Efficacy and Optimization of Palivizumab Injection Regimens Against Respiratory Syncytial Virus Infection

Abstract

IMPORTANCE Infection with the respiratory syncytial virus (RSV) is the leading cause of hospitalizations in children, accounting for more than 90 000 hospitalizations every year in the United States. For children who are at risk for severe RSV infections, the American Academy of Pediatrics recommends immunoprophylaxis with a series of up to 5 injections of the antibody palivizumab administered monthly, beginning on November 1 of each year. However, many practitioners initiate injections at the onset of RSV season as indicated by local surveillance. OBJECTIVES To evaluate the effectiveness of current regimens for palivizumab injections across different cities and to design an optimized regimen. DESIGN, SETTING, AND PARTICIPANTS We performed a mathematical modeling study of the risk for hospitalization due to RSV infection. The model accounted for the pharmacokinetics of the antibody, the timing of the injections, and seasonal patterns of RSV, including geographic and year-to-year variability. We used the model to estimate the efficacy of current regimens, including the American Academy of Pediatrics recommendation, and to design a more effective injection regimen, the optimized fixed start (OFS), which uses city-specific initiation dates. Participants were the approximately 700 000 individuals who had specimens tested for RSV by National Respiratory and Enteric Virus Surveillance System laboratories in 18 US cities from July 1, 1994, through June 30, 2011 (a total of 725 741 tests). INTERVENTIONS Different palivizumab injection regimens. MAIN OUTCOMES AND MEASURES The primary outcome measure was reduction in hospitalizations due to RSV infections. The secondary measures were cost (number of palivizumab doses) and duration of protection (in days). RESULTS The American Academy of Pediatrics–recommended 5-injection regimen is expected to reduce hospitalization risk by a median of 2.7% (range, −2.2% to 6.1%) compared with the conventional regimen based on RSV surveillance. The 5-injection OFS regimen is expected to further reduce risk by a median of 6.8% (range, 4.9% to 14.8%), and the 4-injection OFS regimen is expected to achieve efficacy comparable to that of the conventional 5-injection regimen while reducing costs by 20%. CONCLUSIONS AND RELEVANCE Modified palivizumab regimens can improve protection for children at risk for severe outcomes of RSV infection and thereby lower rates of hospitalization due to RSV.

Question 1: Palivizumab for all children with Down syndrome?

“…It primarily affects infants, and approximately 1% of children of this age in Europe and the USA will be hospitalised over the bronchiolitis season, which typically runs from November to March 1 2. Palivizumab is a humanised monoclonal antibody which provides passive immunity to the recipient, and although not a cure for RSV has shown to be effective in reducing hospitalisation rates (by 55%–72%) in high-risk groups 3. It is usually given prophylactically, with a maximum of five doses 1 month apart starting in the autumn to those considered at greater risk: infants who are ex-premature <29 weeks, evidence of chronic lung disease (CLD), CHD, pulmonary abnormality, neuromuscular disease and significant immunosuppression 4…”

Use of Palivizumab in Germany – Report from the German Synagis™ Registry 2009 – 2016

“…Although no safety alerts derived from studies with more than 5 monthly injections [1,4,5,16] it has not been proven, that more than 5 palivizumab doses result in any benefit in terms of protection in late starting RSV seasons. Accumulation of palivizumab after repeated administration may result in a better level of protection after repeated dosing [2,11,22]. This argumentation (together with cost issues) has been followed by the latest recommendation of the AAP in 2014 which recommended that clinicians may administer up to a max of 5 monthly doses during the RSV season to infants who qualify in the first year of life and that qualifying infants born during the RSV season may require fewer doses [2].…”

Local variations in the timing of RSV epidemics

“…Starting prophylaxis too soon is an inefficient use of resources, as the cost of Palivizumab is high and the risk of infection is low before the seasonal RSV epidemic begins; starting prophylaxis too late can put susceptible infants at risk for a severe RSV infection as they would not be protected when local RSV transmission begins. To optimize the use of resources and maximize the protection afforded to high-risk infants, it is critical to understand variations in RSV epidemic timing between locations so that prophylaxis can be appropriately timed [7]. …”