Palivizumab in the prevention of severe respiratory syncytial virus infection in children with congenital heart disease; a novel cost-utility modeling study reflecting evidence-based clinical pathways in Spain

The human respiratory syncytial virus (RSV) is known to cause acute lower respiratory tract infections (LRTIs) during infancy and childhood. RSV activity can vary geographically, with the peak season for temperate climates lasting any time between November and April [1, 2]. Approximately, 60% of infants are infected during their first RSV season and almost all by the age of two [3]. In these infants, RSV infection may result in complications (e.g. bronchiolitis and acute respiratory or ventilatory failure) necessitating hospitalization and sometimes mechanical ventilation with transfer to an intensive care unit (ICU) [4]. Globally, 34 million episodes of acute LRTIs, 3.4 million hospitalizations and 199,000 deaths are estimated to occur due to RSV each year [3].

The clinical burden associated with RSV infection differs considerably between patients. In most cases, RSV infection presents itself as a common cold and requires no medical attention. However, in other cases, patients have serious negative health consequences that are known to result in respiratory problems that can last into adulthood. The economic burden of RSV has been estimated at an annual cost of € 47 million for the Spanish National Health Care System [5].

In general, three subgroups of children are considered to be at increased risk of severe infection: children with congenital heart disease (CHD), children with chronic lung disease (CLD), and infants who are prematurely born (i.e. born prior to the 37th week of gestation). Within this latter group, children are further stratified by their gestational age and the presence of additional risk factors such as contact with other children and lack of breast feeding [6]. In the present cost-utility analysis, we focus on children with CHD.

Given the significant humanistic and economic burden of RSV infection in high risk groups [5‐8], prevention of infection is highly recommended by the Spanish Association of Pediatrics (Asociación Española de Pediatría) [9, 10] as well the Spanish Society of Pediatric Cardiology and Congenital Heart Disease (Sociedad Española de Cerdiolohia Pediatrica y Cardiopatias Congenitas) [11]. To date, no RSV vaccine or antiviral therapy exists and the most effective method of prevention is prophylaxis with palivizumab [12]. Palivizumab is an FDA- and EMA-approved prescription injection of RSV-targeting antibodies and was granted access to most markets in the late 1990s [2]. During an RSV season, it is administered monthly via the intramuscular route, at a dose of 15 mg/kg [13].

The efficacy of palivizumab has been demonstrated in three randomized, double-blind, placebo-controlled clinical trials: the IMpact trial (n = 1502), [14] the MAKI trial (n = 429), [15] and the Feltes trial (n = 1287) [16]. The IMpact trial investigated the reduction in RSV-related hospitalizations among premature infants or children with CLD during the first RSV season of their life. Results from this trial showed that palivizumab prophylaxis was associated with a 55% (95% confidence interval [CI] 38–72%) reduction in hospitalizations. The more recent MAKI trial focused on parent-reported wheezing patterns in late preterm infants who received palivizumab or placebo (no prophylaxis). The study demonstrated a 47% (95% CI 14–80%) reduction in the number of patients suffering from recurrent wheezing and proved that palivizumab treatment significantly reduced the need for RSV-related outpatient visits in mild cases of RSV infection. The Feltes study included children (≤2 years of age) with CHD and demonstrated that palivizumab recipients had a 45% (95% CI 23–67%) relative risk reduction (RRR) in RSV hospitalizations.

Previously, several health economic evaluations comparing palivizumab prophylaxis with placebo have been performed [17‐25]. Among these, a handful of evaluations focused on children with CHD [24‐27]. Although the evaluations differed in terms of the modeling approach, input data, model outcomes and the estimated results, none of the studies sufficiently captured the impact of the complicated disease course in children with CHD. Specifically, the risk of delayed and complicated heart surgery as a severe RSV-related complication was not incorporated. Additionally, previously published studies did not consider patients with MA-RSV, long-term respiratory sequelae of RSV infection (asthma and allergic sensitization), and the impact of hospital-acquired nosocomial infections. The present study assessed the cost-utility of prophylaxis with palivizumab versus no prophylaxis in children with CHD in Spain, using a health economic model that captured the complexities of the RSV disease course as well as the specific clinical pathway of CHD patients. The analysis was conducted from a societal perspective.

Table 4 presents the base case analysis results, both undiscounted and discounted. Fewer patients in the palivizumab arm had MA-RSV infections and RSV-H when compared to the no prophylaxis arm. Considering a hypothetical cohort of 1000 children, palivizumab prophylaxis was estimated to prevent 62 MA-RSV cases and 44 RSV-H cases, including 21 delayed surgeries and four immediate surgeries despite the infection. The prevented MA-RSV and RSV-H cases were predicted to result in fewer patients with long-term respiratory sequelae. In the discounted analysis, over a lifetime horizon, incremental QALYs, LYs, and costs were estimated to be 0.11, 0.07, and € 1693, respectively, yielding an ICER of € 15,748 per QALY gained and € 24,936 per LY gained. The corresponding figures in the undiscounted analysis were 0.21, 0.17, € 1511, € 7212 per QALY gained, and € 9085 per LY gained, respectively.

