E

SAa

b

c

d

e

f

g

h

a

KCINRV

1

hhr5rtsIycec

diNW

GU

0d

Vaccine 27S (2009) F67–F74

Contents lists available at ScienceDirect

Vaccine

journa l homepage: www.e lsev ier .com/ locate /vacc ine

conomic evaluation of a routine rotavirus vaccination programme in Indonesia

iswanto Agus Wilopoa,∗, Paul Kilgoreb, Soewarta Kosenc, Yati Soenartod, Sri Aminahe,nton Cahyonof, Maria Ulfag, Abu Tholibh

Centre of Reproductive Health, Department of Public Health, Faculty of Medicine, Gadjah Mada University, Yogyakarta, IndonesiaDivision of Translational Research, International Vaccine Institute, Seoul, Republic of KoreaNational Institute of Health Research and Development (BALITBANG), Ministry of Health, Jakarta, IndonesiaDepartment of Paediatrics, Faculty of Medicine, Gadjah Mada University, Dr. Sardjito Hospital, Yogyakarta, IndonesiaDepartment of Paediatrics, Wirosaban Hospital, Yogyakarta, IndonesiaDepartment of Paediatrics, Purworejo District Hospital, IndonesiaDistrict Health Office, Purworejo District, IndonesiaDepartment of Microbiology, Faculty of Medicine, Gadjah Mada University, Yogyakarta, Indonesia

r t i c l e i n f o

eywords:ost-effectiveness

ndonesia

a b s t r a c t

An economic evaluation was undertaken to assess the potential for introducing rotavirus vaccine intoIndonesia’s National Immunization Program. For a projected birth cohort of 4.2 million children was

ational immunization programmeotavirusaccine

followed until 5 years of age, a routine rotavirus vaccination programme could potentially avert 488,547cases of diarrhoea treated in outpatient hospital facilities, 176,375 hospitalizations, and 8148 deaths.Assuming a cost of US$ 14 per vaccine course, the incremental cost-effectiveness ratio would equalUS$ 120.46 per disability adjusted life years averted, making routine vaccination highly cost-effectivegiven Indonesia’s Gross National Income per capita of US$ 1560. At a cost per vaccine course of US$ 3.79(societal perspective) or US$ 2.70 (health-care system perspective), routine rotavirus vaccination could

in In

be potentially cost-saving

. Introduction

In Indonesia, diarrhoeal diseases remain a significant publicealth concern because the prevalence of diarrhoeal morbidityas not changed significantly in recent decades [1], and diarrhoeaemains the third leading cause of death among children less than

years of age [2]. Recent surveillance studies have shown thatotavirus diarrhoea is a significant cause of paediatric hospitaliza-ions and death in the country [3–7]. Such hospitalizations result inignificant economic burden for both the government and families.n Asia, 30–55% of hospital admissions for acute gastroenteritis in

oung children are due to rotavirus infection, particularly in thosehildren younger than 3 years. We have previously assessed thepidemiology of rotavirus infection and the characteristics of theirculating strains in anticipation of the availability of rotavirus

Abbreviations: DALY, disability adjusted life years; DPT,iphtheria–tetanus–pertussis; EPI, Expanded Programme on Immunization; ICER,

ncremental cost-effectiveness ratio; IDHS, Indonesia Demographic Health Survey;BDS, National Disease Burden Study; NIP, National Immunisation Programme;HO, World Health Organization.∗ Corresponding author at: Department of Public Health, Faculty of Medicine,adjah Mada University, Jl. Farmako 1, Gedung IKM Lantai 1, Fakultas Kedokteran,GM, Yogyakarta 55281, Indonesia. Tel.: +62 274 565602; fax: +62 274 548156.

E-mail address: sawilopo@yahoo.com (S.A. Wilopo).

264-410X/$ – see front matter © 2009 Elsevier Ltd. All rights reserved.oi:10.1016/j.vaccine.2009.09.040

donesia.© 2009 Elsevier Ltd. All rights reserved.

vaccines [4,8]. These data show that rotavirus is responsible forapproximately 57% (range, 43–67%) of hospitalizations due to diar-rhoea among children less than 5 years of age [9,10].

Two rotavirus vaccines (Rotarix® and RotaTeq®) are now avail-able and have been included into the National ImmunizationProgrammes (NIP) of several countries [11–14]. These vaccines areorally administered and have been shown to be efficacious and safein large clinical trials undertaken predominantly in high and mid-dle income countries [15,16]. Among children who have receivedeither Rotarix® or RotaTeq®, protection against severe rotavirusgastroenteritis extends into the second year of follow-up and thesevaccines can be co-administered with other routine childhood vac-cines. Although the World Health Organization (WHO) has recentlymade global recommendations on the use of these vaccines, lessdata are available on the efficacy of these two vaccines in low-income countries, particularly in Africa and Asia. Several othercandidate rotavirus vaccines are also undergoing clinical testing[11–14].

Before routine immunization with rotavirus vaccine can be rec-ommended for Indonesian children, policy-makers need to assess

the expected health and economic benefits of a vaccination pro-gram [17,18]. In addition to the need for data on vaccine safety andefficacy, decisions whether to implement these new vaccines willrequire assessment of cost-effectiveness [19–24]. Ideally, coun-tries considering the introduction of rotavirus vaccines will need

F ccine 27S (2009) F67–F74

tme[

vnsocc

2

2

wrcpDbbysrbbi(anbDoc

ta1naN(pns3tfycrrbr

l4aaedEw

sebu

rden

ofro

tavi

rus

dia

rrh

oea

wit

han

dw

ith

out

an

atio

nal

rou

tin

ero

tavi

rus

vacc

inat

ion

pro

gram

inIn

don

esia

for

a1-

year

birt

hco

hor

t(n

=4.

2m

illi

on)

foll

owed

thro

ugh

5ye

ars

ofag

e.

Tota

ldia

rrh

oea

case

s(n

)R

otav

iru

sw

ith

out

vacc

inat

ion

(n)

Rot

avir

usa

sp

erce

nta

geof

allc

ause

dia

rrh

oea

Rat

eaR

otav

iru

sw

ith

vacc

inat

ion

(n)

Prev

ente

dby

vacc

inat

ion

(n)

Perc

enta

gere

du

ctio

nd

ue

tova

ccin

atio

n

13,8

0510

,651

773.

