Current strategies in the prevention of respiratory syncytial virus disease

Respiratory syncytial virus immune globulin 

Data from animal and observational studies indicated that RSV antibody titres of over 100 reduce the frequency of RSV infection and lower respiratory tract illness caused by both types A and B,33., 34. which set the stage for clinical experimentation with RSV immune globulin (RSV-IGIV) as a protective, prophylactic agent against RSV disease. RSV-IGIV is an intravenously administered, human-derived polyclonal product containing concentrated neutralising antibody to RSV. The safety and efficacy of RSV-IGIV have been proven in two large-scale studies.35., 36.

The first study evaluated 249 infants with a mean age of 8 months who were premature (n=60), preterm infants with bronchopulmonary dysplasia (n=102) and infants with congenital heart disease (n=87). Eighty-one infants were allocated in a random fashion to high-dose immune globulin (750mg/kg), 79 infants to a similar low-dose regimen (150mg/kg) and 89 to a control group. The high-dose cohort of infants had fewer respiratory tract infections, hospitalisations, hospital days and days in intensive care and received less ribavarin.35

The second study was a randomised, double-blind, placebo-controlled trial involving 54 centres in the USA between 1994 and 1995.36 Five hundred and ten children with bronchopulmonary dysplasia (BPD) with or without prematurity received 750mg/kg RSV-IGIV (n=250) or a placebo of 1% albumin (n=260) intravenously every 30 days. Treatment with RSV-IGIV reduced hospitalisation by 41%, with a further overall reduction in the severity of RSV illness, as evidenced by the total number of RSV hospitalised days per 100 children and the number of days with an increased oxygen requirement. Further effectiveness was proved by a reduction in the number of all admissions for respiratory tract infections.

Whereas RSV-IGIV is effective in the prevention of hospitalisation for RSV, admissions to intensive care and the incidence of mechanical ventilation concerns still, however, remain about its everyday use in clinical practice.37 It is a blood-derived product with the small possibility of transmission of infectious pathogens. RSV-IGIV has to be intravenously administered under medical surveillance, which is time-consuming. In addition, it has a high viscosity, which in combination with the large-volume dosage of 750mg/kg, has the potential to precipitate fluid overload in infants with BPD or cyanotic congenital heart disease, resulting in a trend towards higher mortality in the latter group.37., 38. Despite its limitations, RSV-IGIV may still have a role to play in the coverage of a broad spectrum of viral infections, especially in severely immunocompromised patients.36., 38. However, the cost of prophylaxis with RSV-IGIV for the prevention of hospitalisation from a payer’s perspective and a number-needed-to-treat analysis indicate no measurable benefit unless targeted towards high-risk infants with BPD who are less than 3 months of age.39., 40.

Respiratory syncytial virus prophylaxis with palivizumab 

The RSV virus is composed of several glycoproteins, of which the F and G glycoproteins play a pivotal role in the genesis of RSV illness. The G protein enables the virus to attach to respiratory epithelial cells, whereas the F protein enables fusion and further attachment to infected cells via a syncytial process. This progressively results in the formation of the typical multi-nucleated giant cell, which is the pathological hallmark of the virus. The F and G proteins are the major targets of neutralising antibodies and the blocking effect of RSV-IGIV when administered prophylactically has been conclusively demonstrated.35., 36., 37. It is not surprising therefore that early experimental trials focused on the development of an antibody to the F protein, which is widely conserved among all RSV strains and will either neutralise or inhibit the fusion of the virus to epithelial cells.

A humanised monoclonal antibody (palivizumab) was genetically engineered through a complex process by grafting a predetermined antigenic recognition site derived from a murine antibody on to a human immunoglobulin protein framework.41., 42. The product underwent several phase I trials, primarily in the cotton tail mouse, demonstrating a potency 50–100 times greater than that of an equivalent dose of RSV-IGIV and a 99% reduction in lung RSV titres, with serum palivizumab concentrations of 25–30μg/ml. The safety, tolerance and pharmacokinetics of palivizumab were established in phase II trials in premature infants and infants with BPD.43., 44. Patients who were less than 35 weeks’ gestation and less than 6 months of age, and infants with BPD who were younger than 24 months, were evaluated to determine the appropriate human dose that would produce a preventive serum level against RSV equivalent to that demonstrated to be effective in the animal models. It was ascertained that an intramuscular dose of 15mg/kg palivizumab given monthly sustained a concentration of over 40μg/ml in majority of the treated patients.43., 44.