Probabilistic sensitivity analyses demonstrated that the probabilities of palivizumab prophylaxis being cost-effective at a threshold of € 30,000 per QALY, € 50,000 per QALY and € 100,000 per QALY were 92.7%, 99.6% and 100.0%, respectively. Results of all simulations (100%) fell in the upper right quadrant of the CE plane, denoting both positive incremental QALYs and costs. Simulation results are shown in Fig. 3 (scatter plot of incremental results) and Fig. 4 (cost-effectiveness acceptability curve).

Table 5 presents summary results of the scenario analyses in terms of the ICER per QALY gained. Due to the base case ICER being well below the generally accepted cost-effectiveness threshold, most analyses assessed the detrimental impact of a particular scenario on the ICER. Applying 5% discount rates (costs and effects), considering a 10-year and 30-year time horizon increased the ICER to € 22,009 per QALY, € 33,654 per QALY, and € 19,307 per QALY, respectively. Model results were also sensitive to various assumptions concerning long-term respiratory sequelae. If allergic sensitization was not considered in the model, the ICER increased to € 22,055 per QALY. Expectedly, the ICERs increased further, when both allergic sensitization and asthma were excluded from the evaluation (€ 28,333 per QALY). Additionally, the model was sensitive to the scenario which assumed that in 90% of all prophylaxis administrations a 100 mg vial was used whereas in 10% of all administrations, both, a 50 mg and 100 mg vial was used. This scenario resulted in an increase in the base case ICER to € 26,249 per QALY. Overall, the scenario analyses revealed that the base case ICER was robust to changes in other parameters (e.g. incidence of sequelae, MA-RSV, quality of life). Therefore, it was concluded that palivizumab remained cost-effective even under extreme scenarios.

This current study estimated the cost-utility of palivizumab prophylaxis versus placebo in Spain from the societal perspective, using a novel cost-effectiveness model reflecting evidence-based clinical pathways. The base case model results indicated that palivizumab prophylaxis yields additional QALYs and LYs at additional costs. In the discounted analysis, incremental QALYs, LYs, and costs were estimated to be 0.11, 0.07, and € 1693, respectively, yielding an ICER of € 15,748 per QALY gained and € 24,936 per LY gained. The corresponding figures in the undiscounted analysis were 0.21, 0.17, € 1511, € 7212 per QALY gained, and € 9085 per LY gained, respectively. Probabilistic sensitivity analyses demonstrated that the probability of palivizumab prophylaxis being cost-effective at a € 30,000 per QALY threshold was 92.7%.

A recent review of cost-effectiveness studies assessing palivizumab versus no prophylaxis in children with CHD summarized the currently available evidence [53]. This literature review found that only four economic evaluations focused solely on the CHD subpopulation [24‐27]. However, several additional analyses examined CHD populations in conjunction with other high-risk subgroups [21, 40, 41, 54‐56]. The studies included in the review were fairly recent; most assessments were published in or after 2008 [21, 24, 40, 54‐56] and covered a number of countries including Germany [24], the UK [27, 41], and the US [26, 56]. Most studies were based on a cost-utility analysis, i.e., the incremental cost per additional QALY was estimated; however, one evaluation assessed the incremental costs of a prevented hospitalization [25]. In each study, the model structure was based on the design and primary outcome of the pivotal trial [2, 16], so that the reduction of RSV-related hospitalization by palivizumab prophylaxis could be directly reflected. Thus, models typically included RSV hospitalization and non-hospitalization health states. Frequently, the health state capturing RSV hospitalization considered days spent in both ICU and the general pediatric ward. If the cost-effectiveness of palivizumab was assessed in multiple risk groups (e.g. children with CHD and children with CLD), the same model structure was assumed to be applicable to all considered subgroups. None of the studies explicitly incorporated the risk of complicated and delayed surgery due to RSV infection in children with CHD, nor did they consider the risk of MA-RSV infection. Some of the studies took account of the risk of long-term sequelae in children with history of RSV-hospitalization [21, 40, 41, 54, 55]. These studies typically included asthma as the single respiratory sequelae and assumed that it persisted for a limited number of years [21, 40, 41, 54, 55]. While our study adopted the approach used in previous studies that modeled the impact of respiratory sequelae, we used two additional sources [29, 36] to model asthma and allergic sensitization sequelae, linked to MA-RSV. Case fatality rates during RSV hospitalization varied markedly across the studies [21, 24‐27, 40, 41, 54‐56]. Many studies used a lower case fatality rate for patients who received palivizumab prophylaxis than for those who did not, i.e., in these studies palivizumab prophylaxis was assumed to reduce the risk of case fatality [21, 24, 26, 27, 40, 41, 54‐56]. For the current model, equal case fatality rates were applied for children hospitalized for RSV infection.

