Palivizumab for the prevention of respiratory syncytial virus infection

Variability in indications

Respiratory syncytial virus is an RNA virus of the Paramyxoviridae family. The virus uses surface glycoproteins G and F, which lack neuraminidase and hemagglutinin activity, to infect cells. Palivizumab is a humanized mouse monoclonal immunoglobulin G1, comprising 95% human and 5% murine amino acid sequences. It is produced by recombinant DNA technology and directed against 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.3

Palivizumab has been approved for use in Canada since 2002. It is effective against both RSV subtypes (A and B). Palivizumab is administered intramuscularly at a dose of 15 mg/kg once every 30 days in a series of 5 monthly intramuscular injections to infants and children during the RSV season. The half-life for palivizumab is in the range of 18 to 21 days; therefore, monthly administration during the RSV season is enough for palivizumab to maintain its serum concentration at a protective level.3 The American Academy of Pediatrics recommends administering palivizumab for 5 consecutive months, covering the peak of the local RSV season.4

Clinical trials

The efficacy of palivizumab has been evaluated in 2 multicentre randomized controlled trials (RCTs), both of which used a primary end point of reduction in hospitalization owing to RSV infection.5,6 One RCT was conducted at 139 centres in the United States, the United Kingdom, and Canada. A total of 1502 children who were premature (ie, gestation for less than or equal to 35 weeks) or who had bronchopulmonary dysplasia (BPD) were randomized to receive injections of either palivizumab (15 mg/kg) or an equivalent volume of placebo by intramuscular injection every 30 days for 5 months.5 Palivizumab prophylaxis resulted in a 5.8% absolute reduction in hospitalization for RSV (10.6% placebo vs 4.8% palivizumab, number needed to treat [NNT] = 17). Children born premature but without BPD had a 6.3% reduction in RSV hospitalization (NNT = 16), while children with BPD had a 4.9% reduction (NNT = 20).5 The palivizumab group also had fewer total RSV hospital days and a lower incidence of ICU admissions, although ICU admission duration was significantly longer in the palivizumab group (P = .02, NNT = 37). There were no significant differences in adverse events between the 2 groups. Reactions at the site of injection were uncommon (1.8% placebo vs 2.7% palivizumab); the most frequent reaction was mild and transient erythema.5

In another RCT, 1287 children with hemodynamically significant congenital heart disease (CHD) received 5 monthly intramuscular injections of 15 mg/kg palivizumab or placebo.6 Palivizumab recipients had a 4.4% reduction in RSV hospitalizations (NNT = 23), a 56% reduction in total days of RSV hospitalization per 100 children, and a 73% reduction in total RSV hospital days with increased supplemental oxygen per 100 children. Adverse events were similar between the treatment groups and no child had the drug discontinued for a related adverse event.6 Therefore, monthly intramuscular injections of palivizumab (15 mg/kg per month) are well tolerated and effective for prophylaxis of serious RSV disease in young children with CHD or BPD.

The IMpact trial suggested an NNT of 16 to 20 infants treated with palivizumab to prevent 1 hospitalization, based on treating all infants born after less than 35 weeks’ gestation; a subsequent study of children with CHD suggested a similar NNT for children younger than 6 months of age. For children older than 6 months of age the NNT was 83.5,6

In general, cost-benefit analyses of palivizumab have found that because of its high cost there are no savings to be gained in health care dollars if all at-risk infants are offered prophylaxis, although some studies have yielded conflicting results.7–10 A recent systematic review and economic evaluation11 has shown that although palivizumab is clinically effective for reducing the risk of serious lower respiratory tract infection requiring hospitalization in high-risk children, if used unselectively in preterm infants without chronic lung disease (CLD) or children with CLD or CHD, the incremental cost-effectiveness ratio is double that which is considered to represent good value for money. However, prophylaxis with palivizumab might be cost-effective for premature children with CLD when they have 2 or more additional risks (male sex, intrauterine growth retardation, low birth weight, maternal smoking, rural residence, breastfeeding for 2 months or less, a birthday in November, December, and January, etc).11

Adverse effects

The most common reported adverse effects of palivizumab are local erythema, pain at the injection site, fever, and rash (1% to 3% of patients).5 In 2 small observational studies investigating the safety and immunological effects of repeated prophylaxis with palivizumab for a second year, no adverse clinical or immune effects were identified, although very rare cases of anaphylaxis have been reported following re-exposure to palivizumab.12,13 In a clinical trial, adverse events in infants with cardiac disease did not differ between treatment and placebo groups.6

Palivizumab is a recombinant product and has no potential for transmitting blood-borne infectious diseases. Moreover, it does not interfere with response to vaccines and does not affect the measles-mumps-rubella or other live virus immunization schedules.

Indications

Most infants should not be considered for RSV prophylaxis with palivizumab. Further, according to the American Academy of Pediatrics, palivizumab is not effective in the treatment of RSV infection and is not approved or recommended for this indication.4

Prophylaxis with palivizumab is only available for high-risk infants during the RSV season. Canadian indications for administration of palivizumab are shown in Table 1.14 According to the American Academy of Pediatrics, children eligible for a maximum of 5 doses include infants younger than 2 years of age who require medical therapy for CLD or CHD, premature infants born before 31 weeks’ gestation, and certain infants with neuromuscular disease or congenital abnormalities of the airways.4 Premature infants with a gestational age of 32 to 35 weeks with at least 1 risk factor and born 3 months before or during RSV season are eligible for a maximum of 3 doses.4

Conclusion

Palivizumab should only be considered for infants most vulnerable to severe RSV illness with a high likelihood of hospitalization, particularly in the first 6 months of life. Palivizumab is not effective in the treatment of RSV disease and is not approved or recommended for this indication.