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Monoclonal antibody for reducing the risk of respiratory syncytial virus infection in children

  1. Tea Andabaka1,*,
  2. Jason W Nickerson2,
  3. Maria Ximena Rojas-Reyes3,
  4. Juan David Rueda4,
  5. Vesna Bacic Vrca5,
  6. Bruno Barsic6

Editorial Group: Cochrane Acute Respiratory Infections Group

Published Online: 30 APR 2013

Assessed as up-to-date: 8 AUG 2012

DOI: 10.1002/14651858.CD006602.pub4


How to Cite

Andabaka T, Nickerson JW, Rojas-Reyes MX, Rueda JD, Bacic Vrca V, Barsic B. Monoclonal antibody for reducing the risk of respiratory syncytial virus infection in children. Cochrane Database of Systematic Reviews 2013, Issue 4. Art. No.: CD006602. DOI: 10.1002/14651858.CD006602.pub4.

Author Information

  1. 1

    Ewopharma Ltd, Zagreb, Croatia

  2. 2

    Institute of Population Health, Ottawa, Ontario, Canada

  3. 3

    Pontificia Universidad Javeriana, Department of Clinical Epidemiology and Biostatistics, Faculty of Medicine, Bogota, DC, Colombia

  4. 4

    Pontificia Universidad Javeriana, Departamento de Cirugía, Bogota, Cundinamarca, Colombia

  5. 5

    University Hospital Dubrava, Department of Hospital Pharmacy, Zagreb, Croatia

  6. 6

    University of Zagreb, School of Medicine, Hospital for Infectious Diseases, Department of Intensive Care, Zagreb, Croatia

*Tea Andabaka, Ewopharma Ltd, Zadarska 80 / 2, Zagreb, 10000, Croatia. Tea.Andabaka@gmail.com.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 30 APR 2013

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Summary of findings    [Explanations]

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

 
Summary of findings for the main comparison. Palivizumab compared to placebo for high risk of severe respiratory syncytial virus infection

Palivizumab compared to placebo for high riskof severe respiratory syncytial virus infection

Patient or population: patients at high risk of severe respiratory syncytial virus infection
Settings: hospital
Intervention: palivizumab
Comparison: placebo

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

PlaceboPalivizumab

Hospitalisation for RSV infectionStudy populationRR 0.49
(0.37 to 0.64)
2831
(3 studies)
⊕⊕⊕⊕
high

101 per 100050 per 1000
(37 to 65)

Moderate

100 per 100049 per 1000
(37 to 64)

All-cause mortalityStudy populationRR 0.69
(0.42 to 1.15)
2831
(3 studies)
⊕⊕⊕⊝
moderate1

28 per 100019 per 1000
(12 to 32)

Moderate

42 per 100029 per 1000
(18 to 48)

Total RSV hospital days per 100 childrenSee commentSee commentNot estimable2789
(2 studies)
⊕⊕⊕⊝
moderate2
Data on standard deviations missing; meta-analysis not possible.

Admission to ICUStudy populationRR 0.5
(0.3 to 0.81)
2789
(2 studies)
⊕⊕⊕⊕
high

34 per 100017 per 1000
(10 to 28)

Moderate

34 per 100017 per 1000
(10 to 28)

Mechanical ventilation for RSV infectionStudy populationRR 1.1
(0.2 to 6.09)
2789
(2 studies)
⊕⊝⊝⊝
very low1,3

13 per 100014 per 1000
(3 to 80)

Moderate

12 per 100013 per 1000
(2 to 73)

Supplemental oxygen therapy for RSV infectionStudy populationNot estimable0
(0)
See commentNumbers not reported in any of the three studies

See commentSee comment

Moderate


Number of children reporting any SAEStudy populationRR 0.88
(0.8 to 0.96)
1287
(1 study)
⊕⊕⊕⊕
high

631 per 1000555 per 1000
(505 to 606)

Moderate

631 per 1000555 per 1000
(505 to 606)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; ICU: intensive care unit; RR: risk ratio; RSV: respiratory syncytial virus; SAE: serious adverse event

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1No statistical significance in results and very wide 95% CIs around estimates of effect.
2Data on standard deviations missing in both studies.
3Substantial heterogeneity across the two studies; point estimates of effect on opposite sides.

 Summary of findings 2 Palivizumab compared to motavizumab for high risk of severe respiratory syncytial virus infection

 

Background

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Description of the condition

Respiratory syncytial virus (RSV) is one of the most important viral pathogens to cause acute respiratory infections (ARIs) in children (Nair 2010), with virtually all children having been infected with RSV at least once by their second birthday (Red Book 2012). In the United States (US), RSV infection is associated with substantial childhood morbidity, necessitating inpatient and outpatient care (Hall 2009a).

RSV infection carries a considerable disease burden, with an estimated 2.1 million children under five years of age requiring medical care in the US each year. Among children with RSV-related illnesses, approximately 3% are hospitalised, 25% are treated in emergency departments and 73% are treated by paediatricians. In the US each year, it is estimated that in children under five, RSV infection accounts for one out of every 334 hospitalisations, one out of 38 visits to an emergency department and one out of 13 visits to a primary care physician (Hall 2009a). Globally, it is estimated that RSV causes about 34 million episodes of acute lower respiratory tract infections in children under five, resulting in about 3.4 million hospitalisations each year (Nair 2010). RSV has also been shown to be the most important viral cause of death in children under five, especially in those younger than one year (Fleming 2005; Shay 2001; Thompson 2003). In data compiled by the Centers for Disease Control and Prevention (CDC), RSV pneumonia causes about 2700 adult and paediatric deaths each year in the US (Thompson 2003). Globally, it is estimated to result in up to 199,000 deaths per year (Nair 2010).

The exact timing of the RSV season varies by location and year (Mullins 2003). In temperate climates of the US, RSV outbreaks usually begin in November or December, peaking in January or February and end by March or April; whereas in tropical or subtropical climates, RSV activity correlates with rainy seasons and may be present throughout the year (AAP 2009; Hall 2009b; Simoes 2003). The most recent RSV season for which data are available in the US was July 2010 to June 2011, and this RSV season had a median duration of 19 weeks (CDC 2011). Knowledge of RSV seasonality can be used by clinicians and public health officials to determine when to consider RSV as a cause of ARIs and when to provide RSV immunoprophylaxis to children at high risk of serious disease (Red Book 2012).

The incubation period of infection frequently lasts four to six days. Inoculation of the virus happens through the upper respiratory tract (URT), followed by infection of the respiratory epithelium. The mechanism by which the virus spreads along the respiratory tract is not clear, but may occur through cell-to-cell transfer along intracytoplasmic bridges or through the aspiration of nasopharyngeal aspirations, and may involve the conducting airways at all levels (Domachowske 1999; Hall 2009b). Transmission of RSV is usually by direct or close contact with RSV-contaminated secretions. The virus can survive for several hours on surfaces, and for approximately half an hour on hands, reinforcing the need for stringent infection control policies within health facilities to reduce nosocomial infections. Transmission of the virus among household and child care contacts is common.

RSV initially manifests in infants as an upper respiratory tract infection, but progresses to a lower respiratory tract infection in approximately 20% to 30% of infants with varying degrees of severity, ranging from mild to life-threatening respiratory failure (Red Book 2012). Bronchiolitis usually develops one to three days following common cold symptoms such as nasal congestion and discharge, mild cough, fever and reduced appetite. As the infection progresses and the small airways are affected, other symptoms may develop, such as rapid breathing, wheezing, persistent cough and difficulty feeding, which can result in dehydration. Apnoea (a pause in breathing for more than 15 or 20 seconds) is the presenting symptom in up to 20% of infants admitted to hospital with RSV and may be the first symptom of bronchiolitis (Arms 2008; Hall 1979; Ralstone 2009). While most cases of RSV infection are not severe, in severe cases oxygenation may worsen and a child may develop acute respiratory or ventilatory failure, necessitating mechanical ventilation and admission to an intensive care unit (ICU). Approximately 1% to 3% of all children under 12 months of age will require hospitalization for the treatment of lower respiratory tract infection resulting from RSV (Red Book 2012).

Characteristics that are most frequently associated with RSV illness requiring hospitalization include male sex, chronic co-existing medical conditions, lower socio-economic status, smoke exposure, contact with other children and lack of breast-feeding (Hall 2009a). Characteristics that increase the risk of severe RSV illness are preterm birth, cyanotic or complicated congenital heart disease, especially conditions that cause pulmonary hypertension, chronic lung disease of prematurity (formerly called bronchopulmonary dysplasia) and immunodeficiency (Purcell 2004).

 

Description of the intervention

The observation that passively transferred maternal RSV-neutralising antibodies provided some protection from severe lower respiratory tract (LRT) disease has led to the development of passive immunity products to prevent and modify the severity of RSV infection. The first product available for this use was a respiratory syncytial virus immune globulin intravenous (RSV-IVIG, RespiGam), a polyclonal human RSV-neutralising antibody (a combination of different immunoglobulin molecules), administered intravenously during RSV-risk months. RSV-IVIG is no longer available.

In 1996, palivizumab (Synagis) entered into clinical trials. Palivizumab is an anti-RSV monoclonal antibody (a set of identical immunoglobulin molecules), administered intramuscularly at a dose of 15 mg/kg once every 30 days. The efficacy and safety of palivizumab has been evaluated in multicentre randomized controlled trials (RCTs), which in two trials demonstrated 45% and 55% decreases in RSV-related hospitalisations (Feltes 2003; IMpact-RSV 1998). In both trials, palivizumab prophylaxis was generally safe and well tolerated. In June 1998, palivizumab was licensed by the US Food and Drug Administration (FDA) for prevention of serious LRT disease caused by RSV in paediatric patients who are at an increased risk of severe disease (AAP 2009).

In 2008, MedImmune filed for FDA approval of motavizumab (Numax, Rezield), another RSV-neutralising monoclonal antibody intended for the same indication. The efficacy and safety of motavizumab and palivizumab were compared in a multinational non-inferiority RCT (Carbonell-Estrany 2010). However, the FDA did not approve motavizumab for RSV prophylaxis, due to concerns regarding ts safety and efficacy. Serious concerns were raised with regards to non-fatal hypersensitivity adverse events, which were three times higher in the motavizumab group than in the palivizumab group. Additional questions were raised with regards to geographical stratification of study patients, since measures of motavizumab's non-inferiority relied heavily on data obtained from the 9% of participants enrolled in southern hemisphere countries. Removing this population led the FDA to determine that in the US population motavizumab did not meet the non-inferiority criterion relative to palivizumab. In December 2010, the company announced it had discontinued further development of motavizumab for the prophylaxis of serious RSV disease. Therefore, palivizumab is currently the only product approved for prevention of serious RSV disease in infants and children with chronic lung disease, with a history of preterm birth (35 weeks gestation or less), or with haemodynamically significant congenital heart disease (AAP 2009).

The cost of immunoprophylaxis with palivizumab is high and economic analyses have failed to demonstrate overall savings in healthcare dollars if all infants who are at risk receive prophylaxis (ElHassan 2006; Garcia-Altes 2010; Hampp 2011; Wang 2011). In the USA, it is considered that a total of five monthly doses for infants and young children with chronic lung disease, congenital heart disease or preterm birth born before 32 weeks gestation will provide an optimal balance of benefit and cost, even with variation in the season's onset and end (AAP 2009).

 

How the intervention might work

Respiratory syncytial virus is a ribonucleic acid (RNA) virus of the Paramyxoviridae family. The virus uses attachment (G) and fusion (F) surface glycoproteins to infect cells. Palivizumab is a humanised mouse monoclonal immunoglobulin G1, produced by recombinant DNA technology and directed to an epitope of the F glycoprotein of RSV. Palivizumab binds to this glycoprotein and prevents viral invasion of the host cells in the airway. This reduces viral activity and cell-to-cell transmission and blocks the fusion of infected cells (Johnson 1997). As a result, preventive use of palivizumab may be associated with reduced risk for developing LRT disease (Hall 2010).

 

Why it is important to do this review

In a previous Cochrane systematic review, the pooled effects of RSV-IVIG and palivizumab were assessed together, compared to placebo, with the last search performed in March 1999 (Wang 1999). That review included three studies with RSV-IVIG and one with palivizumab prophylaxis. The review was withdrawn from The Cochrane Library in 2003, as the authors could not commit time to update it. Since then, RSV-IVIG has been withdrawn from the market, methodologies of performing systematic reviews have changed and additional RCTs with palivizumab have been conducted. A new team of authors took over this review in 2007 and published a protocol which focused on effectiveness and safety of prophylaxis with palivizumab (Lozano 2007). The protocol was withdrawn from The Cochrane Library in 2010, as the authors could not commit time to writing a review.

Unlike the review by Wang 1999, ours focuses on palivizumab prophylaxis, in terms of effectiveness and safety, as well as its cost-effectiveness. We expect that our findings will provide comprehensive and up-to-date evidence on RSV immunoprophylaxis with palivizumab in infants and children at high risk of severe RSV disease.

 

Objectives

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

  1. To assess the effectiveness and safety of palivizumab prophylaxis compared with placebo, or another type of prophylaxis, in reducing the risk of complications (hospitalization due to RSV infection) in high-risk infants and children.
  2. To assess the cost-effectiveness (or cost-utility) of palivizumab prophylaxis compared with no prophylaxis in infants and children in different risk groups.

 

Methods

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Criteria for considering studies for this review

 

Types of studies

To study the effectiveness and safety of palivizumab, we included randomized controlled trials (RCTs) comparing palivizumab prophylaxis with a placebo, no prophylaxis or another type of prophylaxis in preventing serious LRT disease caused by RSV in paediatric patients at high risk of RSV disease.

To study cost-effectiveness (or cost-utility), we included full economic evaluation studies (cost-effectiveness analyses and cost-utility analyses) comparing palivizumab prophylaxis with no prophylaxis. We considered for inclusion health economics studies conducted alongside high-quality randomized trials, and economic modelling studies based on data from high-quality randomized trials or based on a comprehensive systematic review of the literature. We excluded partial economic evaluation studies that report cost analyses, or cost-outcome descriptions, due to the large number of available full economic evaluations. We also excluded economic evaluations of prophylaxis with RSV-IVIG, due to the fact that palivizumab is the only approved product for this purpose, and these analyses would be of no importance to health funds or patients.

 

Types of participants

We included infants and children at high risk of developing LRT disease caused by RSV, i.e. those with chronic lung disease (or bronchopulmonary dysplasia), congenital heart disease, immunodeficiency, chronic neuromuscular disease, congenital anomalies or those born preterm. We excluded children with cystic fibrosis as a related Cochrane Review has already been published on that topic (Robinson 2012).

 

Types of interventions

We compared passive immunisation of palivizumab (15 mg/kg dose, any setting and regimen) with placebo, no prophylaxis or another type of prophylaxis. In the critical assessment of health economics studies, we compared palivizumab prophylaxis with no prophylaxis.

 

Types of outcome measures

 

Primary outcomes

  1. Hospitalisation for RSV infection.
  2. All-cause mortality.

 

Secondary outcomes

 

Effectiveness outcomes

  1. RSV-specific outpatient medically attended lower respiratory tract infection (MALRI).
  2. Number of days in hospital attributable to RSV infection per 100 randomized children.
  3. Admission to intensive care unit (ICU).
  4. Number of days in the ICU per 100 randomized children.
  5. Mechanical ventilation for RSV infection.
  6. Number of days of mechanical ventilation per 100 randomized children.
  7. Supplemental oxygen therapy for RSV infection.
  8. Number of days of supplemental oxygen therapy per 100 randomized children.
  9. Bronchodilator therapy for RSV infection.
  10. Number of days of bronchodilator therapy per 100 randomized children.

 

Safety outcomes

  1. Number of children reporting any adverse event (AE).
  2. Number of children reporting related AE.
  3. Number of children reporting any serious adverse event (SAE).
  4. Number of children reporting related SAE.

 

Economic evaluation outcomes

  1. Effectiveness outcome measures: hospitalization for RSV infection avoided (number of RSV hospitalisations avoided due to the use of prophylaxis), or any other effect measure reported by study authors such as quality-adjusted life-year (QALY), life-year gained (LYG) or life-year lost (LYL).
  2. The direct medical costs associated with:
    • administration of palivizumab (palivizumab injections, administration by physicians, nurses or both);
    • length of hospital stay;
    • days of mechanical ventilation;
    • days in ICU;
    • need for supplemental oxygen;
    • incidence of complications such as air leak syndrome and aggregated bacterial infections;
    • treatment of adverse events;
    • number of outpatient visits;
    • number of outpatient emergency department visits.
  3. The indirect medical costs associated with:
    • number of days off work (parents or caregivers);
    • patient out-of-pocket expenses;
    • future lost productivity of a child.
  4. Incremental cost-effectiveness ratios (ICERs) expressed as incremental costs per hospitalization avoided, per quality-adjusted life-years (QALY) and per life-years gained (LYG).

