Review
Preventing severe respiratory syncytial virus disease: passive, active immunisation and new antivirals Joanna Murray,1 Sonia Saxena,2 Mike Sharland3 1
Department of Primary Care and Public Health, Imperial College London, London, UK 2 Department of Primary Care and Public Health, Imperial College London, London, UK 3 Paediatric Infectious Diseases Unit, St George’s NHS Trust London, London, UK Correspondence to Professor Mike Sharland, Paediatric Infectious Diseases Unit, St George’s NHS Trust London, London SW17 0QT, UK; mike.sharland@stgeorges. nhs.uk Received 8 October 2013 Revised 29 December 2013 Accepted 30 December 2013 Published Online First 24 January 2014
ABSTRACT In most high-income countries palivizumab prophylaxis is considered safe, efficacious and cost-effective for preventing respiratory syncytial virus (RSV) hospital admissions among specific subgroups of infants born preterm, with chronic lung disease or with congenital heart disease. Virtually all babies acquire RSV during infancy and previously healthy babies are not eligible to receive palivizumab. Emerging evidence suggests some benefit of palivizumab use in reducing recurrent wheeze among infants born preterm. Better longitudinal studies are needed to examine its clinical and cost-effectiveness on recurrent and chronic respiratory illness and associated healthcare burden on resources in the community and hospitals. Since 99% of child deaths attributed to RSV occur in resource poor countries where expensive prophylaxis is not available or affordable, palivizumab has limited potential to impact on the current global burden of RSV lower respiratory tract infection (LRTI). A range of candidate vaccines for active immunisation against RSV are now in clinical trials. Two promising new antivirals are also currently in phase I/II trials to test their effectiveness in preventing severe RSV LRTI. These agents may be effective in preventing severe disease and phase III studies are in development. In the absence of effective active immunisation against RSV infection, population level approaches to prevent severe RSV LRTI should continue to focus on reducing prenatal and environmental risk factors including prematurity, smoking and improving hygiene practices.
INTRODUCTION
To cite: Murray J, Saxena S, Sharland M. Arch Dis Child 2014;99:469–473.
Respiratory syncytial virus (RSV) infection is a major cause of acute respiratory infection worldwide and each year results in an estimated 33.8 million new episodes of lower respiratory tract infections (LRTIs) among children aged less than 5 years.1 Mortality estimates vary from 66 000 to 199 000 child deaths annually thought to be attributed to RSV, 99% of these occurring in resource poor countries.1 In the UK the RSV-attributed death rate in infants has been estimated to be 8.4 per 100 000.2 Most children will have been infected with RSV by 2 years of age and approximately 10% of these episodes are severe enough to require hospital admission.1 In the UK, RSV infection is the leading cause of hospitalisation in children under 1 year of age, with an estimated admission rate of 31 per 1000 children under 1 year admitted in England.3–5 Some infants are at increased risk of hospital admission, including those who are born preterm or have congenital heart defects or chronic lung disease.6 Extensive systematic review evidence suggests there are no available treatments that clearly
Murray J, et al. Arch Dis Child 2014;99:469–473. doi:10.1136/archdischild-2013-303764
shorten the natural course of infection or provide clinical improvements in RSV bronchiolitis symptoms.7–11 Hence, the mainstay of management for infants infected with RSV remains supportive care including nasogastric feeding, oxygen therapy and intensive care for a small proportion (approximately 3%) of more severely affected infants.4 7 12 There is currently no effective vaccine against RSV infection. The only product currently licensed for prophylactic use to provide short-term protection against serious RSV infection among certain high risk infants, is passive immunotherapy with Palivizumab (Synagis, MedImmune), a humanised mouse monoclonal antibody against RSV infection, which targets the surface RSV fusion glycoprotein, preventing RSV entry into host cells and thereby preventing or reducing the severity of RSV infection.13 14 The aim of this article was to review the evidence of the safety, efficacy and costeffectiveness of palivizumab immunoprophylaxis for the prevention of RSV hospital admissions among high-risk infants in the UK and discuss new options under development.
