Acta Tropica 148 (2015) 77–88 Contents lists available at ScienceDirect Acta Tropica jo ur nal home p age: www.elsev ier .com/ locate /ac ta t ropica Economic evaluation of Chagas disease screening in Spain In˜aki Imaz-Iglesiaa,∗, Lucía García-San Miguelb, L. Eduardo Ayala-Morillasc, Lidia García-Pérezd, Jesús González-Enríqueza, Teresa Blasco-Hernándeze, María Be a Spanish Health Technology Assessment Agency, Instituto de Salud Carlos III, REDISSEC, Spanish Research Network on Chronic Diseases Health Services, Madrid, Spain b Department of Preventive Medicine, Hospital Puerta de Hierro, Majadahonda, Madrid, Spain c Department of Preventive Medicine, Hospital Clínico Universitario San Carlos, Madrid, Spain d Health Assessment Department, Canary Islands Health Agency, Canary Foundation for Health Research, REDISSEC, Spanish Research Network on Chronic Diseases Health e National Cent f Department o g Spanish Healt Unit of Prevent a r t i c l Article history: Received 13 A Accepted 17 A Available onlin Keywords: Chagas disease Costs and cost Screening Spain ∗ Correspon E-mail add lidia.garciaper asarria@isciii.e http://dx.doi.o 0001-706X/© Services, Canary Islands, Spain re for Tropical Medicine, Instituto de Salud Carlos III, Madrid, Spain f Preventive Medicine, Hospital Universitario La Princesa, Madrid, Spain h Technology Assessment Agency, Instituto de Salud Carlos III, REDISSEC, Spanish Research Network on Chronic Diseases Health Services, ive Medicine and Public Health, University of Alcala, Madrid, Spain e i n f o pril 2015 pril 2015 e 25 April 2015 s analysis a b s t r a c t Although Spain is the European country with the highest Chagas disease burden, the country does not have a national control program of the disease. The purpose of this study is to evaluate the efficiency of several strategies for Chagas disease screening among Latin American residents living in Spain. The following screening strategies were evaluated: (1) non-screening; (2) screening of the Latin Ameri- can pregnant women and their newborns; (3) screening also the relatives of the positive pregnant women; (4) screening also the relatives of the negative pregnant women. A cost-utility analysis was carried out to compare the four strategies from two perspectives, the societal and the Spanish National Health System (SNHS). A decision tree representing the clinical evolution of Chagas disease throughout patient’s life was built. The strategies were compared through the incremental cost-utility ratio, using euros as cost mea- surement and quality-adjusted life years as utility measurement. A sensitivity analysis was performed to test the model parameters and their influence on the results. We found the “Non-screening” as the most expensive and less effective of the evaluated strategies, from both the societal and the SNHS perspectives. Among the screening evaluated strategies the most efficient was, from both perspectives, to extent the antenatal screening of the Latin American pregnant women and their newborns up to the relatives of the positive women. Several parameters influenced significantly on the sensitivity analyses, particularly the chronic treatment efficacy or the prevalence of Chagas disease. In conclusion, for the general Latin American immigrants living in Spain the most efficient would be to screen the Latin American mothers, their newborns and the close relatives of the mothers with a positive serology. However for higher prevalence immigrant population the most efficient intervention would be to extend the program to the close relatives of the negative mothers. © 2015 Elsevier B.V. All rights reserved. ding author. Tel.: +34 918222088; fax: +34 3877841. resses: imaz@isciii.es (I. Imaz-Iglesia), lucigasan@hotmail.com (L.G.-S. Miguel), leam29@gmail.com (L.E. Ayala-Morillas), ez@sescs.es (L. García-Pérez), jgonza@isciii.es (J. González-Enríquez), tblasco@isciii.es (T. Blasco-Hernández), bmartinagueda@yahoo.es (M.B. Martín-Águeda), s (A. Sarría-Santamera). rg/10.1016/j.actatropica.2015.04.014 2015 Elsevier B.V. All rights reserved.lén Martín-Águedaf, Antonio Sarría-Santamerag 78 I. Imaz-Iglesia et al. / Acta Tropica 148 (2015) 77–88 1. Introduction Chagas disease is an infection caused by the protozoa Try- panosoma cruzi. It is spread mostly by insects known as Triatominae or kissing b children. Th 15–20 year quences su severe cond ders as meg 2011; Mand Acute p ization of th Chain React low or abse infection (H Treatme achieves pa 2010; Gued phase there ication. Ant even thoug Moreover, r disease the ranging fro Molina et a Chagas d a wide geo some 8 mil tality of 20 America, Ch and the fou Years) (Brav Spain is of immigra first Europe Navarro et disease var population It is estima diagnosis, s potential ri et al., 2012) Althoug blood and be of conc Autonomou in 17 Auto including a part of ante (Navarro et the nationa plan (Navar Because of several st population descendant 2. Method A cost-u strategies fo and the Spa and events were includ updated to 2013. The main outcome measurement was quality- adjusted life years (QALYs). The following four strategies were compared: on-screening”. other and newborn”. All pregnant Latin American women re screened as part of the routine antenatal control. In case a positive