 

Search methods for identification of studies

 

Electronic searches

To identify studies on effectiveness and safety, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) 2012, Issue 7, part of The Cochrane Library, www.thecochranelibrary.com (accessed 8 August 2012), which contains the Cochrane Acute Respiratory Infections Group's Specialised Register, MEDLINE (1996 to July week 4, 2012), EMBASE (1996 to August 2012), CINAHL (1996 to August 2012) and LILACS (1996 to August 2012).

We searched MEDLINE and CENTRAL using the keywords and MeSH terms in Appendix 1. We used the Cochrane Highly Sensitive Search Strategy for identifying randomized trials in MEDLINE; sensitivity- and precision-maximising version (2008 revision); Ovid format (Lefebvre 2011). We adapted this search strategy to search EMBASE (Appendix 2), CINAHL (Appendix 3) and LILACS (Appendix 4). In addition, we ran a search in MEDLINE and EMBASE for adverse effects based on the search strategy developed by Golder (Golder 2006) (Appendix 5). We did not use any language or publication restrictions.

To identify economic studies we based our search strategy on the search strategy in Appendix 1 and searched the NHS Economic Evaluations Database (NHS EED) 2012, Issue 4, part of The Cochrane Library, www.thecochranelibrary.com (accessed 9 August 2012), Health Economics Evaluations Database (HEED, searched 9 August 2012) and Paediatric Economic Database Evaluations (PEDE, 1980 to 2009, searched 29 July 2011). We also searched for economic evaluations in MEDLINE (1996 to July week 4, 2012) and EMBASE (1996 to August 2012) using a filter based on the work of Glanville 2009.

 

Searching other resources

We searched the reference lists of relevant studies and review articles to identify additional eligible studies and trial reports. We searched appropriate clinical trials databases utilising the World Health Organization's (WHO) International Clinical Trials Registry Platform (ICTRP), www.who.int/ictrp/ (accessed 9 August 2012, search terms: respiratory syncytial virus, palivizumab and synagis). We contacted the drug manufacturer (MedImmune LLC), trial authors and content experts to obtain information on ongoing or unpublished studies.

 

Data collection and analysis

 

Selection of studies

Two review authors (TA, JWN) independently examined titles and abstracts for the selection of eligible studies. We removed records that did not report on RCTs and where palivizumab was used as a prophylaxis. We retrieved the full texts of potentially relevant reports and we linked multiple reports of the same study. Two review authors (TA, JWN) independently examined the full-text reports to determine which studies met the eligibility criteria. We resolved disagreements by discussion and consultation with a third review author (BB).

Two review authors (TA, JDR) independently examined titles and abstracts for the selection of health economics studies to be included in the critical review of economic data. We removed records that were not reporting on cost-effectiveness or cost-utility analysis of palivizumab prophylaxis. We retrieved full texts of potentially relevant reports (i.e. health economics studies conducted alongside randomized trials or economic modelling studies based on a meta-analysis of data from randomized trials or based on a comprehensive systematic review of literature). Two review authors (TA, JDR) independently examined full-text reports to determine which studies met the eligibility criteria. Any disagreements were resolved by discussion and consultation with a third review author (MXRR). Only full economic evaluations with high methodological and reporting quality (see Assessment of risk of bias in included studies) were included.

 

Data extraction and management

Two review authors (TA, JWN) independently extracted data from eligible RCTs using customised data collection forms. The data collection forms were tested on a pilot sample of articles. Details on the source, eligibility and reasons for exclusion, methods, potential source of bias, participants, settings, interventions, outcomes and results were collected. Review authors were not blinded to the names of the authors, institutions, journals or results of a study. We attempted to contact trial authors for any of the missing data from studies. Any disagreements were resolved by discussion or consultation with a third review author (BB). We entered all collected data into the Review Manager (RevMan 2012) software for analysis.

Two review authors (TA, JDR) independently extracted data on the following aspects of each included economic evaluation study.

  1. General information: population, intervention, comparator, results in clinical outcomes, costs of specific resources, study setting and sources of funding.
  2. Methods: type of economic evaluation, study perspective, economic outcome measurements and time horizon.
  3. Results: incremental costs, incremental effectiveness, discount rate, currency and price year of the reported values, and the final incremental cost-effectiveness ratios reported.

 

Assessment of risk of bias in included studies

Two review authors (TA, JWN) independently assessed risk of bias in the included RCTs using The Cochrane Collaboration's tool for assessing risk of bias, which addresses the following domains: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting and other biases, such as funding. We recorded each piece of information extracted for the 'Risk of bias' tool, together with the precise source of this information. We tabulated the risk of bias for each included RCT, along with a judgement of 'low', 'high' or 'unclear' risk of bias, as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a).

Since none of the included economic evaluations (EEs) were conducted alongside a RCT, their quality could not be assessed using The Cochrane Collaboration's standard tool for assessing risk of bias in RCTs. Therefore, we critically appraised the quality of EEs using the Drummond checklist (Drummond 1996). We used an adapted Drummond checklist (Appendix 6) which addresses the following methodological and reporting aspects.

  1. Was a well-defined question posed?
  2. Was a comprehensive description of the competing alternatives given?
  3. Does the paper provide evidence that the programme would be effective (i.e. would the programme do more harm than good)?
  4. Were all important and relevant resource use (costs) and health outcome consequences for each alternative identified, measured accurately in appropriate units prior to evaluation, and valued credibly?
  5. Were costs and health outcomes consequences adjusted for different times at which they occurred (i.e. was discounting applied)?
  6. Was an incremental analysis of the consequences and costs of alternatives performed?
  7. Was an adequate sensitivity analysis performed?

For each main efficacy and safety outcome in  Summary of findings for the main comparison and  Summary of findings 2, we assessed the overall quality of the evidence using the GRADE approach (Atkins 2004), as described in Appendix 7.

 

Measures of treatment effect

We calculated risk ratios (RRs) and their associated 95% confidence intervals (CIs) for dichotomous outcomes and for adverse events. We planned to report the mean post-intervention value, as well as the mean difference (MD) between treatment groups and their associated 95% CIs for continuous outcomes, but due to the lack of data on measures of dispersion for continuous outcomes (such as standard deviations), only a narrative summary is provided for those results. We analyzed count data in the following way.

  1. Total days of RSV hospitalization per 100 randomized children as continuous data.
  2. Total days in the ICU per 100 randomized children as continuous data.
  3. Total days of mechanical ventilation per 100 randomized children as continuous data.
  4. Total days of supplemental oxygen therapy per 100 randomized children as continuous data.

If it was not clearly stated in the study that total days were expressed as means per 100 randomized children, we contacted the study authors to attempt to clarify whether indexing was used, or not. Total days were expressed as means per 100 randomized children in all studies but one, where they were expressed as means and standard deviations per one child (Feltes 2011). In order to be consistent across studies, for Feltes 2011 the values per 100 randomized children were calculated and entered into RevMan for analysis.

We summarised the results reported in included economic evaluations, such as incremental cost, incremental effectiveness and incremental cost-effectiveness ratio, in  Table 1,  Table 2,  Table 3 and  Table 4, and we provided a commentary on tabulated results.

For readers to easily benchmark variations among different studies and settings, the final incremental cost-effectiveness ratios are also reported in 2011 Euros (EUR) as 'ICER present values'. Higher ICER values are indicative of less favorable results for the investigated intervention. The values of ICERs provided by study authors were adjusted for the time value of money, so that the cash flows inter projects over time are expressed on a common basis in terms of their present value. However, the use of these data for extrapolation of results among countries or throughout years is not anticipated, since the costs of the technologies and medical practices may have changed substantially throughout years and settings (the oldest included study Joffe 1999 uses the 1995 USD price year). Only the present values of ICERs from similar and closer date studies that have evaluated the same effectiveness measure (e.g. hospitalization avoided, or QALY gained) should be taken into account while assessing the variation of ICER that could be expected if the technology would be adopted in similar settings.

We calculated the present values of ICERs at 2011 EUR in two steps. Firstly, we converted the values reported in the study in their original currency to Euros at the same price year, by multiplying the ICER reported value with the appropriate money exchange rate given in Appendix 8. Secondly, we multiplied those values with the appropriate gross domestic product (GDP) deflator given in Appendix 9, in order to get the final ICER present values at 2011 EUR.

We expressed all currencies as the currency abbreviation and amount (e.g. EUR 1376.50), using the ISO 4217 currency abbreviations available at http://www.xe.com/iso4217.php/. We chose Euros for present value calculations, as the majority of included studies were conducted in Europe. More details about present value calculations are given in Appendix 10.

 

Dealing with missing data

There are several types of missing data in a systematic review or meta-analysis as described in Table 16.1.a in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b). The problem of missing studies and outcomes is addressed in the Assessment of reporting biases section of this review. A common problem is missing summary data, such as standard deviations (SDs) for continuous outcomes. The methods outlined in section 16.1.3 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b) for imputing missing values were considered. However, because the majority of studies in this review had missing SDs, we decided to not impute them. Studies were not excluded from the review because of missing summary data; rather, we contacted trial authors to attempt to obtain more information. Because authors have not provided the requested information, the results of available continuous data are summarised in a narrative way. The potential impact of missing data on the review's findings are addressed in the Discussion section.

 

Assessment of heterogeneity

We assessed heterogeneity between included studies using the Chi2 test and I2 statistic (Higgins 2003). We considered a Chi2 P value of less than 0.10 to be indicative of statistical heterogeneity of intervention effects. However, if studies have a small sample size, or are few in number, the Chi2 test has low power and should be interpreted with caution. In order to quantify inconsistency across studies, we calculated an I2 statistic. We interpreted the I2 statistic in the following way: heterogeneity might not be important (I2 statistic value of 0% to 40%); heterogeneity may be moderate (I2 statistic of 30% to 60%); heterogeneity may be substantial (I2 statistic of 50% to 90%); and considerable heterogeneity (I2 statistic of 75% to 100%).

 

Assessment of reporting biases

Possible reporting biases are assessed on two levels: within-study and between-studies.

We examined within-study selective outcome reporting as a part of the overall 'Risk of bias' assessment (see Assessment of risk of bias in included studies). We attempted to find protocols for included studies and compare the outcomes stated in the protocols with those reported in the publications. If protocols were not found, we compared the outcomes listed in the methods section of a publication with those whose results are reported.

We planned to create a funnel plot of effect estimates against their standard errors (SEs) to assess possible between-studies reporting bias, if there were at least 10 RCTs included in the review. However, this was not the case. We would consider possible explanations if we found asymmetry of the funnel plot, either by inspection or statistical tests, and we would have taken into account the interpretation of the overall estimate of treatment effects.

 

Data synthesis

We performed a fixed-effect meta-analysis for the estimation of pooled effects whenever there was no indication of heterogeneity between included studies (I2 statistic < 40%). When some indication of heterogeneity between trials was identified (I2 statistic > 40%), we used a random-effects model.

We did not perform pooled calculations of economic data. Rather, the characteristics and results of included economic studies are presented in a descriptive way in  Table 1,  Table 2,  Table 3 and  Table 4.

 

Subgroup analysis and investigation of heterogeneity

We planned to perform subgroup analyses for effectiveness and safety data, based on the presence of risk factors (preterm birth, chronic lung disease, congenital heart disease, immunodeficiency, chronic neuromuscular disease and congenital anomalies), in case there were at least three studies per subgroup in a specific comparison. However, that was not the case, and no subgroup analysis was performed.

The economic data (incremental cost, incremental effectiveness and incremental cost-effectiveness ratio) are reported separately for studies that evaluated the impact of passive immunisation given during the neonatal period or within the first six months of life ( Table 2), and for studies that evaluated the impact of passive immunisation given to children aged six months and older ( Table 3). In each of the two groups, data are presented separately for three subgroups, according to the baseline risk factors: preterm birth (≤ 35 weeks gestation), chronic lung disease of prematurity or bronchopulmonary dysplasia, and congenital heart disease. Additionally, the economic data are reported separately in  Table 4 for studies that evaluated the impact of passive immunisation given at any time from birth to five years of age, to a high-risk population of infants and children born preterm, with or without bronchopulmonary dysplasia, or with congenital heart disease.

 

Sensitivity analysis

The sensitivity analysis takes into account those biases that could significantly impact on the outcomes of the included studies. As previously noted in the Assessment of risk of bias in included studies section, The Cochrane Collaboration's tool for assessing risk of bias in RCTs was used (categorised as 'low', 'high' and 'unclear'), focusing on domains such as random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting and other biases, such as the source of funding of the included studies.

We had planned to perform a sensitivity analysis to assess how the results of the meta-analysis would be affected by excluding studies determined to be at high risk of bias. However, all of the included efficacy and safety studies were of high overall methodological and reporting quality, and we meta-analysed all of these trials without performing a sensitivity analysis.

 

Results

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Description of studies

 

Results of the search

With duplicates removed, the electronic searches identified 630 records for effectiveness studies and 413 records for adverse effects studies. We screened titles and abstracts and 12 studies were identified as potentially eligible for inclusion. We retrieved the full-text articles. After reading the full texts, five studies were excluded and seven were found eligible for inclusion according to Criteria for considering studies for this review.

By searching the clinical trials registries, we identified three additional RCTs (NCT00233064; NCT00240929; NTR1023). According to available data, the three trials are not eligible for inclusion in this review. However, in an attempt to retrieve more information about them, they are listed under Studies awaiting classification.

The electronic searches for economic evaluations identified 703 records, with duplicates removed. We screened titles and abstracts and 58 studies were identified as potentially eligible for inclusion. After reading the full texts, 24 studies were excluded and 34 were found eligible for inclusion in this review according to Criteria for considering studies for this review. No other potentially eligible economic evaluations were found as a result of searching the reference lists of relevant studies and review articles.

 

Included studies

Of the seven included RCTs, three compared palivizumab with placebo (Feltes 2003; IMpact-RSV 1998; Subramanian 1998) and four compared motavizumab with palivizumab (Abarca 2009; Carbonell-Estrany 2010; Feltes 2011; Fernandez 2010). In all trials palivizumab was delivered intramuscularly, except in Subramanian 1998 where it was delivered intravenously. One study was a dose-escalation study (Subramanian 1998) and only data for the recommended approved dose of 15 mg/kg were included in our analyses. From all trials, data extracted for the analyses referred to five monthly injections of the study drug, except for Abarca 2009, where four or five doses were applied, and Fernandez 2010, where palivizumab and motavizumab were used sequentially, and only safety data after the first two doses were extracted for analysis. In Abarca 2009, only the second year of the study was a RCT eligible for inclusion. In all studies, children were followed up for 150 days after randomization (30 days after the final dose).

Of the 34 included economic evaluation studies, three were conducted in Italy (Chirico 2009; Chiroli 2005; Ravasio 2006), six in the US (ElHassan 2006; Hampp 2011; Joffe 1999; Lofland 2000; Weiner 2012; Yount 2004), four in the UK (Bentley 2011; Embleton 2007; Nuijten 2007; Wang 2011), five in Spain (Garcia-Altes 2010; Lazaro y de Mercado 2006; Lazaro y de Mercado 2007; Nuijten 2010; Raya Ortega 2006), four in Canada (Harris 2011; Lanctot 2008; Smart 2010; Tam 2009), one in France (Hascoet 2008), one in Korea (Kang 2009), two in Mexico (Mayen-Herrera 2011; Salinas-Escudero 2012), one in Sweden (Neovius 2011), two in the Netherlands (Nuijten 2009a; Rietveld 2010), two in Germany (Nuijten 2009b; Roeckl-Wiedmann 2003), two in Austria (Resch 2008; Resch 2012) and one in New Zealand (Vogel 2002).

Lazaro y de Mercado 2006 evaluated the economic impact of RSV immunoprophylaxis in children with bronchopulmonary dysplasia, children with congenital heart disease and in preterm infants born at 32 to 35 weeks' gestational age, presenting with two or more of the additional risk factors described by the Spanish Neonatology Society. The authors did not report data separately for any of the subgroups or categories of interest in this review. Kang 2009 is a study conducted in Korea, with only information from the abstract available. Similarly, for Bentley 2011 and Mayen-Herrera 2011 only the information from abstracts was available. The trial authors did not respond to e-mails asking for the full text. Characteristics of these four studies are presented in  Table 1, but the economics results were not included in the related 'Additional tables' ( Table 2;  Table 3;  Table 4).

