Respiratory syncytial virus (RSV) is the most important cause of lower respiratory tract infection (LRTI) in infants and children and is associated with substantial morbidity in both inpatient and outpatient settings.1 Overall, RSV is associated with 20% of hospitalizations, 18% of emergency department visits, and 15% of office visits for acute respiratory infections from November to April.1 Bronchiolitis hospitalizations in children younger than 2 years of age significantly increased from 3.3% in 2002 to 5.5% in 2007, mainly because of RSV infections in the United States.2 In Canada, inpatient care of RSV illness costs $18 million (US dollars) yearly, accounting for 62% of the total cost of this disease.3 The magnitude of the costs is understandable, as virtually all children become infected with RSV within 2 years after birth, and 1% requires hospitalization.4 Recurrent wheezing following serious RSV-associated LRTI is a common phenomenon of the disease that might persist until adulthood.5 Palivizumab is a humanized monoclonal antibody that provides immunoprophylaxis against RSV when given monthly during the RSV season. It significantly reduced hospitalizations in high-risk infants, including preterm infants with and without bronchopulmonary dysplasia (BPD) and children with hemodynamically significant congenital heart disease (CHD).6,7 In clinical trials, the most common adverse events occurring at least 1% more frequently in palivizumab-treated patients than controls were upper respiratory infection, otitis media, fever, and rhinitis.8 Since its license in 1998, about 40 methodologically different economic studies have been performed to prove cost-effectiveness of the product. The majority of cost-effectiveness analyses revealed costs of palivizumab exceeding anticipated savings from reduced RSV hospitalizations.9 Only a minority of studies performed cost-effectiveness analyses using incremental cost-effectiveness ratios (ICERs) as costs per quality-adjusted life years (QALY) gained.10,11 In addition, different contingents of country-specific epidemiologic data reinforced result diversity. The use of palivizumab always has to be discussed in the light of the continuing burden of RSV disease, its limited treatment modalities, and the rising awareness of chronic morbidity after RSV LRTI (post-RSV wheezing disorder). The long-term health effect of late-preterm birth and late-preterms' comorbidities are especially underestimated.12,13
In 2008,14 we used a decision tree model to compare direct and indirect costs and benefits of palivizumab prophylaxis for RSV in preterm infants, children with BPD, and children with CHD. The primary analysis was performed from the payer's perspective (Austrian National Health insurer) and the secondary analysis from the societal perspective, including indirect costs. The costs per QALY discounted (5% rate) from the payer's perspective for children with BPD, preterm infants, and children with CHD were €21,672, €14,439, and €9754, respectively, and accounted for €15,741, €4623, and €917, respectively, from the societal perspective.
Given the change in medication prices, the objective of this study was to reevaluate palivizumab cost-effectiveness in Austria with updated 2010 values and incorporation of long-term epidemiologic data to assess the effects of local cost changes.
MATERIALS AND METHODS
The decision tree model developed and published by Nuijten et al11 was adapted for this study (Fig. 1). The data sources were literature, including palivizumab clinical trials, official price and tariff lists, national epidemiologic statistics, and data from a still ongoing national noninterventional study in 33 to 35 weeks' gestational age (wGA) premature infants.15 Epidemiologic long-term data on RSV-associated hospitalizations was acquired from a local database (1993–2002) and a nationwide electronic epidemiologic monitoring system16 called RSV-Hotline (2002–2009). In this electronic file, only members of the Austrian RSV 29–32 study group17 and selected members of the Working Group of Neonatology and Pediatric Intensive Care Medicine of the Austrian Society of Pediatrics and Adolescent Medicine are able to voluntarily enter data of children hospitalized because of RSV LRTI. The database included gestational age, gender, chronological age at hospitalization, evidence of first or subsequent RSV-associated admission, evidence of palivizumab prophylaxis, and presence of additional risk factors, including BPD; chronic pulmonary disease, including cystic fibrosis; CHD; neuromuscular disease; immunodeficiency syndromes; siblings; crowding; day care attendance; passive tobacco smoking; and low socioeconomic status. Data were analyzed regarding year-to-year variations of onset, duration, peak, and end of RSV seasons, of median duration of hospitalization, and admission rate to the pediatric intensive care unit (PICU). RSV season was defined as occurring between November and April and divided into an early- (November–January) and a late-peaking season (February–April).18
The pharmacoeconomic analysis was conducted using the following 2 kinds of analyses: a cost-effectiveness analysis (CEA) and a cost-utility analysis, for analyzing comparatively palivizumab with no RSV disease prevention therapy. A CEA is an economic analysis, where costs are assessed monetarily and results nonmonetarily. Nonmonetary units are, for example, (1) gained life years, (2) avoided inpatient days, and (3) clinical parameters. Then, a cost-utility analysis was carried out. Such an analysis follows the principle of a CEA. Costs are assessed monetarily; the utility is assessed as a nonmonetary but utility-adjusted outcome, the QALYs. The benefit of using QALYs is that both patient mortality and morbidity are taken into account, demonstrating treatment benefit and providing a more complete measurement of treatment efficacy. Most CEA research relies on QALYs.
