly selected infected person. The 5 mean of this distribution is R0. The calibrated value of the transmission probability was 6 0.15. 7 8 Effectiveness of interventions 9 Prophylaxis—We use current estimates of antiviral efficacy (AVE) of oseltamivir (table 10 2). (11-15) For prophylactic use of oseltamivir, we assumed the relative reduction of the 11 probability of becoming infected given exposure susceptibility to infection (AVES) to be 12 0.30 during a single day of exposure. For both therapeutic and prophylactic use, we 13 assumed the relative reduction of the probability for symptomatic disease given infection 14 (AVED) to be 0.60. Combining the two effects gives the antiviral efficacy for 15 symptomatic disease given exposure (AVESD) of 0.72 (AVESD = 1- [1- AVES][1- 16 AVED]). We assumed the antiviral efficacy for infectiousness (AVEI) to be 0.62. (15) 17 The effect of antiviral agent on people who take it while latent or incubating is the same 18 as the therapeutic effect. 19 For a low-efficacy vaccine, we assumed the vaccine efficacy for susceptibility to 20 infection (VES) to be 0.30, and vaccine efficacy for infectiousness (VEI) to be 0.50. (16) 21 We assumed that two doses of vaccine would be needed. (17) 22 23 Treatment—Oseltamivir effectively reduces incidence of otitis media, bronchitis, 24 pneumonia, influenza-related hospitalisations, and mortality, and improves quality of life. 7 1 (18-21) We assumed that oseltamivir treatment has no impact on the course of illness 2 once otitis media, bronchitis, or pneumonia develops. To calculate probabilities of events 3 when individuals are treated with oseltamivir, we applied the relative reduction in event 4 rates as observed in clinical trials. Treatment with oseltamivir reduces illness by 1 day in 5 the model, and hence also reduces transmission. 6 7 8 Additional sensitivity analysis It is uncertain whether a pandemic will occur before the shelf life of stockpiled 9 oseltamivir or low-efficacy pandemic vaccine will expire. We therefore considered a 10 scenario where we assumed that a pandemic occurs within the next 33 years. (8) This 11 means oseltamivir and/or low-efficacy vaccine is stockpiled but the chance of a pandemic 12 occurring and the stockpile not being wasted is only 0.33.We assumed complete renewal 13 of the oseltamivir stockpile every 5 years, and the low-efficacy vaccine stockpile every 2 14 years, and calculated the discounted expected costs. Costs and quality adjusted life years 15 (QALYs) are discounted at 3% per annum in line with US guidelines for economic 16 evaluations. (22) 17 Assuming a pandemic occurs within 33 years, and that stockpiles need to be 18 renewed, does not substantially change results. FTAP and prevaccination no longer 19 dominate no intervention because of the increased stockpiling cost. Nevertheless, the 20 ranking of strategies remains otherwise the same, with incremental cost-utility ratios 21 below $46 000 (table A13). 22 8 1 Appendix References 2 1 with antiviral agents. Am J Epidemiol 2004;159:623-33. 3 4 Longini IM, Jr, Halloran ME, Nizam A, Yang Y. Containing pandemic influenza 2 Germann TC, Kadau K, Longini IM Jr, Macken CA. Mitigation strategies for 5 pandemic influenza in the United States. Proc Natl Acad Sci USA 2006;103:5935- 6 40. 7 3 of Commerce. http://www.census.gov/main/www/cen2000.html. 8 9 US Census Bureau. United States Census 2000. Washingon DC: US Department 4 Weycker D, Edelsberg J, Halloran ME, Longini IM, Nizam A, Ciuryla V, et al. 10 Population-wide benefits of routine vaccination of children against influenza. 11 Vaccine 2005;23:1284-93. 