32,

503

8,14

876

.5b

n38

6,68

620

9,97

054

50.0

33,5

9517

6,37

584

.0it

3,48

9,61

869

7,92

420

[8]

166,

220

9,46

748

8,54

770

.047

8,00

036

7,83

077

8686

,440

281,

390

83.0

d

ssed

per

1000

chil

dre

nle

ssth

anfi

veye

ars

ofag

e.ot

avir

us

dea

ths

pre

ven

ted

byva

ccin

atio

nis

mid

-poi

nt

betw

een

84%

and

70%

from

refe

ren

ce[1

5].

esd

isab

ilit

y-ad

just

edli

fe-y

ear.

red

uct

ion

ofD

ALY

sd

ue

tova

ccin

atio

n[1

9].

68 S.A. Wilopo et al. / Va

o know the local prevalence of rotavirus disease (morbidity andortality), as well as financial costs associated with rotavirus dis-

ase [17,18]. These data have recently been collected for Indonesia4].

This economic evaluation assesses the potential for rotavirusaccine to be introduced into Indonesia’s NIP. In this report, theational disease burden of rotavirus is assessed from primary andecondary sources of surveillance data. The WHO generic protocoln cost assessment was used to determine the direct cost of health-are services for rotavirus-specific diarrhoea as well as the indirectosts to individual patient in Indonesia [25].

. Materials and methods

.1. Disease burden estimates

The total number of diarrhoea cases and deaths nationally asell as disability-adjusted life years (DALY) associated with diar-

hoea was obtained from the National Disease Burden Study (NBDS)onducted in Indonesia [26]. The NBDS study used a spreadsheetrogramme based on methods described in the Global Burden ofisease Study [27,28]. The DALY calculation inputs population datay age group and sex [29], disease incidence and case-fatality ratesy age group and sex [2], a life-table model [29], parameters forears lost to disability or disability weights [26], and other con-tants for the model, including a weighting factor and discountingate [27]. This program provides a range of results including num-er of cases by disease and age group, numbers of death and deathsy disease and age group, years of life lost due to premature mortal-

ty (YLL) by disease and age group, years of life lost due to disabilityYLD) by disease and age group, and total DALYs lost by disease andge group. We used this program to obtain estimates for the annualumber of all diarrhoea diseases in children <5 years age, the num-er of children <5 years of age that died due to diarrhoea, and theALYs due to diarrhoea (Table 1). This program was also used tobtain number of deaths and DALYs from rotavirus diarrhoea forhildren <5 years based on estimated rotavirus case-fatality rates.

In our analysis, the annual incidence of diarrhoea was estimatedo be 2400 per 10,000 children <5 years for both sexes [26], and thennual rotavirus incidence was estimated to be 1400 and 1300 per0,000 for boys and girls <5 years, respectively [3,8]. The estimatedumber of diarrhoeal deaths was derived from a national surveynd verbal autopsy data which was also used in the IndonesianDBS. In this report, the mortality rate attributable to diarrhoea

overall case-fatality rate) among children aged 0–4 years was 2.8er 10,000 children with all-cause diarrhoea. Because there areo national-level rotavirus-specific mortality estimates in Indone-ia, we assumed that rotavirus-specific mortality (4.0 [males] and.8 [females] per 10,000 children <5 years of age) which equatedo 77% of all cause diarrhoea deaths (Table 1). The higher case-atality rate for rotavirus-specific diarrhoea in children under <5ears compared with rates for all-cause diarrhoea is consistent withlinical experience in Indonesia. These disease and case-fatalityates were applied with appropriate age-weighting and a discountate of 3% to calculate the number of health events that occur in airth cohort followed for five years with and without a universalotavirus immunisation programme (Table 1) [26–28].

Among the 4.2 million births annually in Indonesia (20.633 mil-ion children aged <5 years in 2008), it was estimated that a total of.845 million children will suffer from diarrhoea. The DALYs associ-ted with all-cause and rotavirus-specific diarrhoea were 478,000

nd 367,830, respectively (Table 1). Rotavirus-specific diarrhoeavents used in the model were derived from age-specific rates ofiarrhoea reported in the IDHS-2007 [1] and the National Socialconomic Survey [2] by applying the total number of childrenith diarrhoea children (4.845 million) annually in the NDBS. We Ta

ble

1Es

tim

ated

dis

ea

Ou

tcom

ety

pe

Dea

thH

osp

ital

izat

ioO

utp

atie

nt

vis

DA

LYc

aR

ates

exp

reb

Prop

orti

onr

cD

ALY

den

otd

Perc

enta

ge

ccine 2

dddincihEcfwotiotTrrstTicovrc

2

2

wIltfdmyYtt2(ndh

2

hehcqe[thdpcm

S.A. Wilopo et al. / Va

erived the proportion of rotavirus-specific diarrhoeal episodes byividing rotavirus-specific events by the total number of all-causeiarrhoeal events [8]. This estimate was validated with other stud-

es undertaken in Indonesia [8]. In Indonesia, it is recognized thatot all diarrhoea cases present to health-care facilities as manyhoose to self-administer treatment at home. Based on availablenformation, we assumed that 80% of diarrhoea cases attendedospital or outpatient facilities (3.876 million children <5 years).stimates of inpatient hospitalizations and outpatient diarrhoeaases were calculated separately since the costs of treatment dif-er. Similarly, diarrhoea treated in private and public hospitalsere calculated separately for the same reasons. The percentage

f rotavirus-specific diarrhoeal episodes (38%) among all outpa-ients with diarrhoea was available from the study undertakenn the PHCs in Purworejo district and likely reflects the presencef active case ascertainment in surveillance as well as perceptionhat severe watery diarrhoea requires prompt medical attention.o avoid over-estimating costs of outpatient diarrhoea due tootavirus were assumed that 20% of outpatient diarrhoea was due tootavirus. As a conservative estimate based on recent surveillancetudies, the proportion of rotavirus-specific diarrhoeal hospitalisa-ions (range, 54–57%) among inpatients was assumed to be 54% [3].he proportion rotavirus deaths prevented by vaccination of 76.5%s also a conservative estimate based on reported rotavirus vac-ine efficacy against rotavirus-specific hospitalizations (84%) andutpatient (70%) visits [15]. Based on economic analysis of uni-ersal rotavirus immunsation in Vietnam [19], we estimated thatotavirus vaccine would result in an 83% reduction in DALYs asso-iated with rotavirus-specific diarrhoea (Table 1).