METHODS Relevant articles were identified by searching The Cochrane Library, EMBASE, MEDLINE, Google Scholar and PUBMED databases for studies published from 1 January 1990 to 30 April 2013. Searches were carried out using MeSH terms and various combinations of the following keywords: “respiratory syncytial virus”, “RSV”, “respiratory syncytial virus infections”, “bronchiolitis”, “bronchiolitis, viral”, “palivizumab”, “Synagis”, “immunoprophylaxis”, “efficacy”, “safety”, “costeffectiveness”, “cost benefit analysis”, “cost analysis”, “economic analysis”, “hospital admission”. Relevant publications were identified by title and abstract and full text where required. We included findings from clinical trials, observational studies and postmarketing studies but excluded articles that were not published in English and abstracts that were not available as complete publications. Reference lists from selected papers and recent review articles were also examined.
EFFICACY OF PALIVIZUMAB The efficacy and safety of palivizumab was established through two large randomised, double-blind, placebo-controlled trials, which found palivizumab safely and effectively reduces RSV hospitalisation rates and serious complications among high-risk infants.15–17 The IMpact study was a multicentre, randomised, double-blind placebo-controlled trial in infants aged less than or equal to 35 weeks’ gestational age or those with chronic lung disease aged 469
Review less than 24 months (n=1502) were randomised to receive five injections of palivizumab (15 mg/kg) or equivalent volume of placebo every 30 days. The trial found that those receiving palivizumab (n=500) had a highly significant 55% reduction in RSV hospital admissions compared to the placebo group (n=1002).15 In addition, secondary outcomes reported showed infants receiving palivizumab spent fewer days in hospital and required fewer days of supplemental oxygen than those receiving placebo, but there was no statistically significant difference in requirement for intensive care or ventilation between the two groups. Another randomised controlled trial (RCT) compared palivizumab use (n=639) to placebo (n=648) among children aged up to 24 months with haemodynamically significant congenital heart disease.14 16 This study reported a 45% reduction in RSV hospital admissions among those receiving palivizumab (5.3% compared with 9.7%). Mortality was also examined as a secondary outcome in both these RCTs, with infants in control groups found to have slightly higher mortality rates, though neither trial was sufficiently powered for examining this outcome. A recent Cochrane systematic review analysed data from three RCTs (including those described above) comparing palivizumab with placebo (n=2831) and four RCTs comparing palivizumab with motavizumab (n=8265), among infants born preterm, with congenital heart disease or chronic lung disease.18 They concluded that prophylaxis compared to placebo was associated with a 51% reduction in risk of RSV hospitalisation (RR=0.49 95% CI 0.37 to 0.64) and a 50% reduction in admissions to intensive care units (RR=0.50 95% CI 0.30 to 0.81). In addition, pooled analysis revealed a reduction in all-cause mortality, though this was statistically non-significant (RR=0.69 95% CI 0.42 to 1.15).18 It is perhaps most useful though to consider the number of children that need to be treated to prevent a hospital episode. It is estimated that 17 preterm infants need to receive prophylaxis to prevent a single RSV hospital admission.19 Methodological limitations of these trials also need to be considered, since some were not designed with sufficient statistical power to confirm efficacy.
