| | Oseltamivir for Influenza Postexposure Prophylaxis: Economic Evaluation for Children Aged 1–12 Years in the U.S.BackgroundPostexposure prophylaxis (PEP) with oseltamivir (Tamiflu) has been shown to be effective and is approved in children exposed to a case of influenza in a household setting. Given limited healthcare budgets, it is important to understand the costs and cost effectiveness of PEP in children. PurposeThis study aims to estimate the cost effectiveness of oseltamivir PEP for children aged 1–12 years in the U.S. MethodsA decision-tree model with a 1-year time horizon was used to assess the cost effectiveness of oseltamivir PEP for 10 days at approved doses compared with no prophylaxis for children aged 1–12 years who were exposed to a household index case of influenza from the U.S. societal and payer perspectives. Model inputs included U.S. influenza epidemiology data, efficacy data from oseltamivir PEP clinical trials, direct medical resource use and costs for PEP and influenza treatment derived from large U.S. databases, and indirect costs based on caregiver lost productivity. Base-case estimates were tested in extensive sensitivity analyses. ResultsFor the societal perspective, the model estimated 12,184 fewer cases of influenza per 100,000 children exposed and an incremental cost-effectiveness ratio of $41,452 per quality-adjusted life-year (QALY) gained. Results were most sensitive to the influenza attack rate, PEP protective efficacy, and prescribing patterns for initiating PEP. Probabilistic sensitivity analyses showed that oseltamivir PEP was likely to be cost effective for all willingness-to-pay threshold values above $34,300 per QALY gained. Results were similar for the payer perspective. ConclusionsAlthough there is no official cost-effectiveness threshold in the U.S., results from the current study show that when compared with no prophylaxis, oseltamivir PEP for children has cost-effectiveness ratios similar to those of vaccines for preventing influenza. Background  In the U.S., 15 million to 60 million people, or 5%–20% of the population, develop influenza each year.1 During annual epidemics, more than 40% of preschool-aged children2, 3, 4, 5, 6 and 30% of school-aged children2, 7, 8, 9, 10 may become ill with influenza. Influenza is responsible for more than 226,000 hospitalizations annually, with the highest hospitalization rates found in young children and older adults.11 Influenza also is associated with 8%–10% of fatalities during the peak of influenza season each year.12 Direct medical care costs for influenza in the U.S. have been estimated at $3 billion to $10 billion annually,13, 14, 15 including $55 million in hospitalization costs for children.16 Total costs to society may be higher than direct medical costs alone because of the indirect costs associated with caregivers' time lost to care for sick children.14, 15, 17, 18, 19 Influenza epidemics occur in the U.S. each year, despite an active vaccination program. Reasons include a mismatch of the vaccine with the circulating virus and low uptake of vaccination, especially in healthy adults and children. For example, the uptake of recommended routine vaccination was less than 30% in children aged 6–23 months and less than 20% in preschool children aged 2–5 years for the 2006–2007 influenza season.20 Several studies have shown that vaccinating children lowers the attack rate in children, in their household contacts,21, 22 and in the community as a whole.23, 24, 25 Postexposure prophylaxis (PEP) with an antiviral is a critical adjunct to vaccination. The American Academy of Pediatrics recommends prophylaxis with a neuraminidase inhibitor (oseltamivir [Tamiflu] for children aged ≥1 year or zanamivir [Relenza] for children aged ≥5 years) after exposure to influenza to control outbreaks in institutional or family settings.26 Oseltamivir clinical studies have demonstrated efficacy of 7- to 10-day PEP in preventing influenza infections when given within 2 days of exposure to a household index case.27, 28 The protective efficacy of PEP with oseltamivir was significant, ranging between 64% in children (p=0.0188) and 89% in adults (p<0.001). Recently, the CDC issued interim recommendations for antiviral prophylaxis with a neuraminidase inhibitor after exposure to influenza H1N1 virus.1 Given limited healthcare budgets, it is important to understand the costs and cost effectiveness of PEP with oseltamivir in addition to its clinical efficacy. In this study, the cost effectiveness of oseltamivir PEP for children aged 1–12 years is estimated. This population