The base case cost-effectiveness study was conducted from a healthcare system's perspective. Therefore, all direct (medical) costs were relevant. The base case analysis included medical costs associated with administration of palivizumab and costs of RSV hospitalization and did not include future medical costs related to post-RSV wheezing disorder and indirect costs. Copayments by patients were also not included. The analysis from the societal perspective included the direct medical and indirect costs relating to the future productivity losses of the child (scenario analyses). The CEA was based on a lifetime follow-up period to capture the effect of palivizumab on long-term morbidity and mortality resulting from an RSV infection. Because of the fact that an increased risk of chronic wheezing after hospitalization for RSV during infancy is debated, a scenario analysis including post-RSV wheezing disorder as a long-term effect throughout childhood was undertaken.
The model was developed via Microsoft Excel (Microsoft Corp, Redmond, WA) and Data TreeAge Pro 2005 (version 6, TreeAge Software, Inc; Williamstown, MA). The economic analysis was calculated according to the Austrian Guidelines for Health Economic Evaluations.19 Costs were represented using recent data from 2010. For the calculation, among others, current valid Austrian data of children with RSV infection were used. Costs and outcomes were discounted at a rate of 5% when the time horizon of the model extended beyond 1 year. This discount rate varied in a sensitivity analysis from 3% to 10%.
Unfortunately, there is no established threshold for cost per QALY gained expressed in costs in Austria. In United Kingdom, the willingness to pay is an amount of £30,000 (National Institute for Health and Clinical Excellence) equivalent to €36,095, and in the United States the amount is $50,000 (Medicare) equivalent to €40,693 (values from June 26, 2010).
Stratification According to Different Risk Groups
Various gestational subgroups like all preterm infants, <33 wGA infants, 33 to 35 wGA infants, children with BPD, and children with CHD were considered, who might develop an RSV infection leading to hospitalization. Data from these populations regarding length of hospital stay (LOS) and PICU length of stay were based on long-term local and nationwide epidemiologic data (mentioned previously in the text). A proportion of the surviving children developed long-term sequelae like post-RSV wheezing disorder. Clinical assumptions were supported by data from the IMpact6 and Feltes et al7 trials as well as data from the studies of Sigurs et al5,20–22 showing that the frequency of recurrent wheezing was significantly higher in the RSV group compared with controls. The input data for the model are shown in Table 1.
Utilities and Life Expectancy
The utilities were derived from Greenough et al's study23 using the Health Utility Index (HUI 2) for children with a history of RSV infection. The study showed a median utility of 0.88 for high-risk children with RSV hospitalization and 0.95 for high-risk children without RSV hospitalization. The assumption for this model was that beyond the age of 16 years, there will be no difference in utility between the various high-risk patients regardless of the development of RSV and the development of long-term respiratory morbidity following an RSV hospitalization. It was further assumed that all patients older than 16 years will have perfect health (utility = 1). A further assumption related to the indirect costs, production losses were valued with the human capital approach according to health economic guidelines, where the production of a person is valued at the market price.