Overall, 22 studies evaluated the economic impact of RSV immunoprophylaxis given during the neonatal period or within the first few months of life (Chirico 2009; ElHassan 2006; Embleton 2007; Hampp 2011; Hascoet 2008; Lanctot 2008; Lofland 2000; Neovius 2011; Nuijten 2007; Nuijten 2009a; Nuijten 2010; Ravasio 2006; Raya Ortega 2006; Resch 2008; Resch 2012; Rietveld 2010; Roeckl-Wiedmann 2003; Salinas-Escudero 2012; Smart 2010; Vogel 2002; Wang 2011; Weiner 2012); 10 studies evaluated the economic impact of RSV immunoprophylaxis given to children aged six months and older (Chiroli 2005; Hampp 2011; Harris 2011; Nuijten 2007; Nuijten 2009b; Resch 2008; Resch 2012; Tam 2009; Wang 2011; Yount 2004); and three studies evaluated the economic impact of RSV immunoprophylaxis given to a high-risk population of infants and children up to five years of age, either born preterm, with or without bronchopulmonary dysplasia, or with congenital heart disease (Garcia-Altes 2010; Joffe 1999; Lazaro y de Mercado 2007).

The study conducted by Wang 2011 reported a set of ICER values obtained when passive immunisation is given to infants and children at different birth ages (up to 24 months of life), with different gestational ages, and with or without other comorbidity (chronic lung disease or congenital heart disease). The results from Wang 2011 are presented as ranges of values for the following subgroups of interest in this review.

  • Infants up to six months of age who were born at 35 weeks of gestation or less, without chronic lung disease or congenital heart disease.
  • Infants up to six months of age who were born at 35 weeks of gestation or less, with chronic lung disease.
  • Infants up to six months of age who were born at more than 35 weeks of gestation, with congenital heart disease.
  • Children from 6 to 24 months of age who were born at 35 weeks of gestation or less, without chronic lung disease or congenital heart disease.
  • Children from 6 to 24 months of age who were born at 35 weeks of gestation or less, with chronic lung disease.
  • Children from 6 to 24 months of age who were born at more than 35 weeks of gestation, with congenital heart disease.

 

Excluded studies

Of the five excluded safety and effectiveness studies, four were not RCTs (Korbal 2003; Martinez 2002; Parmigiani 2001; Takeuchi 2002), and one did not assess effects of palivizumab prophylaxis (Meissner 1999).

Of the 24 excluded economic studies, most were partial economic evaluations that reported cost analyses or cost-outcome descriptions (Banerji 2009; Buckley 2010; Chan 2003; Clark 2000; Datar 2012; Farina 2002; Krilov 2010; Lapena Lopez 2003; Lee 2001; Marchetti 1999; Marques 2010; McCormick 2002; Meberg 2006; Rackham 2005; Reeve 2006; Rodriguez 2008; Vann 2007; Wegner 2004; Wendel 2010), two were neither a cost-effectiveness nor a cost-utility analysis (Numa 2000; Shireman 2002), one analyzed a combined effect of RSV-IVIG and palivizumab used together as prophylaxis (Stevens 2000), one was a systematic review of economic evaluations, and not a primary analysis (Strutton 2003), and one economic evaluation (Wang 2008) was later updated and reported by the same author in a more recent publication (Wang 2011).

 

Risk of bias in included studies

For efficacy and safety studies, see the 'Risk of bias' tables in Characteristics of included studies. We performed complete 'Risk of bias' assessment for all included RCTs. The methods used in some included studies were not clearly described; some data and explanations were missing and this could be a source of potential bias. Additionally, all of the included studies were sponsored by, and included authors from, the manufacturer of palivizumab, MedImmune. This does not, in of itself, imply any bias in the results and we have listed this as having an 'unclear' potential impact. Further explanation of these risks of bias is provided in the subsequent sections of this review.

The GRADE quality ratings of evidence for the main outcomes are summarised in  Summary of findings for the main comparison and  Summary of findings 2.

Results of the quality assessment of economic evaluation studies are summarised in Appendix 6.

 

Allocation

Randomisation was performed in all seven included studies. Methods of random sequence generation were clearly described in all trials except for Subramanian 1998 where insufficient information was given, with 'unclear' risk of bias. Study drugs were identical in appearance and their allocation was concealed in Carbonell-Estrany 2010; Feltes 2003; Feltes 2011; IMpact-RSV 1998 and Subramanian 1998; while methods of allocation concealment were 'unclear' in Abarca 2009 and Fernandez 2010.

 

Blinding

Adequate blinding of participants and study personnel was clearly stated in Carbonell-Estrany 2010; Feltes 2003; Feltes 2011; IMpact-RSV 1998 and Subramanian 1998. There were no details available in Abarca 2009 and Fernandez 2010, resulting in an 'unclear' risk of bias.

 

Incomplete outcome data

In six studies, comparable attrition rates were reported in both intervention groups, with reasons for attrition provided, making the risk of bias 'low' (Carbonell-Estrany 2010; Feltes 2003; Feltes 2011; Fernandez 2010; IMpact-RSV 1998; Subramanian 1998). In Abarca 2009, the risk of bias was 'high', because the reasons for attrition of patients between season one and season two were not given.

 

Selective reporting

For three of the seven included trials, protocols were registered in appropriate clinical trials databases, and for all of them the same outcomes were reported in protocols and in final published reports (Carbonell-Estrany 2010; Feltes 2011; Fernandez 2010). For all seven included trials, the outcomes listed in the methods were also reported in the results section of the final trial reports. RSV-specific outpatient medically attended lower respiratory tract infection was assessed in two studies (Carbonell-Estrany 2010; Feltes 2011), and in both of them in just a subset of patients, either in patients from selected study sites (Carbonell-Estrany 2010) or in patients in season two only (Feltes 2011). No explanations were provided, making the risk of reporting bias in these trials 'high'. In three trials, several outcomes of interest (total RSV-hospital days, days in the ICU, days of mechanical ventilation and days of supplemental oxygen therapy) were reported incompletely; data on standard deviations were missing and the risk of reporting bias in these trials was 'high' (Carbonell-Estrany 2010; Feltes 2003; IMpact-RSV 1998). None of the studies had prespecified nor reported the incidence and duration of bronchodilator therapy for RSV infection. Since this was not one of the key outcomes of this review, this does not present a risk of reporting bias.

 

Other potential sources of bias

All of the seven included randomized controlled trials were sponsored by the drug manufacturing company, and many of the study authors were its employees or consultants, or they received research grants and compensations from the company. This represented an 'unclear' risk of bias for all included RCTs.

Of the 34 economic evaluations eligible for inclusion, conflict of interest was clearly stated in 21 studies that were either funded by the drug manufacturing company, or included authors who were employees of the manufacturing company (Bentley 2011; Chirico 2009; Chiroli 2005; Hascoet 2008; Lanctot 2008; Lazaro y de Mercado 2006; Lofland 2000; Mayen-Herrera 2011; Neovius 2011; Nuijten 2007; Nuijten 2009a; Nuijten 2009b; Nuijten 2010; Ravasio 2006; Resch 2008; Resch 2012; Roeckl-Wiedmann 2003; Salinas-Escudero 2012; Tam 2009; Vogel 2002; Weiner 2012). For 10 studies no conflict of interest was declared (ElHassan 2006; Embleton 2007; Garcia-Altes 2010; Hampp 2011; Joffe 1999; Raya Ortega 2006; Rietveld 2010; Smart 2010; Wang 2011; Yount 2004); and for three studies it was not completely clear whether they were funded by the industry or not (Harris 2011; Kang 2009; Lazaro y de Mercado 2007).

 

Effects of interventions

See:  Summary of findings for the main comparison Palivizumab compared to placebo for high risk of severe respiratory syncytial virus infection;  Summary of findings 2 Palivizumab compared to motavizumab for high risk of severe respiratory syncytial virus infection

 

Palivizumab compared to placebo

Three randomized controlled trials (RCTs) compared palivizumab prophylaxis with a placebo in a total of 2831 patients, who were either born preterm and less than six months old, or less than two years old and with bronchopulmonary dysplasia (IMpact-RSV 1998; Subramanian 1998), or were less than two years old and with haemodynamically significant congenital heart disease (Feltes 2003). None of the included RCTs were performed in children with immunodeficiency, chronic neuromuscular disease or congenital anomalies. For all efficacy and safety outcomes, results were expressed as per intention-to-treat (ITT) population, which included all randomly assigned patients eligible for inclusion into the study. There was no indication of statistical heterogeneity across studies for most of the assessed outcomes, with the exceptions being the total days in the intensive care unit (ICU), and the incidence and total number of days of mechanical ventilation.

Palivizumab recipients had a statistically significant 51% relative risk reduction in respiratory syncytial virus (RSV) hospitalisations compared with placebo recipients (risk ratio (RR) was 0.49, 95% confidence interval (CI) 0.37 to 0.64) ( Analysis 1.1; Figure 1), as well as a statistically significant 50% relative risk reduction in admissions to the ICU (RR 0.50, 95% CI 0.30 to 0.81) ( Analysis 1.4; Figure 2), while the number of patients requiring mechanical ventilation for RSV infection seemed similar in the two groups (RR 1.10, 95% CI 0.20 to 6.09) ( Analysis 1.6). However, in case of mechanical ventilation, statistical heterogeneity between the two trials may be substantial (I2 statistic 60%; random-effects model applied) and results should be interpreted with caution.

 FigureFigure 1. Forest plot of comparison: 1 Palivizumab versus placebo, outcome: 1.1 Hospitalisation for RSV infection.
 FigureFigure 2. Forest plot of comparison: 1 Palivizumab versus placebo, outcome: 1.4 Admission to ICU.

In both efficacy trials, total days were expressed as means per 100 randomized children (Feltes 2003; IMpact-RSV 1998). However, since data on days were reported incompletely, meta-analysis was not possible. Children randomly assigned to placebo had approximately twice as many days of hospitalization due to RSV infection ( Analysis 1.3), and two to three times more days of supplemental oxygen therapy per 100 randomized children ( Analysis 1.8), compared to palivizumab recipients. Results for total days in the ICU ( Analysis 1.5) and total days of mechanical ventilation per 100 randomized children ( Analysis 1.7) were quite heterogenous across the two trials. Feltes 2003, which included children with congenital heart disease, showed significantly fewer days in the ICU, and lower incidence and fewer days of mechanical ventilation in children treated with palivizumab compared with placebo. On the other hand, IMpact-RSV 1998, which included children born preterm with or without bronchopulmonary dysplasia, reported results with the opposite trend.

In all trials, mortality was reported as an all-cause mortality expressed per ITT population. Monthly prophylaxis with palivizumab, when compared to placebo, was associated with a statistically non-significant 31% relative risk reduction in all-cause mortality (RR 0.69, 95% CI 0.42 to 1.15) ( Analysis 1.2).

Overall, rates of adverse events (AEs) and serious adverse events (SAEs) were consistent with the underlying medical conditions in this high-risk population. The proportion of children with any AE was similar between the two groups (RR 0.99, 95% CI 0.97 to 1.01) ( Analysis 1.9), as well as the proportion of children with AE related to the study drug (RR 1.09, 95% CI 0.85 to 1.38) ( Analysis 1.10). On the other hand, palivizumab recipients had a statistically significant 12% relative risk reduction in any SAE compared with placebo (RR 0.88, 95% CI 0.80 to 0.96) ( Analysis 1.11; Figure 3), and a statistically non-significant 86% relative risk reduction in SAE related to study drug (RR 0.14, 95% CI 0.01 to 2.80) ( Analysis 1.12). However, only one study assessed these two outcomes (Feltes 2003). Common adverse events (when reported) included fever, injection site reactions and upper respiratory infections.

 FigureFigure 3. Forest plot of comparison: 1 Palivizumab versus placebo, outcome: 1.11 Number of children reporting any SAE.

 

Palivizumab compared to motavizumab

Four RCTs compared motavizumab prophylaxis with palivizumab prophylaxis in a total of 8265 patients, who were either born preterm and less than six months old, or less than two years old and with chronic lung disease of prematurity (Abarca 2009; Carbonell-Estrany 2010; Fernandez 2010), or were less than two years old and had haemodynamically significant congenital heart disease (Feltes 2011). None of the included RCTs were performed in children with immunodeficiency, chronic neuromuscular disease or congenital anomalies. Efficacy outcomes were assessed in two studies (Carbonell-Estrany 2010; Feltes 2011) and their results were expressed as per ITT population; while for safety outcomes (adverse events) results were expressed per safety population, which included all patients who received any study medication and had any safety follow-up. In order to be consistent with the objectives of this review, palivizumab was considered an intervention and motavizumab a control in all further analyses. There was no indication of statistical heterogeneity of intervention effects across studies.

Palivizumab recipients had a statistically non-significant 36% relative increase in the risk of hospitalization due to RSV infection, when compared with motavizumab recipients (RR 1.36, 95% CI 0.97 to 1.90) ( Analysis 2.1; Figure 4). In a subset of patients, RSV-specific outpatient medically attended lower respiratory tract infections (MALRIs) were assessed. The risk of outpatient MALRI specific for RSV infection in the palivizumab group was twice that of the motavizumab group (RR 1.98, 95% CI 1.25 to 3.13) ( Analysis 2.2; Figure 5). Palivizumab recipients had a statistically non-significant 68% relative risk increase in admission to the ICU compared with motavizumab recipients (RR 1.68, 95% CI 0.89 to 3.19) ( Analysis 2.5), as well as a statistically non-significant 49% relative risk increase in incidence of supplemental oxygen therapy for RSV infection (RR 1.49, 95% CI 0.98 to 2.26) ( Analysis 2.9), while the risk of mechanical ventilation in the palivizumab group was almost four times that of the motavizumab group (RR 3.79, 95% CI 1.26 to 11.42) ( Analysis 2.7; Figure 6).

 FigureFigure 4. Forest plot of comparison: 2 Palivizumab versus motavizumab, outcome: 2.1 Hospitalisation for RSV infection.
 FigureFigure 5. Forest plot of comparison: 2 Palivizumab versus motavizumab, outcome: 2.2 RSV-specific outpatient MALRI.
 FigureFigure 6. Forest plot of comparison: 2 Palivizumab versus motavizumab, outcome: 2.7 Mechanical ventilation for RSV infection.

In all trials but one (Abarca 2009), mortality was reported as all-cause mortality. In order to be consistent, for Abarca 2009 we reported the all-cause deaths, and for all four studies we expressed mortality per ITT population. Children randomly assigned to palivizumab had a statistically non-significant 26% relative risk reduction in all-cause mortality compared with motavizumab recipients (RR 0.74, 95% CI 0.38 to 1.43) ( Analysis 2.3).

In Carbonell-Estrany 2010 total days were expressed as means per 100 randomized children, while for Feltes 2011 we calculated the means and standard deviations per 100 randomized children from the data originally reported per one child, and entered them in analyses. Since data on standard deviations are missing in Carbonell-Estrany 2010, only data from Feltes 2011 contributed to the meta-analysis, and results should be interpreted with caution. Children randomly assigned to palivizumab prophylaxis had approximately twice as many total RSV-hospital days, with a statistically non-significant mean difference (MD) of 24.95 days per 100 randomized children (MD 24.95, 95% CI -21.59 to 71.49) ( Analysis 2.4), three to five times more days in the ICU, MD being 21.34 days per 100 randomized children (MD 21.34, 95% CI -13.69 to 56.37) ( Analysis 2.6), seven to eight times more days of mechanical ventilation (MD 16.06, 95% CI -16.60 to 48.72) ( Analysis 2.8), and two to three times more days of supplemental oxygen therapy per 100 randomized children (MD 28.42, 95% CI -13.64 to 70.48) ( Analysis 2.10), compared to motavizumab recipients.

Again, rates of AEs and SAEs were consistent with the underlying medical conditions in this high-risk population. No significant differences were found in the proportion of children with any AE (RR 1.00, 95% CI 0.99 to 1.02) ( Analysis 2.11), with AE related to study drug (RR 0.98, 95% CI 0.73 to 1.32) ( Analysis 2.12), with any SAE (RR 1.04, 95% CI 0.96 to 1.13) ( Analysis 2.13), or with SAE related to study drug (RR 0.88, 95% CI 0.32 to 2.43) ( Analysis 2.14) between palivizumab and motavizumab recipients. Common adverse events (when reported) included fever, upper respiratory infections, cough and rhinitis.