was chosen because vaccination uptake is typically low in this age group and because children play an important role in the magnitude of an influenza epidemic. Methods Model Overview The model evaluated the cost effectiveness of PEP with oseltamivir at approved doses for 10 days in the U.S. for preventing influenza in children aged 1–12 years and was adapted from a previously published United Kingdom (UK) model.29 The model used a decision-tree framework with a 1-year time horizon and assumed that children had one known exposure during the year to a household index case of influenza-like illness (ILI; Figure 1). The model followed a population of 100,000 children. The attack rate was defined as the percentage of the exposed population that experienced symptoms following infection with influenza virus. The model compared costs and outcomes for children who visited a primary care physician (PCP) and received oseltamivir PEP with costs and outcomes for children who did not receive PEP. A proportion of the exposed population developed influenza; this proportion was calculated from the attack rate and was reduced by the efficacy of PEP for those who received PEP. Children who developed influenza received symptomatic treatment with over-the-counter (OTC) medications. No significant differences were observed between the PEP arm and the no-prophylaxis arm of the clinical trial in the duration of illness or complication rates among children who developed influenza.27 Therefore, all children in the model who developed influenza, regardless of receiving PEP, were assumed to experience the same duration and severity of symptoms and to be at the same risk for influenza-related complications (i.e., pneumonia, bronchitis, and otitis media); for hospitalization; or for death. Rates of hospitalization and death differed between those with uncomplicated influenza and those with influenza-related complications. Adverse events associated with oseltamivir PEP were mild and self-limiting; therefore, treatment costs and utility decrements were not included in the model. This assumption has been made in other cost-effectiveness analyses of PEP.30, 31 The model followed children through a series of medical events and estimated morbidity, mortality, and costs accrued during the year. The model generated outcomes for the societal and healthcare payer perspectives. For the societal perspective, both direct and indirect costs were considered. For the healthcare payer perspective, only direct reimbursable medical costs were considered. Model Input Data Epidemiologic data inputs The model used an influenza attack rate of 18.9%, which was observed in the placebo arm of the oseltamivir PEP clinical trial among children aged 1–12 years in the intention-to-treat (ITT) population.27 This attack rate was chosen because it reflects the higher attack rate expected among individuals exposed to a household index case rather than the lower average seasonal attack rate in the general population. Moreover, the Hayden study27 was the only PEP clinical trial to our knowledge with a subanalysis specific to children. For children who developed influenza in the model, mean symptom duration and complication rates were obtained from the confirmed influenza population in the placebo arm of the oseltamivir treatment clinical trial in children.32 Other natural history data, such as influenza-related hospitalization rates and mortality rates, were derived from large U.S. database studies11, 33 (Table 1). | | |  | | Point estimate | Range for sensitivity analysis | Distribution | Reference | |
|---|
| Prophylaxis protective efficacy | 0.644 | 0.1580, 0.8500 | Lognormala | 27 | | | Attack rate | 0.189 | 0.1222,0.2667 | Betaa | 27 | | | Probability of developing a secondary complication | | | | Bronchitis | 0.2766 | 0.2214,0.3354 | Betaa | 32 | | | Pneumonia | 0.2766 | 0.2214,0.3354 | Betaa | 32 | | | Otitis media | 0.2128 | 0.1630,0.2672 | Betaa | 32 | | | Probability of hospitalization | | | | Influenza | 0.0014 | 0.0011,0.0017 | Triangleb | 11c | | | Bronchitis | 0.0014 | 0.0011,0.0017 | Triangleb | Assumptiond | | | Pneumonia | 0.0128 | 0.0119,0.0137 | Betaa | 34 | | | Hospital length of stay (days) for those treated in an inpatient setting | | | | Influenza | 4.56 | 3.89,5.23 | Normala | 35 | | | Bronchitis | 2.90 | 2.74,3.06 | Normala | 35 | | | Pneumonia | 3.71 | 3.51,3.91 | Normala | 35 | | | Probability of mortality (per 1000) | | | | Influenza | 0.016 | 0.013,0.019 | Triangleb | 33e | | | Bronchitis | 0.016 | 0.013,0.019 | Triangleb | Assumptiond | | | Inpatient pneumonia | 