serology test, the newborns were also tested. sitive mother cluster”. This strategy included the previous ategy “Mother and newborn”, but added the screening of luster of the positive mother. The cluster was defined as first and second degree relatives of the mother. When the ther’s serology was positive, her cluster was tested. egative mother cluster”. This strategy included the previ- s two strategies, but added screening of the cluster of the gative mother. The cluster was defined as the first and sec- d degree relatives of the mother, but in this strategy, only ults born in Latin America were tested but not children. It was umed that all children were born in Spain and thus vertical nsmission would be unlikely. odelling ecisi ent t ente 1 an ing. T vera fe. dec d int nche roba pop ther ldbe wbor sitive th a p sitive ther gativ th a nugs. Acute clinical manifestations are usually seen in e chronic stage occurs in 10–30% of those infected, s after the acute infection. Chronic infection conse- ch as myocardial injury, cardiac dilation, arrhythmia, uction abnormalities, and gastrointestinal tract disor- aesophagus and megacolon, are irreversible (Heymann, ell, 2010; Akhavan, 2000). hase diagnosis is usually confirmed by direct visual- e parasite in the blood (micromethod) or Polymerase ion (PCR). In the chronic phase, the parasitemia can be nt so serological studies are the most used to detect the eymann, 2011; Mandell, 2010). nt reduces acute disease duration, severity, and rasitological cure in a high percentage of cases (Mandell, es et al., 2011). However, at indeterminate or chronic are not suitable markers for measuring parasite erad- ibody titers (IgG specific) may remain high for years h the parasite has been eliminated (Guedes et al., 2011). egarding the pharmacological treatment of the chronic re is a wide range of efficacy results in the literature, m 8 to 71% (Guedes et al., 2011; Lee et al., 2013; Pérez- l., 2009). isease is endemic in the Latin American region, with graphic distribution. It is estimated that there may be lion people infected in the world, with an annual mor- ,000 (Mandell, 2010; Fiusa Lima et al., 2011). In Latin agas disease has been estimated to be the first tropical rth infectious disease in DALYs (Disability-Adjusted Life o and Medici, 2000). the European country that receives the largest share nts from Latin America, so it is estimated to be the an country in Chagas disease burden (Lee et al., 2013; al., 2012). In Spain the regional prevalence of Chagas ies depending on the national origin of the immigrant that has settled in each region (Basile et al., 2011). ted that, in our country, there may be 90% of under- o most of the infected population do not know their sk of develop the chronic disease in the future (Navarro . h, in Spain, there is a parasitological control of donated organs, potential vertical transmission continues to ern (Ministerio de Sanidad, 2013). At present, some s Communities (the country is geographically divided nomous Communities) carry out Chagas screening serology test for all pregnant Latin American women, as natal care, but this practice is not extended to all regions al., 2012). In addition, Chagas disease is not included in l surveillance system, and there is no national control ro et al., 2012; Sicuri et al., 2011). of that, we found pertinent to evaluate the efficiency rategies for Chagas disease screening of the immigrant of Latin American residents in Spain and their potential s. s tility analysis was carried out to compare four screening r Chagas disease in Spain, considering both, the societal nish National Health System (SNHS) perspective. Costs of Chagas disease occurring throughout patient’s life ed in the model. Costs were measured in Euros and (A) “N (B) “M we of (C) “Po str a c the mo (D) “N ou ne on ad ass tra 2.1. M A d repres lation in 201 screen nosis a their li The divide six bra event p The (1) Mo chi (2) Ne (3) Po wi (4) Po mo (5) Ne wion tree was built using TreeAge Pro 2011® in order to he clinical evolution of the Chagas disease. The popu- ring the model was Latin American resident in Spain d their potential descendants at the moment of the he population was followed from 30 years old (diag- ge age according to Lee et al. (2013) until the end of ision tree started with a decision node, which was o the four screening strategies. From all the strategies s were set representing six populations with different bilities (Fig. 1). ulations can be described as follows: s. The Latin American women living in Spain during their aring period. ns. The potential newborns of those mothers. mother adult cluster. The adult relatives of a mother ositive serology. mother children cluster. The children relatives of a with a positive serology. e mother adult cluster. The adult relatives of a mother egative serology. Fig. 1. First branches of the decision tree. I. Imaz-Iglesia et al. / Acta Tropica 148 (2015) 77–88 79 (6) Others. The rest of the Latin American population not screened in any strategy. Populations were estimated as follows: • Latin Ame according (INEbase, • Potential potential tro et al. one woul of 322,39 estimated • Initial po tion (excl the 2011 their pote • Cluster: Latin Am Domíngu the house tives (“Re be adults 0.375–0.6 Clinical e for the scre tree. Once a infected cou (false negat disease pha digestive d positive) re All of the br (Fig. 2). All the p borns beca vertical tran (Fig. 3). 