 

Economic impact of immunoprophylaxis given at neonatal period or within the first six months of life

Out of the 22 studies that evaluated the economic impact of RSV immunoprophylaxis given during the neonatal period or within the first few months of life, 18 studies reported on preterm infants born at or before 35 weeks gestational age without other co-morbidities (Chirico 2009; ElHassan 2006; Embleton 2007; Hampp 2011; Lanctot 2008; Neovius 2011; Nuijten 2007; Nuijten 2010; Ravasio 2006; Raya Ortega 2006; Resch 2008; Resch 2012; Roeckl-Wiedmann 2003; Salinas-Escudero 2012; Smart 2010; Vogel 2002; Wang 2011; Weiner 2012); nine studies reported on preterm infants with bronchopulmonary dysplasia or chronic lung disease (Chirico 2009; Embleton 2007; Hascoet 2008; Lofland 2000; Nuijten 2009a; Ravasio 2006; Rietveld 2010; Roeckl-Wiedmann 2003; Wang 2011); and three studies reported on infants with congenital heart disease (Hascoet 2008; Nuijten 2009a; Wang 2011).

Of the studies evaluating immunoprophylaxis in preterm infants without other co-morbidities, 12 (Chirico 2009; Hampp 2011; Lanctot 2008; Nuijten 2007; Nuijten 2010; Resch 2008; Resch 2012; Ravasio 2006; Raya Ortega 2006; Salinas-Escudero 2012; Smart 2010; Wang 2011) reported costs from the payer's perspective, or from both the payer's and societal perspectives. Six studies (ElHassan 2006; Embleton 2007; Ravasio 2006; Raya Ortega 2006; Roeckl-Wiedmann 2003; Salinas-Escudero 2012) reported a time horizon different than the lifetime (e.g. one year, eight years, 14 years, 18 years). In studies where evaluation was conducted from the payer's perspective and with a lifetime horizon (Chirico 2009; Lanctot 2008; Nuijten 2007; Nuijten 2010; Resch 2008; Resch 2012; Smart 2010; Wang 2011), the incremental cost-effectiveness ratio (ICER) present values at 2011 EUR expressed per quality-adjusted life-year (QALY) or life-year gained (LYG), vary widely across the studies (from EUR 7282 to EUR 27,068 per QALY, and from EUR 10,724 to EUR 36,098 per LYG). All of those studies considered different mortality rates for the intervention and non-intervention groups in the economic models, making the assumption that palivizumab prophylaxis has an effect on mortality, since there is evidence suggesting that palivizumab modifies the RSV hospitalization rates. Wang 2011 reported a range of ICERs in this population (from EUR 133,478 to EUR 1,651,357 per QALY); lower ICERs were obtained when passive immunisation is given during the neonatal period to preterm infants born at less than 24 weeks of gestational age, and higher ICERs (less favorable for the use of palivizumab) were obtained when prophylaxis was given to infants three to six months of age, born at 32 to 34 weeks of gestational age.

In studies evaluating preterm infants without other co-morbidities, with a one-year time horizon (Embleton 2007; Raya Ortega 2006; Roeckl-Wiedmann 2003; Vogel 2002), the effectiveness outcome measure was averted hospitalization. While Raya Ortega 2006 adopted the payer's perspective, Embleton 2007, Roeckl-Wiedmann 2003 and Vogel 2002 reported results from the societal perspective. The incremental costs per hospitalization averted for palivizumab prophylaxis were rather high in Embleton 2007 (EUR 72,780); while the ICERs reported by Roeckl-Wiedmann 2003 and Vogel 2002 were quite lower, and similar between them (EUR 29,199 and EUR 24,617 respectively). Roeckl-Wiedmann 2003 included the mortality benefits for the use of palivizumab prophylaxis and Vogel 2002 did not. However, Vogel 2002 considered a much lower total amount of the drug in the economic model.

Economic evaluations reporting incremental costs per LYG or QALY in preterm infants with bronchopulmonary dysplasia (or chronic lung disease), adopting the payer's perspective (Chirico 2009; Ravasio 2006; Wang 2011), showed rather favorable cost-effectiveness results for the use of palivizumab (from EUR 2968 to EUR 3317 per QALY, and from EUR 4707 to EUR 6253 per LYG). Wang 2011 reported a range of ICERs for this population (from EUR 17,113 to EUR 112,943 per QALY). All three studies allowed a mortality difference and difference in the risk of long-term sequelae in their models. ICER values reported in preterm infants with bronchopulmonary dysplasia (or chronic lung disease) were systematically lower than those reported in preterm infants without other comorbidity, indicating that palivizumab prophylaxis is more cost-effective in infants with bronchopulmonary dysplasia than in those born preterm without other comorbidity.

All three studies that evaluated the economic impact of RSV prophylaxis in infants with congenital heart disease (Hascoet 2008; Nuijten 2009a; Wang 2011) adopted a lifetime time horizon. However, analyses were conducted from different perspectives, and they included different mortality rates and different risks of sequelae (asthma or recurrent wheezing) in their models, which finally made them incomparable. The ICERs expressed per QALY or LYG showed big variations across studies. Wang 2011 reported on infants with acyanotic and cyanotic congenital heart disease, adopting the payer's perspective. The range of ICER values obtained in infants with acyanotic congenital heart disease was lower (more favorable) than the range of ICER values in infants with cyanotic congenital heart disease. In both cases, ICER values were dramatically higher than those reported by the other two studies in infants with congenital heart disease, which adopted the societal perspective. All three studies that reported results for infants with congenital heart disease also reported results for preterm infants with bronchopulmonary dysplasia (or chronic lung disease) and within-study comparisons were possible. In Hascoet 2008 and Nuijten 2009a, ICERs reported for infants with congenital heart disease showed to be systematically lower than the ICERs reported for infants with bronchopulmonary dysplasia (or chronic lung disease), while Wang 2011 showed the opposite trend in results.

 

Economic impact of immunoprophylaxis given to children aged six months and older

Out of 10 studies that evaluated the economic impact of RSV immunoprophylaxis given to children aged six months and older, two studies reported on children born at or before 35 weeks of gestational age without other co-morbidities (Tam 2009; Wang 2011); nine studies reported on children with congenital heart disease (Chiroli 2005; Hampp 2011; Harris 2011; Nuijten 2007; Nuijten 2009b; Resch 2008; Resch 2012; Wang 2011; Yount 2004); and five studies reported on children with bronchopulmonary dysplasia or chronic lung disease (Hampp 2011; Nuijten 2007; Resch 2008; Resch 2012; Wang 2011).

Tam 2009 and Wang 2011 performed evaluations from the payer's perspective in children born at or before 35 weeks of gestation without other co-morbidities, adopting a lifetime time horizon, and allowing the mortality benefits for the use of palivizumab prophylaxis. The ICER values expressed per QALYs varied across the studies substantially; Wang 2011 reported dramatically higher values than Tam 2009 (EUR 655,409 and EUR 29,663 respectively).

From the studies that analyzed the economic impact of passive immunisation given to children with congenital heart disease, six studies adopted a lifetime time horizon and a payer's perspective (Nuijten 2007; Nuijten 2009b; Resch 2008; Resch 2012; Wang 2011; Yount 2004). All six studies allowed a mortality difference and difference in the risk of long-term sequelae between the interventions. The ICER values expressed per QALYs reported in Wang 2011 and Yount 2004 were dramatically higher than those reported in other studies. Also, Wang 2011 and Nuijten 2007 reported on children with acyanotic and cyanotic congenital heart disease. The range of ICER values obtained in children with acyanotic congenital heart disease was lower than the range of ICER values in children with cyanotic congenital heart disease, indicating that palivizumab prophylaxis is more cost-effective among the first ones.

Hampp 2011 and Harris 2011 used the RSV hospitalization averted, and one day of RSV hospitalization averted as the effectiveness outcome measures, respectively. Hampp 2011 adopted a payer's perspective, and did not include the mortality benefits for the use of palivizumab into the model. Harris 2011 adopted a societal perspective, and included the mortality benefits into the model. Finally, the ICERs in the two studies differed substantially (EUR 689,645 per hospitalization averted and EUR 11,669 per one day of hospitalization averted, respectively).

All five studies that performed analyses in children with bronchopulmonary dysplasia or chronic lung disease adopted the payer's perspective. Hampp 2011 reported values of ICERs per hospitalization avoided, and did not allow a mortality difference or a difference in the risk of long-term sequelae between the interventions. Nuijten 2007; Resch 2008; Resch 2012 and Wang 2011 reported ICERs per LYGs and/or QALYs, thereby adopting a lifetime time horizon, and allowing the mortality benefits for the use of palivizumab prophylaxis. The ICERs from these analyses are quite consistent across studies (from EUR 25,459 to EUR 36,794 per QALY, and from EUR 36,774 to EUR 50,557 per LYG). Again, the range of ICER values reported in Wang 2011 was very wide.

Resch 2012 reported on the same patient populations as Resch 2008, and conducted the analysis in the same country (Austria), by adopting a similar modelling approach. However, it incorporated changes in the total amount of the drug used, the medication costs and overall consumption of resources, and it included some new country-specific epidemiologic data. These changes led to obtaining more favorable ICERs as compared to ICERs reported in Resch 2008, both in children with congenital heart disease, and in children with bronchopulmonary dysplasia (or chronic lung disease).

 

Economic impact of immunoprophylaxis given to high-risk infants and children (born preterm, with or without bronchopulmonary dysplasia, or with congenital heart disease) up to five years of age

Three studies evaluated the economic impact of RSV immunoprophylaxis given to a mixed population of high-risk infants and children (preterm infants with or without bronchopulmonary dysplasia, infants with congenital heart disease, preterm children with or without bronchopulmonary dysplasia, and children with congenital heart disease) (Garcia-Altes 2010; Joffe 1999; Lazaro y de Mercado 2007). Garcia-Altes 2010 reported results from the payer's perspective, adopting a lifetime time horizon, and allowing for mortality difference between the treatments. Lazaro y de Mercado 2007 reported results from the societal perspective, adopting a lifetime time horizon, and allowing the mortality difference as well as the difference in the risk of long-term sequelae between the treatments. Both studies were conducted in Spain. The final results of ICERs expressed per LYGs differ immensely (EUR 174,642 and EUR 6256 respectively). We could not calculate the ICER present values at 2011 EUR for results reported in Joffe 1999, since exchange rates for Euros are not available for 1995.

 

Funding and results in economic evaluations

Overall, of the 34 included economic evaluations, 21 studies were funded by the drug manufacturing company, 10 studies had no conflict of interest declared and three studies were unclear as to whether they were industry funded or not (Characteristics of included studies).

All of the industry-sponsored economic evaluations supported the cost-effectiveness of palivizumab prophylaxis, except for Lofland 2000, which gave ranges of ICER values and left the conclusions at reader's discretion, Roeckl-Wiedmann 2003 which suggested a more restrictive policy, and Vogel 2002 that reported no cost savings with palivizumab prophylaxis.

All of the economic evaluations that were not industry-sponsored suggested within their final conclusions that palivizumab was not cost-effective in the analyzed settings, according to the established threshold values, and that a more restrictive passive immunisation policy should be used. The only exception was Smart 2010, which had the methodology based on Lanctot 2008 (industry-funded) and reported that palivizumab prophylaxis is cost-effective. Yount 2004 suggested that the routine use of palivizumab should be further evaluated.

Regarding the three studies where funding was questionable, Harris 2011 reported receiving a very small honorarium from the sponsoring company, and suggested that palivizumab was not cost-effective. For Kang 2009 only an abstract was available, suggesting that the use of palivizumab was cost-effective, with no details provided about the funding. In Lazaro y de Mercado 2007 no conflict of interest was declared, and cost-effectiveness of palivizumab was suggested, but should be noted that for the economic evaluation performed on the same topic by the same authors in 2006 (Lazaro y de Mercado 2006), the authors received a grant from the drug manufacturing company.

 

Discussion

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Summary of main results

 

Efficacy and safety evidence

The primary objective of this review was to assess the effects of palivizumab prophylaxis compared to placebo, or another type of prophylaxis (e.g. motavizumab), in reducing the risk of hospitalization due to respiratory syncytial virus (RSV) infection in high-risk infants and children.

Palivizumab prophylaxis was associated with a statistically significant reduction in RSV hospitalisations, when compared to placebo. The magnitude of this effect is considerable; palivizumab reduced the risk of RSV hospitalization by half. Children treated with palivizumab prophylaxis spent fewer days in hospital, were admitted to the intensive care unit (ICU) less often, and had fewer days of supplemental oxygen therapy for RSV infection than the placebo recipients. These results suggest a favorable effect of palivizumab prophylaxis on the incidence of serious lower respiratory tract RSV disease in children at high risk.

Results for the total days spent in the ICU and the incidence and total days of mechanical ventilation were inconsistent between the two trials, possibly due to different severity of underlying medical conditions in children included in the trials. Children with haemodynamically significant congenital heart disease experienced fewer days in the ICU, and lower incidence and fewer days of mechanical ventilation when treated with palivizumab prophylaxis compared with placebo, while children born preterm, with or without bronchopulmonary dysplasia, having less severe baseline risk factors for RSV disease, showed the opposite trend in results. It could be that a drug has a larger relative effect in sicker populations. But also, medical practices, guidelines and recommendations on when to discharge from an ICU, and when to initiate and wean mechanical ventilation, differ substantially in different settings.

When palivizumab was compared to motavizumab prophylaxis, there was an obvious trend of increase in the risk of acquiring severe lower respiratory tract RSV disease in patients receiving palivizumab. The risk of hospitalization due to RSV infection was increased by one-third in palivizumab patients. Children treated with palivizumab had more admissions to intensive care, a higher need for supplemental oxygen therapy and more instances of mechanical ventilation than the children treated with motavizumab prophylaxis.

However, the results of trials comparing palivizumab and motavizumab should be interpreted with caution. The US Food and Drug Administration (FDA) cited methodological concerns (among others) in its review of a licensing application for motavizumab, specifically with regards to the laboratory testing of RSV, which may have biased the results toward motavizumab over palivizumab. The FDA also expressed concerns regarding both motavizumab's safety and efficacy. The non-fatal hypersensitivity adverse events were found to be three times higher in the motavizumab group than in the palivizumab group. Also, motavizumab's non-inferiority results are largely driven by data obtained from southern hemisphere countries, representing only about 9% of the total patient population. Removing this population led the FDA to determine that in the US population motavizumab did not meet the non-inferiority criterion relative to palivizumab (FDA 2010). These issues have implications for assessing the risk of bias in Carbonell-Estrany 2010, and the results should be interpreted with this in mind.

Total days in the hospital due to RSV infection, days spent in the ICU, receiving mechanical ventilation or with supplemental oxygen therapy were all much higher in palivizumab than in motavizumab-treated patients.

Data on days were summarised and presented as days per 100 randomized children in a study arm, and not as days per one child. That is why they are expected to be proportional to the number (or better, to the rate) of patients hospitalised from that study arm. For example, if two children out of 100 are hospitalised in one group, and one child out of 100 is hospitalised in the other group, and if each child from both groups stays in the hospital for five days, in the first group we would have 10 hospital days per 100 randomized children, and in the second five hospital days per 100 randomized children. The larger the incidence of RSV hospitalisations, the bigger are the numbers of days. This is a common problem in almost all RCTs in this review: results on total days presented in this way could be misleading. We cannot interpret them as a measure of severity of the disease, once a child has acquired an RSV infection. For both clinicians and patients it would be more beneficial for study authors to express the mean number of days per one child in future studies.

Another common problem of almost all studies reporting data on days is their incomplete reporting. Measures of dispersion were not provided and we cannot be confident about the precision of the results.

RSV-specific outpatient medically attended lower respiratory tract infections were assessed for motavizumab and palivizumab patients in two studies. Motavizumab was associated with statistically significant reduction in RSV-specific outpatient MALRIs when compared to palivizumab; the risk in the palivizumab group was twice that of the motavizumab group. However, this outcome was assessed in just a subset of patients, either in patients from selected study sites or in patients in season two only, making the risk of bias in these results high.

Palivizumab-treated children had lower mortality rates than children treated with placebo or motavizumab. However, it was hard to draw any conclusions since all studies expressed mortality as deaths due to any cause, regardless of their relation to study drug or to RSV infection. We were surprised to find that within-study mortality rates differed substantially between the studies (e.g. Carbonell-Estrany 2010 reports an all-cause mortality rate 30 times that of Feltes 2003). The difference could be attributed to different sample sizes and different underlying medical conditions in patient populations in the two studies.

For both comparisons we analyzed the proportion of children with adverse events in four categories, depending on the seriousness of the adverse event (AE) and its relatedness to the study drug. Unfortunately, we could not analyse a specific adverse event or adverse events grouped by organ systems, due to different reporting methodologies in studies.

