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A Markov model examining the public health impact and cost-effectiveness of mass vaccination using Live Attenuated Human Rotavirus Vaccine (RIX4414) in a developing Asian country Johnie Rose, MD1 Rachael L. Hawthorn, PhD1 Brook Watts, MD, MS2 Mendel E. Singer, PhD1 1. Case Western Reserve University School of Medicine Dept. of Epidemiology and Biostatistics 2. Louis Stokes Cleveland Veterans Affairs Medical Center This presentation was made possible, in part, through financial support from the School of Graduate Studies at Case Western Reserve University. Background 527,000 deaths globally in children ≤ 5 Incidence similar worldwide Most mortality occurs in lower income countries. – 23% of deaths occur in India. Deadly symptomatic triad – Fever – Diarrhea – Vomiting Wide agreement that vaccination is most promising means to reduce mortality Rotavirus Immunity and Vaccination Natural infection Æ partial immunity – First infections tend to be most severe. Multifactorial mechanism of natural immunity – Vaccine development long focused on outer capsid proteins VP7 (G protein) VP4 (P protein) RIX4414 – Monovalent G1P[8] – Most common strain – Homotypic protection > Heterotypic protection The Developing World Greater strain diversity Efficacy data scarce WHO worldwide recommendation pending Multiple competing needs Objectives To estimate the public health impact of mass vaccination with RIX4414 for an Indian birth cohort To examine the incremental costeffectiveness and affordability of such a program Methods The Markov Model Monte Carlo simulation – Tracking individuals’ vaccination and Rotavirus natural infection history 3 states: well, symptomatic, dead Perspective = health care system (all direct medical costs) Strategies – No vaccination – Vaccination at 2 and 4 months as part of WHO Expanded Program on Immunization Horizon = 60 one-month cycles Rotavirus infection history Age Vaccination history Infection? - 1st Severity? - Asymptomatic - 2nd - 3rd - Mild to moderate - Severe Health outcomes Utilization? - Home - Outpatient - Inpatient Cost outcomes Burden of Disease Incidence – Based on birth cohort study1 Morbidity p(Symptoms | Infection)1 p(Severe | Symptoms)1 Infection 1 .47 .28 Infection 2 .32 .19 Infection 3 .25 0 Mortality – Severe + No treatment = At risk for death – Calibrated to known Indian Rotavirus mortality of 1/250 (typical for developing world)2 RIX4414 Characteristics Estimated coverage = known DTP coverage3 – DPT-1: .81 – DPT-3: .62 Efficacy against severe disease estimated for India: .804 – Compare to efficacy from trials in… 11 Latin America countries and Finland4: .847 Six European countries5: .958 Efficacy conferred by single dose: .625 x full6 Waning of vaccine efficacy: 0.049 annually5 Utilization p(Site | Severity) = p(Severity | Site) * p(Site) P(Severity) Treatment site Outpatient Hospital Non-severe symptomatic infection .141 .00721 Severe infection .575 .0973 Costs Vaccine: Rs 285 (143 to 570) per dose – ≈ $US 7 (3.50 to 14.00) per dose – Price recently paid by Brazilian government7 – Administration: Rs 20.4 (10.2 to 81.6)8,9 Treatment of diarrhea – Based on 2008 cost study from Vellore India performed according to WHO protocol10 Cost-effectiveness ICER in 2007 Rupees per LYS Discounting – Costs: 3% – Health benefits: 3% Cost-effectiveness criterion – ≤1x pcGDP = “Very cost-effective” by WHO standard11 Results Outcomes Rotavirus-related events per 100,000 children No vaccination Severe infections Hospitalizations Deaths 18,260 2,367 398 Vaccination Change 11,279 -6,981 (-38.2) 1,555 -812 (-34.3) 235 -163 (-41.0) Cost-effectiveness Mean cost (2007 Rupees) Marginal cost Mean years of life lost Life years saved (LYS) No vaccination 106.5 -- 2.06627 -- Vaccination 538.9 432.4 2.01237 0.05390 ICER: Rs 8,023 / LYS (≈US$197 / LYS) Indian pcGDP: Rs 37,907 (≈US$930) “Very cost-effective” ICER (Rs / LYS) 8,023 Total Marginal Cost to Government Net cost to government per child X Annual births in India Net cost to government in one year / Dept of Health annual budget12 Percent of Dept of Health Budget Rs 463.8 US$ 11.38 25,000,000 Rs 11.60B US$ 285M Rs 100.19B US$ 2.46B 11.6% Sensitivity Analysis Only scenario with ICER > 1x pcGDP – Probability that severe infection results in hospitalization: .575 Æ .863 – Rs 51,637 / LYS = US$ 1,267 / LYS = 1.4 pcGDP Acceptability Curve 1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Rs. 0 Indian pcGDP Rs 37,907 Rs. 50,000 Rs. 100,000 Willingness to Pay WTP = 1x pcGDP: Cost-effective in 94.7% of parameter samples Discussion Limitations Lack of India/Asia-specific data, particularly… – Epidemiological – Utilization Herd immunity effects not taken into account Implications In India, adding RIX4414 to vaccination schedule – would likely save several thousand lives annually – Would likely be “very cost-effective” Affordable? – Substantial international assistance needed Opportunity costs? – Development of native vaccines? – Resources for existing programs? Questions? Supplemental Slides Burden of