MOTAVIZUMAB Motavizumab, another humanised monoclonal IgG antibody, was developed as an alternative passive immunotherapeutic to palivizumab, with the aim of achieving improved binding affinity and virus neutralising activity.20 A phase III double-blinded RCT found motavizumab was non-inferior when compared to palivizumab, with a 26% reduction in RSV hospital admissions compared with palivizumab.21 However, recipients of motavizumab were at increased risk of adverse skin reactions compared with those receiving palivizumab. Motavizumab has therefore not been licensed for use in any country due to concerns over its safety regarding the increased hypersensitivity reactions.15 16 MedImmune have discontinued development of its use for prophylaxis against RSV but are continuing research into its possible use for treatment of RSV infection.17 20
UK GUIDANCE Guidance for the use of palivizumab in the UK is provided by the Joint Committee for Vaccination and Immunisation ( JCVI) RSV subgroup. In 2010 the group released recommendations for palivizumab use but also highlight the limited evidence base on which their decisions were based.17 Current JCVI guidance states that palivizumab is only cost-effective and recommended for use in particular subgroups of infants at most risk of severe disease (see box 1).17 470
COST-EFFECTIVENESS Despite evidence of the safety and efficacy of palivizumab prophylaxis, it remains expensive and difficult to deliver, requiring 5 monthly intramuscular injections. The estimated cost for a single dose of palivizumab for an infant aged 6 months, weighing 7.5 kg, is £1023, meaning the total estimated cost per patient receiving the required five doses is just over £5000 each.14 22 Several economic evaluations have examined the costeffectiveness of palivizumab prophylaxis in high risk children. The most recent review of the economic evidence concluded that the cost-effectiveness of palivizumab is inconsistent across different studies—depending on the threshold used and the consumption of healthcare resources taken into consideration.18 In addition, when interpreting cost-effectiveness studies the different average weights of infants used in the analysis should be carefully examined as this can have a considerable effect on the conclusions reached. A Health Technology Assessment considered population subgroups with different combinations of risk factors for whom the use of palivizumab may be cost-effective. The study reported that at a willingness-to-pay threshold of £30 000 per quality adjusted life year (QALY), prophylaxis with palivizumab is only cost-effective among subgroups of children with no chronic lung disease or congenital heart disease if they have at least two other risk factors besides gestational age at birth (including being male, multiple births, siblings at school, smoking exposure and household overcrowding).23 A Canadian cost-effectiveness study mirrored these recommendations, also concluding that immunoprophylaxis was most cost-effective for infants born at a gestational age of 32–35 weeks with more than two other risk factors for RSV hospital admission.24 Elsewhere in Europe, the undiscounted incremental cost-effectiveness ratio (ICER) for use of palivizumab varies. The ICER is estimated to be €6142 per QALY among all high risk infants in Spain and in the Netherlands is estimated to be €12 738/QALY in infants born preterm or with bronchopulmonary dysplasia and €4256 for infants with congenital heart complications.25 26 We were unable to find any formal cost-effectiveness studies from lower or middle income countries, as the considerable costs prohibit even minimal use in many countries.
OTHER HIGH-RISK INFANTS It is notable that none of the RCTs testing the impact of palivizumab prophylaxis to date have included children with
Box 1 Recommended recipients of palivizumab immunoprophylaxis in the UK. ▸ Children aged
Preventing severe respiratory syncytial virus disease: passive, active immunisation and new antivirals Joanna Murray,1 Sonia Saxena,2 Mike Sharland3 1
Department of Primary Care and Public Health, Imperial College London, London, UK 2 Department of Primary Care and Public Health, Imperial College London, London, UK 3 Paediatric Infectious Diseases Unit, St George’s NHS Trust London, London, UK Correspondence to Professor Mike Sharland, Paediatric Infectious Diseases Unit, St George’s NHS Trust London, London SW17 0QT, UK; mike.sharland@stgeorges. nhs.uk Received 8 October 2013 Revised 29 December 2013 Accepted 30 December 2013 Published Online First 24 January 2014
ABSTRACT In most high-income countries palivizumab prophylaxis is considered safe, efficacious and cost-effective for preventing respiratory syncytial virus (RSV) hospital admissions among specific subgroups of infants born preterm, with chronic lung disease or with congenital heart disease. Virtually all babies acquire RSV during infancy and previously healthy babies are not eligible to receive palivizumab. Emerging evidence suggests some benefit of palivizumab use in reducing recurrent wheeze among infants born preterm. Better longitudinal studies are needed to examine its clinical and cost-effectiveness on recurrent and chronic respiratory illness and associated healthcare burden on resources in the community and hospitals. Since 99% of child deaths attributed to RSV occur in resource poor countries where expensive prophylaxis is not available or affordable, palivizumab has limited potential to impact on the current global burden of RSV lower respiratory tract infection (LRTI). A range of candidate vaccines for active immunisation against RSV are now in clinical trials. Two promising new antivirals are also currently in phase I/II trials to test their effectiveness in preventing severe RSV LRTI. These agents may be effective in preventing severe disease and phase III studies are in development. In the absence of effective active immunisation against RSV infection, population level approaches to prevent severe RSV LRTI should continue to focus on reducing prenatal and environmental risk factors including prematurity, smoking and improving hygiene practices.
INTRODUCTION
To cite: Murray J, Saxena S, Sharland M. Arch Dis Child 2014;99:469–473.