As we expected, considering the underlying medical conditions in this high-risk population, rates of AEs and SAEs were high in all treated patients. Palivizumab was associated with a statistically significant reduction in the proportion of children reporting any SAE compared to placebo. After having confirmed the efficacy of palivizumab prophylaxis, these results are self explanatory. Palivizumab reduces the risk of severe RSV disease after the RSV infection has occurred, and thereby minimises hospitalisations, or possibly some life-threatening conditions or significant disabilities, which are all considered serious adverse events. It should also be noted that this result came from one study only. The proportion of children reporting any adverse event related to study drug, or any adverse event at all, was similar in palivizumab and placebo patients. Post-marketing surveillance data included in the Synagis (palivizumab) product leaflet provide additional insight into potential adverse events encountered, specifically: severe acute hypersensitivity reactions and anaphylaxis, which are described as rare and very rare (respectively) (FDA 2009).

We did not find any differences in the proportion of children reporting AE when palivizumab was compared to motavizumab in any of the four categories assessed. The proportion of children reporting any AE was similar between the two groups, and additional analyses of other groupings of AEs did not demonstrate any significant difference.

 

Economic evidence

In all included economic studies, a cost-effectiveness or a cost-utility analysis was conducted that compared the clinical and financial consequences of palivizumab prophylaxis and no prophylaxis in infants and children at high risk. In this section, the Drummond definitions of the types of economic evaluations were followed (Drummond 1996) and all studies were classified into a health sector (payer's) or a societal perspective.

In general, costs and outcomes can be combined in three different ways, resulting in three different types of analyses: cost–benefit analysis (where both inputs and outcomes are considered in monetary terms); cost–utility analysis (where inputs are considered in terms of costs, and outcomes are measured in utility measures, such as quality-adjusted life-years (QALYs)); and cost–effectiveness analysis (where inputs are measured in terms of costs, and outcomes are measured using measures specific to the disease). A QALY is estimated in terms of a year of life, adjusted by the amount of quality that the life is lived at. Therefore, one year lived at full quality is 1 QALY, but one year lived at half quality equates to 0.5 QALYs, and half a year at full quality is also 0.5 QALYs. Different diseases and conditions can be compared using the cost–utility analysis and, therefore, these types of analyses are especially used by governmental approval groups, such as the UK National Institute for Health and Clinical Excellence, which often sets a threshold of utility gains per cost for all drugs and health technologies. A cost–effectiveness analysis usually compares the costs and outcomes of similar treatments for specific conditions. However, it would not provide data on the incremental cost–effectiveness ratio (ICER) per QALY, and if such data are required, would need to be modelled from the cost–effectiveness data.

Whether an intervention is cost-effective or not, and whether it should be provided or not, depends on the cost-effectiveness threshold established by the decision makers in a particular country. Following the recommendations of the Commission on Macroeconomics and Health, the World Health Organization (WHO) has derived three categories of cost-effectiveness using the nominal gross domestic product (GDP) per capita as a measure:

  • highly cost-effective (ICER is less than one GDP per capita);
  • cost-effective (ICER is between one and three times GDP per capita); and
  • not cost-effective (ICER is more than three times GDP per capita).

The nominal GDP per capita for the European Union (EU) for year 2011, as calculated by the World Bank, was USD 34,848 (EUR 24,621.37) (available at http://data.worldbank.org/). Using this GDP to calculate the cost-effectiveness threshold, the immunoprophylaxis would be cost-effective for the EU countries if the ICER present value at 2011 EUR is lower than EUR 73,864.11 per QALY. However, this threshold is substantially higher than the thresholds established by particular EU countries, e.g. the United Kingdom's cost-effectiveness threshold has been in the range of GBP 20,000 to GBP 30,000 for over 10 years now (EUR 22,791.74 to EUR 34,187.61 respectively, using the 2011 exchange rates).

As Peter Jacobson (Jacobson 2001) stated: "Cost control is a primary objective of the managed care environment. It is no longer possible to provide health care without regard to cost or patient demand. The question is not whether there will be cost containment, but how to structure and oversee its implementation. The use of cost-effectiveness analysis (CEA) in making clinical and payment decisions has become a significant cost containment approach, however CEA should be treated as one piece of evidence to be considered by health care sector to define way of action rather than being used to determine the standard of care."

We presented and discussed economic data separately according to age and subgrouped data according to underlying medical conditions because, clinically, these patients are likely to have different baseline risks for serious complications due to RSV infection. We further classified the economic evaluations by whether they adopted the payer's or the societal perspective. We also debated about the main economic results obtained from the included studies and about variations in methodological approaches among studies that may justify the differences in cost-effectiveness results.

Data on cost–effectiveness of RSV immunoprophylaxis with palivizumab versus no prophylaxis are based on simulation modelling, rather than the direct collection of costs and outcomes. Data for the evaluations were drawn from a wide variety of sources, including the palivizumab clinical trials, published literature, hospital databases, country-specific price/tariff lists and national population statistics. Country-specific data sources were also used for economic measures and information on therapeutic choices. Clinical events and utilities in the majority of analyses are not country-specific and therefore were derived from international studies.

The main outcomes considered for cost-effectiveness analyses in the included economic studies were hospitalization due to RSV infection (ordinary ward or ICU) and life-years gained (LYGs). For cost-utility analysis, outcomes considered were QALYs. Challenges in the cost–utility approach for this specific problem lie in modelling of costs and QALY gains in the lifetime follow-up period to capture the impact of palivizumab on long-term morbidity and mortality, resulting from severe RSV infection beyond the RSV hospitalization period. Under the assumption that RSV hospitalisations are associated with clinical and economic consequences beyond the clinical trial period; a proportion of children may develop long-term sequelae (e.g. wheezing or asthma) leading to a reduction of QALYs and additional medical costs. It is known that the rates used to populate the economic models will drive the final results of the analyses towards higher or lower ICER values. The reduction in RSV hospitalization rate due to palivizumab prophylaxis corresponds to data available from the palivizumab clinical trials (e.g. IMpact-RSV 1998) that considered only one season period of follow-up, which is 150 days from the point of randomization (30 days after the last scheduled palivizumab injection). Therefore, for the economic models that adopted the lifetime time horizon it was necessary to extrapolate the efficacy data from the palivizumab clinical trials (reduction in the rate of RSV hospitalisations) to calculate the likely number of LYGs and QALYs gained from the use of palivizumab prophylaxis. Regardless of the time horizon considered in the analysis, if authors assumed that differences in RSV hospitalization rates allow for differences in mortality rates between the palivizumab prophylaxis and non-prophylaxis group, and thus populated the models from the beginning with differential mortality rates, the final results will favour palivizumab use, particularly if the societal perspective was adopted.

Modelling costs depend on the perspective of the analysis. The analyses performed from the societal perspective included not only the direct medical costs, but also costs for management of wheezing or asthma, and future lost productivity of a child resulting from mortality (a small proportion of children will die, which will lead to a lifetime loss of productivity benefits). The analyses that adopted the payer's perspective considered only direct medical costs. Generally, analyses that included direct medical costs associated with asthma (i.e. when asthma was included into the disease pathway modelled) showed moderately more favorable ICERs for palivizumab prophylaxis, while analyses that included the long-term indirect costs due to lost lifetime productivity following childhood mortality, showed a substantial improvement in the cost-effectiveness of prophylaxis with palivizumab. It means that palivizumab prophylaxis is more cost-effective if it has a long-term effect on the incidence of asthma and mortality.

A very important consideration that should be taken into account while interpreting the economic results presented in this review is that effectiveness data used to populate the models come from follow-up studies performed in hospitalised children, RSV-infected or not, with or without the underlying medical conditions (such as bronchopulmonary dysplasia or congenital heart disease); none of the studies measured the long-term impact that palivizumab prophylaxis could have on asthma and mortality in these high-risk populations. So, data used by study authors to populate the economic models are based on unsupported assumptions. Whether or not these assumptions and modelling practices lead to underestimation or overestimation of the mortality rates in children born preterm or with underlying heart or lung disease, that have received immunoprophylaxis with palivizumab, is unclear.

Currently there are no longitudinal trials providing robust data on long-term effects of palivizumab prophylaxis on a child's morbidity and mortality beyond the standard follow-up period. The forthcoming results from one investigator-initiated RCT (NTR1023) that assessed the number of wheezing days in preterm children during the first year of life, and the quality of life and asthmatic symptoms up to six years of age, might be offering some answers to this question.

Owing to particular problems described above, and due to the fact that mortality rates could drive the final cost-effectiveness ratios, it is important to discuss the methodological approaches used by the authors to model this outcome in their economic analyses. Methods that were used for reporting, calculating and adjusting the probabilities of death that entered the models differed considerably across studies. In most cases, the absolute values of probabilities of death were not reported and the exact organisation of decision tree models was not presented. Some study authors directly modelled different mortality rates for patients receiving palivizumab prophylaxis and no prophylaxis. In some of the studies, models included difference in life-years gained between the two intervention groups, and this fact necessarily implies that a difference in mortality was also allowed. Some study authors assumed different mortality rates for hospitalised versus non-hospitalised patients. In other instances, different mortality rates were assumed for patients hospitalised with or without the RSV infection. Again, some other studies assumed the same mortality rates for the two intervention groups, but calculated the probabilities of death according to the related hospitalization rates in the two groups. The bottom line is that all these studies took into account that palivizumab prophylaxis reduces the rate of RSV-related hospitalisations, and this directly translates into reduced mortality risk in palivizumab group compared to no intervention group. Rare authors did not model a mortality benefit associated to the use of prophylaxis, but this was the case only in studies with a short time horizon (one year), and with final costs expressed per hospitalization avoided (the exception being the ElHassan 2006 study).

Other important differences in economic models included in this review are the different total amount of the drug, different resources and services consumed (depending on a healthcare system in a particular country), different overall costs (dependent on the costs that specific services/resources have in a specific country), different time horizons and different discount rates.

Each of the factors described could easily account for large differences in cost-effectiveness results across studies. An additional aspect that we have studied, while interpreting the economic results presented in this review, is whether the analysis was funded by the drug manufacturing company or not. Almost all included studies that were sponsored by the industry supported the cost-effectiveness of palivizumab prophylaxis, while practically all included studies that were not sponsored by the industry suggested that palivizumab was not cost-effective.

We made attempts to classify studies according to all these differing assumptions included in economic models, in an effort to identify premises that would be necessary for palivizumab prophylaxis to be regarded as acceptably cost-effective. However, by analysing the information available from the study reports, it became obvious that a huge problem lies in the lack of standardisation of the modelling approaches adopted in economic studies, and these differences can easily lead to big variations in cost-effectiveness results, making them almost incomparable. The use of palivizumab prophylaxis for reducing the risk of severe RSV infection might not be cost-effective enough to be considered a standard healthcare policy in the majority of low- and middle-income countries, because of the high costs of the drug. However, patient needs and individual risks should be considered in each case that physicians encounter in their everyday clinical practice.

 

Economic impact of immunoprophylaxis given at neonatal period or within the first six months of life

In an attempt to find systematic differences that could explain the variations in results of the studies reporting on preterm infants without other comorbidity, we analyzed patient populations, effectiveness outcomes, perspective taken and other methodological parameters. The doses of palivizumab varied across studies (from 3 to 6 doses at 15 mg/kg); gestational ages of preterm infants entered into the models differed between the studies; incremental effectiveness of palivizumab prophylaxis varied substantially across studies (i.e. RSV hospitalisations avoided, risk of asthma included, lower mortality rates due to palivizumab use). Finally, the included studies reported significant differences in economic results, coming primarily from the consumption of resources taken into account, and from the modelling approaches adopted. Many analyses considered a lifetime follow-up period to capture the impact of palivizumab on a long-term morbidity and mortality resulting from severe RSV infection. Since the available data from palivizumab clinical trials are all limited to a single RSV season, the way of modelling the evaluations presents an important source of variations leading to such differences in ICERs.

 

Economic impact of immunoprophylaxis given to children aged six months and older

Two studies evaluated the economic impact of RSV immunoprophylaxis in preterm children without other co-morbidities. The ICER values expressed per QALYs varied across these two studies substantially, making it difficult for decision-makers to identify the real magnitude of the economic impact that the palivizumab prophylaxis has in this population.

In the studies evaluating the economic impact of passive immunisation given to children with congenital heart disease, substantially higher ICER values expressed per QALYs and LYGs were reported by Wang 2011 and Yount 2004. These studies had comparable methodological characteristics to other studies, and they both included mortality benefits and lower risk of long-term sequelae for children receiving palivizumab prophylaxis. We did not find any clear explanations for this variation, other than that these two studies were the only ones not funded by the drug manufacturer.

Results from studies performed in children with bronchopulmonary dysplasia (or chronic lung disease) aged six months and older are quite consistent and rather high. Whether palivizumab prophylaxis is a cost-effective alternative, and whether it should be adopted as part of routine care in this population, depends on the threshold value set by the decision-makers in a particular country.

 

Economic impact of immunoprophylaxis given to high-risk infants and children (born preterm, with or without bronchopulmonary dysplasia, or with congenital heart disease) up to five years of age

From the evidence presented in the three included studies, it is very difficult to define the real economic impact that the RSV prophylaxis strategy has in a mixed population of high-risk infants and children.

 

Overall completeness and applicability of evidence

The review includes all relevant RCTs and economic evaluations identified by an up to date literature search, making this evidence report up to date and current. We had prespecified RSV hospitalization and mortality as the primary efficacy and safety outcomes, and they were reported by most of the RCTs included.

This report presents evidence about the effects of palivizumab prophylaxis in infants and children at high risk for the development of serious RSV disease, in terms of its efficacy, safety and cost-effectiveness.

 

Quality of the evidence

A total of seven RCTs and 34 economic evaluations were included in this review. The quality of evidence reflects the extent to which we are confident that an estimate of the effect is correct.

The quality of evidence was assessed and summarised for each main efficacy and safety outcome in this review by using the GRADE approach implemented in the GRADEpro software (GRADEpro 2008). The GRADE quality rating was high or moderate for all outcomes assessed, with minor exceptions. Data on several important outcomes were not reported in all included studies. Some measurements were missing standard deviations and meta-analysis was not possible.

When palivizumab was compared to placebo, the quality of the evidence was high for RSV hospitalization, admission to ICU and for number of children reporting any serious adverse events. We downgraded the quality for all-cause mortality to moderate, due to imprecision of results; for mechanical ventilation the quality rating was very low, due to very serious heterogeneity and imprecision of data; while for total RSV hospital days, standard deviations were missing and meta-analysis was not possible, and we downgraded the quality of evidence to moderate. When palivizumab was compared to motavizumab, the quality of evidence was high for mechanical ventilation and for the number of children reporting any serious adverse events. For RSV hospitalization, all-cause mortality, admission to ICU and supplemental oxygen therapy, the quality of evidence was moderate due to imprecision of results; while for total RSV hospital days a standard deviation was missing in one study and could not be provided by the authors, and data were imprecise in the other study; we downgraded the quality of evidence to low.

It should be noted that there are methodological and other concerns raised by the US Food and Drug Administration (FDA), with regards to some studies in which motavizumab was evaluated (Carbonell-Estrany 2010 among others), which resulted in rejecting a license application for motavizumab in 2010. A concern raised by the FDA was that the Carbonell-Estrany 2010 study may have utilised laboratory testing procedures which may have biased the study toward motavizumab over palivizumab. Another concern was related to hypersensitivity reactions which were more prevalent in children who received motavizumab compared to palivizumab. Further concerns were raised with regards to the geographic distribution of patients enrolled in Carbonell-Estrany 2010. Namely, motavizumab's efficacy results relative to palivizumab were largely driven by data from southern hemisphere countries, representing roughly 9% of the total data set. When compared with the northern hemisphere results, a substantial geographic heterogeneity of the treatment effect was observed (FDA 2010).

Results of the quality assessment of economic evaluation studies are summarised in Appendix 6. We assessed all included economic evaluations according to their full-text publications, except for Bentley 2011; Kang 2009 and Mayen-Herrera 2011, where only abstracts were available. In general, the included economic evaluations met the methodological and reporting aspects evaluated, and their results can be considered valid. In economic evaluations conducted by Chiroli 2005; Embleton 2007; Lofland 2000; Rietveld 2010 and Roeckl-Wiedmann 2003 the discounting was not applied to costs and consequences. However, it is considered to be methodologically correct since the time horizon used in these analyses was one year, making the discounting unnecessary. Studies conducted by Raya Ortega 2006 and Lofland 2000 were the only economic evaluations that did not meet three or more of methodological criteria assessed. The authors did not identify, measure accurately and value credibly relevant costs and consequences, and we cannot be confident in the final results presented in these studies.

Overall, the methodological and reporting quality of included economic evaluations was good, which is consistent with the criteria that we set for considering types of studies for inclusion. However, variations in the consumption of resources and in modelling approaches taken into account by a specific study appear to be a big drive for significant differences in the cost-effectiveness results.