No clinical data exist that suggest a reduced life expectancy due to childhood RSV infection. Therefore, the life expectancy of the general population was derived from epidemiologic data of Austrian Nationals Statistics.25 Mortality data for high-risk children with CHD came from the trial by Feltes et al7; data for other patient groups were taken from the study by Sampalis.26
Palivizumab Administration and Costs
The administration of palivizumab in high-risk children took place at the pediatrician's office; therefore, 4 consultations and injection costs (mean, 3.98 shots) were calculated. In Austria, inpatient treatment is compensated through diagnosis-related groups—the Austrian so-called “System der leistungsorientierten Krankenanstaltenfinanzierung (LKF-System).” According to the initial diagnosis subject to ICD-10 codes, a certain lump sum is defined for each treatment group. The point value changes on a yearly basis, so the calculations were done with a point value of 1 EUR. Therefore, a sensitivity analysis was conducted.
Hospitalization and Treatment Costs
The hospitalization rates in the preterm infants, <33 wGA infants, 33 to 35 wGA infants, children with BPD, and children with CHD are shown in Table 1. LOS for each subgroup was based on data from the Austrian RSV-Hotline,16 revealing 10 days (median) for infants born at 33 to 35 wGA and 13 days (median) for infants born at <33 wGA. Twenty-five percent of all inpatient children were admitted to the ICU for an average stay of 1.89 days for the 33 to 35 wGA subgroup and 0.96 days for the <33 wGA subgroup. The mean weight at the first palivizumab administration was 3.9 kg (standard deviation, 1.4 kg; Min/Max, 2.0 kg/9.3 kg). The costs of inpatient treatment of pneumonia due to RSV are shown in Table 2.
Direct costs linked to particular therapy and relevant for the chosen healthcare system's perspective were assessed and quantitatively documented. Direct costs comprised medication cost of palivizumab in Austria. The cost of 1 vial of 50 or 100 mg of palivizumab was €556 or €907, respectively, according to the Austrian reimbursement price.27 The mean number of injections per child and season was 3.98 with total costs of €3336 per RSV season.15
Costs for treatment comprised the following: consultation costs in the outpatient setting as well as inpatient costs. For Austria, the costs of consultations of General Practitioner and Specialist represent a weighted average based on tariff catalogues of 5 provincial health insurances.28–32 Unit costs for pediatric consultations, hospitalization, and pediatric ICU are shown in Table 2. The administration costs for RSV prophylaxis amount to €44.20 for 4 consultations and €10.52 for 3.98 intramuscular injections per RSV season.
The lump sum cost of hospitalization amounts to €2494 for a mean LOS of 4.8 days according to the LKF-system. Referring to the LOS of 10 and 13 days, respectively, the costs were €3350 and €4345, respectively. One day in the PICU included costs of €932, resulting in €1761 for 1.89 days (33–35 wGA) and €894.72 for 0.96 days (<33 wGA). Not only short-term, but also the long-term consequences of recurrent wheezing due to RSV infection were considered in further analysis. Von der Schulenburg et al33 calculated the annual costs associated with asthma in Germany. These direct medical costs were adjusted for the year 2010 according to the consumer price index for Austria. The discounted cost (5%) per child per lifetime was €23,033.
Production losses because of mortality of high-risk children were valued with the human capital approach, where the production of a person is valued in the market (in this scenario, the sex-specific average gross salary) price.34 These estimates led to a productivity cost estimate of € 201,513 for a lifetime.
Epidemiologic data during the past 16 RSV seasons were based on a total of 1579 children hospitalized because of RSV LRTI, 1144 nationwide and 435 regionally. During the study period, the median month of peak RSV hospitalization rates was March, median onset of season was mid-October, and median end of season was May. Median duration of season was 8 months, ranging from 5 to 12 months. RSV infection occurred in the off-season (May–October) 23% of the time (40/180 months). There were 4 early-peaking and 12 late-peaking seasons, without a strict order of appearance. Six seasons showed a biphasic cycle, and 3 seasons showed continuing RSV activity throughout the year. Analysis also revealed cycling activity of RSV with severe seasons being followed by mild ones and vice versa (Fig. 2).18
Table 3 shows the base case analyses of the high-risk subgroups. The ICER for the first outcome measure (life years gained—LYG) reflects the additional costs per LYG for a patient who is treated with palivizumab; these amount to €34,956 for all preterm infants, €35,056 for <33 wGA infants, €35,233 for 33 to 35 wGA infants, €35,611 for children with BPD, and €8956 for children with CHD (discounted).