2.815 | 2.545,3.098 | Betaa | 35 | | | Outpatient pneumonia | 1.056 | 0.704,1.408 | Trianglef | 35, 36 | | | Otitis media | 0.016 | 0.013,0.019 | Triangleb | Assumptiond | | | 1-day utility value for influenza with or without complications | 0.5579 | One-time QALY adjustment was varied, see below | 37 | | | One-time QALY adjustment (per episode)g | | | | Influenza—outpatient | 0.007 | 0.002,0.009 | Triangleh | Calculatedh | | | Influenza—inpatient | 0.009 | 0.003,0.012 | Triangleh | Calculatedh | | | Pneumonia—outpatient | 0.012 | 0.012,0.046 | Triangleh | Calculatedh | | | Pneumonia—inpatient | 0.017 | 0.014,0.076 | Triangleh | Calculatedh | | | Bronchitis—outpatient | 0.012 | 0.008,0.046 | Triangleh | Calculatedh | | | Bronchitis—inpatient | 0.016 | 0.008,0.072 | Triangleh | Calculatedh | | | Otitis media | 0.008 | 0.004,0.042 | Triangleh | Calculatedh | | | | |
| a Ranges were calculated using the 95% CI around the point estimate. bRanges for sensitivity analysis were calculated as ±20% of the base-case value. cCalculated from the observed hospitalization rate for children aged <5 years (18.5 per 100,000) and the average percentage of the population at risk for influenza across 22 seasons (13.3%) from Thompson et al.11 (0.000185÷0.133=0.0014) dAssumed to be the same as influenza without complication eCalculated from the observed mortality rate for children aged <5 years (0.2 per 100,000) and the average percentage of the population at risk for influenza over 23 seasons (12.4%) from Thompson et al.33 (0.000002÷0.124=0.000016) fRanges for sensitivity analysis were calculated by varying the base-case reduction in mortality of 62.5% for outpatients compared with inpatients to a 50% reduction and a 75% reduction. gCalculated according to the following equation: QALYs lost per episode=(1–utility value) × duration of illness÷365. Duration of illness equals 5.71 days for outpatient influenza,32 10 days for outpatient bronchitis or pneumonia,38 and 7 days for otitis media.38 Duration of illness for inpatient cases equals hospital length of stay plus half of the outpatient duration. hSee Appendix A (available online at www.ajpm-online.net) for methodology for base-case value and for ranges used in sensitivity analysis.39, 40, 41 |
Clinical efficacy data inputs Protective efficacy of oseltamivir PEP (0.644) was derived from the observed reduction in the number of influenza cases among children aged 1–12 years in the ITT population, which included both vaccinated and unvaccinated children27 (Table 1). The protective efficacy of oseltamivir PEP was applied to the attack rate to calculate the number of children who developed influenza among those who received PEP. The number of children who developed influenza among those who did not receive PEP was calculated using the placebo attack rate. Utility inputs The utility value for children who developed influenza was 0.5579 for each day a child had influenza symptoms.37 Children who did not develop influenza were assumed to have a utility value of 1.0 for the entire year. Quality-adjusted life-years (QALYs) were calculated in the model by applying the utility value to the duration of symptoms or complications, assuming children remained healthy (utility value=1.0) for the remainder of the year (Table 1). In addition, the incremental QALY estimates include QALYs gained as a result of a reduction in premature mortality because of fewer cases of influenza. The model estimated QALYs lost for premature mortality using the average remaining life expectancy of a child aged 7 years (71.1 years)42 discounted at an annual rate of 3% (29.3 QALYs lost).43 Resource use inputs Resources used in the model included drugs (oseltamivir PEP, OTC drugs, and antibiotics); PCP and specialist physician visits; hospitalizations; and time lost from work or usual activities for caregivers. The payer perspective excluded nonreimbursable costs such as copayment(s) borne by the child's family, costs for OTC drugs, and time costs. Children who received oseltamivir PEP visited a PCP and received one 10-day prescription of oseltamivir PEP. Caregivers lost time from work or usual activities for the PCP visit (Table 2). Children who did not receive oseltamivir PEP did not use these resources. Children who did not develop influenza had no further resource use in the model. | | | | Resource | Type of cost | Unit cost ($) | Units per episode | Reference | |
|---|