 

Potential biases in the review process

Given our comprehensive search strategy and contact with the study authors and the drug manufacturer, it is unlikely that we missed any relevant studies. Two authors independently screened and selected studies, and extracted all data for RCTs and for economic evaluations. This we believe minimises errors in data extraction and biases. The quality of RCTs and economic evaluations was very good, although some studies did not report certain quality characteristics.

However, our review has several limitations, besides the fact that all included randomized controlled trials and two-thirds of the included economic evaluations were funded by the drug manufacturing company. We were limited in that palivizumab versus placebo, and palivizumab versus motavizumab comparisons only had three and four studies, respectively. Out of the total of seven RCTs, three were just safety studies (Abarca 2009; Fernandez 2010; Subramanian 1998), without having evaluated the efficacy outcomes (except for one study where RSV hospitalisations were reported). That means that for most of the outcomes we assessed, we only had data from two studies that contributed to our analyses. Also, in one of the RCTs that we included (Subramanian 1998), the study drug was applied intravenously and not in the recommended approved dosing regimen, intramuscularly. In another study (Fernandez 2010), we presented safety information after two doses and not after the regular five doses of the study drug.

Two RCTs were conducted in children with haemodynamically significant congenital heart disease, and five RCTs in children born preterm, with or without chronic lung disease. We performed analyses in this review for all high-risk patient populations combined. In case we had three or more studies for each patient subpopulation, and for each comparison, we would have performed a subgroup analysis according to the presence of risk factors.

 

Agreements and disagreements with other studies or reviews

Our results agree with a previous Cochrane systematic review (Wang 1999) performed in children born preterm, with congenital heart disease or with bronchopulmonary dysplasia. However, in Wang 1999 the pooled effects of polyclonal (RSV-IVIG) and monoclonal (palivizumab) RSV-neutralising antibodies were assessed, in comparison to placebo. The review included four studies in a pooled analysis, three with RSV-IVIG and one (IMpact-RSV 1998) with palivizumab prophylaxis. Wang 1999 reports practically identical relative risk reduction in RSV hospitalisations (RR 0.48, 95% CI 0.37 to 0.64) and in admissions to ICU (RR 0.47, 95% CI 0.29 to 0.77); similar results in the incidence of mechanical ventilation (RR 0.99, 95% CI 0.48 to 2.07) and the opposite trend of a relative risk increase in mortality (RR 1.15, 95% CI 0.63 to 2.11), for RSV prophylaxis compared to placebo.

 

Authors' conclusions

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

 

Implications for practice

Palivizumab prophylaxis is effective in reducing the frequency of hospitalisations due to respiratory syncytial virus (RSV) infection, i.e. in reducing the incidence of serious lower respiratory tract RSV disease in children with chronic lung disease, congenital heart disease or those born preterm. Even though our search also included children with immunodeficiency, chronic neuromuscular disease or congenital anomalies, no studies were found for those patient populations, and no conclusions can be drawn for them. Also, it would be beneficial to have longitudinal studies that could demonstrate the long-term effects of RSV prophylaxis on a child's morbidity and mortality beyond the standard follow-up period of 30 days after completion of the prophylaxis regimen.

The results of incremental costs per hospitalization averted, life-year gained (LYG) or quality-adjusted life-year (QALY gained) showed substantial variations across the included economic evaluations, not only due to the differences in baseline risks of studied patient populations. Several sources of variation, including the source of funding, have led to incomparable cost-effectiveness results in evaluations performed in similar populations. How cost-effective palivizumab prophylaxis actually is in a high-risk population of infants and children is unclear. The use of palivizumab prophylaxis for reducing the risk of severe RSV infection might not be cost-effective enough to be considered a standard healthcare policy in the majority of low- and middle-income countries, because of the high costs of the drug. However, patient needs and individual risks should be considered individually by the attending physician.

 
Implications for research

A more precise definition of underlying medical conditions in the patient population at highest risk of severe RSV infection is necessary. Having a small number of efficacy studies for a specific subgroup of patients limited our ability to analyse data in that way. There are no published studies performed in children with immunodeficiency, chronic neuromuscular disease or congenital anomalies, all of whom may derive some benefit from RSV prophylaxis. Cohort studies are needed to determine the long-term effects of immunoprophylaxis on asthma, mortality and other important clinical outcomes. Conducting investigator-initiated studies would be beneficial, since all of the RCTs included in this review were sponsored by the manufacturer.

Evidence on the efficacy and safety of palivizumab prophylaxis in each subgroup of patients, together with the data about its cost-effectiveness in a specific population and setting, could be used for reconsidering current recommendations and developing national guidelines on when to provide RSV immunoprophylaxis. Also, the introduction of a low-cost vaccine against RSV would reduce the inequitable distribution and would make RSV prophylaxis available to the poorest countries where severe lower respiratory tract infections carry a substantial disease burden.

 

Acknowledgements

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

The review authors wish to acknowledge Juan Manuel Lozano, Catalina Escovar and Verónica Vásquez, authors of the original protocol on which our review was based. The review authors also wish to thank Dario Sambunjak, Anne Lyddiatt, Karl Gallegos, Teresa Neeman, Ludovic Reveiz, Amina Foda, Nancy Banasiak, Charles Woods, Annabelle Enriquez, Cody Meissner, Theresa Wrangham and Michael Adena for commenting on the draft protocol/review. Author MXRR is a PhD candidate of the doctoral programme in Salud Pública y Metodología de la Investigación Biomédica of the Departament de Pediatria, d'Obstetrícia i Ginecologia i de Medicina Preventiva, Universitat Autònoma de Barcelona, Spain.

 

Data and analyses

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
Download statistical data

 
Comparison 1. Palivizumab versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Hospitalisation for RSV infection32831Risk Ratio (M-H, Fixed, 95% CI)0.49 [0.37, 0.64]

 2 All-cause mortality32831Risk Ratio (M-H, Fixed, 95% CI)0.69 [0.42, 1.15]

 3 Total RSV hospital days per 100 children22789Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 4 Admission to ICU22789Risk Ratio (M-H, Fixed, 95% CI)0.50 [0.30, 0.81]

 5 Days in the ICU per 100 children22789Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 6 Mechanical ventilation for RSV infection22789Risk Ratio (M-H, Random, 95% CI)1.10 [0.20, 6.09]

 7 Days of mechanical ventilation per 100 children22789Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 8 Days of supplemental oxygen therapy per 100 children22789Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]

 9 Number of children reporting any AE11287Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.97, 1.01]

 10 Number of children reporting related AE32831Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.85, 1.38]

 11 Number of children reporting any SAE11287Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.80, 0.96]

 12 Number of children reporting related SAE11287Risk Ratio (M-H, Fixed, 95% CI)0.14 [0.01, 2.80]

 
Comparison 2. Palivizumab versus motavizumab

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Hospitalisation for RSV infection27870Risk Ratio (M-H, Fixed, 95% CI)1.36 [0.97, 1.90]

 2 RSV-specific outpatient MALRI23026Risk Ratio (M-H, Fixed, 95% CI)1.98 [1.25, 3.13]

 3 All-cause mortality48265Risk Ratio (M-H, Fixed, 95% CI)0.74 [0.38, 1.43]

 4 Total RSV hospital days per 100 children27870Mean Difference (IV, Fixed, 95% CI)24.95 [-21.59, 71.49]

 5 Admission to ICU27870Risk Ratio (M-H, Fixed, 95% CI)1.68 [0.89, 3.19]

 6 Days in the ICU per 100 children27870Mean Difference (IV, Fixed, 95% CI)21.34 [-13.69, 56.37]

 7 Mechanical ventilation for RSV infection27870Risk Ratio (M-H, Fixed, 95% CI)3.79 [1.26, 11.42]

 8 Days of mechanical ventilation per 100 children27870Mean Difference (IV, Fixed, 95% CI)16.06 [-16.60, 48.72]

 9 Supplemental oxygen therapy for RSV infection27870Risk Ratio (M-H, Fixed, 95% CI)1.49 [0.98, 2.26]

 10 Days of supplemental oxygen therapy per 100 children27870Mean Difference (IV, Fixed, 95% CI)28.42 [-13.64, 70.48]

 11 Number of children reporting any AE48238Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.99, 1.02]

 12 Number of children reporting related AE31625Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.73, 1.32]

 13 Number of children reporting any SAE48238Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.96, 1.13]

 14 Number of children reporting related SAE31625Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.32, 2.43]

 

Appendices

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Appendix 1. MEDLINE and CENTRAL search strategy

1 Respiratory Syncytial Virus Infections/
2 respiratory syncytial viruses/ or respiratory syncytial virus, human/
3 (respiratory syncytial vir* or rsv).tw.
4 Respiratory Tract Infections/
5 (acute respiratory infection* or acute respiratory tract infection*).tw.
6 (lower respiratory tract infection* or lrti).tw.
7 exp Bronchiolitis/
8 bronchiolit*.tw.
9 pneumonia/ or pneumonia, viral/
10 pneumon*.tw.
11 or/1-10
12 palivizumab.tw,nm.
13 synagis.tw,nm.
14 exp Antibodies, Monoclonal/
15 (monoclonal antibod* or mab or mabs).tw.
16 Antiviral Agents/
17 Antibodies, Viral/
18 or/12-17
19 11 and 18

 

Appendix 2. Embase.com search strategy

#21. #16 AND #20 524 29 Jul 2011
#20. #17 OR #18 OR #19 858,638 29 Jul 2011
#19. random*:ab,ti OR placebo*:ab,ti OR factorial*:ab,ti OR crossover*:ab,ti OR 'cross over':ab,ti OR 'cross-over':ab,ti OR volunteer*:ab,ti OR allocat*;ti,ab OR
assign*:ab,ti OR ((singl* OR doubl*) NEAR/1 blind*):ab,ti AND [embase]/lim 818,196 29 Jul 2011
#18. 'single blind procedure'/exp OR 'double blind procedure'/exp OR 'crossover procedure'/exp AND [embase]/lim 110,071 28 Jul 2011
#17. 'randomised controlled trial'/exp AND [embase]/lim 214,265 28 Jul 2011
#16. #10 AND #15 6,262 28 Jul 2011
#15. #11 OR #12 OR #13 OR #14 238,285 28 Jul 2011
#14. 'monoclonal antibody':ab,ti OR 'monoclonal antibodies':ab,ti OR mabs:ab,ti OR mab:ab,ti AND [embase]/lim 149,633 28 Jul 2011
#13. 'monoclonal antibody'/de OR 'virus antibody'/de OR 'antivirus agent'/de AND [embase]/lim 176,627 28 Jul 2011
#12. palivizumab:ab,ti OR synagis:ab,ti AND [embase]/lim 495 28 Jul 2011
#11. 'palivizumab'/de AND [embase]/lim 1,410 28 Jul 2011
#10. #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 174,739 28 Jul 2011
#9. pneumon*:ab,ti AND [embase]/lim 104,459 28 Jul 2011
#8. 'pneumonia'/de OR 'virus pneumonia'/de AND [embase]/lim 67,722 28 Jul 2011
#7. bronchiolit*:ab,ti AND [embase]/lim 6,906 28 Jul 2011
#6. 'bronchiolitis'/exp AND [embase]/lim 9,404 28 Jul 2011
#5. 'acute respiratory infection':ab,ti OR 'acute respiratory infections':ab,ti OR 'lower respiratory tract infection':ab,ti OR 'lower
respiratory tract infections':ab,ti OR lrti:ab,ti AND [embase]/lim 5,440 28 Jul 2011
#4. 'respiratory tract infection'/de AND [embase]/lim 27,544 28 Jul 2011
#3. 'respiratory syncytial virus':ab,ti OR 'respiratory syncytial viruses':ab,ti OR rsv:ab,ti AND [embase]/lim 9,483 28 Jul 2011
#2. 'respiratory syncytial pneumovirus'/de AND [embase]/lim 8,983 28 Jul 2011
#1. 'respiratory syncytial virus infection'/de AND [embase]/lim 440 28 Jul 2011

 

Appendix 3. CINAHL (Ebsco) search strategy

S29 S19 and S28 72
S28 S20 or S21 or S22 or S23 or S24 or S25 or S26 or S27 157323
S27 (MH "Quantitative Studies") 6708
S26 TI placebo* OR AB placebo* 17633
S25 (MH "Placebos") 5979
S24 TI random* OR AB random* 85911
S23 TI (singl* blind* or doubl* blind* or tripl* blind* or trebl* blind* or singl* mask* or doubl* mask* or trebl* mask* or tripl* mask*) OR AB (singl* blind* or doubl* blind* or tripl* blind* or trebl* blind* or singl* mask* or doubl* mask* or trebl* mask* or tripl* mask*) 12936
S22 TI clinic* trial* OR AB clinic* trial* 24108
S21 PT clinical trial 48680
S20 (MH "Clinical Trials+") 96829
S19 S11 and S18 473
S18 S12 or S13 or S14 or S15 or S16 or S17 17036
S17 (MH "Antiviral Agents") 7987
S16 (MH "Antibodies, Viral") 1337
S15 TI (monoclonal antibod* or mab or mabs) OR AB (monoclonal antibod* or mab or mabs) 2004
S14 (MH "Antibodies, Monoclonal+") 7068
S13 TI (palivizumab or synagis) OR AB (palivizumab or synagis) 108
S12 (MH "Palivizumab") 61
S11 S1 or S2 or S3 or S4 or S5 or S6 or S7 or S8 or S9 or S10 14405
S10 (MH "Pneumonia, Viral") 182
S9 TI pneumon* OR AB pneumon* 8786
S8 (MH "Pneumonia") 4052
S7 TI bronchiolit* OR AB bronchiolit* 622
S6 (MH "Bronchiolitis+") 558
S5 TI (acute respiratory infection* or acute respiratory tract infection* or lower respiratory tract infection* or lrti) OR AB (acute respiratory infection* or acute respiratory tract infection* or lower respiratory tract infection* or lrti) 836
S4 (MH "Respiratory Tract Infections") 2921
S3 TI (respiratory syncytial vir* or rsv) OR AB (respiratory syncytial vir* or rsv) 748
S2 (MH "Respiratory Syncytial Viruses") 241
S1 (MH "Respiratory Syncytial Virus Infections") 701

 

Appendix 4. LILACS search strategy

> Search > (MH:"Respiratory Syncytial Virus Infections" OR "Infecciones por Virus Sincitial Respiratorio" OR "Infecções por Vírus Respiratório Sincicial" OR MH:"Respiratory Syncytial iruses" OR "Virus Sincitiales Respiratorios" OR "Vírus Sinciciais Respiratórios" OR MH:"Respiratory Syncytial Virus, Human" OR "Virus Sincitial Respiratorio Humano" OR "Vírus sincicial Respiratório Humano" OR "respiratory syncytial virus" OR "respiratory syncytical viruses" OR rsv OR MH:"Respiratory Tract Infections" OR "Infecciones del Sistema Respiratorio" OR "Infecções Respiratórias" OR "respiratory infection" OR "respiratory infections" OR "respiratory tract infections" OR "respiratory tract infection" OR "Infecciones del Tracto Respiratorio" OR "Infecciones Respiratorias" OR "Infecções do Trato Respiratório" OR "Infecções do Sistema Respiratório" OR MH:Bronchiolitis OR bronchiolit$ OR Bronquiolitis OR Bronquiolite OR MH:C08.127.446.135$ OR MH:C08.381.495.146.135$ OR C08.730.099.135$ OR MH:Pneumonia OR Neumonía OR pneumon$ OR Pulmonía OR "Inflamación Pulmonar" OR "Inflamação Pulmonar") AND (palivizumab OR synagis OR MH:"Antibodies, Monoclonal" OR "Anticuerpos Monoclonales" OR "Anticorpos Monoclonais" OR MH:D12.776.124.486.485.114.224$ OR MH:D12.776.124.790.651.114.224$ OR MH:D12.776.377.715.548.114.224$ OR "monoclonal antibodies" OR "monoclonal antibody" OR mab OR mabs OR MH:"Antiviral Agents" OR Antivirales OR Antivirais OR MH:"Antibodies, Viral" OR "Anticuerpos Antivirales" OR "Anticorpos Antivirais") > clinical_trials

 

Appendix 5. Adverse effects search strategy in MEDLINE and EMBASE

 
MEDLINE (Ovid)

1 palivizumab.tw,nm. (502)
2 synagis.tw,nm. (74)
3 1 or 2 (507)
4 (ae or de or po or to).fs. (3302629)
5 (safe or safety or side effect* or undesirable effect* or treatment emergent or tolerability or toxicity or adrs).tw. (634946)
6 (adverse adj2 (effect or effects or reaction or reactions or event or events or outcome or outcomes)).tw. (176894)
7 4 or 5 or 6 (3675600)
8 3 and 7 (155)

 
EMBASE.com

#9. #7 OR #8 273 1 Aug 2011
#8. 'palivizumab'/exp/dd_ae,dd_to AND [embase]/lim 131 1 Aug 2011
#7. #3 AND #6 219 1 Aug 2011
#6. #4 OR #5 822,846 1 Aug 2011
#5. (adverse NEAR/2 (effect OR effects OR reaction OR reactions OR event OR events OR outcome OR outcomes)):ab,ti AND [embase]/lim 206,008 1 Aug 2011
#4. safe:ab,ti OR safety:ab,ti OR 'side effect':ab,ti OR 'side effects':ab,ti OR 'undesirable effect':ab,ti OR 'undesirable effects':ab,ti OR 'treatment emergent':ab,ti OR tolerability:ab,ti OR toxicity:ab,ti OR adrs:ab,ti AND [embase]/lim 700,278 1 Aug 2011
#3. #1 OR #2 1,426 1 Aug 2011
#2. palivizumab:ab,ti OR synagis:ab,ti AND [embase]/lim 495 1 Aug 2011
#1. 'palivizumab'/de AND [embase]/lim 1,410 1 Aug 2011

 

Appendix 6. Quality assessment of included economic evaluations by using the adapted Drummond checklist


Study IDWell-defined question?Competing alternatives described?Effectiveness established?Relevant costs and consequences (conseq.) identified?Costs and conseq. measured accurately?Costs and conseq. valued credibly?Discounting performed?Incremental analysis of costs and conseq. performed?Sensitivity analysis performed?