Disease Velazquez FR, Matson DO, Calva JJ, et al. Rotavirus infections in infants as protection against subsequent infections. N Engl J Med 1996 Oct 3; 335(14): 1022-8. Estimating Setting-specific Efficacy Indian13-15 prevalence G1P[8] .275 G1P[_] / G_P[8] .238 G_P[_] .487 Strain-specific efficacy against severe rotavirus .908 (.705 to .982) 4 .869 (.628 to .966) Product .250 (.194 to .270) .207 4 (.149 to .230) .714 .347 (,201 to .911) 16 (.098 to .444) Weighted efficacy Based on previously validated technique17 .804 (.441 to .944) Diarrhea Treatment Costs (2008 Rs) Item Base Range One dose of RIX4414 285.2 142.6, 570.4 Administration (per dose) 20.4 10.2, 81.6 Source Distribution for UA 7 Triangular 8, 9 Triangular Hospital treatment of rotavirus infection Paid by patient’s family 2444.3 1833, 3055 10 Normal Subsidized by govt 189.4 142.1, 236.8 10 Normal Direct non-medical 39.9 29.9, 49.9 10 Normal Indirect 0 -- 10 n/a Outpatient treatment of rotavirus infection Paid by patient’s family 156.2 117.2, 195.3 10 Normal Subsidized by govt 52.1 39.1, 65.1 10 Normal Direct non-medical 23.6 17.7, 29.5 10 Normal Indirect 1.8 1.4, 2.3 10 Normal 15.4 11.3, 18.8 17 Normal Oral rehydration solution Sensitivity and Uncertainty Analyses Parameter Category Range Distribution type Calculated incidence and severity ± 50% Normal Vaccine efficacy Confidence bounds reported in trials Beta Utilization ± 50% Beta Costs ± 25% Normal • Uncertainty analysis: 2nd order Monte Carlo Simulation • 1,000 parameter samples • 100,000 iterations per sample References 1. 2. 3. 4. 5. Velazquez FR, Matson DO, Calva JJ, Guerrero L, Morrow AL, CarterCampbell S, et al. Rotavirus infections in infants as protection against subsequent infections. N Engl J Med. 1996 Oct 3;335(14):1022-8. Glass RI, Bresee JS, Turcios R, Fischer TK, Parashar UD, Steele AD. Rotavirus vaccines: targeting the developing world. J Infect Dis. 2005 Sep 1;192 Suppl 1:S160-6. Immunization Profile - India. Geneva: World Health Organization; 2008 [updated 2008 Aug 28, 2008; cited 2008 September 3]; Available from: http://www.who.int/vaccines/globalsummary/immunization/countryprofilere sult.cfm. Ruiz-Palacios GM, Perez-Schael I, Velazquez FR, Abate H, Breuer T, Clemens SC, et al. Safety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis. N Engl J Med. 2006 Jan 5;354(1):11-22. Vesikari T, Karvonen A, Prymula R, Schuster V, Tejedor JC, Cohen R, et al. Efficacy of human rotavirus vaccine against rotavirus gastroenteritis during the first 2 years of life in European infants: randomised, double-blind controlled study. Lancet. 2007 Nov 24;370(9601):1757-63. References 6. Lopez P, Linhares A, Perez-Schael I, Ruiz-Palacios G, Costa Clemens S, Sanchez N, et al. Early protection against severe rotavirus gastroenteritis RIX4414 experience in Latin America. 24th Annual Meeting of the European Society of Infectious Diseases; 2006 May 3-5; Basel, Switzerland. 2006. 7. Parashar UD, Glass RI. Public health. Progress toward rotavirus vaccines. Science. 2006 May 12;312(5775):851-2. 8. Podewils LJ, Antil L, Hummelman E, Bresee J, Parashar UD, Rheingans R. Projected cost-effectiveness of rotavirus vaccination for children in Asia. J Infect Dis. 2005 Sep 1;192 Suppl 1:S133-45. 9. Isakbaeva ET, Musabaev E, Antil L, Rheingans R, Juraev R, Glass RI, et al. Rotavirus disease in Uzbekistan: cost-effectiveness of a new vaccine. Vaccine. 2007 Jan 4;25(2):373-80. 10. Mendelsohn AS, Asirvatham JR, Mkaya Mwamburi D, Sowmynarayanan TV, Malik V, Muliyil J, et al. Estimates of the economic burden of rotavirusassociated and all-cause diarrhoea in Vellore, India. Trop Med Int Health. 2008 Jul;13(7):934-42. 11. The World health report 2002 - reducing risks, promoting healthy lives [monograph on the internet]. Geneva: World Health Organization; 2002 [updated 2002; cited 2009 February 17]; pages 106-8]. Available from: http://www.who.int/whr/2002/en/. References 12. Union Budget 2007-2008. Indian National Information Centre; 2007 [updated 2007; cited 2008 November 22]; Available from: http://indiabudget.nic.in/ub200708/bag/bag4-2.pdf 13. Banerjee I, Ramani S, Primrose B, Moses P, Iturriza-Gomara M, Gray JJ, et al. Comparative study of the epidemiology of rotavirus in children from a communitybased birth cohort and a hospital in South India. J Clin Microbiol. 2006 Jul;44(7):2468-74. 14. Sharma S, Ray P, Gentsch JR, Glass RI, Kalra V, Bhan MK. Emergence of G12 rotavirus strains in Delhi, India, in 2000 to 2007. J Clin Microbiol. 2008 Apr;46(4):1343-8. 15. Samajdar S, Ghosh S, Chawla-Sarkar M, Mitra U, Dutta P, Kobayashi N, et al. Increase in prevalence of human group A rotavirus G9 strains as an important VP7 genotype among children in eastern India. J Clin Virol. 2008 Nov;43(3):334-9. 16. Rose J, Singer ME. Projecting vaccine efficacy : accounting for geographic strain variations. Pharmacoeconomics. 2008;26(3):185-9. 17. Patel AB, Dhande LA, Rawat MS. Economic evaluation of zinc and copper use in treating acute diarrhea in children: A randomized controlled trial. Cost Eff Resour Alloc. 2003 Aug 29;1(1):7.