2.2. Parame Data we Ministry of of medical case. The so in the table values were case analys information according t 2.2.1. Disea We appl vided by Ba American in 2015), obta was adopte the Latin Am the sensitiv The prev mother wa who estima ter of the p of the nega by 2.25 for the positive mother cluster (resulting 0.0724), and was decreased by 0.44 for the negative mother cluster (resulting 0.0141). For newborns and children cluster of the positive mother the ence nsid issio pro evo is d ate p rmin Oth ith a have vera livin pro rns b % in ures nsid prob re. S onic 2010 ted b mo ed th and 013) % of t sease 2001 erica a we ected hile ve di lly, fic li and Disea ll ac or C 2007 The rn), rolog nfirm tion wo m sts epea ing c ing y: n r of . atme s of i tions y we , trea egimrican women with childbearing potential (15–49 years) to the 2011 National Census (INEbase, 2015): 685,952 2015). newborns: assuming that all women with childbearing had the same characteristics as those described by Cas- in 2011 (Castro Martín and Rosero-Bixby, 2011), each d bear 0.47 children in Spain. Therefore a total number 7 potential newborns (Range: 196,665–331,108) was . pulation entering the model: Latin American popula- uding Caribbean islands) living in Spain according to National Census (INEbase, 2015): 2130,871 people and ntial newborns (322,397): a total of 2453,267 people. “Household composition” of 2.4 persons per every erican mother (range 1.8–3) (Requena and Sánchez- ez, 2011) was assumed. It was also assumed that half of hold members would be first and second degree rela- latives component”: 0.5; range: 0.25–0.75), 50% would and 50% children (“Children component”: 0.5; range: 25). vents related with Chagas disease were modelled both ened and the non-screened populations in the decision mother is screened can be infected or no infected. The ld be diagnosed (true positive) or remained undetected ive). The infected could be at the indeterminate chronic se (without symptoms) or develop the cardiac or the isease. All diagnosed mothers (true positive and false ceived treatment and so could develop adverse events. anches ended in a terminal node that represented death opulations have the same branches except for new- use only they can acquire the acute disease through smission. In some cases the acute disease can be lethal ters re obtained from official sources when available (i.e. Health and National Statistics Institute). Best evidence literature published on PubMed was selected for each urces of information for each parameter are described s below. For each parameter an average and a range of estimated. The average value was used for the base is and the range for the sensitivity analysis. When no was found for the ranges ±10% or ±25% was applied o the author’s criteria. se prevalence and evolution ied Chagas disease prevalence by country of origin pro- sile et al. (Basile et al., 2011) to the number of Latin migrants by country of origin living in Spain (INEbase, ining an average prevalence of 0.0322. That prevalence d for the base case, although the range of prevalence of erican countries provided by Basile et al. was tested in ity analysis (Table 1). alence of the adult cluster of the positive and negative s adjusted according to Mott et al. (Mott et al., 1976), ted the increased risk of being infected for the clus- ositive mother and the decreased risk for the cluster tive mother. The general prevalence was multiplied preval was co transm The disease disease termin indete years). tive, w would same a people The newbo and 35 two fig was co The literatu ing chr et al., separa ease is report cardiac et al., 2 20–30 tive di Prata, PanAm ian dat the inf ease, w digesti Fina scienti disease 2.2.2. We tions f et al., 2007). newbo ond se for co centra first t PCR te tive, r screen Accord strateg numbe (Fig. 4) Tre source menda so the model mary rwas assumed to be the vertical transmission rate. It ered that our population does not have risk of vectorial n of the disease. posal of Lee et al. (2013)was assumed to estimate the lution parameters. According to that study the chronic iagnosed on average at the age of 30 years at an inde- hase. Some of the infected persons would live with the ate disease all of their lives without symptoms (52.1 er persons develop a chronic disease, cardiac or diges- mean duration of 24.8 years. The serious chronic disease an average duration of 13.2 years. It was assumed the ge life expectancy for Spanish than for Latin American g in Spain. bability of developing acute disease among infected y vertical transmission has been reported between 20 two studies. We assumed the median between these . A mortality rate of 1% as published by Mandell et al. ered (Mandell, 2010). abilities of developing chronic disease are varied in the ome authors reported global probabilities of develop- disease between 30 and 40% (Lescure et al., 2010; Rassi ; Pinto-Dias, 2000). Others reported the probabilities etween cardiac and digestive disease. The cardiac dis- re frequent than the digestive disease. Some authors at two thirds