This provided the impetus for the single, largest, international multi-centre, randomised, double-blind, placebo-controlled trial of RSV prophylaxis (IMpact), which was conducted in 139 centres across the USA, UK and Canada.45 Infants less than 2 years of age with BPD requiring supportive medical treatment for 6 months prior to study entry and preterm infants less than 35 weeks’ gestation and less than 6 months of age at the time of enrolment were randomised to five monthly injections of palivizumab 15mg/kg (n=1002) or placebo (n=500). The primary objective of the IMpact RSV study group was to evaluate the rate of hospitalisation with confirmed RSV infection.

Patients allocated to treatment with palivizumab had a 55% overall reduction in the number of hospital admissions as a result of RSV illness compared with the placebo group (P<0.001). The subgroup analysis similarly showed a 59% reduction in hospitalisation for infants with BPD (n=762), 47% for infants less than 32 weeks’ gestation (n=1111), 78% for all infants without BPD (n=740), 80% for preterm infants between 32 and 35 weeks’ gestation (n=373) and 82% for premature infants without chronic lung disease between 32 and 35 weeks’ gestation (n=335). The trial also established that infants who received palivizumab had a significant reduction in the number of days of hospitalisation per 100 children (P<0.001), days with increased oxygen requirement per 100 children (P<0.001) and hospital days with moderately severe lower respiratory tract infection (P<0.001). Both arms of the trial showed a similar rate of treatment-related adverse events, establishing the short-term safety of the drug. It should be noted that a difference in the rate of admission to intensive care was not demonstrated because of the small sample size (n=28).

It was disappointing at first glance that the beneficial effect of palivizumab was lowest in the highest-risk groups of infants who were less than 32 weeks’ gestation and those with BPD. Several studies have demonstrated that preterm infants under 33 weeks’ gestation have a greater risk of apnoea and more commonly require intensive care and ventilation when admitted to hospital than to those over 36 weeks’ gestational age.9., 12., 46. The IMpact trial was, however, not designed to evaluate secondary outcomes and therefore did not have adequate power to show a statistically significant difference in the subgroups.

Overview of the international studies with palivizumab 

After the IMpact trial, palivizumab received USA Food and Drug Administration approval in June 1998 and European sanction for use in 1999. The American Academy of Pediatrics47 recommended the use of palivizumab prophylaxis for:

Recently published reports of a combined analysis of RSV prophylaxis in prospective and retrospective studies since 1998 continue to demonstrate the effectiveness of palivizumab in reducing the number of RSV-related hospitalisations.49., 50. The weighted mean RSV hospitalisation rate in 11 studies for infants with chronic lung disease less than 2 years of age was 18.4% (untreated group) vs. 5.6% (RSV prophylaxis). Ten studies included the subgroup of infants between 29 and 32 weeks’ gestation without chronic lung disease, the analyses showing a reduction in hospitalisation rate from 10.3% to 2.0%. For infants between 32 and 35 weeks’ gestation without chronic lung disease, there was an overall reduction in hospitalisation from 9.8% to 1.5% in four studies. The hospitalisation rates in the IMpact trial in the untreated group, vs. the group receiving prophylaxis, of infants with BPD less than 2 years of age, infants between 29 and 32 weeks’ gestational age without BPD and infants of 32–35 weeks’ gestation without BPD were 12.8% vs. 7.9%, 8.5% vs. 1.6% and 9.8% vs. 2.9% respectively.

Table 1 shows a comparison of the number of patients needing treatment to prevent one case of RSV hospitalisation in the IMpact trial compared with the combined analysis of three subgroups of infants.49., 50. The data confirm that the results of the IMpact trial in preterm infants less than 35 weeks’ gestation are equally applicable in reality and are even more significant in reducing the RSV hospitalisation rate in the highest-risk group of infants less than 2 years of age with chronic lung disease (38% vs. 69%).

Table 1. Comparison of the number of patients needing treatment to prevent one case of respiratory syncytial virus (RSV) hospitalisation (NNT) in the IMpact trial45 versus a combined analysis (CA) of three subgroups of infants.49., 50.

	Gestational age in weeks	29–32	32–35	Bronchopulmonary dysplasia <2 years
	Number of patients	4854	2829	3675
	Number of studies	4	10	11
	% Reduction in RSV hospitalisation rate
	IMpact	81	79	38
	CA	80	85	69
	NNT
	IMpact	14	13	20
	CA	12	12	8

Palivizumab may have an equally significant effect on infants over 33 weeks’ gestation. The Pediatric Investigators Collaborative Network on Infection in Canada reported an incidence of intensive care admission for infants less than 32 weeks’ gestation, compared with those between 33 and 36 weeks and those over 37 weeks, of 10% vs. 21% vs. 53%. The rate of mechanical ventilation was also systematically higher with increasing gestational age: 14% vs. 19% vs. 46%.51 The increased respiratory support and length of hospitalisation for infants over 36 weeks’ gestation compared with younger preterms is supported in the scientific literature.52 Infants between 33 and 36 weeks constitute 3–5% of all live births and appear to sustain serious morbidity because of their younger age at the time of admission.53 The argument against prophylaxis in this infant cohort is that a substantial health-care expenditure would be incurred in the prevention of hospital admission. The American Academy of Pediatrics recommends that these infants should receive palivizumab only in the presence of additional risk factors.16., 17., 47.