The second outcome parameter was the QALY. The incremental cost-utility ratio (ICUR) amounted to discounted costs of €26,212 (all preterm infants), €26,292 (preterm infants <33 wGA), €24,392 (preterm infants 33–35 wGA), €24,654 (infants with BPD), and €8484 (infants with CHD).
The cost-effectiveness of palivizumab became more favorable when costs of recurrent wheezing treatment were taken into consideration (Table 4). The ICER amounted to €31,300 for all preterm infants, €31,778 for those <33 wGA, €31,578 for those 33 to 35 wGA, €32,522 for infants with BPD, and €8253 for infants with CHD and reflected the costs per LYG of a patient who was treated with palivizumab. Concerning the QALY outcome, the ICUR amounted to €21,669 (all preterm infants), €23,833 (preterm infants <33 wGA), €21,862 (preterm infants 33–35 wGA), €22,515 (infants with BPD), and €7818 (infants with CHD).
The results from the societal perspective were substantially more cost-effective in all study populations. Table 4 shows the results when indirect costs were considered. The ICER amounted to €22,822 for preterm infants, €24,178 for those <33 wGA, €23,100 for those 33–35 wGA, €25,356 for infants with BPD, and €3214 for those with CHD and reflected the additional costs per LYG for a patient who was treated with palivizumab. Concerning the QALY outcome, the ICUR amounted to €15,800, €18,133, €15,992, €17,554, and €3045, respectively.
A further scenario analysis was conducted which included infants of 33 to 35 wGA and a maximum number of 7 injections for 1 season. The base case analysis (only direct medical costs without asthma) revealed an ICER of €45,322. The ICUR for the base case amounted to a discounted cost of €31,377. When asthma (recurrent wheezing) costs were included in the analysis, the ICER of the first outcome measure (LYG) amounted to €41,667 and to an ICUR of €28,846 (discounted) referring to the QALY. When considering indirect costs, the ICER became more cost-effective. The ICER amounted to €33,189 for the outcome measure LYG, and the QALY revealed a lower ICUR of €22,977, as well. The results of this scenario analysis indicate that even when the maximum of 7 doses is assumed, the results are cost-effective.
As economic data (eg, pooled data sets, randomized clinical trials, and not verifiable assumptions) are often incomplete and uncertain, assumptions concerning defined parameters are made. Thus, it is important to conduct sensitivity analyses to prove the stability of base case results. Assumptions and uncertain parameters were varied to examine effects on results. Deterministic sensitivity analyses were conducted (variation of discount rate, vials, inpatient cost, length of stay, and utilities). The variation of the discounting rate with 3% or 10% resulted in cost-effectiveness ratios of €5656/QALY and €15,352/QALY compared with the base case ICUR of €2303/QALY in infants with CHD. Variation of the number of vials used led to an ICUR of €6695/QALY and €1811/QALY compared with the base case ICUR of €8067/QALY in preterm infants. Figure 3 shows the ICER after varying parameters mentioned previously in the text. Results are most sensitive by varying discount rates. The sensitivity analysis confirmed the robustness of the model.
Following the revised recommendations for the use of palivizumab in Austria in 2008,35 new pharmacoeconomic analyses had to be based on broad epidemiologic data. During a 16-year study period, epidemiologic data including more than 1500 children hospitalized because of RSV LRTI were used for this pharmacoeconomic analysis. Seasonal distribution revealed RSV activity peaking in March, and nearly a quarter of RSV activity occurred outside the peak in the entire RSV season from November to April. Thus, an additional model including 7 injections, covering a longer RSV season, was calculated.