.2. Economic burden estimates

.2.1. Study populationEconomic and disease burden data were collected from Pur-

orejo district and Yogyakarta city in Central Java Island ofndonesia. Purworejo district is the site of a demographic surveil-ance study of the Gadjah Mada University and is a member ofhe INDEPTH Network. INDEPTH is an international organisationor the demographic evaluation of populations and their health ineveloping countries. In 2007, the Purworejo district had an esti-ated population of 774,285 including 45,232 children less than 5

ears of age (5.8% of the total population). The total population ofogyakarta was estimated to be 433,539 with 25,812 children lesshan 5 years of age (6%). Based on the Indonesia Population Projec-ion [29] and the Indonesia Demographic Health Survey 2007 (IDHS007) [1], disease burden data from primary health-care centresPHC) and district-level hospitals [8], were extrapolated to estimateational population estimates. Previous studies were used to vali-ate this assessment, including recent surveillance data from sevenospitals in Indonesia [3].

.2.2. Health-care cost data collectionThe economic burden of rotavirus-specific diarrhoea to the

ealth-care system was estimated by combining the number ofach event (i.e. death, hospitalization and outpatient visit at theospitals and PHCs) with information on the direct and indirectosts associated with each event [8]. We used a standardizeduestionnaire from the WHO guideline for conducting cost-ffectiveness analysis of a routine rotavirus vaccination programme25]. Estimates of the per-day and per-visit costs were obtainedhrough interviews with government health officials and private

ospital managers, including Purworejo and Yogyakarta hospitalirectors, paediatric department administrators, regional healthlanners and administrators and owners of private hospitals orlinics. The WHO generic protocol recommends collection of directedical costs (i.e., medication, diagnostics, and bed cost), non-

7S (2009) F67–F74 F69

direct medical costs (transportation) and indirect costs (lost wages)[25]. These data were collected from two different levels of health-care facilities (i.e., 3 hospitals and 6 PHCs). Hospital costs were alsocollected from public and private hospitals. For hospitalization andoutpatient visits, costs were also partitioned into direct medicalcost, non-direct medical cost, and indirect costs. The study alsoused information on health-care utilization practices for childhooddiarrheal illness from the IDHS 2007 [1]. Published reports from thecommunity laboratory at the Purworejo district were also used toassess the proportion of visits to various health-care facilities [30].

For this study, team investigators used questionnaires to con-duct interviews with the parents of children less than 5 years ofage with acute diarrhoea in hospital wards, the PHC and the par-ent’s home. Inpatients were interviewed on the day of discharge,and information on treatment and diagnostic testing was obtainedthrough subsequent review of the child’s medical record as well asdirect interview with their parents. To collect data on the indirectcosts of illness, home visits were conducted by team investiga-tors within two weeks after hospital discharge [8]. The medicaldirect costs for hospitalized patients were calculated by combin-ing patient information on resource use (including length of stay)and unit cost of a hospital bed day, diagnostic tests, and medica-tions using standardized instruments recommended by WHO [25].The bed costs reported were those paid by families to either pub-lic or private hospitals, and do not reflect costs of any governmentsubsidises. The bed cost for the government hospital was basedon the local parliament decree, which is not related to actual gov-ernment spending. For example, the bed cost at the Purworejodistrict hospital was less than US$ 1 per day. We were not ableto estimate the actual cost of a bed day other than that actuallypaid for by families. For the outpatient visits, direct and indirectcosts were mainly calculated from the PHC visits. In contrast, wecalculated the costs of the outpatient hospital visits with the dura-tion of stay excluded since no outpatient facilities offered overnightstay. Parents were asked to estimate the time they lost from paidemployment while taking care of their sick child (in days) and thetime (hours) or distance (in kilometres) and mode of transportationto and from health-care facilities. This information was included inthe model when calculating the indirect costs and the non-medicaldirect costs, respectively.

Based on the above information, medical direct costs forrotavirus-specific diarrhoea in the first 5 years of life were esti-mated for the 2007 Indonesian birth cohort. Similarly, the averagemedical indirect costs per child in the birth cohort were estimatedfor the child’s first 5 years of life. All costs are expressed in 2007US$, where one US$ equals 9.500 Rupiah.

2.3. Rotavirus vaccination effectiveness and costs

The effectiveness of vaccination was calculated by combiningthe estimated vaccine coverage and efficacy information as variablefunctions depending on the age at vaccination. We used a modelthat incorporates information on disease burden, vaccine cover-age, and vaccine effectiveness to obtain the cost-effectiveness of aroutine rotavirus vaccination programme. The age distribution ofthe key rotavirus disease outcomes (hospitalization) was based onour surveillance data from hospitals and PHC. The age-specific ratesfor outpatient visits were the same as for inpatient visits. The totalnumber of events for the annual birth cohort was estimated usingeight age groups (in months): 0–2, 3–5, 6–8, 9–11, 12–23, 24–35,36–47, and 48–59 months.

The expected vaccination status of children in each age groupwas estimated from the National Household Survey [2] and longitu-dinal surveillance data from the Purworejo Community Laboratory[30]. We assumed that the timing of vaccination would be the sameas that of the diphtheria-tetanus-pertussis (DTP) vaccine given at

F ccine

aso8lcfftdli

owcpvcvfciic

2

taaitaahrceavwiIb

2

t

TS

N

70 S.A. Wilopo et al. / Va

ge 6 and 10 weeks, respectively. We used a vaccine with a 2-dosechedule instead of 3 doses because third dose Expanded Programn Immunization (EPI) vaccine coverage of any EPI vaccine is below0% in Indonesia. Based on the National Household Survey and

ongitudinal surveillance data in Purworejo district, rotavirus vac-ine coverage was estimated to be 85% for the 1st dose and 80%or 2nd dose. Rotavirus vaccine efficacy was estimated to be 84%or the prevention of rotavirus-associated hospitalizations, 70% forhe prevention of outpatient visits, and 76.5% for prevention ofeaths (Table 1) [15,16]. It was assumed that efficacy was simi-

ar in younger infants prior to full vaccination and in that in oldernfants there was no loss of efficacy.