12 5 Longini IM Jr., Koopman JS, Haber M, Cotsonis GA. Statistical Inference on 13 risk-specific household and community transmission parameters for infectious 14 diseases. Am J Epidemiol 1988; 128:845-859. 15 6 the epidemic prevention potential. Vaccine 2002;20:3254-62. 16 17 Halloran ME, Longini IM, Cowart DM, Nizam A. Community interventions and 7 Elveback LR, Fox JP, Ackerman E, Langworthy A, Boyd M, Gatewood L. An 18 influenza simulation model for immunization studies. Am J Epidemiol 19 1976;103:152-65. 20 8 Press, 1975. 21 22 23 Kilbourne ED. The influenza viruses and influenza. New York: New York Academic 9 Longini IM, Nizam A, Xu S, Ungchusak K, Hanshaoworakul W, Cummings DA, et el. Containing pandemic influenza at the source. Science 2005;309:1083-7. 9 1 10 Diekmann O, Heesterbeek JA, Metz JA. On the definition and the computation of 2 the basic reproduction ratio R0 in models for infectious diseases in heterogeneous 3 populations. J Math Biol 1990;28:365-82. 4 11 Halloran ME, Hayden FG, Yang Y, Longini IM Jr, Monto AS. Antiviral effects 5 on influenza viral transmission and pathogenicity: observations from household- 6 based trials. Am J Epidemiol 2007;165:212-21. 7 12 Hayden FG, Gubareva LV, Monto AS, Klein TC, Elliot MJ, Hammond JM, et al. 8 Zanamivir Family Study Group. Inhaled zanamivir for the prevention of influenza 9 in families. Zanamivir Family Study Group. N Engl J Med 2000;343:1282-9. 10 11 Hayden FG, Atmar RL, Schilling M, Johnson C, Poretz D, Paar D, et al. Use of 11 the selective oral neuraminidase inhibitor oseltamivir to prevent influenza. N Engl 12 J Med 1999;341:1336-43. 13 12 Welliver R, Monto AS, Carewicz O, Schatteman E, Hassman M, Hedrick J, et al. 14 Oseltamivir Post Exposure Prophylaxis Investigator Group. Effectiveness of 15 oseltamivir in preventing influenza in household contacts: a randomized 16 controlled trial. JAMA 2001;285:748-54. 17 13 Yang Y, Longini IM, Halloran ME. Design and evaluation of prophylactic 18 interventions using infectious disease incidence data from close contact groups. 19 Appl Statist 2006;55:317-30. 20 15 Denis M. Pandemic vaccines: development status [abstract]. Presented at: 21 Pandemic Influenza Vaccines. Building a Platform for Global Collaboration, 28- 22 30 January 2007, Beijing, China. 10 1 16 Bettis R, Iacuzio D, Jung T, Fuchs R, Aultman R, Gyldmark M. Impact of 2 influenza treatment with oseltamivir on health, sleep and daily activities of 3 otherwise healthy adults and adolescents. Clin Drug Invest 2006;26:329-40. 4 17 Sander B, Gyldmark M, Aultman R, Aoki FY. Impact on health outcomes and 5 costs of influenza treatment with oseltamivir in elderly and high-risk patients. J 6 Med Econom 2004;7:67-83. 7 18 Kaiser L, Wat C, Mills T, Mahoney P, Ward P, Hayden F. Impact of oseltamivir 8 treatment on influenza-related lower respiratory tract complications and 9 hospitalizations. Arch Intern Med 2003;163:1667-72. 10 19 Turner D, Wailoo A, Nicholson K, Cooper N, Sutton A, Abrams K. Systematic 11 review and economic decision modelling for the prevention and treatment of 12 influenza A and B. Health Technol Assess 2003;7:1-170. 13 20 medicine. New York: Oxford University Press, 1996. 14 15 Gold MR, Siegel JR, Russell LB, Weinstein MC. Cost-effectiveness in health and 21 Meier CR, Napalkov PN, Wegmuller Y, Jefferson T, Jick H. Population-based 16 study on incidence, risk factors, clinical complications and drug utilisation 17 associated with influenza in the United Kingdom. Eur J Clin Microbiol Infect Dis 18 2000;19:834-42. 19 22 Nature 2004;432:904-6. 20 21 Mills CE, Robins JM, Lipsitch M. Transmissibility of 1918 pandemic influenza. 