While the model presented in this paper better reflects clinical pathways compared to past models, there are a number of limitations that need to be considered in the interpretation of the results. One of the limitations is the lack of available recent randomized trial based efficacy data for palivizumab in children with CHD in Spain. In particular, rates of RSV-H utilized in the model were limited to the pivotal RCTs conducted in a multinational setting more than a decade ago. One can speculate that RSV-H rates in children with CHD may have changed over time, perhaps due to improved socioeconomic or other environmental conditions. The impact of such a scenario was assessed in a deterministic analysis (i.e. assuming 10% relative lower RSV-H rate keeping the efficacy of prophylaxis constant); however, the impact of lower RSV-H rate on the ICER was limited and the conclusion of the study did not change. Additionally, decreasing trends of RSV-H rates have not been confirmed for children with CHD in Spain specifically. In contrast, the available evidence from a retrospective study of hospitalizations for RSV bronchiolitis in children aged <1 year, using nationally representative data for Spain, suggest that RSV-H rates did not decrease over the 2004–2012 assessment period [57]. Overall, given the lack of evidence on decreasing RSV-H rates, it is believed that the model used the best available information in this respect. Another limitation of the study was associated with the available evidence on palivizumab drug costs in Spain. A sophisticated drug cost calculation approach was presented in a previous economic evaluation for the UK, where palivizumab costs were estimated by the required dose, i.e., the number of 100-mg or 50-mg vials needed to administer palivizumab each month [17]. The initial dose was calculated using the infants’ average weight at the start of prophylaxis as reported in the pivotal trial (6.1 kg). Infants’ average weight at each subsequent administration was then estimated using UK-specific WHO growth chart data accounting for the preterm birth. The approach predicted that in 60% of the administrations both a 100-mg and a 50-mg vial would be required. While this approach predicted an ICER of € 26,249 per QALY within the present model framework (please see Table 5), based on local expert opinion it was concluded that the baseline average weight and the applied growth rates do not represent the Spanish setting; these would overestimate the required dose and consequently palivizumab drug costs. To adjust for the lower weight of Spanish infants compared to infants from participating countries of the trial (e.g. US, UK, and Germany), an expert opinion-based drug cost calculation approach was employed. The expert indicated that in 5% of all cases of palivizumab administrations a 50-mg vial was used and in 95% of all cases of palivizumab administrations a 100-mg vial was used (i.e. in no case were a 50-mg vial and 100-mg vial used, in combination, for a single administration). There is ample evidence demonstrating that the Spanish population is shorter and hence are likely to weigh less than the US, the UK or German populations [58]. Furthermore, it has been documented that children with CHD experience a decreased growth trajectory compared with their peers [59]; therefore, applying growth rates for drug cost calculations that represent the overall population might not be clinically plausible. Another possible limitation of the present study was the way case fatality and CHD-specific background mortality were applied. Both were applied during the first year of the simulation (i.e. in the decision tree). However, the case fatality was sourced from a study that examined children with CHD hospitalized for severe RSV LRTI [31] and may thus already include mortality due to CHD in addition to mortality due to an RSV infection. Although the same case fatality was used for the prophylaxis arm and placebo arm, there is a possibility of double counting. To assess the potential impact, a scenario analysis was conducted to investigate the effect of implementing CHD-specific background mortality, starting from the second year onwards, so that there was no overlap. Results show that the discounted ICER decreased to € 14,133 per QALY (Table 5), thus, revealing that the approach that was taken in the base case analysis was conservative. Furthermore, another limitation of the model was related to the long-term respiratory sequelae incorporated into the model. In the base case analysis, it was assumed that children who developed asthma or allergic sensitization were affected by these conditions until the age of 18 and not afterwards. While the assumption that respiratory sequelae have a fixed duration was based on previous cost-effectiveness models presented in peer-reviewed publications [29, 54, 55, 60], one may argue that the duration of asthma or allergic sensitization lasts longer (or potentially shorter) than 18 years. Sensitivity analyses were conducted to test the impact of respiratory sequelae on the model results. It was found that the ICER changed moderately in response to various assumptions on the duration of respiratory sequelae. However, even in the extreme scenario when no respiratory sequela were taken into account, the ICER remained below the € 30,000 per QALY threshold.

In conclusion, the cost-utility analysis using a novel model reflecting evidence-based clinical pathways demonstrated that the high efficacy of palivizumab prophylaxis compared to no prophylaxis resulted in a substantial number of prevented hospitalizations and generated a high number of QALYs gained. Although based on a single trial and associated with uncertainty, there is clear evidence that palivizumab prophylaxis represents a cost-effective treatment option in children with CHD according to generally accepted standards of cost-effectiveness in Spain.