Vaccination costs included the cost of administration, the pricef the vaccine, and expected losses from unused vaccine. Since thereas no recent data on the cost of administering current EPI vac-

ines in Indonesia, a hypothetical administration cost of US$ 0.50er vaccine course was used as the marginal cost of adding a newaccine to EPI [19]. To estimate the immunization program cost, wealculated total costs based on the number of vaccines required toaccinate 4.2 million infants annually. We assumed that the lossesrom unused vaccine (wastage) was 10%. We assumed the nationaloverage of the vaccination program was 80% for rotavirus [1] sim-lar to DTP vaccination coverage [30]. The total cost of a rotavirusmmunisation program was estimated to be the sum of all vaccineosts plus the cost of administering the vaccination programme.

.4. Economic model overview

Economic modelling methods outlined in the WHO generic pro-ocol to estimate health-care costs of rotavirus-specific diarrhoeand cost-effectiveness of rotavirus vaccination were used [25]. Ournalyses were conducted from both the health-care system (takingnto account only direct medical costs) and the societal perspec-ive (taking into account additional costs borne by individuals suchs lost work days) [19,21,31]. This model compared the cost ofhealth intervention (rotavirus vaccination) with the cost of no

ealth intervention. The principal inputs to the model includedates of disease requiring treatment in hospitals and outpatientlinics and their associated health-care costs and the estimatedffectiveness and cost of vaccination. Ideally, the model should alsoccount for the timing of vaccination (children may not receiveaccine precisely at 6 and 10 weeks of age), because the vaccineould not be recommended, and would possibly be less effective,

f introduced at a later age. However, there are no data available inndonesia regarding the timing of routine EPI vaccines that coulde included in this model.

.5. Cost-effectiveness analysis

The primary measures of cost-effectiveness in this study werehe incremental cost-effectiveness ratios (ICERs) expressed as cost

able 2ample distribution of diarrhoea cases by research area, health facility and patient status

Characteristic All-cause diarrhoea outcomes

Public hospital; n (%) Priva

AreaYogyakarta city 184 (100) n.a.Purworejo district 239 (21) 268

StatusInpatient 390 (44) 268Outpatient 33 (7.2) n.a.

Total 423 (31) 268

ote: n.a. denotes not applicable where data could not be obtained; PHC denotes Primary

27S (2009) F67–F74

per DALY averted and cost per life saved [32]. ICERs compare thenet cost of a health intervention with the benefit gained by provid-ing it. For this analysis, the net cost equals the cost of administeringthe rotavirus vaccine minus the medical costs averted by vaccina-tion. The DALY measure included two components: years of life lostdue to premature mortality and years lived with disability for eachtype of patients (i.e., hopitalized or non-hospitalized). The DALYloss from mortality (years of life lost) was calculated using a for-mula that applied the standardized life expectancy for children lessthan one year old [26,27]. The ICER was calculated for a range ofvaccine prices (US$ 1 to US$ 15 per vaccine course). Also calcu-lated was the estimated price at which vaccination would be costneutral (i.e., medical or total costs saved equal the cost of vaccina-tion) and cost-effectiveness (i.e., cost per DALY averted less thanor equal to a particular standard) [26]. ICERs of <US$ 200/DALYare highly cost-effective for developing countries [19,21,28]. TheWorld Bank’s World Development Report 1993: Investing in Healthsuggested that an intervention is very cost-effective if the cost perDALY averted is less than a country’s gross domestic product (GDP)per capita, which for Indonesia was US$ 1560 for 2007.

2.6. Sensitivity and uncertainty analysis

Sensitivity and uncertainty analyses were performed to addressthe potential uncertainty created by some of the assumptions suchas extrapolating regional incidence and cost data to a national level.This approach was conducted to assess the impact of rotavirus-specific diarrhoea rate estimates, vaccine efficacy, per day and pervisit cost estimates (with variable ranges using 95% of lower andupper confidence limits), and vaccine price on the ICER [31].

2.7. Ethical approval

This study was approved by the human subjects research com-mittees at the Faculty of Medicine, Gadjah Mada University and theethics committee of PATH, Seattle, Washington. Informed consentwas obtained from all subjects enrolled in the study [8].

3. Results

3.1. Economic burden of rotavirus diarrhoea

Economic data were collected from 1349 families of childrenwith acute diarrhoea. In Purworejo district, we surveyed 239patients in a public hospital, 268 patients from a private hospital,and 658 patients from a PHC. In Yogyakarta city, we surveyed 184patients from a public hospital, and no patients from a private hos-

pital or PHC. There were 390 inpatients from public hospitals, 268from a private hospital and 233 from PHCs. In addition, there were33 outpatients from public hospitals and 425 from PHC (Table 2).

Total direct medical costs were 1.7 times higher in Purworejodistrict hospitals than in the hospital in Yogyakarta (Table 3). The

in Central Java, Indonesia, 2006 through 2007.

Total; n (%)

te hospital; n (%) PHC; n (%)

n.a. 184 (100)(23) 658 (57) 1,165 (100)

(30) 233 (26) 891 (100)425 (93) 458 (100)

(20) 658 (49) 1,349 (100)

Health-Care Centre.

S.A. Wilopo et al. / Vaccine 27S (2009) F67–F74 F71

Table 3Mean (standard deviation) values for direct and indirect costsa associated with diarrhoea among children less than 5 years of age treated in Purworejo district and Yogyakarta.

Category Hospital PHC Average costb

Public Private

Hospitalization costs(a) Direct medical

Medication and diagnostics 41.05 (32.95) 71.52 (41.17) 36.90 (31.03) 48.28 (37.79)Bed cost per visit 3.45 (2.73) 4.18 (10.96) .09 (.05) 3.97 (7.52)Total 44.50 (33.31) 75.70 (41.34) 36.99 (31.08) 49.66 (38.69

(b) Non-medical direct costs (transportation) 8.34 (7.75) 13.46 (11.69) 4.88 (6.04) 8.69 (9.21)(c) Indirect costs (lost wages) 7.63 (13.90) 8.91 (13.82) 6.04 (11.25) 8.71 (13.23)

Total cost of hospitalization 60.46 (39.89) 98.08 (46.35) 47.92 (35.81) 67.06 (45.26)

Hospitalization according to area(a) Yogyakarta 49.21 (48.81) n.a.c n.a. 49.21 (48.81)(b) Purworejo 67.58 (31.10) 98.08 (46.35) 47.92 (35.81) 83.70 (42.68)