23 Lee GM, Salomon JA, LeBaron CW, Lieu TA. Health-state valuations for 22 pertussis: methods for valuing short-term health states. Health Qual Life Outcomes 23 2005;3:17. 11 1 24 Prosser LA, Ray GT, O'Brien M, Kleinman K, Santoli J, Lieu TA. Preferences 2 and willingness to pay for health states prevented by pneumococcal conjugate 3 vaccine. Pediatrics 2004;113:283-90. 4 25 Cox FM, Cobb MM, Chua WQ, McLaughlin TP, Okamoto LJ. Cost of treating 5 influenza in emergency department and hospital settings. Am J Manag Care 6 2000;6:205-14. 7 26 Rep 2000;49. http://www.cdc.gov/mmwr/index2000.htm 8 9 Centers for Disease Control and Prevention (CDC). MMWR Morb Mortal Wkly 27 Loughlin J, Poulios N, Napalkov P, Wegmuller Y, Monto AS. A study of 10 influenza and influenza-related complications among children in a large US health 11 insurance plan database. Pharmacoeconomics 2003;21:273-83. 12 28 Nettleman MD, White T, Lavoie S, Chafin C. School absenteeism, parental work 13 loss, and acceptance of childhood influenza vaccination. Am J Med Sci 14 2001;321:178-80. 15 29 the United States: priorities for intervention. Emerg Infect Dis 1999;5:659-71. 16 17 30 Physicians Desk Reference. Red Book: Pharmacy's Fundamental Reference (Red Book Drug Topics). Montvale: Thomson PDR, 2006. 18 19 Meltzer MI, Cox NJ, Fukuda K. The economic impact of pandemic influenza in 31 2005 Physician’s Fee and Coding Guide, volume 1. MAG Mutual Healthcare Consultants Inc., December 2004. 20 21 32 The DRG Handbook 2006. Solucient, 2006. 22 33 US Department of Labor: Bureau of Labor Statistics. Compensation cost trends 23 2006. http://www.bls.gov/ncs/ect/home.htm. 12 1 34 US Department of Education Institute of Education Sciences; National Center for 2 Education Statistics. Projections of education statistics to 2015. 3 http://nces.ed.gov/programs/projections. 4 5 13 Table A1 Contact probability matrix Children Pre-school Contact group School Small playgroup Large daycare Elementary Middle High Adults 0.35 – – – – – Large daycare centres – 0.25 – – – – Elementary school – – 0.07 – – – Middle school – – – 0.038 – – Family – – – – 0.038 – Child 0.80 0.80 0.80 0.80 0.80 0.30 Adult 0.30 0.30 0.30 0.30 0.30 0.40 Child 0.20 0.20 0.20 0.20 0.20 0.075 Adult 0.075 0.075 0.075 0.075 0.075 0.10 – – – – – 0.08 Neighbourhood 0.00032 0.00032 0.00046 0.00046 0.00046 0.0022 Community 0.00008 0.00008 0.00011 0.00011 0.00011 0.00055 Small playgroups Household cluster Workgroup 14 Table A2 Probabilities of events Event Bronchitis Pneumonia Otitis media Population Probability of event Source Children 0.006 Meier et al, 2000 (23) Low risk younger adults 0.012 Meier et al, 2000 (23) High risk younger adults 0.021 Meier et al, 2000 (23) Older adults 0.030 Meier et al, 2000 (23) Children 0.002 Meier et al, 2000 (23) Low risk younger adults 0.003 Meier et al, 2000 (23) High risk younger adults 0.004 Meier et al, 2000 (23) Older adults 0.012 Meier et al, 2000 (23) Children 0-4 years 0.310 Data on file 0.025 Mills et al, 2004 (23) Death 15 Table A3 QALY Penalties Event Influenza Bronchitis Pneumonia Otitis media Population QALY penalty Source Children 0.010 Assumption: as low risk younger adults Low risk younger adults 0.010 Data on file High risk younger adults 0.013 Data on file Older adults 0.013 Data on file Children 0.010 Assumption: as influenza Low risk younger adults 0.010 Assumption: as influenza High risk younger adults 0.013 Assumption: as influenza Older adults 0.013 Assumption: as influenza Children 0.220 Lee et al, 2005 (25) Low risk younger adults 0.040 Lee et al, 2005 (25) High risk younger adults 0.040 Lee et al, 2005 (25) Older adults 0.040 Lee et al, 2005 (25) Children <5 years 0.250 Prosser et al, 2004 (26) QALY=quality adjusted life year. 16 Table A4 Resource use Resou Event rce Populatio Probability Probability Probability n group Base Case Low High Source Units Units Units Base Low High 1 3 Source Case Physic Influenza All 0.75 0.5 1 Assumption 1.4 Assumption ian untreated based on visit with Cox et al, Oseltamivi 2000 (27) r Influenza All 1 1 1 Assumption 1.4 1 3 Assumption treated based on with Cox et al, Oseltamivi 2000 (27) r Bronchitis All 1 0.5 1 Assumption 2.4 1 4 Assumption Pneumonia All 1 0.5 1 Assumption 5.7 1 6 Cox et al, 2000 (27) 17 Hospit Otitis Children media <5 years Influenza Children 1 0.5 1 Assumption 3.1 0.0006 0.5 * Base 2 * Base MMWR, 2000 Case Value Case Value 0.5 * Base 2 * Base Case Value Case Value 0.5 * Base 2 * Base Case Value Case Value 0.5 * Base 2 * Base Case Value Case Value 0.5 * Base 2 * Base Case Value Case Value (as influenza) 0.5 * Base 2 * Base Loughlin et al, Case Value Case Value 0.5 * Base 2 * Base Case Value Case Value 0.5 * Base 2 * Base Case Value Case Value (28) on Bronchitis Pneumonia Antibi All All Otitis Children media <5 years Influenza Children 0.0190 0.0006 0.15 0.0006 0.27 otics Adults Bronchitis Children 5 Expert opinion alisati Adults 1 0.28 0.63 18 Cox et al, 2000 (27) Assumption Cox et al, 2000 (27) Assumption 1 2003 (29) Cox et al, 2000 1 (27) Loughlin et al, 2003 (29) 1 Adults 0.46 0.5 * Base 2 * Base Case Value Case Value Assumption 1 based on Cox et al, 2000 (27) Pneumonia Children Adults Otitis Children media <5 years OTC All medic 0.63 0.36 0.63 1 0.5 * Base 2 * Base Case Value Case Value 0.5 * Base 2 * Base Case Value Case Value 0.5 * Base 2 * Base Case Value Case Value 0.5 * Base 1 Loughlin et al, 1 2003 (29) Cox et al, 2000 1 (27) Loughlin et al, 1 2003 (29) Assumption 1 Case Value ation Produ Caretaker ctivity of ill child Children 2 days/ episode loss 1 5 Nettleman et al, 2001 (30) due to illness 19 Ill adult Adults 2 days/ 1 5 episode Meltzer et al, 1999 (31) Produ Household 2.5 days/ ctivity week loss 1 5 Nettleman et al, 2001 (30) due to school closur e Teachers 5 days/ Nettleman and other week et al, 2001 professiona (30) ls OTC=over the counter. 20 Table A5 Unit costs Resource Oseltamivir Population groups All Unit cost ($) 23.04 Unit Course of Source Data on file treatment/prophylaxis Low-efficacy vaccine All Low-efficacy vaccine delivery 16.65 Dose Red Book (32) 9.29 Person vaccinated Assumption based on Average Medicare Reimbursement, 2005 (33): in case of pandemic mass vaccination at a cost of 50% of usual cost Physician All 93 Visit Medicare National Average Allowance (33) Influenza hospitalisation Children 3492 Hospitalisation Assumption: as bronchitis Low risk younger adults 3425 Hospitalisation Assumption: as bronchitis High risk younger adults 4694 Hospitalisation Assumption: as bronchitis Children 3492 Hospitalisation DRG Handbook, 2006 (34) Low risk younger adults 3425 Hospitalisation DRG Handbook, 2006 (34) and older adults Bronchitis hospitalisation 21 High risk younger adults 4694 Hospitalisation DRG Handbook, 2006 (34) Children 3957 Hospitalisation DRG Handbook, 2006 (34) Low risk younger adults 3895 Hospitalisation DRG Handbook, 2006 (34) High risk younger adults 6612 Hospitalisation DRG Handbook, 2006 (34) and older adults Pneumonia hospitalisation and older adults Otitis media hospitalisation Children <5 years 2935 Hospitalisation DRG Handbook, 2006 (34) Antibiotics Children 4.12 Course of treatment Red Book30 (Amoxicillin 500 mg daily for 5 days) Adults 8.23 Course of treatment Red Book (30) (Amoxicillin 1000 mg daily for 5 days) OTC medications All