The study used an adapted decision tree model to examine the cost-effectiveness of palivizumab in preterm infants, in those born at <33 wGA and at 33 to 35 wGA, in children with BPD, and in children with CHD, which has been used in a former analysis.14 The primary perspective of the study was that of the healthcare payer, and scenario analysis included the perspective of society. The use of palivizumab resulted, in the base case analysis, in an overall ICUR of €26,212/QALY for preterm infants, €24,654 for children with BPD, and €8484 for those with CHD.
An additional scenario analysis including long-term sequelae like recurrent wheezing led to a moderately lower ICER for all patient populations, which was further improved by inclusion of indirect costs, especially in the CHD children. In comparison with the results of our previous Austrian study,14 there were certain variations. We calculated discounted cost per QALY of €20,704 in preterm infants, €31,867 in children with BPD, and €11,390 in the CHD population. Variations resulted mainly from the incorporation of more and new country-specific epidemiologic data. Both studies showed more favorable results when the costs of asthma treatment were taken into consideration. Sensitivity analyses confirmed the robustness of the model. However, a limitation of the model was that a probabilistic sensitivity analysis was not provided in this study. But unlike previous studies, this study was not restricted to a short-term time horizon but rather included long-term discounted costs of asthma and productivity loss, some important parameters in the context of RSV disease. Results are somewhat limited by the estimated utilities for asthma as far as there exist no reference data. The cost-effectiveness study of palivizumab in the United Kingdom showed that in preterm infants and children with BPD, prophylaxis with palivizumab compared with no prophylaxis resulted in an ICER of £16,720/QALY after discounting. In babies with CHD, the use of palivizumab resulted in an ICER of £6664/QALY after discounting. These results are under the United Kingdom threshold.11
In a retrospective cohort study, propensity-matched premature infants born at ≤36 wGA and/or with birth weight of ≤2499 g with RSV LRTI during 5 RSV seasons (2001–2006) were analyzed regarding first-year healthcare costs and utilization. The 2 cohorts with and without RSV LRTI were compared excluding the birth hospitalization in a national United States health plan.36 As a result, 2995 infants with RSV LRTI matched to 2995 control infants with RSV LRTI had $9115 higher healthcare costs (RSV LRTI group, $19,559; control group, $10,444; P < 0.001) in the first year of life. Late-preterm infants (33–36 wGA) with an RSV hospitalization incurred $21,977 higher costs (P < 0.001) and those with an outpatient RSV LRTI incurred $3898 higher costs (P < 0.001) compared with corresponding controls. Similar results were found among infants ≤32 wGA with higher costs in the RSV LRTI group. Rates of all-cause hospitalizations, emergency department visits, and ambulatory visits were significantly higher among infants with RSV LRTI compared with controls.
The economic costs of RSV LRTIs are high, especially for high-risk infants. In Horn and Smout's study of 304 infants hospitalized for bronchiolitis or RSV pneumonia at 9 children's hospitals in the United States from 1995 to 1996, rates of ICU admission were 31.3% overall, as high as 48.4% in infants born at 33 to 35 wGA, and 39.3% in those born at ≤32 wGA.14 Intubation was required in 16.4% overall, 38.7% of those born at 33 to 35 wGA, and 21.4% of those born at ≤32 wGA. In the subgroup born at ≤35 wGA, mean PICU length of stay was 5.8 to 7.7 days, and mean hospital stay was 6.8 to 8.4 days.37 Estimates of the cost of RSV-related hospitalization varied. Using data from a large managed care organization, Joffe et al38 calculated the mean cost of a hospitalization for RSV as $8502 in 1995 dollars, but Robbins et al39 calculated a higher “plausible estimate” of $15,000 to $25,000 per RSV hospital admission. A more recent poster abstract report estimated the mean cost of RSV hospitalization, in 2007 dollars, to be $9014 in full-term infants (n = 1983), $13,876 in infants born at <33 wGA, and $18,403 in infants born at 33 to 36 wGA.40 In addition to considering the short-term clinical end point of RSV hospitalization, it is evident that further evaluation of the long-term effect of lung morbidity after RSV infection is required to ensure a better understanding of the healthcare effect of premature birth.12,13
Rates of compliance with RSV prophylaxis range from 25% to 100% and are more variable than those observed in clinical trials (92% and 93%).41 Home health programs have been associated with better compliance rates, ranging from 64% to 94% in these groups. Other factors that negatively affect compliance include limited access to care, parental perception of limited benefits with prophylaxis, transportation problems, and language difficulties. Thus, noncompliance diminishes the value of the expense already incurred for previously administered palivizumab doses and could result in hospitalization and higher costs.