Total cost of hospitalization 60.46 (39.89) 98.08 (46.35) 47.92 (35.81) 67.06 (45.26)

Outpatient costs(a) Medical direct cost

Medication and diagnostic 7.24 (10.99) n.a. 3.65 (10.16) 3.95 (10.16)Registration cost per visit 6.93 (1.87) n.a. .64 (4.15) 1.18 (6.90)Total Medical direct cost 14.17 (24.09) n.a. 4.30 (12.30) 5.13 (13.92)

(b) Non-medical direct cost (transport) 1.43 (1.76) n.a. 0.27 (0.38) .36 (.70)(c) Indirect cost (lost wages) 3.60 (4.84) n.a. 1.07 (3.89) 1.28 (3.89)

Total cost of outpatients 19.21 (26.48) n.a. 5.63 (12.81) 6.78 (14.91)

Outpatients by areasYogyakarta 19.21 (26.48) n.a. n.a.Purworejo n.a. n.a. 5.63 (12.82) 5.63 (12.82)

Total cost of outpatients 19.21 (26.48) n.a. 5.63 (12.82) 6.78 (14.91)

valu

cltppepwsTctgmnttUa

a Costs expressed in 2007 US dollars (1 USD = Rp 9500).b Because values shown are weighted by sample size in each category, total meanc n.a. denotes not applicable where data could not be obtained.

ost of a private hospital visit was 1.6 times higher than a pub-ic one. The cost of outpatient treatment at a hospital was almosthree times higher than incurred at a PHC. These costs are com-arable with our previous study in these areas [4]. The cost ofublic hospital inpatient stay accounted for the majority of medicalxpenditures for patients (68%, US$ 41.05 of 60.46). The public hos-ital cost was higher in Purworejo district (US$ 67.58) comparedith Yogyakarta (US$ 49.21), despite a slightly shorter hospital

tay (mean stay, 3.6 days in Purworejo vs. 4.7 days in Yogyakarta).he main reason that the direct medical cost of Purworejo hospitalare was high compared to Yogyakarta (mean and standard devia-ion: US$ 53 ± 37.52 vs. US$ 27.90 ± 37.70) appeared to be due to areater use of unnecessary antibiotics in Purworejo district [8]. Theean cost of an outpatient visit at Purworejo district hospital was

ot available due to a small number of cases. At Yogyakarta hospi-

al, the mean cost of an outpatient clinic visit was US$ 19.21, whilehe outpatient clinic visit cost at PHCs in Purworejo district wasS$ 5.63. Parents’ lost income due to a child’s illness was highestmong outpatients attending public hospital facilities (US$ 3.60)

Table 4Mean costsa per child less than 5 years of age associated w

Category Mean costb (9

Hospitalizatio

Medical direct 49.66 (47.20–Non-medical direct 8.69 (8.11–9Indirect 8.71 (7.87–9

Total 67.06 (64.19–

a Costs expressed in 2007 US dollars (1 USD = Rp 9500).b Mean costs are average values across type of facilitie

Table 3).c 95% confidence interval used as range of values for sen

es may differ from the sum of subcategory mean values.

compared with any other outpatient clinic or PHC (1.07). For thecost-effectiveness analysis, the estimates of medical direct, indi-rect and societal costs for rotavirus diarrhoea from Table 3 weresimplified (Table 4). Inpatient costs were about 10 times higherthan outpatient costs.

Extrapolating our cost-estimates for the Purworejo andYogyakarta districts (Table 4) to national level of rotavirus diar-rhoea disease burden estimates (Table 1), the rotavirus-associatedeconomic burden from a health-care system perspective was US$14.536 million per year (US$ 3.46 per birth annually) in medicaldirect costs and US$ 2.169 million per year (US$ 0.52 per birth annu-ally) in non-medical direct costs. The total cost (direct and indirect)was US$ 19.527 million (US$ 4.65 per birth annually) (Table 5).

3.2. Economic benefit of vaccination

Extrapolating from case-fatality rate for all diarrhoea androtavirus diarrhoea nationally, we estimate that there would be13,805 deaths of children aged 0–4 years attributable to rotavirus

ith rotavirus diarrhea in Indonesia.

5% confidence intervalc)

ns Outpatient visits

52.10) 5.13 (3.75–6.51).27) .36 (0.29–.43).55) 1.28 (.88–1.69)

69.92) 6.78 (5.30–8.26)

s (public hospital, private hospital, and PHC) (see

sitivity analysis (see Tables 5 and 6).

F72 S.A. Wilopo et al. / Vaccine 27S (2009) F67–F74

Table 5Economic burden of rotavirus-specific diarrhoea in Indonesia.

Category Total mean costa in 1000s (95% confidence interval) Annual average total cost per childb

Hospitalization Outpatient visits Total cost

Medical direct 10,956 (10,413–11,494) 3,580 (2,617–4,544) 14,536 (13,031–16,038) 3.46 (3.10–3.82)Non-medical direct 1,917 (1,789–2,045) 251 (202–300) 2,169 (1,992–2,345) 0.52 (0.47–0.56)Indirect 1,922 (1,736–2,107) 8,93 (614–1,180) 2,815 (2,350–3,286) 0.67 (0.56–0.78)

Total cost of expenditures 14,795 (14,162–15,426) 4,732 (3,699–5,765) 19,527 (17,861–21,191) 4.65 (4.25–5.05)

a Costs expressed in 2007 US dollars (1 USD = Rp 9500).b Based on a 1-year birth cohort (n = 4.2 million).

Table 6Economic benefits of rotavirus-specific diarrhoea vaccination (mean and 95% confidence intervals) according to cost saved by vaccination in Indonesia.

Category Costsa (in 1000s) Annual average total cost per childb

Hospitalization Outpatients Total cost of expenditures

Medical direct 9,163 (8,710–9,614) 2,506 (1,832–3,180) 11,670 (10,542–12,794) 2.78 (2.51–3.05)Non-medical direct 1,604 (1,497–1,711) 176 (142–210) 1,779 (1,638–1,921) 0.42 (0.39–0.46)Indirect 1,607 (1,452–1,762) 625 (430–826) 2,233 (1,882–2,588) 0.53 (0.45–0.62)

35)

dv1N(toIpp(1

3

itawdcHpia

1

3

tc(vp

v

tion. The analysis gave a break-even price and range per course ofUS$ 2.70 (US$ 2.39–3.01) from a health system perspective and US$3.79 (US$ 3.45–4.13) from a societal perspective (Fig. 2).

