The Cost Effectiveness of RSV Prophylaxis: Using Decision Analysis to Build a Better Guideline Melony E. S. Sorbero, PhD, MS, MPH

Sorbero Purpose To evaluate the cost effectiveness of current AAP recommendation for use of RSV prophylaxis. Focus on premature infants without CLD. Identify more cost-effective alternative recommendations.

Sorbero Background Respiratory syncytial virus (RSV) is the primary cause of lower respiratory tract illness in young children. Generally resolves uneventfully in otherwise healthy children. High risk populations may develop severe and sometimes fatal lower respiratory tract infections. RSV infection annually contributes up to 126,300 pediatric hospitalizations in the U.S. Estimated annual hospitalization costs for RSV pneumonia in children <=4 years: $300 - $400 million (1998 $) +. Annual mortality due to RSV in infants and children is estimated to range from to over 2, ( + Howard et al. J of Peds 2000; ++ Shay DK et al. J Infect Dis 2001; +++ Institute of Medicine. In: New Vaccine Development: Establishing Priorities: Vol I. Wash DC Nat Aca Press 1986)

Sorbero Background There may also be long-term health consequences due to severe RSV infections: –Increased risk of asthma and other respiratory conditions –Duration of increased risk up to 10 years A causal relationship between morbidity and severe RSV infection has not been shown. (Meissner HC at al. Pediatr Infect Dis J. 1999; Sigurs et al. Am J Resp Crit Care Med 2000; Sampalis J Pediatr 2003 )

Sorbero Background Prematurity increases risk of severe RSV infection. (Stevens TP et al. Arch Ped Adoles Med 2000) RSV Hospitalization Rate by Gestational Age at Birth

Sorbero Background Worldwide RSV epidemics occur yearly –United States: November – April –Peak: January – March (most areas) –Peak: 2 – 3 months earlier (Southeast) 80% RSV admissions occur within 4 months discharge from NICU. Respiratory Illness Hospitalization Rate by Month of Discharge from NICU in Infants <= 32 Weeks GA (Cunningham CK, McMillan JA, Gross SJ Pediatrics 1991)

Sorbero Background No vaccine available for RSV. 2 products available in U.S. for passive immuno-prophylaxis against RSV. Respiratory Syncytial virus immunoglobulin intravenous (RSV-IGIV) (RespiGam; MedImmune, Inc, Gaithersburg, MD), containing high- titer RSV antibodies. Palivizumab, (Synagis; MedImmune, Inc, Gaithersburg, MD), is a humanized monoclonal antibody that binds to the F-protein of RSV. Require monthly treatments during RSV season. Synagis less costly and more effective of two.

Sorbero American Academy of Pediatrics (AAP) Recommendations for Prophylaxis Use Released in 1998; updated in Infants younger than age 2 years who currently receive or have recently required medical therapy for CLD. Infant born 28 weeks gestation who are 12 months old at the start of the RSV season. Infants born at 29 to 32 weeks who are 6 months old at the start of the RSV season. Infants born between 32 and 35 weeks of gestation with risk factors. (Red Book, 2000)

Sorbero Synagis Efficacy of Synagis in prevention of severe RSV infection in premature infants without CLD: 82%. Synagis is available in 50 and 100 mg vials. The cost is $725 per 50 mg and $1370 per 100 mg vial. Synagis has a shelf life of 6 hours making drug wastage nearly inevitable.

Sorbero Study Design Developed decision analytic model. Societal perspective. Two versions: w/ and w/o asthma. Impact of asthma modeled with semi-Markov processes. Conducted CEA on models with asthma; CBA on models w/o asthma. Seven hypothetical cohorts of premature infants without CLD born at 24 – 32 weeks gestational age (GA). Assumed discharged from NICU at 36 weeks post-conceptual age.

Sorbero Model Assumptions Risk of RSV hospitalization obtained from published literature. –Gestational age specific probabilities –Seasonal pattern of hospitalization Efficacy of palivizumab adapted from IMpact study. Costs: year 2002 dollars Costs include: –Hospital costs –Cost of pulmonary clinic visits for Synagis injections –Emergency room visit cost –Drug costs –Cost of hours missed from work by parents for visits and hospitalization

Sorbero Models with Asthma Increased risk of asthma varies with chronologic age. Duration for increased asthma risk: 10 years Includes quality of life adjustment for asthma. Incorporates national estimates of annual asthma cost Future benefits and costs discounted at 3%

Sorbero Effect of Gestational Age on Expected Costs

Sorbero Incremental Cost-Effectiveness Ratio Incremental cost-effectiveness ratio (ICER): Cost 1 – Cost 2 = QALY 1 – QALY 2 Cost (Synagis) – Cost (No Synagis) QALY (Synagis) – QALY (No Synagis) Current suggested standards for ICER : – Accepted zone : $200,000 – Not generally accepted zone: > $200,000 / QALY

Sorbero Effect of Gestational Age on ICER

Sorbero Why is the ICER so high? Substantial difference in costs, even without drug wastage Very small difference in QALYs: –No proven mortality benefit –No proven long-term quality of life improvement –Change in quality of life due to asthma is small:.03 Treating many infants at low risk for hospitalization

Sorbero Large variation within GA in ICER

Sorbero Improving the Recommendations Cost Effectiveness Simulations modifying the AAP guidelines Assume no drug wastage Restrict to 1 st RSV season Younger age cutoffs (Discharged Sept. through March) Restrict to infants born 27 weeks GA or less if discharged before RSV season; up to 30 weeks GA if discharged during RSV season

Sorbero ICER by GA and Month of Discharge with new Recommendation

Sorbero ICER by GA with New Recommendation $103,053 $171,224 $216,830 $280,083

Sorbero Conclusion In our model for premature infants without CLD, incremental Cost / QALY: –Was high for all gestational ages; Many ICER were over $1 million. –Large amount of variation across months. Simulations identified more cost-effective options. Pursue strategies to minimize drug wastage. AAP guidelines could be revisited to make them more cost effective.

Sorbero Limitations Some costs were based on local estimates. May have underestimated cost from family members missing work due to infant hospitalized with RSV. Unclear whether causal relationship between severe RSV infection and asthma and other long-term health consequences; need for additional research. Decrease in quality of life due to asthma based on adults.

Sorbero University of Rochester Collaborators Department of Pediatrics, Division of Neonatology/Infectious Disease Dr. Nahed El Hassan Dr. Timothy Stevens Dr. Caroline Hall Department of Community and Preventive Medicine Dr. Andrew Dick