| Costs for PEP | | | | | | | Oseltamivir PEP | Direct | 40.68 | 2.01 bottles | 44, 45, 46 | | | Copayment | Directa | 25.00 | 1.0 copayment | Assumptionb | | | PCP visit | Direct | 63.99 | 1.0 visit | 47 | | | Value of caregiver time, per hourc | Indirect | 14.56 | 2 hours | 48, 49d | | | Costs for treating outpatient cases | | | | | | | OTC medications | Directa | 5.00 | 1.0 package | 46d | | | Antibiotics for bronchitis or pneumonia | Direct | 56.60 | 1.0 prescription | 38, 45, 46e | | | Antibiotics for otitis media | Direct | 63.45 | 1.0 prescription | 38, 45, 46f | | | PCP visit | Direct | 63.99 | | 47, 50 | | | Influenza | | | 1.13 visits | | | | Bronchitis | | | 1.09 visits | | | | Pneumonia | | | 2.24 visits | | | | Otitis media | | | 2.51 visits | | | | Specialist visit | Direct | 96.36 | | 47, 50 | | | Influenza | | | 0.29 visits | | | | Bronchitis | | | 1.6 visits | | | | Pneumonia | | | 0.68 visits | | | | Otitis media | | | 0.69 visits | | | | Value of caregiver time, per dayc | Indirect | 116.45 | 3.2 days | 48, 52d | | | Costs for treating inpatient cases | | | | | | | OTC medications | Directa | 5.00 | 1.0 package | 46d | | | PCP visit | Direct | 63.99 | 2.0 visits | 47, 50 | | | Hospitalization, per day | Direct | | | | | | Influenza | | 1523 | 4.56 days | 35d | | | | | SE=67.26 | SE=0.34 | | | | Bronchitis | | 1459 | 2.90 days | 35d | | | | | SE=47.09 | SE=0.08 | | | | Pneumonia | | 1613 | 3.71 days | 35d | | | | | SE=46.80 | SE=0.10 | | | | Value of caregiver time, per dayc | Indirect | 116.45 | 5.5 days | 48, 52d | | | | |
| a Direct costs included in the societal perspective only bBased on typical copayment for a Tier 2 drug cValue of an unspecified day51 was calculated as the average annual earnings for full-time workers in 200748 divided by 365 days ($42,504÷365=$116.45). Value of an hour was calculated by assuming 8 hours of productive time per day ($116.45÷8=$14.56). dIn sensitivity analysis, caregiver time to receive PEP was varied from 0 to 4 hours, caregiver time for outpatient and inpatient cases was varied from 0 to 5.5 days, OTC drug costs were varied from $0 to $10, and hospitalization cost per day and length of stay were varied using the SE of the mean value. All other parameters were not varied. eBased on weighted average cost of 10 mg/kg azithromycin once daily for 1 day, followed by 5 mg/kg once daily for 4 days, as indicated for children with nonhospitalized pneumonia38 fBased on weighted average cost of 90 mg/kg amoxicillin once daily for 5–10 days or 14 mg/kg cephalosporin once daily for 5–10 days, as indicated for children with acute infection of otitis media38 |
Children who developed influenza in the model received an average of one OTC medication; children who developed an influenza-related complication additionally received one course of empiric antibiotics as recommended by clinical treatment guidelines.38 For children treated on an outpatient basis, a comprehensive U.S. database on outpatient care50 was used to estimate the average number of PCP and specialist visits. Hospitalized children were assumed to have two PCP visits; all other resource use was assumed to be captured in the cost of the hospitalization (Table 2). To care for sick children, caregivers lost an average of 3.2 days for outpatient cases and 5.5 days for inpatient cases (Table 2).52 Cost inputs The dose of oseltamivir PEP oral suspension was weight-based according to the current prescribing information for children aged 1–12 years and given once daily for 10 days.44 The average number (2.01) of bottles of oseltamivir per child was estimated based on the weight distribution of children in the U.S. aged 1–12 years45 and the indicated dosing schedule. Antibiotic doses for infectious complications were calculated using the weight-based approach and using the dosing indicated for children in the Sanford Guide.38 Unit costs for oseltamivir PEP, OTC drugs, and antibiotics were taken from the wholesale acquisition costs in the 2008 Red Book.46 Unit costs for physician visits were obtained from the Medicare Resource-Based Relative Value Scale schedule.47 Costs per episode were calculated by applying unit costs to the number of each resource used (Table 2). Hospitalization length of stay and costs were derived from the Healthcare Cost and Utilization Project's Nationwide Inpatient Sample35 for children aged 1–12 years with any listed diagnosis code for influenza, pneumonia, or bronchitis (all cases of otitis media were assumed to be treated on an outpatient basis; Table 1, Table 2). The methodology for this analysis is described elsewhere53 (see Appendix B, available online at www.ajpm-online.net). Indirect costs for time lost from work or usual activities for a caregiver were calculated by