Total costs 12,374 (11,845–12,902) 3,312 (2,589–4,0

a Costs expressed in 2007 US dollars (1 USD = Rp 9500).b Based on a 1-year birth cohort (n = 4.2 million).

iarrhoea and 10,651 of these deaths could be prevented throughaccination (Table 1). Overall we estimate a loss of 86 DALYs per000 children. Introduction of a rotavirus vaccine into Indonesia’sIP could prevent approximately 8148 (76.5%) deaths, 176,375

84%) hospitalizations and 488,547 (70%) outpatient visits to hospi-al facilities (Table 1). Multiplying our cost estimates by the numberf health-care visits averted, introduction of a rotavirus vaccine intondonesia’s NIP could save US$ 11.670 million per year (US$ 2.78er birth annually) in medical direct costs and US$ 1.779 millioner year (US$ 0.42 per birth annually) in non-medical direct costsTable 6). The total costs (direct and indirect) saved would be US$5.687 million (US$ 3.73 per birth annually).

.3. Cost of rotavirus vaccination program

At a cost per child (per course) of US$ 14 (cost of vaccine whenntroduced into Brazil’s NIP in 2006) and with a vaccine adminis-ration cost of US$ 0.50 per child, with a vaccine coverage of 80%nd wastage of 10%, a national rotavirus immunisation programould cost US$ 53.424 million annually ([((4.2 million chil-ren × 80% coverage) + (10% wastage × (4.2 million children × 80%overage))) × US$ 14 + (4.2 million × 80% coverage) × US$ 0.5)]).ere, we assumed that the administration cost of vaccine is an inde-endent from the coverage and price of vaccine. Further analysis

ncluded a range of price estimates, from US$ 1.00 to US$ 15.00, forcourse of rotavirus vaccine (Figs. 1 and 2).

The ICER was 120.46 assuming a cost per vaccine course of US$4:

Total cost of vaccination (53, 424, 000) − Total cost of no vaccination (19, 527, 000)Total DALY without vaccination (367, 830) − Total DALY with vaccination (86, 440)

.4. Break-even analysis

Given the foregoing assumptions, the cost estimate of vaccina-ion program was expressed as a linear regression between totalost of vaccination program and the vaccine price per course of child

Fig. 1), where the cost of vaccination program = 1.68 + 3.696 (theaccine cost per child) or the vaccine price = ([the cost of vaccinationrogram − 1.68]/3.696).

The medical-break even price (the point at which the cost ofaccination would be offset by the medical costs averted but not

15,687 (14,434–16,937) 3.73 (3.44–4.03)

including non-medical direct cost), the cost of a rotavirus immu-nization program should equal US$ 11.670 million (Table 6). Usingthis number we can substitute in the equation to get the vaccinecost per child to be US$ 2.70 (Fig. 1). A similar calculation for thesocietal break-even cost (medical direct, non-medical direct andindirect costs of US$ 15.687 million) would be US$ 3.79 per vaccinecourse (Fig. 1).

3.5. Sensitivity and uncertainty analysis

Uncertainty limits for total health care and societal costs(Table 5) and benefits of vaccination (Table 6) were set at the upperand lower 95% confidence limits (Fig. 2). Uncertainty in the efficacyagainst death and the cumulative incidence of morbidity due torotavirus disease could have a significant impact on ICER but werenot considered in this analysis. Ranges of values were based on the95% the confidence intervals of the health care and societal costsand benefits of vaccination using the previous a regression equa-

Fig. 1. Rotavirus vaccine: medical and societal costs in Indonesia, 2007 (mean, US$).

S.A. Wilopo et al. / Vaccine 2

Fd

4

mNeh5nerpooabcwUcpobbfccV6Arc[fNUchnG0ntv

si

ig. 2. Rotavirus vaccine: medical and societal cost in Indonesia, 2007 (95% confi-ence intervals limits in US$).

. Discussion

This economic evaluation provides information for decisionaking for the introduction of rotavirus vaccine into Indonesia’sIP. Considerable health care and societal costs result from thestimated 209,970 hospitalizations, 697,924 outpatient visits toospital facilities, and 10,651 deaths per year in children less thanyears old attributable to rotavirus. Total direct costs (medical andon-medical direct costs i.e., transportation) and indirect costs (lostarnings) were US$ 19.527 million (US$ 4.65 per child). This costepresents 0.3% of Indonesia’s Gross National Income of US$ 1560er capita. This estimate of total direct costs is lower than a previ-us study undertaken in Vietnam (0.5%) [19]. With the introductionf rotavirus vaccine into the NIP, 80.3% of the total costs could beverted (total burden divided by benefits or US$ 15.687 dividedy US$ 19.527) and at a vaccine price of US$ 14 per course, theost per DALY averted would be US$ 120.46. If the cost per courseas US$ 361.1 and US$ 123.6, the ICER would be US$ 4680 andS$ 1560 equivalent to three and one times Indonesian GDP perapita respectively. This would suggest that even at these higherrices rotavirus vaccine could be considered cost-effective basedn the thresholds proposed by the World Bank [19,28]. The medicalreak-even price, the point at which the cost of vaccination woulde offset by the medical costs averted was US$ 2.70 (2.39–3.01)or a vaccine course. Inclusion of non-medical direct and indirectosts, the societal break-even price was US3.79 (3.5–4.13) per vac-ine course. The main driver of cost-effectiveness is vaccine cost.accine price reported from the USA and other countries (US$2.50 per dose or US$ 187.50 for a three-dose course). [11,14]lthough considered cost-effective from a US perspective, othereports have suggested that at this price rotavirus vaccine is notost-effective in both developed and developing country settings20–24,33]. However Brazil obtained rotavirus vaccine for US$ 14or a two dose course when the vaccine was introduced into itsIP in 2006. At a cost per course of US$ 14 the ICER would beS$ 120.46 per DALY averted, which would be considered highlyost-effective for Indonesia since ICERs of <US$ 200/DALY areighly cost-effective for developing countries [19,21,28]. To buildational ownership and encourage evidence-based decisions, theAVI Alliance requires a small co-payment (currently between US$.15 and US$ 0.30 per vaccine dose) from GAVI-eligible countries forew vaccines [34]. It is anticipated that this will also be the price

hat GAVI-eligible countries will be required to pay for rotavirusaccines.