Productivity loss general Ill working adult, population caretaker of ill child Productivity loss teachers Teachers 5.00 Episode Assumption 923.00 Week Bureau of Labor Statistics 2006 (35) 931.00 Week Projections of education statistics to 2015 (36) Productivity loss other Other staff working at professionals schools 923.00 22 Week Bureau of Labor Statistics 2006 (35) Time and travel cost to obtain Index case 29.00 Household Calculated based on 20 mile roundtrip ($0.485/mile) and 45 minutes of patient’s oseltamivir time Time and travel cost to obtain Person vaccinated 14.50 Person vaccinated vaccine Assumption: 50% of time and travel cost to obtain oseltamivir OTC=over the counter. 23 Table A6 Results (ranked by expected QALYs) for R0=1.6 Illness attack Deaths QALYs* Incremental Courses Total cost in rate (%) per 1000 per 1000 QALYs† per 1000 per 1000 million $ per 1000 No intervention 34 9 21 227 – – 0.13 HTAP25 25 5 21 304 77 250 0.10 Treatment only 31 5 21 318 91 – 0.13 HTAP 21 4 21 344 117 395 0.09 HTAP50 21 4 21 345 117 394 0.09 School closure 3.5 0.89 21 407 180 – 2.56 FTAP 0.5 0.09 21 424 197 100 0.003 FTAP25 0.5 0.09 21 424 197 98 0.003 Prevaccination 0.2 0.04 21 426 198 – 0.023 HTAP25 and school closure 0.1 0.02 21 426 199 2 2.56 HTAP and school closure 0.1 0.02 21 426 199 2 2.56 HTAP50 and school closure 0.1 0.02 21 426 199 2 2.56 FTAP50 and school closure 0.05 0.01 21 426 199 4 2.56 FTAP25 and school closure 0.04 0.01 21 426 199 4 2.56 FTAP and school closure 0.04 0.01 21 426 199 4 2.56 Intervention 24 Prevaccination and school 0.02 0.00 21 426 199 – 2.59 0.5 0.09 21 706 479 101 0.006 closure FTAP50 HTAP=household targeted antiviral prophylaxis; FTAP=full targeted antiviral prophylaxis; QALY=quality adjusted life year. *Expected average quality adjusted life expectancy; †Compared to no intervention. 25 Table A7. Results (ranked by expected QALYs) for R0=2.0 Total cost in Illness attack Deaths QALYs* Incremental Courses million $ rate (%) per 1000 per 1000 QALYs† per 1000 per 1000 per 1000 No intervention 52 13 21 129 – – 0.20 FTAP25 52 13 21 135 6 250 0.20 FTAP50 51 13 21 141 12 500 0.20 HTAP25 50 11 21 173 44 250 0.19 School closure 44 11 21 183 54 – 2.73 HTAP50 46 9 21 222 93 500 0.19 Treatment only 51 9 21 232 103 250 0.20 HTAP25 and school closure 39 9 21 236 107 250 2.72 Prevaccination 31 8 21 242 113 – 0.16 HTAP 42 7 21 258 129 680 0.18 FTAP 26 5 21 304 175 2958 0.14 HTAP50 and school closure 29 5 21 313 184 484 2.70 HTAP and school closure 29 5 21 313 184 483 2.70 FTAP25 and school closure 7 2 21 391 261 250 2.60 Intervention 26 FTAP and school closure 3 1 21 415 286 347 2.59 FTAP50 and school closure 3 1 21 415 286 347 2.59 0.2 0.05 21 425 296 – 2.59 Prevaccination and school closure HTAP=household targeted antiviral prophylaxis; FTAP=full targeted antiviral prophylaxis; QALY=quality adjusted life year. *Expected average quality adjusted life expectancy; †Compared to no intervention. Note: QALY ranking differs from illness attack rate ranking because QALYs take into account the differences in morbidity and mortality (life expectancy) across age groups, i.e. it is important in which age groups cases and deaths occur. 27 Table A8 Incremental cost-utility for non-eliminated strategies (pandemic occurs within 1 year) for R0=2.0 Total cost in Incremental million $ Incremental cost QALYs† Incremental cost-utility per 1000 per 1000* ($) per 1000 QALYs per 1000† ratio* FTAP 0.14 – 21 304 – – FTAP50 and school closure 2.59 2.44 21 415 111 22 037 Prevaccination and school closure 2.59 2.45 21 425 121 20 241 Intervention FTAP=full targeted antiviral prophylaxis; QALY=quality adjusted life year. *Compared to FTAP; †Expected average quality adjusted life expectancy. 