applying the value of a caregiver's time to the time estimates for visiting a PCP to receive PEP or for caring for a child who develops influenza. The value of caregiver time was estimated using the average annual salary for full-time workers48, 51 and applied to all caregivers, regardless of employment status, in order to capture the value of time lost from work or usual activities (Table 2). All costs are in 2008 U.S. dollars and were inflated using the medical care component of the consumer price index where necessary.54 Model outcomes The model estimated direct and indirect costs on an average, per-child basis for the oseltamivir PEP arm and the no-prophylaxis arm from the societal and payer perspectives. Health outcomes included the probability of developing influenza, the average number of symptom days per child, and the incremental QALYs per child. Using these cost and health outcomes, the incremental cost per influenza case avoided, per symptom day avoided, and per QALY gained were calculated. Sensitivity and variability analyses To understand how sensitive the cost-effectiveness results were to input parameter uncertainty, one-way and probabilistic sensitivity analyses were conducted using appropriate ranges and distributions. Variability analyses also were conducted to test variations in prescribing patterns (e.g., prescribing PEP without a PCP visit); drug pricing methods (e.g., retail drug costs); and seasonal attack rates. Results Base-Case Results For 100,000 children receiving PEP compared with no prophylaxis, there were 12,184 fewer cases of influenza and 3.78 fewer deaths in the 1-year model period. On average, a child receiving oseltamivir PEP experienced 0.0023 more QALYs and 1.02 more symptom-free days than a child not receiving prophylaxis (Table 3). From a payer perspective, the per-child cost of receiving PEP was $138, compared with a cost of $49 without PEP, yielding incremental costs per case of influenza avoided of $731 and per QALY gained of $38,050 (Table 3). From a societal perspective, including all direct costs and indirect costs related to caregiver time, the per-child cost of receiving PEP was $218, compared with a cost of $121 without PEP, yielding incremental costs per case of influenza avoided of $796 and per QALY gained of $41,452 (Table 3). Sensitivity and Variability Analysis Results One-way sensitivity analysis testing parameter uncertainty found that the results were most sensitive to the protective efficacy of PEP and, to a lesser extent, the attack rate. For the societal perspective, the incremental cost per QALY gained ranged from $19,719, when the upper bound for attack rate (26.7%) was tested, to $271,390, when the lower bound for protective efficacy (0.158) was tested. The results were much less sensitive to the other parameters tested (see Appendix C, available online at www.ajpm-online.net). Results from the probabilistic sensitivity analysis found that oseltamivir PEP was cost effective compared with no prophylaxis in 19.1%, 73.2%, and 93.4% of simulation runs at willingness-to-pay thresholds of $20,000, $50,000, and $100,000 per QALY gained, respectively. The threshold above which oseltamivir PEP was cost effective in more than 50% of simulation runs was $34,300 per QALY gained (see Appendix D, available online at www.ajpm-online.net). Results of the variability analysis indicated that the societal-perspective cost-effectiveness ratio was much lower when a higher attack rate (30%) was used ($13,841 per QALY gained) or when PEP was prescribed without an additional physician visit ($1,672 per QALY gained; Table 4). The ratio was higher when retail drug costs were used ($49,823 per QALY gained) and when a lower attack rate (8%) was used ($143,481 per QALY gained). | | | | Scenario description | Perspective | Incremental cost per QALY gained ($) | Incremental cost per case avoided ($) | |
|---|
| Base casea | Payer | 38,050 | 731 | | | Societal | 41,452 | 796 | | | Lower attack rate (8%) | Payer | 108,520 | 2084 | | | Societal | 143,481 | 2756 | | | Higher attack rate (30%) | Payer | 18,979 | 365 | | | Societal | 13,841 | 266 | | | Cost of oseltamivir (AWP=$48.82) | Payer | 45,048 | 865 | | | Societal | 48,450 | 931 | | | Retail drug costsb | Payer | 46,420 | 892 | | | Societal | 49,823 | 957 | | | No additional PCP visit for exposed family members to receive PEP | | | | | | | |