Some interventions that are cost-effective may also be cost-aving if the treatment costs averted are greater than the cost ofntroducing the health intervention. Although health interventions

7S (2009) F67–F74 F73

that result in improved health and save money are very good invest-ments, there are relatively few such interventions that can achievethis outcome with the exception of some of the traditional low costEPI vaccines. The results from Indonesia indicate that a rotavirusvaccination program would be cost-neutral at a break-even priceof US$ 2.39–3.01 (health-care perspective) to US$ 3.45–4.13 (soci-etal perspective). However, even if such a program is consideredpotentially cost-saving, it might not be affordable by the Indone-sian Government in the shorter term with its limited resourcesand budget constraints. Indonesia’s total annual expenditure onhealth care was around US$ 50 per capita in 2007 or 3% of the GDP[2]. There are competing demands for health-care expenditures atboth governmental and individual levels, thus external resourcesmay initially be needed to invest in a rotavirus vaccination pro-gram, including the current efforts underway to manufacture arotavirus vaccine in Indonesia. In this situation, WHO suggests thatoutside resources should be made available for this investment,and the GAVI Alliance is actively encouraging such investments[12].

The WHO generic protocol [25] used in this study was easy tounderstand and practical to implement in the Indonesian setting.The data created realistic ranges, rather than simple point esti-mates, that could be incorporated into the sensitivity analyses. Thisallows for robust conclusions to be drawn from the data obtainedfrom the various available sources and rates of disease created byextrapolation of the estimates from our study sites to a nationallevel. The standardized analysis provides an initial excellent basisto evaluate the cost-effectiveness of a vaccine in Indonesia and tocompare estimates of cost-effectiveness between other countries[19–22,31].

A limitation of our analysis is that it was assumed that therewas no loss of effectiveness over the years, and that there was thesame vaccine efficacy for all ages, including the first two monthswhen full immunization would not yet have been achieved. Thisassumption may have overestimated vaccine effectiveness but con-versely this analysis did not consider any possible herd immunityeffects of rotavirus vaccination. It is also possible the estimate that77% of all diarrhoea deaths were due to rotavirus may have over-estimated rotavirus mortality. As with any economic evaluationthere is uncertainty about the parameters used and sensitivity anal-yses using lower and upper 95% confidence limits on disease burdenand cost estimates were therefore undertaken. However there isstill the possibility of greater variations in the original estimatesof these parameters. The bed cost in this study is noted to be lessthan the medications and diagnostics (Table 3), and reflects the costactually paid by families rather than any costs borne by governmentsubsidises. It is therefore possible that this study under-estimatedthe direct medical costs from a government perspective. WHOCHOICE estimates for Indonesia for cost per bed day by hospitallevel in International $ for 2000 for primary, secondary and ter-tiary level were 26.54, 34.62, 47.29 for in-patients and 7.90, 11.21,16.58 for out-patients respectively (http://www.who.int/choice/country/idn/cost/en/index.html). These 2000 WHO CHOICE esti-mates for Indonesia are similar to our 2007 total direct medicalcosts for in-patients (44.50) and outpatients (14.17) in public hos-pitals (Table 3).

Rotavirus disease causes considerable morbidity and mortalityamong Indonesian children and substantial costs to the Indone-sian health-care system. Vaccination can effectively reduce thisburden and health-care costs. For a birth cohort of 4.2 millionchildren, the vaccination could prevent more than 8000 deaths

from rotavirus disease. If rotavirus vaccine could be administeredfor less than US$ 2.70 per course it would be potentially cost-saving from the Indonesian health-care perspective and at lessthan US$ 3.79 per course as cost-saving from a societal perspec-tive.

F ccine

C

F

m((

A

PwGW

R

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

74 S.A. Wilopo et al. / Va

onflict of interest

None declared by the authors.

unding

This work was mainly performed under a collaborative agree-ent with the Program for Appropriate Technology in Health

PATH) and was funded in part by the GAVI Alliance and US CDCcontract number GAV 1142-01-07234-LPS).

cknowledgements

We are grateful to the field workers and epidemiologists at theurworejo Health Office and the physicians, nurses, and staff at Pur-orejo and Yogyakarta Regional Hospitals and staff of the CHN-RL,MU, especially Drs. Rosyid, Agung Nugroho, and Althaf Setiawan.e thank Tony Nelson for critical review of the manuscript.

eferences

[1] Central Bureau Statistics (CBS), National Family Planning Coordinating Board(NFPCB), Ministry of Health (MOH), ORC Macro. Indonesia demographic healthsurvey 2007. Calverton, MD, USA: ORC Macro and CBS; 2009.

[2] Central Bureau Statistics. National household survey from the national socialeconomic survey (Susenas): 2005 health modul. Jakarta: CBS; 2006.

[3] Soenarto Y. Epidemiology of rotavirus in Indonesia. In: National rotavirus sem-inar. Yogyakarta March 15, 2008.

[4] Wilopo SA, Soenarto Y, Bresee Y, Tholib A, Aminah S, Cahyono A, et al. Surveil-lance to determine the disease burden and the epidemiology of rotavirusin Indonesia. Technical Report Series, 06, 2008. Yogyakarta: Departmentof Public Heatlh, Faculty of Medicine, Gadjah Mada University; 2008, p.1–23.

[5] Oyofo BA, Subekti D, Tjaniadi P, Machpud N, Komalarini S, Setiawan B, et al.Enteropathogens associated with acute diarrhea in community and hospitalpatients in Jakarta, Indonesia. FEMS Immunol Med Microbiol 2002;34(October(2)):139–46.

[6] Putnam SD, Sedyaningsih ER, Listiyaningsih E, Pulungsih SP, Komalarini, Soe-narto Y, et al. Group A rotavirus-associated diarrhea in children seekingtreatment in Indonesia. J Clin Virol 2007;40(4):289–94.

[7] Subekti D, Lesmana M, Tjaniadi P, Safari N, Frazier E, Simanjuntak C, et al. Inci-dence of Norwalk-like viruses, rotavirus and adenovirus infection in patientswith acute gastroenteritis in Jakarta, Indonesia. FEMS Immunol Med Microbiol2002;33(March (1)):27–33.