Rietveld et al42 performed a CEA by combining estimates of individual hospitalization costs and monthly hospitalization risks, with immunization costs, parental costs, and efficacy of passive immunization for a reference case with the highest hospitalization risks and costs of hospitalization during the RSV season (male; gestational age, ≤28 weeks; birth weight, ≤2500 g; having BPD; aged 0 months at the beginning of the RSV season [October]), including various sensitivity analyses and a cost-neutrality analysis in the Netherlands. Although cost-effectiveness of passive immunization varied strongly by child characteristics and seasonal month, incremental costs per hospitalization averted were always high. These data were mostly limited to the model of a single constructed case scenario that does not reflect epidemiologic data being essentially needed.
In addition to all the different factors (genetic, pulmonary, cardiac, and immunologic) that are associated with increased susceptibility to develop severe RSV bronchiolitis, it is thought that the virus itself has unique characteristics that play a significant role in its ability to cause (or to be associated with) long-term pulmonary sequelae. To go into details of “the chicken and the egg” discussion, we refer to a recent article by Bont and Ramilo.43
A comparable study to our pharmacoeconomic model from Spain using country-specific observational hospitalization data was performed for preterm children born at ≤32 wGA.44 The use of palivizumab produced an undiscounted ICUR of €6142 per QALY, and a discounted ICUR of €12,814 per QALY that provided a cost-effective method of prophylaxis against severe RSV disease requiring hospitalization among preterm infants in Spain. By use of a 2-decision analytic model (with and without accounting for increased risk of asthma), cost-effectiveness was revealed in some preterm infants without BPD with a model that accounted for increased risk of severe recurrent wheezing.45 In contrast to our data, the authors used hypothetical cohorts of infants without chronic lung disease born at 26 to 32 weeks' gestation.
Two actual papers on cost-effectiveness were published during the revision process of our manuscript. One study from Sweden used the same pharmacoeconomic model and revealed cost-effectiveness based on a willingness-to-pay of 500.000 SEK (∼€54.000)/QALY in infants born at <29 weeks of gestation if severe RSV infection was assumed to increase subsequent asthma or mortality risk.46 The other study came from Florida, US, evaluating cost-effectiveness of palivizumab based on actual costs by observing incidence rates of RSV-associated hospitalizations in various pediatric risk groups over only 1 season from 2004 to 2005.46 Many epidemiologic studies on RSV-related hospitalizations in high-risk children concluded that an observational period for a minimum of 2 RSV seasons is necessary17; this is particular due to an often observed mild RSV season being followed by a season with increased RSV activity. In that view Hampp et al47 described a very low RSV incidence that partly contributed to their conclusion that palivizumab costs by far exceed the savings by prevention of RSV hospitalization. Additionally, the authors neither included indirect costs nor costs associated with post-RSV wheezing and ignored the increased mortality rate associated with RSV hospitalization reported by Sampalis in 2003.26
In conclusion, our results suggest palivizumab being cost-effective in prevention of RSV disease in high-risk infants. Use of Austrian long-term epidemiologic data further increased the validity of the results for the Austrian healthcare setting and confirmed conclusions of a previous cost-effectiveness study.14 The possibility of misclassification of RSV-related hospitalizations with subsequent underestimation of RSV-related costs emphasizes cost-effectiveness. Reimbursement of prophylaxis with palivizumab by health insurance companies thus is now based on cost-effectiveness provided by Austrian data.
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