Respiratory Syncytial Virus

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					  The Cost Effectiveness of RSV
   Prophylaxis: Using Decision
Analysis to Build a Better Guideline



                     Melony E. S. Sorbero, PhD, MS, MPH
                      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-2 0607
                                           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 200 ++ to over 2,700 +++.

        (+Howard et al. J of Peds 2000; ++Shay DK et al. J Infect Dis 2001; +++ Institute of Medicine. In:
                                                                                                             Sorbero-3 0607
        New Vaccine Development: Establishing Priorities: Vol I. Wash DC Nat Aca Press 1986)
                                    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-4 0607
                                        Background

• Prematurity increases risk of severe RSV infection.

                          RSV Hospitalization Rate by Gestational Age at Birth

                   25%
                         20.60%
                   20%

                                          14.60%
                   15%
  Percent RSV
                                                         11.30%
 Hospitalization
                   10%
                                                                         6.40%
                   5%


                   0%
                           =< 26 W.        27 - 28 W.     > 28 - 30 W.   > 30 - 32 W.
                                            Gestational Age at Birth

                                  (Stevens TP et al. Arch Ped Adoles Med 2000)          Sorbero-5 0607
                                   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
                  45%    42%                                     41%
                  40%
                  35%
                  30%                 27%
    Probability of 25%
   hospitalization 20%
                                                    15%
                  15%
                  10%
                   5%
                   0%
                           Jan.       Feb. - Apr.   May - Aug.   Sept. - Dec.
                                         Month of Discharge


                     (Cunningham CK, McMillan JA, Gross SJ Pediatrics 1991)
                                                                                Sorbero-6 0607
                          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-7 0607
      American Academy of Pediatrics (AAP)
      Recommendations for Prophylaxis Use
• Released in 1998; updated in 2003.
• 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-8 0607
                       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-9 0607
                      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-10 0607
                      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-11 0607
                   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-12 0607
                                   Effect of Gestational Age on Expected Costs
                     9,000


                     8,000
                                                                      $ 8,000
                     7,000    $ 7,298
Expected Costs ($)




                     6,000                                                                           Synagis: AAP Recommendations:
                                                                                                     Infants: 29 - 32 weeks if = < 6 months old at the
                                                                                                                                                                  Synagis
                     5,000   Synagis: AAP Recommendations:                                           start of the RSV season
                             Infants: = < 28 weeks if = < 12 months old at
                             the start of the RSV season
                     4,000                                                                                                                                         No
                                                                                                                                                  $ 4,092        Synagis
                     3,000   $ 2,184

                     2,000                                            $ 1,548

                                                                                                                                                  $ 678
                     1,000


                        0
                              24 - 26                  27                       28                   29 - 30                  31                     32
                                                                                                                                                            Sorbero-13 0607
                                                                             Gestational Age at Birth (Weeks)
           Incremental Cost-Effectiveness Ratio


• Incremental cost-effectiveness ratio (ICER):

                                 Cost1 – Cost2 =
                                 QALY1 – QALY2
                         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-14 0607
                                                                   Effect of Gestational Age on ICER
                                     2,000,000
Incremental Cost / QALY ($ / QALY)




                                     1,800,000
                                                                                                 $1,500,351                                        $1,855,000
                                     1,600,000                                                     / QALY                                            / QALY
                                                             With Drug Wastage
                                     1,400,000
                                                                                                                                                  $1,481,965
                                     1,200,000                                                                                   $ 906,310
                                                                                                                                                    / QALY
                                                                                                                                   / QALY
                                     1,000,000   $830,152                                      $1,268,679
                                                  / QALY                                         / QALY
                                      800,000

                                      600,000
                                                     $685,720                                                               $657,780
                                                      / QALY             Without Drug                                        / QALY
                                      400,000
                                                                          Wastage
                                      200,000
                                                                     Acceptable Zone =< $ 200,000 / QALY
                                            0
                                                   24 - 26                  27                     28                      29 - 30           31    32

                                                                                              Gestational Age at Birth (Weeks)                          Sorbero-15 0607
                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-16 0607
            Large variation within GA in ICER


       $3,500,000
       $3,000,000
       $2,500,000                                         24-26 weeks
ICER




       $2,000,000                                         27 weeks
       $1,500,000                                         28 weeks
       $1,000,000                                         29-30 weeks
         $500,000
               $0

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                              Month of Discharge


                                                                   Sorbero-17 0607
Improving the Recommendation’s Cost Effectiveness


• Simulations modifying the AAP guidelines
• Assume no drug wastage
• Restrict to 1st 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-18 0607
ICER by GA and Month of Discharge with new
            Recommendation

       $600,000
       $500,000
       $400,000                        26 weeks
ICER




                                       27 weeks
       $300,000
                                       28 weeks
       $200,000
                                       30 weeks
       $100,000
            $0




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                  Month of Discharge


                                             Sorbero-19 0607
       ICER by GA with New Recommendation



       $300,000
                                                     $280,083
       $250,000
       $200,000                         $216,830
ICER




                                                                 ICER
       $150,000              $171,224

       $100,000
                  $103,053
        $50,000
            $0
                  26 weeks   27 weeks   28 weeks   29-30 weeks
                             Month of Discharge


                                                                   Sorbero-20 0607
                     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-21 0607
                        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-22 0607
            University of Rochester Collaborators



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




                                                                      Sorbero-23 0607

				
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