[8] Wilopo SA, Kilgore P, Kosen S, Soenarto Y, Aminah S, Cahyono A, et al. Surveil-lance to estimate disease burden, cost of child care utilization, cost–benefitand cost-effectiveness evaluations of immunization programs for rotavirusdiarrhea in Indonesia: expanded surveillance. Report no.: technical report 09.Yogyakarta; 2008.

[9] Bresee JS, Hummelman E, Nelson EA, Glass RI. Rotavirus in Asia: the value ofsurveillance for informing decisions about the introduction of new vaccines. JInfect Dis 2005;192(September (Suppl. 1)):S1–5.

10] Nelson EAS, Bresee JS, Parashar UD, Widdowson MA, Glass RI. Rotavirus epi-demiology: The Asian Rotavirus Surveillance Network. Vaccine 2008;26(26):

3192–6.

11] Dennehy PH. Rotavirus vaccines: an overview. Clin Microbiol Rev 2008;21(1):198–208.

12] Glass RI, Parashar UD, Bresee JS, Turcios R, Fischer TK, Widdowson MA,et al. Rotavirus vaccines: current prospects and future challenges. Lancet2006;368(July (9532)):323–32.

[

[

27S (2009) F67–F74

13] Glass RI, Bresee J, Jiang B, Parashar U, Yee E, Gentsch J. Rotavirus and rotavirusvaccines. Adv Exp Med Biol 2006;582:45–54.

14] Lepage P, Vergison A. Prevention of childhood rotavirus disease through theuse of Rotarix and RotaTeq vaccines. Exp Opin Biol Ther 2007;7(12):1881–92.

15] Ruiz-Palacios GM, Pérez-Schael I, Velázquez RF, Abate A, Breuer T, CostaClemens SAC, et al. Safety and efficacy of an attenuated vaccine against severerotavirus gastroenteritis. N Engl J Med 2006;354(1):11–22.

16] Vesikari T, Matson DO, Dennehy P, Van Damme P, Santosham M, RodriguezZ, et al. Safety and efficacy of a pentavalent human–bovine (WC3) reassortantrotavirus vaccine. N Engl J Med 2006;354(January (1)):23–33.

17] Bjorvatn B. Issues to be considered for the introduction of new vaccines intonational vaccination programmes. In: Kaufmann SHE, Lambert P-H, editors. Thegrand challenge for the future. Basel, Switzerland: Birkhäuser Verlag; 2005. p.269–85.

18] Kimman TG, Boot HJ, Berbers GAM, Vermeer-de Bondt PE, Ardine de WitG, de Melker HE. Developing a vaccination evaluation model to supportevidence-based decision making on national immunization programs. Vaccine2006;24(22):4769–78.

19] Fischer TK, Anh DD, Antil L, Cat ND, Kilgore PE, Thiem VD, et al. Health carecosts of diarrheal disease and estimates of the cost-effectiveness of rotavirusvaccination in Vietnam. J Infect Dis 2005;192(November (10)):1720–6.

20] Isakbaeva ET, Musabaev E, Antil L, Rheingans R, Juraev R, Glass RI, et al.Rotavirus disease in Uzbekistan: cost-effectiveness of a new vaccine. Vaccine2007;25(2):373–80.

21] Melliez H, Levybruhl D, Boelle PY, Dervaux B, Baron S, Yazdanpanah Y. Cost andcost-effectiveness of childhood vaccination against rotavirus in France. Vaccine2008;26(5):706–15.

22] Newall AT, Beutels P, Macartney K, Wood J, MacIntyre CR. The cost-effectivenessof rotavirus vaccination in Australia. Vaccine 2007;25(52):8851–60.

23] Widdowson MA, Meltzer MI, Zhang X, Bresee JS, Parashar UD, Glass RI. Cost-effectiveness and potential impact of rotavirus vaccination in the United States.Pediatrics 2007;119(4):684–97.

24] Zomer TP, van Duynhoven YTHP, Mangen MJJ, van der Maas NAT, Vennema H,Boot H, et al. Assessing the introduction of universal rotavirus vaccination inthe Netherlands. Vaccine 2008;26(29–30):3757–64.

25] WHO. Guidelines for estimating economic burden of diarrhoeal diseases withfocus on assessing the costs of rotavirus diarrhoeal. Geneva: WHO; 2005.

26] Kosen S. The National Disease Burden Study: national estimates and lifeexpectancy estimates of 7 regions in Indonesia (Studi Beban Penyakit Nasional:Beban penyakit dan umur harapan hidup produktif, perkiraan nasional danperkiraan tujuh kawasan di Indonesia). Jakarta: Indonesia Health Research andDevelopment; 2008.

27] Murray CJ, Lopez A. Global mortality, disability, and the contribution of riskfactors: global burden of disease study. Lancet 1997;349:1436–42.

28] World Bank. World development report 1993: investing in health. Washington,DC, The World Bank; 1993.

29] Central Burae Statistics, National Planning Burae (Bappenas), UNFPA. ProyeksiPenduduk Indonesia (Indonesia Population Projection). Jakarta: Biro PusatStatistik (BPS); 2005.

30] Wilopo SA. Estimating the effect of DTP vaccination on child mortality: descrip-tive analysis of demographic and health surveillance data in the Districtof Purworejo (Estimasi Pengaruh Vaksin DPT Pada Kematian Anak: Analisadiskriptif data survailan demografi dan kesehatan di Kabupaten Purworejo).BKM 2008; 24:139–50.

31] Moennig P. Designing and conducting cost-effectiveness analyses in health: apractical approach. 2nd ed. San Francisco: Jossey-Bass, John Wiley and Sons,Inc.; 2008.

32] Rheingans R. Costing rotavirus diarrhea and estimating cost-effectiveness ofvaccination. Paper presented at the annual asia rotavirus surveillance networkmeeting. Bangkok; 2003.

33] Jit M, Edmunds WJ. Evaluating rotavirus vaccination in England andWales. Part II. The potential cost-effectiveness of vaccination. Vaccine2007;25(20):3971–9.

34] Madhi SA, Levine OS, Hajjeh R, Mansoor OD, Cherian T. Vaccines to preventpneumonia and improve child survival. Bulletin of the World Health Organiza-tion 2008; 86(5):365–73.