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Therapeutic Advances Indian Pediatrics 2001; 38: 1265-1269 |
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Palivizumab |
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Piyush Gupta
Respiratory syncytial virus (RSV) affects 50-70% of all infants within the first year of life and causes significant respiratory illness especially in those born with prematurity, chronic lung disease, congenital heart disease, and multiple congenital ano-malies(1). In 1996, a polyclonal RSV-enriched immunoglobulin (RSV-IGIV) was approved for passive prophylaxis against these infections(2). However, RSV-IGIV requires intravenous administration in a relatively large volume, and thus, attempts were deviated at developing a monoclonal antibody that could be used in a smaller volume intramuscularly facilitating better compliance. Palivizumab is the first RSV specific humanized monoclonal antibody to gain approval by the FDA in June 1998 for preven-tion of RSV infections in high-risk infants. The generic name, palivizumab is derived from ‘pali’ a short form of ‘palliation’, ‘viz’ for ‘virus’, ‘u’ for humanized and ‘mab’ for monoclonal antibody(3). Structure and Function Palivizumab is a mouse-human chimaeric neutralizing monoclonal antibody (IgG1) which specifically inhibits an epitope at the A antigenic site of the F protein of RSV, thus preventing fusion of the virion with the cell membrane. As the F protein has 92% homology between RSV subtypes A and B, palivizumab is highly active in vitro against both subtypes of RSV isolates(3,4). Only 5% sequences in palivizumab have mouse origin, the rest are derived from human sources. The antibody is humanized by recombinant methods by inserting the complimentarity determining regions from an F protein specific neutralizing murine monoclonal antibody into a human IgG1 framework. Pharmacodynamics Palivizumab effectively neutralizes a broad range of clinical isolates of RSV. It is 20 to 30 times more active than RSV-IGIV, and 4 to 5 times more potent than felvizumab, another humanized monoclonal antibody directed against RSV(5). Animal studies with palivizumab have shown reduced pulmonary replication of both RSV subtypes by more than 99%(4-6). In a multicentric, double blind, randomized trial, palivizumab signifi-cantly decreased RSV replication in deep tracheal secretions of RSV infected infants on mechanical ventilation(7). Prophylaxis with palivizumab does not interfere with the mounting of a protective immune response after a subsequent RSV challenge. Pharmacokinetics The pharmacokinetic properties of palivizumab have been investigated in pre-term infants (£35 weeks of gestation) with or without BPD, and those who had undergone hematopoietic stem cell transplantation. In high-risk infants, palivizumab has a mean plasma elimination half-life (t½) of 20 days after IV administration and approximately 24 days after IM administration, which is similar to that of human IgG1. Trough serum concentrations following intramuscular injec-tion are similar to those after IV administra-tion. Palivizumab has been found to be safe and well tolerated in monthly doses upto 15 mg/kg(8). Therapeutic Trials The IMpact-RSV Study Group Trial (1996-97) This multicentric, double-blind, placebo controlled randomized trial enrolled 1502 children with prematurity (£35 weeks), or bronchopulmonary dysplasia requiring on-going medical treatment. Children receiving palivizumab prophylaxis had a lower inci-dence of RSV-attributable hospitalization, fewer RSV hospital days, fewer days with increased supplemental oxygen, and fewer days with a moderate or severe lower respira-tory tract illness. Palivizumab recipients were also admitted less frequently to intensive care. It had no effect on the incidence or total number of days of ventilation(9). In view of the findings of the IMpact-RSV group, the AAP Committee on Infectious Diseases and Committee on Fetus and New-born revised its guidelines on prevention of RSV infection(10). The revision included indications for use of palivizumab and up-dating recommendations on the use of RSV-IGIV. The salient points of these recom-mendations are depicted in Table I. Table I__AAP Recommendations on RSV Prophylaxis: Key Points
1998-1999 Season Out of 56,000 infants in USA and Canada receiving prophylaxis with palivizumab, 1839 patients were reviewed in this multicentric study(11). Only 2.3% children receiving palivizumab prophylaxis were hospitalized with RSV lower respiratory tract infection. This compared favorably with the rates observed in IMpact-RSV trial, in which prophylaxis reduced hospitalization from 10.6% in placebo group to 4.8% in those receiving prophylaxis. Dosage and Administration Palivizumab is administered intra-muscularly in a dose of 15 mg/kg once a month during the RSV season. In Northern Hemisphere, April to September is the RSV season whereas in United States March to November is the RSV season. In our hospital, the maximum number of RSV bronchiolitis are reported to occur between December to February (unpublished observation). Presently, Palivizumab is available in North and South America, Europe, Kuwait and Australia. It is still not available in India. The drug is marketed in packing of 100 mg vials. The opened vials must be used within 6 hours. Assuming the current exchange rate of US $, the cost of 100 mg is approximately 50,000 Indian Rupees. Thus, the cost of RSV prevention for a 4 kg patient receiving 5 doses of palivizumab per RSV season at a dose of 15 mg/kg/dose works up to be Rs. 1.5 lakhs! This is a conservative assumption because once reconstituted, the drug has a shelf life of 6 hours, making some drug wastage inevitable. Simultaneous use of the drug in multiple patients may minimize wastage(12). Side Effects and Tolerability Palivizumab has fewer adverse effects than RSV-IGIV. Side effects include erythema, pain, induration, and bruising at the injection site. A very small percentage of patients have systemic symptoms like vomit-ing, diarrhea and fever. There is no evidence of enhanced RSV disease among children receiving prophylaxis. Mild or moderate ele-vation of aspartate aminotransferase occurs in a small percentage of patients; however, a corresponding pattern in alanine amino-transferase elevation is not seen in all(9). Escape mutants, i.e. resistant viruses to palivizumab have not been identified after the administration of this product. Palivizumab does not interfere with measles containing vaccine or varicella vaccine administra-tion(10). Studies are currently underway to evaluate the tolerability of palivizumab in children with congenital heart disease where RSV-IGIV is contraindicated. Indian Context RSV is an established cause of infectious respiratory hospitalization in under five children in developed countries but limited data is available from India regarding the epidemiology of RSV infections in children. Before recommending this very expensive drug for Indian children, it is absolutely necessary to obtain current data on the magnitude of RSV disease, especially among high-risk groups. This should be followed by studies evaluating cost benefit analyses of such intervention. It has been estimated that the cost of prophylaxis with palivizumab would be more than 10 times the actual cost of excess hospitalization in untreated patients(13,14). This magnitude is likely to be much more in India where cost of hospitalization is likely to be lower. Considering the results of the IMpact study, this excess cost would not be associated with a decreased mortality or decreased need for mechanical ventilation. In addition, these high-risk infants would still be at risk of succumbing to other more common viral and bacterial infections. It has also been felt that palivizumab has no role to play in the vast majority of infants admitted with RSV bronchiolitis. No potent cost-effective prophylactic agent is available till date(15). Prevention in future may be achieved with the development of a safe, effective, and cheaper vaccine against RSV infection. Contributors: DG collected the reference and resource material, and drafted the manuscript, which was edited by PG. The overall concept and framework of the article was provided by PG. He will act as guarantor of the paper. Funding: None. Competing interests: None stated.
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