Respiratory syncytial virus (RSV) infection is a major cause of acute respiratory infection worldwide and each year results in an estimated 33.8 million new episodes of lower respiratory tract infections (LRTIs) among children aged less than 5 years.1 Mortality estimates vary from 66 000 to 199 000 child deaths annually thought to be attributed to RSV, 99% of these occurring in resource poor countries.1 In the UK the RSV-attributed death rate in infants has been estimated to be 8.4 per 100 000.2 Most children will have been infected with RSV by 2 years of age and approximately 10% of these episodes are severe enough to require hospital admission.1 In the UK, RSV infection is the leading cause of hospitalisation in children under 1 year of age, with an estimated admission rate of 31 per 1000 children under 1 year admitted in England.3–5 Some infants are at increased risk of hospital admission, including those who are born preterm or have congenital heart defects or chronic lung disease.6 Extensive systematic review evidence suggests there are no available treatments that clearly
Murray J, et al. Arch Dis Child 2014;99:469–473. doi:10.1136/archdischild-2013-303764
shorten the natural course of infection or provide clinical improvements in RSV bronchiolitis symptoms.7–11 Hence, the mainstay of management for infants infected with RSV remains supportive care including nasogastric feeding, oxygen therapy and intensive care for a small proportion (approximately 3%) of more severely affected infants.4 7 12 There is currently no effective vaccine against RSV infection. The only product currently licensed for prophylactic use to provide short-term protection against serious RSV infection among certain high risk infants, is passive immunotherapy with Palivizumab (Synagis, MedImmune), a humanised mouse monoclonal antibody against RSV infection, which targets the surface RSV fusion glycoprotein, preventing RSV entry into host cells and thereby preventing or reducing the severity of RSV infection.13 14 The aim of this article was to review the evidence of the safety, efficacy and costeffectiveness of palivizumab immunoprophylaxis for the prevention of RSV hospital admissions among high-risk infants in the UK and discuss new options under development.
METHODS Relevant articles were identified by searching The Cochrane Library, EMBASE, MEDLINE, Google Scholar and PUBMED databases for studies published from 1 January 1990 to 30 April 2013. Searches were carried out using MeSH terms and various combinations of the following keywords: “respiratory syncytial virus”, “RSV”, “respiratory syncytial virus infections”, “bronchiolitis”, “bronchiolitis, viral”, “palivizumab”, “Synagis”, “immunoprophylaxis”, “efficacy”, “safety”, “costeffectiveness”, “cost benefit analysis”, “cost analysis”, “economic analysis”, “hospital admission”. Relevant publications were identified by title and abstract and full text where required. We included findings from clinical trials, observational studies and postmarketing studies but excluded articles that were not published in English and abstracts that were not available as complete publications. Reference lists from selected papers and recent review articles were also examined.
EFFICACY OF PALIVIZUMAB The efficacy and safety of palivizumab was established through two large randomised, double-blind, placebo-controlled trials, which found palivizumab safely and effectively reduces RSV hospitalisation rates and serious complications among high-risk infants.15–17 The IMpact study was a multicentre, randomised, double-blind placebo-controlled trial in infants aged less than or equal to 35 weeks’ gestational age or those with chronic lung disease aged 469
Review less than 24 months (n=1502) were randomised to receive five injections of palivizumab (15 mg/kg) or equivalent volume of placebo every 30 days. The trial found that those receiving palivizumab (n=500) had a highly significant 55% reduction in RSV hospital admissions compared to the placebo group (n=1002).15 In addition, secondary outcomes reported showed infants receiving palivizumab spent fewer days in hospital and required fewer days of supplemental oxygen than those receiving placebo, but there was no statistically significant difference in requirement for intensive care or ventilation between the two groups. Another randomised controlled trial (RCT) compared palivizumab use (n=639) to placebo (n=648) among children aged up to 24 months with haemodynamically significant congenital heart disease.14 16 This study reported a 45% reduction in RSV hospital admissions among those receiving palivizumab (5.3% compared with 9.7%). Mortality was also examined as a secondary outcome in both these RCTs, with infants in control groups found to have slightly higher mortality rates, though neither trial was sufficiently powered for examining this outcome. A recent Cochrane systematic review analysed data from three RCTs (including those described above) comparing palivizumab with placebo (n=2831) and four RCTs comparing palivizumab with motavizumab (n=8265), among infants born preterm, with congenital heart disease or chronic lung disease.18 They concluded that prophylaxis compared to placebo was associated with a 51% reduction in risk of RSV hospitalisation (RR=0.49 95% CI 0.37 to 0.64) and a 50% reduction in admissions to intensive care units (RR=0.50 95% CI 0.30 to 0.81). In addition, pooled analysis revealed a reduction in all-cause mortality, though this was statistically non-significant (RR=0.69 95% CI 0.42 to 1.15).18 It is perhaps most useful though to consider the number of children that need to be treated to prevent a hospital episode. It is estimated that 17 preterm infants need to receive prophylaxis to prevent a single RSV hospital admission.19 Methodological limitations of these trials also need to be considered, since some were not designed with sufficient statistical power to confirm efficacy.