28 Table A9 Results (ranked by expected QALYs) for mortality=5% Incremental Total cost in Illness attack rate Deaths QALYs* QALYs† Courses million $ (%) per 1000 per 1000 per 1000 per 1000 per 1000 No intervention 50 25 20 864 – – 0.19 FTAP25 48 24 20 895 31 246 0.18 FTAP50 45 22 20 932 68 481 0.18 HTAP25 48 22 20 943 79 250 0.19 School closure 39 20 20 999 135 – 2.72 HTAP50 42 17 21 059 195 498 0.17 Treatment only 49 17 21 063 199 243 0.20 HTAP 41 14 21 108 244 651 0.17 Prevaccination 26 13 21 122 258 – 0.14 HTAP25 and school closure 31 14 21 123 259 204 2.69 FTAP25 and school closure 23 11 21 178 314 150 2.66 FTAP50 and school closure 22 11 21 197 333 279 2.66 HTAP50 and school closure 27 10 21 209 345 374 2.68 HTAP and school closure 24 9 21 237 373 395 2.67 Intervention 29 FTAP 23 9 21 246 382 2,447 0.12 FTAP and school closure 6 2 21 380 516 640 2.61 Prevaccination and school closure 4 2 21 380 516 – 2.62 HTAP=household targeted antiviral prophylaxis; FTAP=full targeted antiviral prophylaxis; QALY=quality adjusted life year. *Expected average quality adjusted life expectancy; †Compared to no intervention. Note: QALY ranking differs from illness attack rate ranking because QALYs take into account the differences in morbidity and mortality (life expectancy) across age groups, i.e. it is important in which age groups cases and deaths occur. 30 Table A10 Results (ranked by expected QALYs) for work loss for teachers and other staff due to school closure=50% Incremental Total cost in Illness attack rate Deaths QALYs* QALYs† Courses million $ (%) per 1000 per 1000 per 1000 per 1000 per 1000 No intervention 50 13 21 141 – – 0.19 FTAP25 48 12 21 157 16 246 0.18 FTAP50 45 11 21 175 34 481 0.18 HTAP25 48 11 21 181 40 250 0.19 School closure 39 10 21 210 69 – 2.06 HTAP50 42 8 21 239 98 498 0.17 Treatment only 49 8 21 241 100 243 0.19 HTAP 41 7 21 264 123 651 0.17 Prevaccination 26 6 21 271 130 – 0.14 HTAP25 and school closure 31 7 21 273 132 204 2.04 FTAP25 and school closure 23 6 21 300 159 150 2.00 FTAP50 and school closure 22 5 21 310 169 279 2.00 HTAP50 and school closure 27 5 21 316 175 374 2.02 HTAP and school closure 24 4 21 330 189 395 2.02 Intervention 31 FTAP 23 5 21 351 210 2447 0.12 FTAP and school closure 6 1 21 403 262 640 2.24 Prevaccination and school closure 4 1 21 403 262 – 2.26 HTAP=household targeted antiviral prophylaxis; FTAP=full targeted antiviral prophylaxis; QALY=quality adjusted life year. *Expected average quality adjusted life expectancy; †Compared to no intervention. Note: QALY ranking differs from illness attack rate ranking because QALYs take into account the differences in morbidity and mortality (life expectancy) across age groups, i.e. it is important in which age groups cases and deaths occur. 32 Table A11 Results (ranked by expected QALYs) for low resource use scenario Incremental Total cost Illness attack Deaths QALYs* QALYs† Courses in million $ rate (%) per 1000 per 1000 per 1000 per 1000 per 1000 No intervention 50 13 21 141 – – 0.09 FTAP25 48 12 21 157 16 246 0.09 FTAP50 45 11 21 175 34 481 0.09 HTAP25 48 11 21 181 40 250 0.10 School closure 39 10 21 210 69 – 1.53 HTAP50 42 8 21 239 98 498 0.10 Treatment only 49 8 21 241 100 243 0.11 HTAP 41 7 21 264 123 651 0.10 Prevaccination 26 6 21 271 130 – 0.08 HTAP25 and school closure 31 7 21 273 132 204 1.53 FTAP25 and school closure 23 6 21 300 159 150 1.51 Intervention 33 FTAP50 and school closure 22 5 21 310 169 279 1.51 HTAP50 and school closure 27 5 21 316 175 374 1.52 HTAP and school closure 24 4 21 330 189 395 1.52 FTAP 23 5 21 351 