Cost of respiratory syncytial virus prophylaxis 

The cost of prophylaxis with palivizumab per patient per season is significant. Each patient requires a minimum of five monthly doses that are currently dispatched as single, 50mg or 100mg vials, and it is estimated that the annual cost would be approximately $4500 US per patient. Few of the current studies rigorously evaluate the economic burden of RSV illness and its prevention by palivizumab prophylaxis. The inconsistencies in methodology make it difficult to compare studies, and the majority focus on direct costs such as hospital-based charges that vary significantly between institutions while ignoring indirect costs and productivity losses incurred per patient.4., 5., 54., 55. Of even greater importance is the need for long-term outcome data on subjects receiving prophylaxis.

In a recent publication, palivizumab was found to be more cost-effective than RSV-IGIV for preventing hospitalisation in infants requiring respiratory support at under 36 weeks’ gestation.52 A cost–benefit assessment of palivizumab, when utilised in accordance with defined guidelines, realised economic advantages in the prevention of hospitalisations for RSV infection.55 Palivizumab was also determined to be most cost-effective for premature infants less than 32 weeks’ gestation who were oxygen dependent for more than 28 days and discharged during the RSV season.4 A sensitivity analysis comprising a high-risk cohort of 42 infants who were either preterm or had BPD determined that the cost per hospitalisation averted ranged from $2171 to $48630 US.56 The authors recommended that the data could be applied to other institutions but the death of one patient in the study coloured their findings.

Pharmaco-economic studies of palivizumab using decision analytic models based on the IMpact trial and phase III and IV evaluative data on the hospitalisations for RSV of infants who received or did not receive prophylaxis, estimate a cost saving of $9635 US or less across hospital charges per patient treated. An increase in the economic effectiveness of palivizumab was predicted, with further reduction in hospitalisation rates evident in post-marketing studies.5., 57. Two studies from Liverpool, UK, and Sydney, Australia, could not justify the cost–benefit of palivizumab in the prevention of RSV based on their low admission rates for RSV disease and attendant mortality.58., 59. Currently available cost-effectiveness data are insufficient to justify universal recommendations.

Barriers to the use of palivizumab in practice 

Several controversies have been addressed with regard to the general use of palivizumab for all premature infants below 32 weeks’ gestation and even infants categorised as potentially high risk with BPD. In the main, the concerns focus on the cost-effectiveness of the product, based on the cost per vial and the number needed to treat to prevent hospitalisation. Palivizumab is expensive but its current cost can be justified by the complexity of the technological processes involved in its production.42 Published economic evaluations of palivizumab embrace cost analyses that do not critically appraise the broad spectrum of costs and outcomes involving study subjects, the hospital, the payer and the resources consumed by the health organisation, community and parents in the care of affected children. The cost-effectiveness of palivizumab therefore remains undetermined in the absence of stringent methodological studies encompassing comprehensive, unbiased, cost–benefit and cost–utility analyses of the prevention strategy.

Palivizumab is not 100% efficacious because it is a neutralising antibody administered over a pre-set period of time. Treated infants with complex multi-system disease and those exposed to a large viral inoculum may therefore develop RSV infections requiring both hospitalisation and mechanical ventilation. If the severity of illness in treated patients were also ameliorated in comparison to patients not receiving prophylaxis, the benefit of palivizumab in terms of financial expenditure would be more transparent. The number-needed-to-treat (NNT) to prevent one hospitalisation in the IMpact trial, especially in the high-risk group of infants with BPD (NNT=20) is posed as a counterargument to the use of palivizumab. However, more recent evidence (see Table 1 above) from observational studies delineates an equivalence in the number of infants requiring treatment to prevent one hospitalisation for infants between 29 and 35 weeks’ gestation and further reductions in the number requiring prophylaxis to avert hospitalisation in BPD patients (NNT=8).

The effect of education as a strategy in preventing RSV disease cannot be dismissed. This component comprised an essential part of the IMpact trial, which still resulted in a 10.6% hospitalisation rate in patients not receiving prophylaxis. Strategic hand-washing programmes targeted at health-care workers to prevent RSV nosocomial transmission have had limited success.60 In reality, active worldwide educational campaigns may have little effect on the baseline incidence of RSV hospitalisation (7.6–36.7%) in untreated patients because of lack of compliance.49., 50. It is generally accepted that the use of palivizumab in any setting should be based on local and country-wide surveillance data of RSV activity and its economic health impact on an annual basis.61