Download A Markov model examining the public health impact and cost

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
ƒ VP7 (G protein)
ƒ 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…
ƒ 11 Latin America countries and Finland4: .847
ƒ 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.
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treating acute diarrhea in children: A randomized controlled trial. Cost Eff Resour
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