210 2447 0.08 FTAP and school closure 6 1 21 403 262 640 1.49 4 1 21 403 262 – 1.51 Prevaccination and school closure 34 Table A12 Results (ranked by expected QALYs) for high resource use scenario Incremental Total cost Illness attack Deaths QALYs* QALYs† Courses in million $ rate (%) per 1000 per 1000 per 1000 per 1000 per 1000 No intervention 50 13 21 141 – – 0.48 FTAP25 48 12 21 157 16 246 0.46 FTAP50 45 11 21 175 34 481 0.43 HTAP25 48 11 21 181 40 250 0.46 School closure 39 10 21 210 69 – 4.79 HTAP50 42 8 21 239 98 498 0.41 Treatment only 49 8 21 241 100 243 0.46 HTAP 41 7 21 264 123 651 0.39 Prevaccination 26 6 21 271 130 – 0.25 HTAP25 and school closure 31 7 21 273 132 204 4.72 FTAP25 and school closure 23 6 21 300 159 150 4.64 Intervention 35 FTAP50 and school closure 22 5 21 310 169 279 4.63 HTAP50 and school closure 27 5 21 316 175 374 4.68 HTAP and school closure 24 4 21 330 189 395 4.65 FTAP 23 5 21 351 210 2447 0.24 FTAP and school closure 6 1 21 403 262 640 4.48 4 1 21 403 262 – 4.49 Prevaccination and school closure 36 Table A13 Incremental cost-utility for non-eliminated strategies (pandemic occurs within 33 years) Total cost in Incremental million $ Incremental cost in QALYs Incremental QALYs cost-utility per 1000 million $ per 1000 per 1000 per 1000 ratio ($) No Intervention 0.12 – 13 566 – – Prevaccination 0.15 0.03 13 649 83 333 FTAP 0.31 0.16 13 700 52 3160 FTAP and school closure 1.80 1.49 13 733 33 45 234 Prevaccination and school closure 1.71 1.39 13 733 33 42 279 Intervention FTAP=full targeted antiviral prophylaxis; QALY=quality adjusted life year. 37 Table A14 Detailed base case results (ranked by expected QALYs) QALYs* Scenario per 1000 Cost Intervention ($) Cost Treatment ($) Cost total ($) Direct Indirect Total Direct Indirect Total Direct Indirect Total Baseline 21 141 0 0 0 79 352 107 565 186 918 79 352 107 565 186 918 FTAP25 21 157 3 351 575 3 926 75 840 102 941 178 781 79 191 103 516 182 707 FTAP50 21 175 6 612 1 154 7 766 71 139 97 243 168 381 77 751 98 396 176 147 HTAP25 21 181 5 439 2 028 7 467 75 968 104 143 180 111 81 407 106 171 187 578 School Closure 21 210 0 2 563 285 2 563 285 63 908 88 292 152 200 63 908 2 651 577 2 715 485 HTAP50 21 239 10 837 4 158 14 995 66 492 91 902 158 394 77 330 96 059 173 389 Treatment Only 21 241 5 337 7 021 12 358 77 128 105 238 182 365 82 464 112 259 194 723 HTAP 21 264 14 166 5 601 19 767 63 359 87 721 151 079 77 525 93 321 170 846 Vaccination 21 271 22 323 20 214 42 537 39 161 54 462 93 623 61 484 74 676 136 160 HTAP25 and School Closure 21 273 4 469 2 565 097 2 569 566 51 010 71 724 122 733 55 479 2 636 821 2 692 300 FTAP25 and School Closure 21 300 3 380 2 563 918 2 567 298 37 861 51 796 89 656 41 240 2 615 714 2 656 954 38 FTAP50 and School Closure 21 310 6 295 2 564 482 2 570 777 35 489 48 711 84 199 41 784 2 613 193 2 654 976 HTAP50 and School Closure 21 316 8 169 2 566 617 2 574 786 43 158 62 054 105 212 51 327 2 628 671 2 679 998 HTAP and School Closure 21 330 8 632 2 566 815 2 575 447 39 571 57 046 96 617 48 203 2 623 861 2 672 064 FTAP 21 351 35 407 6 944 42 350 33 837 48 127 81 964 69 244 55 071 124 315 FTAP and School Closure 21 403 14 412 2 565 881 2 580 294 9 932 14 691 24 623 24 344 2 580 572 2 604 917 Vaccination and School Closure 21 403 22 323 2 583 500 2 605 823 6 964 10 051 17 015 29 287 2 593 551 2 622 838 HCP=health care payer; FTAP=full targeted antiviral prophylaxis; HTAP=household targeted antiviral prophylaxis, QALY=quality adjusted life year. 39 Figures Figure A1 Overview of the disease transmission simulator 40 Figure A2 Schematic representation of social contact structure for one community 41