MOTAVIZUMAB Motavizumab, another humanised monoclonal IgG antibody, was developed as an alternative passive immunotherapeutic to palivizumab, with the aim of achieving improved binding affinity and virus neutralising activity.20 A phase III double-blinded RCT found motavizumab was non-inferior when compared to palivizumab, with a 26% reduction in RSV hospital admissions compared with palivizumab.21 However, recipients of motavizumab were at increased risk of adverse skin reactions compared with those receiving palivizumab. Motavizumab has therefore not been licensed for use in any country due to concerns over its safety regarding the increased hypersensitivity reactions.15 16 MedImmune have discontinued development of its use for prophylaxis against RSV but are continuing research into its possible use for treatment of RSV infection.17 20
UK GUIDANCE Guidance for the use of palivizumab in the UK is provided by the Joint Committee for Vaccination and Immunisation ( JCVI) RSV subgroup. In 2010 the group released recommendations for palivizumab use but also highlight the limited evidence base on which their decisions were based.17 Current JCVI guidance states that palivizumab is only cost-effective and recommended for use in particular subgroups of infants at most risk of severe disease (see box 1).17 470
COST-EFFECTIVENESS Despite evidence of the safety and efficacy of palivizumab prophylaxis, it remains expensive and difficult to deliver, requiring 5 monthly intramuscular injections. The estimated cost for a single dose of palivizumab for an infant aged 6 months, weighing 7.5 kg, is £1023, meaning the total estimated cost per patient receiving the required five doses is just over £5000 each.14 22 Several economic evaluations have examined the costeffectiveness of palivizumab prophylaxis in high risk children. The most recent review of the economic evidence concluded that the cost-effectiveness of palivizumab is inconsistent across different studies—depending on the threshold used and the consumption of healthcare resources taken into consideration.18 In addition, when interpreting cost-effectiveness studies the different average weights of infants used in the analysis should be carefully examined as this can have a considerable effect on the conclusions reached. A Health Technology Assessment considered population subgroups with different combinations of risk factors for whom the use of palivizumab may be cost-effective. The study reported that at a willingness-to-pay threshold of £30 000 per quality adjusted life year (QALY), prophylaxis with palivizumab is only cost-effective among subgroups of children with no chronic lung disease or congenital heart disease if they have at least two other risk factors besides gestational age at birth (including being male, multiple births, siblings at school, smoking exposure and household overcrowding).23 A Canadian cost-effectiveness study mirrored these recommendations, also concluding that immunoprophylaxis was most cost-effective for infants born at a gestational age of 32–35 weeks with more than two other risk factors for RSV hospital admission.24 Elsewhere in Europe, the undiscounted incremental cost-effectiveness ratio (ICER) for use of palivizumab varies. The ICER is estimated to be €6142 per QALY among all high risk infants in Spain and in the Netherlands is estimated to be €12 738/QALY in infants born preterm or with bronchopulmonary dysplasia and €4256 for infants with congenital heart complications.25 26 We were unable to find any formal cost-effectiveness studies from lower or middle income countries, as the considerable costs prohibit even minimal use in many countries.
OTHER HIGH-RISK INFANTS It is notable that none of the RCTs testing the impact of palivizumab prophylaxis to date have included children with
Box 1 Recommended recipients of palivizumab immunoprophylaxis in the UK. ▸ Children aged