| a Base case: the attack rate is 18.9%, the costs of oseltamivir ($40.68) and of all other drugs are based on the wholesale acquisition costs, and an initial visit to a PCP to receive oseltamivir PEP is assumed. bRetail drug costs for brand name drugs were $50.99 for oseltamivir, $25.89 for amoxicillin, $148.28 for cefdinir, and $64.70 for azithromycin (www.drugstore.com),55 which resulted in a cost per course of $102.59 for oseltamivir PEP and a cost per episode of $64.70 for bronchitis/pneumonia and $87.08 for otitis media. |
Results from the sensitivity and variability analyses were consistent across perspectives. Discussion The base-case results for the societal perspective showed that oseltamivir PEP costs an additional $41,452 per QALY gained or $796 per case avoided compared with no prophylaxis. Results were similar for the payer perspective. One-way sensitivity analysis showed that the model results were highly sensitive to the protective efficacy of oseltamivir PEP and the attack rate observed in the clinical trial. Probabilistic sensitivity analyses showed that oseltamivir PEP was likely to be cost effective for all willingness-to-pay thresholds above $34,300 per QALY gained. Results of the variability analysis showed that variations in the attack rate across seasons and the PCP visit to receive PEP had the largest impact on the results. Interestingly, with high attack rates and/or without the need for a physician visit to initiate PEP, oseltamivir PEP is more cost effective than in the base-case analysis and might be both cost-saving and more effective compared with no prophylaxis (see Appendix E, available online at www.ajpm-online.net). This finding could be relevant when influenza is known to be circulating in the community (e.g., high attack rate) and a pediatrician prescribes PEP for exposed sibling(s) over the phone or at an office visit for the index case. Additionally, prescribing PEP without a separate office visit may increase the feasibility of initiating PEP within the indicated time frame (i.e., 2 days after exposure). The current analysis was completed prior to the 2008–2009 outbreak of the influenza H1N1 virus; however, the results may provide insight into the cost effectiveness of oseltamivir PEP for exposed children. The CDC found via in vitro testing that the novel type A (H1N1) virus is susceptible to neuraminidase inhibitors and has recommended 10-day PEP for individuals who have had close contact with a “confirmed, probable, or suspected case” of H1N1 virus and are at high risk for influenza complications.1 The definition of high risk for children (i.e., all children aged <5 years and older children with comorbidities) is the same as for seasonal influenza. Although the attack rates of influenza H1N1 virus during 2008–2009 and the upcoming 2009–2010 seasons are not known, the lack of residual immunity from similar viruses will likely lead to attack rates that are higher than those typically observed for seasonal influenza among children. Accounting for these higher attack rates and the expectation that the efficacy of oseltamivir PEP and the severity of the influenza illness may be similar for the H1N1 virus and seasonal influenza, the result of the current analysis for a high–attack-rate scenario (30%; $13,841 per QALY gained) may provide a reasonable estimate of the cost effectiveness of oseltamivir PEP when used after exposure to the influenza H1N1 virus. If residual immunity increases, attack rates decrease over time, and the virus remains susceptible to oseltamivir, the cost-effectiveness estimates at lower attack rates would likely be more applicable. Thus, PEP may serve as an important supplementary strategy for preventing illness in children at high risk for influenza complications. In comparison with the current results, a recent study56 estimated an average willingness to pay of $469 to prevent an uncomplicated case of influenza in a child aged 1 year. The current study found that the cost per case avoided was higher than this estimate when PEP was prescribed during an office visit ($796 per case avoided) and lower than this estimate when PEP was initiated without a PCP visit (e.g., prescribed over the phone; $32 per case avoided). Comparison across studies, however, should be undertaken with caution. For example, Prosser et al.56 estimated the willingness to pay to avoid a case of uncomplicated influenza, whereas the current results represent the cost of avoiding any case of influenza disease (i.e., uncomplicated or complicated influenza). Influenza PEP is a viable prevention measure in children who have not been vaccinated and as such complements rather than competes with seasonal vaccination. However, it is interesting to compare the estimated cost effectiveness of these two prevention methods