Bentley 2011YesCan't tellYesCan't tellCan't tellCan't tellCan't tellYesYes

Chirico 2009YesYesYesYesYesYesYesYesYes

Chiroli 2005YesYesYesYesYesYesNoYesYes

ElHassan 2006YesYesYesYesYesYesYesYesYes

Embleton 2007YesYesYesYesYesYesNoYesYes

Garcia-Altes 2010YesYesYesYesYesYesYesYesYes

Hampp 2011YesYesYesYesYesYesNoYesYes

Harris 2011YesYesYesYesYesYesNoYesYes

Hascoet 2008YesYesYesYesYesYesYesYesYes

Joffe 1999YesYesYesYesYesYesYesYesYes

Kang 2009YesCan't tellCan't tellYesCan't tellCan't tellYesYesYes

Lanctot 2008YesYesYesYesYesYesYesYesYes

Lazaro y de Mercado 2006YesYesYesYesYesYesYesYesYes

Lazaro y de Mercado 2007YesYesYesYesYesYesYesYesYes

Lofland 2000YesYesYesYesCan't tellCan't tellNoYesYes

Mayen-Herrera 2011YesYesYesCan't tellCan't tellCan't tellYesYesCan't tell

Neovius 2011YesYesYesYesYesYesYesYesYes

Nuijten 2007YesYesYesYesYesYesYesYesYes

Nuijten 2009aYesYesYesYesYesYesNoYesYes

Nuijten 2009bYesYesYesYesYesYesYesYesYes

Nuijten 2010YesYesYesYesYesYesYesYesYes

Ravasio 2006YesYesYesYesYesYesYesYesYes

Raya Ortega 2006YesYesYesNoNoNoNoYesYes

Resch 2008 YesYesYesYesYesYesYesYesYes

Resch 2012YesYesYesYesYesYesYesYesYes

Rietveld 2010YesYesYesYesYesYesNoNoYes

Roeckl-Wiedmann 2003YesYesYesYesYesYesNoNoYes

Salinas-Escudero 2012YesYesYesYesYesYesYesYesYes

Smart 2010YesYesYesYesYesYesYesYesCan’t tell

Tam 2009YesYesYesYesYesYesYesYesYes

Vogel 2002YesYesYesYesYesYesNoNoYes

Wang 2011YesYesYesYesYesYesYesYesYes

Weiner 2012YesYesYesYesYesYesYesYesYes

Yount 2004YesYesYesYesYesYesYesYesYes



 

Appendix 7. GRADE approach for quality assessment of included RCTs

The GRADE approach specifies four levels of quality.

  1. High quality for randomised trials or double-upgraded observational studies.
  2. Moderate quality for downgraded randomised trials or upgraded observational studies.
  3. Low quality for double-downgraded randomised trials or observational studies.
  4. Very low quality for triple-downgraded randomised trials or downgraded observational studies or case series/case reports.

Authors could downgrade randomised trial evidence by one or two levels depending on the presence of five factors.

  1. Serious (- 1) or very serious (- 2) limitation to study quality.
  2. Important inconsistency across the studies (- 1 or - 2).
  3. Some (- 1) or major (- 2) uncertainty about directness.
  4. Imprecise or sparse data (- 1 or - 2).
  5. High probability of reporting bias (- 1).

 

Appendix 8. Money exchange rates


World currencyBase year of the evaluationExchange rate to Euros

Canadian dollar (CAD)20070.6994194213

20100.7927647938

Great British pound (GBP)20031.4194561843

20051.5060315583

20061.4639767907

New Zealand dollar (NZD)20000.4961650904

Swedish krona (SEK)20090.0920369376

United States dollar (USD)1995Not available

19990.9704846756

20021.0583130490

20090.7205825931

20100.8114656949



 

Appendix 9. GDP deflators for present value calculations


CountryBase year of the evaluation GDP deflator for 2011 adjustment 

Austria20061.114357

20101.032669

Canada20071.075445

20101.029121

France20061.082785

Germany20021.154669

20061.089589

Italy20041.151798

20051.129224

20061.106326

20071.086535

Mexico20091.077065

Netherlands20001.249521

20061.092226

New Zealand20001.340948

Spain20061.120584

20081.04751

Sweden20091.041534

UK20031.237114

20051.196183

20061.168906

USA19991.350378

20021.25053

20101.031568



 

Appendix 10. Methods for present value calculations

Present value calculations are used to provide a unique measure to compare cash flows at different times. If the payments were made in the past, their value is enhanced to reflect that those payments could have earned interest in the elapsed time. The most common way of inflation adjustment uses the gross domestic product (GDP) deflator. The GDP is a monetary value of all the finished goods and services produced within country's borders in a specific time period, though GDP is usually calculated on an annual basis. It includes all of private and public consumption, government outlays, investments and exports less imports that occur within a defined territory.

In order to calculate the ICER present values at 2011 Euros, we performed two main steps: currency conversion and inflation adjustment.

Firstly, we converted the values reported in the study in their original currency to Euros at the same price year. When the information about the price year used was not stated by the authors, we took one year prior to the year of publication as a referent year. To be consistent through studies, all the exchange rates used were taken at the same month and day: 16 June (e.g. if value was reported in 2003 USD, to convert it in Euros we used the exchange rate for 16 June 2003). To do this, we used the XE Universal Currency Converter, as it contains historical rate tables for every world currency since 1995 to present date, and is available at http://www.xe.com/ucc/. Money exchange rates used for currency conversions are presented in Appendix 8.

Once the currencies were converted to Euros, we performed the inflation adjustments by using the following formula.

Present value in 2011 EUR = Reported value converted to EUR at base year x GDP deflator

The GDP deflator is the ratio of nominal GDP (the value of aggregate final output at current market prices) to real GDP (its value at base year prices) and can be considered the most comprehensive measure of inflation, since a wide array of goods and services are included in its construction.

GDP deflator = Nominal GDP/Real GDP

For calculating the GDP deflators, we considered not only the price years reported by authors, but also the country where the economic analysis was carried out. We retrieved the World Bank Consumer Price Indexes for these calculations (available at http://data.worldbank.org/indicator/FP.CPI.TOTL). GDP deflators used for inflation adjustments are given in Appendix 9.

 

What's new

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

Last assessed as up-to-date: 8 August 2012.


DateEventDescription

9 June 2013AmendedResults on mortality now included in the Abstract.



 

History

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

Protocol first published: Issue 3, 2007
Review first published: Issue 4, 2013


DateEventDescription

11 August 2010New citation required and major changesA new review team took over this previously withdrawn protocol.

7 September 2009AmendedWithdrawn from The Cochrane Library 2010, Issue 1.

13 May 2008AmendedConverted to new review format.



 

Contributions of authors

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

TA conceived the idea for the review and searched for articles for the background section. TA and JWN completed the literature search and extracted the data for the efficacy and safety analysis. TA and BB conducted the statistical analysis of the efficacy and safety data, and interpreted the results from RCTs. BB contributed to the conception of the idea for the review, defined the statistical methods for efficacy and safety data, and contributed to analysing the results from RCTs. TA and JDR completed the literature search and extracted the data for the economic analysis. MXRR defined the methods for the review of economic evidence, verified study selection and data extraction from economic evaluations, and contributed to analysis of economics data. TA and MXRR performed present value calculations and interpreted the results from economic studies. TA and MXRR wrote the results, discussion and conclusions. All review authors critically edited and approved the review.

 

Declarations of interest

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

This review is in no way funded by commercial entities that could possibly benefit financially from its results. The review authors have no financial interest in the subject matter of the review (e.g. private clinical practice, stocks, legal advice, consultancies, employment).

TA is employed at Allergan.
BB is involved in consultancies for an international epidemiological study on the incidence and characteristics of RSV infections sponsored by Abbott (H09 - 116: RSV Survey in CEE).
MXRR has participated as co-investigator of independent clinical research studies supported in part by Abbott Laboratories, MSD, Astra-Zeneca, GlaxoSmithKline and Sanofi-Aventis.
JWN has received scholarships from the Canadian Society of Respiratory Therapists, Ikaria and the Ontario Graduate Scholarship program (none of which had any role in this review).
JDR and VBV have no potential conflicts of interest to declare.

 

Sources of support

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Internal sources

  • None, Not specified.

 

External sources

  • None, Not specified.

 

Differences between protocol and review

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

In the protocol, we prespecified that we would analyse the number of children with secondary complications as one of the main outcomes. However, since different studies assessed different secondary complications (e.g. otitis media in IMpact-RSV 1998, cardiac surgery/interventional catheterisation earlier than planned in Feltes 2003), the data were not comparable and we discarded this outcome. Due to this, the main outcomes included in the final 'Summary of findings' tables differ to some extent from those prespecified by the protocol. Also, two RCTs assessed RSV-specific outpatient medically attended lower respiratory tract infections (Carbonell-Estrany 2010; Feltes 2011) and we decided to add this outcome in the review, even though we did not prespecify it in the protocol.

In the protocol, we prespecified including not only full, but also partial economic evaluations. However, we included in the review only full economic evaluations assessing cost-effectiveness or cost-utility of palivizumab prophylaxis compared to no intervention taken, due to the fact that a large number of these high-quality studies was available. With the intention of being concise, we did not report specific costs (resources) identified and considered in the obtained total cost per patient in each of the 34 included economic evaluations.

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. References to studies awaiting assessment
  23. Additional references
  24. References to other published versions of this review
Abarca 2009 {published data only}
  • Abarca K, Jung E, Fernandez P, Zhao L, Harris B, Connor EM, et al. Motavizumab Study Group. Safety, tolerability, pharmacokinetics, and immunogenicity of motavizumab, a humanized, enhanced-potency monoclonal antibody for the prevention of respiratory syncytial virus infection in at-risk children. Pediatric Infectious Disease Journal 2009;28(4):267-72.
Bentley 2011 {published data only}
  • Bentley A, Filipovic I, Gooch K, Buesch K. A cost-effectiveness analysis of respiratory syncytial virus (RSV) prophylaxis in infants in the UK. Thorax 2011;66(Suppl 4):A136-7.
Carbonell-Estrany 2010 {published data only}
  • Carbonell-Estrany X, Simões EA, Dagan R, Hall CB, Harris B, Hultquist M, et al. Motavizumab Study Group. Motavizumab for prophylaxis of respiratory syncytial virus in high-risk children: a non-inferiority trial. Pediatrics 2010;125(1):e35-51.
Chirico 2009 {published data only}
Chiroli 2005 {published data only}
  • Chiroli S, Macagno F, Lucioni C. Cost-efficacy analysis of palivizumab in the prevention of respiratory syncytial virus infections in young children with hemodynamically significant congenital heart disease. Italian Journal of Pediatrics 2005;31:188-94.
ElHassan 2006 {published data only}
  • ElHassan NO, Sorbero MES, Hall CB, Stevens TP, Dick AW. Cost-effectiveness analysis of palivizumab in premature infants without chronic lung disease. Archives of Pediatrics and Adolescent Medicine 2006;160:1070-6.
Embleton 2007 {published data only}
  • Embleton ND, Dharmaraj ST, Deshpande S. Cost-effectiveness of palivizumab in infancy. Expert Review of Pharmacoeconomics and Outcomes Research 2007;7(5):445-58.
Feltes 2003 {published data only}
  • Feltes TF, Cabalka AK, Meissner HC, Piazza FM, Carlin DA, Top FH Jr, et al. Cardiac Synagis Study Group. Palivizumab prophylaxis reduces hospitalization due to respiratory syncytial virus in young children with hemodynamically significant congenital heart disease. Journal of Pediatrics 2003;143(4):532–40.
Feltes 2011 {published data only}
  • Feltes TF, Sondheimer HM, Tulloh RMR, Harris BS, Jensen KM, Losonsky GA, et al. Motavizumab Cardiac Study Group. A randomized controlled trial of motavizumab versus palivizumab for the prophylaxis of serious respiratory syncytial virus disease in children with hemodynamically significant congenital heart disease. Pediatric Research 2011;70(2):186-91.
Fernandez 2010 {published data only}
  • Fernandez P, Trenholme A, Abarca K, Griffin MP, Hultquist M, Harris B, et al. Motavizumab Study Group. A phase 2, randomized, double-blind safety and pharmacokinetic assessment of respiratory syncytial virus (RSV) prophylaxis with motavizumab and palivizumab administered in the same season. BMC Pediatrics 2010;10:38-50.
Garcia-Altes 2010 {published data only}
  • Garcia-Altes A, Paladio N, Tebe C, Pons JMV. Cost-effectiveness analysis of the administration of palivizumab as prophylaxis of severe bronchiolitis due to respiratory syncytial virus [Anàlisi cost-efectivitat de l’administració del palivizumab en la profilaxi de les bronquiolitis greus per virus respiratori sincicial]. Pediatria Catalana 2010;70:57-64.
Hampp 2011 {published data only}
  • Hampp C, Kauf TL, Saidi A, Winterstein AG. Cost-effectiveness of respiratory syncytial virus prophylaxis with palivizumab from the perspective of a Southern US medicaid agency. Value in Health 2009;12(7):A301-2.
  • Hampp C, Kauf TL, Saidi AS, Winterstein AG. Cost-effectiveness of respiratory syncytial virus prophylaxis in various indications. Archives of Pediatrics and Adolescent Medicine 2011;165(6):498-505.
Harris 2011 {published data only}
  • Harris KC, Anis AH, Crosby MC, Cender LM, Potts JE, Human DG. Economic evaluation of palivizumab in children with congenital heart disease: a Canadian perspective. Canadian Journal of Cardiology 2011;27:523.e11-.e15.
  • Human DG, Harris KC, Anis AH, Crosby MC, Cender LM, Potts JE. Economic evaluation of palivizumab in children with congenital heart disease: a Canadian perspective. Cardiology in the Young 2010;20(Suppl 1):30.
Hascoet 2008 {published data only}
  • Hascoet JM, Fagnani F, Charlemagne A, Vieux R, Roze JC. Methodological aspects of economic evaluation in pediatrics: illustration by RSV infection prophylaxis in the French setting [Aspects methodologiques de l’evaluation economique du medicament en pediatrie: exemple de la prophylaxie de l’infection a VRS en France]. Archives de Pediatrie 2008;15:1739-48.
IMpact-RSV 1998 {published data only}
  • The IMpact-RSV Study Group. Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. Pediatrics 1998;102(3 Pt 1):531–7.
Joffe 1999 {published data only}
Kang 2009 {published data only}
  • Kang HY, Kim HS, Choi JY, Kim YH. Cost-effectiveness analysis of palivizumab in the prevention of respiratory syncytial virus infection in Korean children with congenital heart disease. Value in Health 2009;12(7):A424.
Lanctot 2008 {published data only}
  • Lanctot KL, Masoud ST, Paes BA, Tarride JE, Chiu A, Hui C, et al. The cost-effectiveness of palivizumab for respiratory syncytial virus prophylaxis in premature infants with a gestational age of 32-35 weeks: a Canadian-based analysis. Current Medical Research and Opinion 2008;24(11):3223-37.
Lazaro y de Mercado 2006 {published data only}
  • Carbonell-Estrany X, Lázaro y de Mercado P. Health economics and RSV. Paediatric Respiratory Reviews 2009;10(Suppl 1):12-3.
  • Lazaro y de Mercado P, Figueras Aloy J, Domenech Martinez E, Echaniz Urcelay I, Closa Monasterolo R, Wood MA. The efficiency (cost-effectiveness) of palivizumab as prophylaxis against respiratory syncytial virus infection in premature infants with a gestational age of 32-35 weeks in Spain [La eficiencia (coste-efectividad) de palivizumab como profilaxis para la infección por virus respiratorio sincitial en prematuros de 32-35 semanas en España]. Anales de Pediatria 2006;65(4):316-24.
Lazaro y de Mercado 2007 {published data only}
  • Lazaro y de Mercado P, Figueras J, Domenech E, Closa R, Echaniz I, Wood MA, et al. Cost-effectiveness of palivizumab in preventing respiratory syncytial virus in premature infants and children with chronic lung disease in Spain [Coste-efectividad de palivizumab para prevenir el virus respiratorio sincitial en niños prematuros y niños con enfermedad pulmonar crónica en España]. Pharmacoeconomics - Spanish Research Articles 2007;4(2):57-68.
Lofland 2000 {published data only}
  • Lofland JH, Touch SM, O'Connor JP, Chatterton ML, Moxey ED, Paddock LE, et al. Palivizumab for respiratory syncytial virus prophylaxis in high-risk infants: a cost-effectiveness analysis. Clinical Therapeutics 2000;22(11):1357-69.
Mayen-Herrera 2011 {published data only}
  • Mayen-Herrera E, Buesch K, Cortina D. Economic evaluation of the use of palivizumab as prophylactic treatment for the reduction of complications associated with respiratory syncytial virus in pre-term patients. Value in Health 2011;14(7):A565-6.
Neovius 2011 {published data only}
Nuijten 2007 {published data only}
  • Nuijten MJC, Wittenberg W, Lebmeier M. Cost effectiveness of palivizumab for respiratory syncytial virus prophylaxis in high-risk children: a UK analysis. Pharmacoeconomics 2007;25(1):55-71.
Nuijten 2009a {published data only}
  • Nuijten M, Lebmeier M, Wittenberg W. Cost effectiveness of palivizumab for RSV prevention in high-risk children in the Netherlands. Journal of Medical Economics 2009;12(4):291-300.
Nuijten 2009b {published data only}
  • Nuijten M, Lebmeier M, Wittenberg W. Cost effectiveness of palivizumab in children with congenital heart disease in Germany. Journal of Medical Economics 2009;12(4):301-8.
Nuijten 2010 {published data only}
  • Nuijten MJ, Wittenberg W. Cost effectiveness of palivizumab in Spain: an analysis using observational data. European Journal of Health Economics 2010;11:105-15.
Ravasio 2006 {published data only}
  • Ravasio R, Lucioni C, Chirico G. Cost-effectiveness analysis of palivizumab versus no prophylaxis in the prevention of respiratory syncytial virus infections among premature infants, with different gestational ages [Costo-efficacia di palivizumab versus non profilassi nella prevenzione delle infezioni da VRS nei bambini pretermine, a diversa età gestazionale]. PharmacoEconomics - Italian Research Articles 2006;8(2):105-17.
Raya Ortega 2006 {published data only}
  • Raya Ortega L, Marquez Calderon S, Navarro Caballero JA, Villegas Portero R. Cost-effectiveness of palivizumab in the prevention of hospital admissions for syncytial respiratory virus in pre-term babies born at 32 to 35 weeks. Sevilla: Andalusian Agency for Health Technology Assessment (AETSA) 2006;Informe 14:1-47.
Resch 2008 {published data only}
  • Resch B, Gusenleitner W, Nuijten MJC, Lebmeier M, Wittenberg W. Cost-effectiveness of palivizumab against respiratory syncytial viral infection in high-risk children in Austria. Clinical Therapeutics 2008;30(4):749-60.
Resch 2012 {published data only}
  • Resch B, Sommer C, Nuijten MJC, Seidinger S, Walter E, Schoellbauer V, et al. Cost-effectiveness of palivizumab for respiratory syncytial virus infection in high-risk children, based on long-term epidemiologic data from Austria. Pediatric Infectious Disease Journal 2012;31(1):e1-8.
Rietveld 2010 {published data only}
  • Rietveld E, Steyerberg EW, Polder JJ, Veeze HJ, Vergouwe Y, Huysman MWA, et al. Passive immunisation against respiratory syncytial virus: a cost-effectiveness analysis. Archives of Disease in Childhood 2010;95:493-8.
Roeckl-Wiedmann 2003 {published data only}
  • Roeckl-Wiedmann I, Liese JG, Grill E, Fischer B, Carr D, Belohradsky BH. Economic evaluation of possible prevention of RSV-related hospitalisations in premature infants in Germany. European Journal of Pediatrics 2003;162:237-44.
Salinas-Escudero 2012 {published data only}
  • Salinas-Escudero G, Martinez-Valverde S, Reyes-Lopez A, Garduno-Espinosa J, Munoz-Hernandez O, Granados-Garcia V, et al. Cost-effectiveness analysis of the use of palivizumab in the prophylaxis of preterm patients in Mexico. Salud Publica de Mexico 2012;54(1):47-59.
Smart 2010 {published data only}
  • Smart KA, Paes BA, Lanctot KL. Changing costs and the impact on RSV prophylaxis. Journal of Medical Economics 2010;13(4):705-8.
Subramanian 1998 {published data only}
  • Subramanian SKN, Weisman LE, Rhodes T, Ariagno R, Sanchez PJ, Steichen J, et al. MEDI-493 Study Group. Safety, tolerance and pharmacokinetics of a humanized monoclonal antibody to respiratory syncytial virus in premature infants and infants with bronchopulmonary dysplasia. Pediatric Infectious Disease Journal 1998;17(2):110-5.
Tam 2009 {published data only}
  • Tam DY, Banerji A, Paes BA, Hui C, Tarride JE, Lanctot KL. The cost effectiveness of palivizumab in term Inuit infants in the Eastern Canadian Arctic. Journal of Medical Economics 2009;12(4):361-70.
Vogel 2002 {published data only}
Wang 2011 {published data only}
  • Wang D, Bayliss S, Meads C. Palivizumab for immunoprophylaxis of respiratory syncytial virus (RSV) bronchiolitis in high-risk infants and young children: a systematic review and additional economic modelling of subgroup analyses. Health Technology Assessment 2011;15(5):1-124. [DOI: 10.3310/hta15050]
Weiner 2012 {published data only}
  • Weiner LB, Masaquel AS, Polak MJ, Mahadevia PJ. Cost-effectiveness analysis of palivizumab among pre-term infant populations covered by medicaid in the United States. Journal of Medical Economics 2012;15(5):997-1018.
Yount 2004 {published data only}

References to studies excluded from this review

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. References to studies awaiting assessment
  23. Additional references
  24. References to other published versions of this review
Banerji 2009 {published data only}
  • Banerji A, Lanctot KL, Paes BA, Masoud ST, Tam DY, Macdonald WA, et al. Comparison of the cost of hospitalization for respiratory syncytial virus disease versus palivizumab prophylaxis in Canadian Inuit infants. Pediatric Infectious Disease Journal 2009;28(8):702-6.
Buckley 2010 {published data only}
  • Buckley BC, Roylance D, Mitchell MP, Patel SM, Cannon HE, Dunn JD. Description of the outcomes of prior authorization of palivizumab for prevention of respiratory syncytial virus infection in a managed care organization. Journal of Managed Care Pharmacy 2010;16(1):15-22.
Chan 2003 {published data only}
  • Chan PWK, Abdel-Latif MEA. Cost of hospitalization for respiratory syncytial virus chest infection and implications for passive immunization strategies in a developing nation. Acta Paediatrica 2003;92(4):481-5.
Clark 2000 {published data only}
  • Clark SJ, Beresford MW, Subhedar NV, Shaw NJ. Respiratory syncytial virus infection in high risk infants and the potential impact of prophylaxis in a United Kingdom cohort. Archives of Disease in Childhood 2000;83(4):313-6.
Datar 2012 {published data only}
  • Datar M, Banahan BF. Palavizumab (Synagis) use and outcomes among medicaid beneficiaries. Value in Health 2012;15(4):A58-9.
Farina 2002 {published data only}
  • Farina D, Rodriguez SP, Bauer G, Novali L, Bouzas L, Gonzalez H, et al. Respiratory syncytial virus prophylaxis: cost-effective analysis in Argentina. Pediatric Infectious Disease Journal 2002;21(4):287-91.
Korbal 2003 {published data only}
  • Korbal P, Mikolajczak A, Szymanski W. Effectiveness of passive immunisation against respiratory syncytium virus in a group of premature infants with birth weight below 1000 grams [Ocena skutecznosci stosowania uodpornienia biernego przeciwko wirusom syncytium nablonka oddechowego (RSV) preparatem Synagis w grupie wczesniakow z masa urodzeniowa ciala ponizej 1000 gramow]. Ginekologia Polska 2003;74(10):1154-9.
Krilov 2010 {published data only}
Lapena Lopez 2003 {published data only}
  • Lapena Lopez de Armentia S, Robles Garcia MB, Martinez Badas JP, Castanon Fernandez L, Mallo Castano L, Herrero Mendoza B, et al. Potential impact and cost-efficacy of bronchiolitis prophylaxis with palivizumab in preterm infants with a gestational age of less than 33 weeks. Anales de Pediatria 2003;59(4):328-33.
Lee 2001 {published data only}
  • Lee SL, Etches P, Robinson JL. Net cost of palivizumab for respiratory syncytial virus prophylaxis during the 1998/99 season in northern Alberta. Paediatrics and Child Health 2001;6(8):525-32.
Marchetti 1999 {published data only}
  • Marchetti A, Lau H, Magar R, Wang L, Devercelli G. Impact of palivizumab on expected costs of respiratory syncytial virus infection in preterm infants: potential for savings. Clinical Therapeutics 1999;21(4):752-66.
Marques 2010 {published data only}
  • Marques T, Cardoso K. Palivizumab prophylaxis: comparative study between immunized and non immunized infants admitted with respiratory syncytial virus infection. Early Human Development 2010;86(Suppl):123-4.
Martinez 2002 {published data only}
  • Martinez JL. Palivizumab in preventing infection caused by respiratory syncitial virus (RSV) [Palivizumab en la prevención de infección por virus respiratorio sincicial]. Revista Chilena de Pediatria 2002;73(1):9-14.
McCormick 2002 {published data only}
Meberg 2006 {published data only}
Meissner 1999 {published data only}
  • Meissner HC, Groothuis JR, Rodriguez WJ, Welliver RC, Hogg G, Gray PH, et al. Safety and pharmacokinetics of an intramuscular monoclonal antibody (SB 209763) against respiratory syncytial virus (RSV) in infants and young children at risk for severe RSV disease. Antimicrobial Agents and Chemotherapy 1999;43(5):1183-8.
Numa 2000 {published data only}
Parmigiani 2001 {published data only}
  • Parmigiani S, Ubaldi A, Capuano C, Magini GM, Bianchi ME. Palivizumab in infants with gestational age ≤ 28 weeks and bronchopulmonary dysplasia. Acta Bio-Medica de l Ateneo Parmense 2001;72(5-6):109-13.
Rackham 2005 {published data only}
  • Rackham OJ, Thorburn K, Kerr SJ. The potential impact of prophylaxis against bronchiolitis due to the respiratory syncytial virus in children with congenital cardiac malformations. Cardiology in the Young 2005;15(3):251-5.
Reeve 2006 {published data only}
Rodriguez 2008 {published data only}
  • Rodriguez SP, Farina D, Bauer G. Respiratory syncytial virus prophylaxis in a high-risk population in Argentina: a cost-effectiveness analysis. Pediatric Infectious Disease Journal 2008;27(7):660-1.
Shireman 2002 {published data only}
  • Shireman TI, Braman KS. Impact and cost-effectiveness of respiratory syncytial virus prophylaxis for Kansas medicaid's high-risk children. Archives of Pediatrics and Adolescent Medicine 2002;156(12):1251-5.
Stevens 2000 {published data only}
  • Stevens TP, Sinkin RA, Hall CB, Maniscalco WM, McConnochie KM. Respiratory syncytial virus and premature infants born at 32 weeks’ gestation or earlier: hospitalization and economic implications of prophylaxis. Archives of Pediatrics and Adolescent Medicine 2000;154(1):55-61.
Strutton 2003 {published data only}
  • Strutton DR, Stang PE. Prophylaxis against respiratory syncytial virus (RSV), varicella, and pneumococcal infections: economic-based decision-making. Journal of Pediatrics 2003;143(Suppl 5):157-62.
Takeuchi 2002 {published data only}
  • Takeuchi Y, Cho H, Yamashita Y, Mishiku Y, Nakao A, Aso T, et al. Safety and pharmacokinetics of palivizumab, administered in infants with a history of prematurity or chronic lung disease. Japanese Journal of Chemotherapy 2002;50(4):215-22.
Vann 2007 {published data only}
  • Vann JJ, Feaganes J, Wegner S. Reliability of medicaid claims versus medical record data: in a cost analysis of palivizumab. Pharmacoeconomics 2007;25(9):793-800.
Wang 2008 {published data only}
  • Wang D, Cummins C, Bayliss S, Sandercock J, Burls A. Immunoprophylaxis against respiratory syncytial virus (RSV) with palivizumab in children: a systematic review and economic evaluation. Clinical Governance: an International Journal 2009;14(2):156-8.
  • Wang D, Cummins C, Bayliss S, Sandercock J, Burls A. Immunoprophylaxis against respiratory syncytial virus (RSV) with palivizumab in children: a systematic review and economic evaluation. Health Technology Assessment 2008;12(36):1-86.
Wegner 2004 {published data only}
  • Wegner S, Vann JJ, Liu G, Byrns P, Cypra C, Campbell W, et al. Direct cost analyses of palivizumab treatment in a cohort of at-risk children: evidence from the North Carolina Medicaid program. Pediatrics 2004;114(6):1612-9.
Wendel 2010 {published data only}
  • Wendel B, Jorden J. Financial impact of a clinically based palivizumab prior authorization program in a medicaid population. Journal of the American Pharmacists Association 2010;50(2):231.

References to studies awaiting assessment

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. References to studies awaiting assessment
  23. Additional references
  24. References to other published versions of this review
NCT00233064 {published data only}
  • NCT00233064. A Phase IV, Randomized, Double-Blind Study to Assess the Immune Reactivity of the Liquid and Lyophilized Formulations of Palivizumab (MEDI-493, Synagis) in Children at High Risk for the Development of Serious RSV Disease. http://apps.who.int/trialsearch/Trial.aspx?TrialID=NCT00233064 (accessed 27 July 2012).
NCT00240929 {published data only}
  • NCT00240929. A Phase II Randomized, Double-Blind, Two-Period Cross-Over Study to Evaluate the Pharmacokinetics, Safety and Tolerability of a Liquid Formulation of Palizvizumab (MEDI-493, Synagis), A Humanized Respiratory Syncytial Virus Monoclonal Antibody, in Children With a History of Prematurity. http://apps.who.int/trialsearch/Trial.aspx?TrialID=NCT00240929 (accessed 27 July 2012).
NTR1023 {published data only}
  • NTR1023. Effect of palivizumab on respiratory syncytial virus-associated burden of disease: a randomized controlled trial. http://apps.who.int/trialsearch/Trial.aspx?TrialID=NTR1023 (accessed 27 July 2012).

Additional references

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. References to studies awaiting assessment
  23. Additional references
  24. References to other published versions of this review
AAP 2009
  • American Academy of Pediatrics, Committee on Infectious Diseases and Committee on Fetus and Newborn. Policy statement-modified recommendations for use of palivizumab for prevention of respiratory syncytial virus infections. Pediatrics 2009;124(6):1694-701.
Arms 2008
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Atkins 2004
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Jacobson 2001
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Mullins 2003
Nair 2010
  • Nair H, Nokes DJ, Gessner BD, Dherani M, Madhi SA, Singleton RJ, et al. Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis. Lancet 2010;375(9725):1545-55.
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References to other published versions of this review

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. References to studies awaiting assessment
  23. Additional references
  24. References to other published versions of this review
Lozano 2007
  • Lozano JM, Escovar C, Vásquez V. Monoclonal antibodies for preventing respiratory syncytial virus infection. Cochrane Database of Systematic Reviews 2007, Issue 3. [DOI: 10.1002/14651858.CD006602.pub2]
Wang 1999
  • Wang EEL, Tang NK. Immunoglobulin for preventing respiratory syncytial virus infection. Cochrane Database of Systematic Reviews 1999, Issue 3. [DOI: 10.1002/14651858.CD001725.pub2]