in children. A recent study40 estimated the cost effectiveness of influenza vaccination from the societal perspective at $9,000–$28,000 per QALY gained for children aged <5 years, $72,000–$79,000 per QALY gained for children aged 5–11 years, and $109,000–$119,000 per QALY gained for children aged 12–17 years. The current results for oseltamivir PEP in children aged 1–12 years ($41,452 per QALY gained) fall between the estimates reported for children aged <5 years and children aged 5–11 years for influenza vaccine.40 Differences in the cost effectiveness of PEP among subgroups of children was not assessed by the current study and is an area for future research. The cost-effectiveness model structure used for the current analysis is widely published and well validated for oseltamivir both as treatment57, 58, 59, 60, 61 and PEP.29 The model considers resistance rates (through variations in protective efficacy), which is especially important in children, in whom resistance rates may be higher than in adults.62 A limitation of the model structure is that it does not account for the possible role of children in spreading the illness and may thus underestimate the societal value of PEP. Another important limitation is that this analysis was specific to a household setting and therefore evaluated only one exposure to a household index case, rather than multiple exposures (a scenario that may be relevant for children in a daycare or school setting). The model inputs have both strengths and limitations. Use of data from a prospective, randomized clinical trial in which protective efficacy and attack rate were specific to the modeled population (children aged 1–12 years) provides results that are relevant for children. However, the relationship between the community attack rate and the attack rate in an exposed population is not well understood. The attack rate in an exposed population likely depends on the community attack rate, which varies both during and across influenza seasons. The sensitivity and variability analyses used here accounted for both the uncertainty in the clinical trial outcome (exposed population attack rate in a single season) and variability across seasons. Finally, the effectiveness of oseltamivir PEP under real-world circumstances may be less than that observed in the clinical trial. The current analysis attempted to account for this by using the protective efficacy from the ITT population, which included contacts who were exposed to an index case with ILI and not necessarily confirmed influenza (62% of index cases).27 The ITT population was chosen to reflect the fact that a parent seeking PEP may not know whether his or her child was exposed to ILI or true influenza. Results from this study show that the cost effectiveness of oseltamivir PEP for preventing influenza in children aged 1–12 years varies widely, depending on the protective efficacy of PEP, the attack rate, and the paradigm used by pediatricians for prescribing PEP and by parents for seeking care. Although there is no official cost-effectiveness threshold in the U.S., results from the current study show that when compared with no prophylaxis, oseltamivir PEP has cost-effectiveness ratios similar to those of vaccines for preventing influenza. We would like to acknowledge Beate Sander (University of Toronto), who developed the original SAVE model for the UK, from which the U.S. model was adapted, and Sean Candrilli (RTI Health Solutions) for his data analysis of the Healthcare Cost and Utilization Project's nationwide inpatient sample. We also would like to thank both Josephine Mauskopf (RTI Health Solutions) and the reviewers for their substantive comments on the manuscript. Financial disclosure: Funding for this study was provided by Roche Laboratories, Inc. Aleksander Winiarski is an employee in the medical information department at Roche Laboratories, Inc. Sandra Talbird and Anita Brogan are employees of RTI Health Solutions, an independent contract research organization, and maintained independent scientific control over the study, including data analysis and interpretation of the final results. Supplementary data References 1. 1CDC. Influenza. 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a Research Triangle Institute (RTI), Health Solutions, Research Triangle Park, North Carolina b Roche Laboratories, Inc., Nutley, New Jersey  Address correspondence and reprint requests to: Sandra E. Talbird, MSPH, RTI Health Solutions, 3040 Cornwallis Road, P.O. Box 12194, Research Triangle Park NC 27709
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