of the chronic patients will develop the one third the digestive disease (Akhavan, 2000; Merino . Others published that the cardiac disease occurred to he chagasic patients (Rassi et al., 2010), and the diges- to 10–20% of the chagasic patients (Rassi et al., 2010; ). We adopted the rates published in the study of the n Health Organization (Akhavan, 2000), where Brazil- re thoroughly collected. They estimated that a 72.8% of would remain in the indeterminate phase of the dis- 18.2% would develop the cardiac disease and 9% the sease. in most of the cases the utilities were gathered from terature. We had to estimate the value only for acute adverse events. se diagnosis and treatment knowledged diagnosis and treatment recommenda- hagas disease were used (Merino et al., 2013; Bern ; González-Tomé et al., 2013; Flores-Chávez et al., screening would start for all populations (except with an antibody test. If the test was positive, a sec- y test using different antigens would be carried out ation. Parasitemia detection through capillary con- or PCR was recommended for newborns during the onths of life. At nine months old, serology and would be carried out simultaneously and if nega- ted until month 18 of age. Diagnostic accuracy and ompliance parameters are described in Table 2. The to these data the following was estimated for each umber of screened population, number of positives, true positives (TP) and positive predictive value (PPV) nt efficacy, adverse events probabilities and their nformation are described in Table 2. Treatment recom- made by Bern et al. are generally followed in Spain, re assumed in our study (Bern et al., 2007). In our tment was indicated for all infected persons. The pri- e was Benznidazole (BNZ) 5–7 mg/kg per day for 60 80 I. Imaz-Iglesia et al. / Acta Tropica 148 (2015) 77–88 days, and t per day for zole. Treatme 97.9% base logical and (Guedes et very differe the parasit or nifurtim et al. (2009 ment of cli assumed th of these tw in other ec 2010).Fig. 2. Decision tree for the Latin American women living in Spain he alternative regime Nifurtimox (NFX) 8–10 mg/kg 90 days when there was no tolerance to Benznida- nt efficacy in the acute phase was estimated to be d on several clinical trials that measured parasito- serological cure with benznidazole or nifurtimox al., 2011). For the chronic disease, the reviews showed nt results. Bruce-Lee (Guedes et al., 2011) estimated ological/serological cure to be 8% with benznidazole ox, however the systematic review by Pérez-Molina ) estimated the clinical cure (defined as no develop- nical events) around 71% only with benznidazole. We at the chronic treatment efficacy could be an average o results (39.5%), which is similar to those identified onomic evaluations (Sicuri et al., 2011; Lescure et al., 2.2.3. Cost The SNH while the s rect non-m 2.2.3.1. Me and treatm related wit tions. Each the results described p Similarl adverse ev analysis, m taminic an weighted bduring their childbearing period. estimations S perspective considered only the direct medical costs, ocietal perspective considered also the direct and indi- edical costs. dical costs. Costs incurred during the Chagas diagnosis ent were estimated and described in Tables 3–5. Costs h diagnosis included microbiology tests and consulta- population followed different itineraries depending on of tests and according to the Chagas diagnosis pathway reviously. y, the costs related to pharmaceutical treatment and ents were estimated including medical visits, control edicines to treat adverse events (corticoids, antihis- d antiemetics) and hospitalization for severe cases y the frequency and type of adverse event. I. Imaz-Iglesia et al. / Acta Tropica 148 (2015) 77–88 81 The cost are summa were only i costs incurr perspective Disease from pharm stage of th ease (cardiFig. 3. Decision tree for the potential new s of pharmacological treatment and their adverse events rized in Table 4. The out of pocket medicine expenses ncluded in the societal perspective, while the medicine ed by the state health system were included in both s. management costs of other interventions different aceutical costs are detailed in Table 5 for every e disease: acute, indeterminate, and chronic dis- ac and digestive). The throughout life frequency of attendance pital were c criteria. 2.2.3.2. Non transport c Indirect non and produc children.borns. to outpatient clinic or need to admission to the hos- alculated according to published data or investigators -medical costs. Direct non-medical costs included osts to attend clinical visits, and home caregiver costs. -medical costs included productivity loss of the patient tivity loss of the parents because of the care for their sick 82 I. Imaz-Iglesia et al. / Acta Tropica 148 (2015) 77–88 Table 1 Disease evolution parameters. Average and range values. Parameter Base case Range References Chagas prevalence among Latin American resident in Spain 0.0322 0.005–0.1875 Basile et al. (2011), INEbase (2015) Chagas prev 8–0.0 Chagas prev 16–0 Vertical tran 4–0.0 Acute diseas 6–0.3 Fatality rate 75–0 Cardiac dise 7–0.2 Digestive dis 8–0.1 Indetermina 65.1 Chronic dise Acute diseas Treatment d Diagnostic p Life expecta Life years lo Life years lo Life years lo Utility for no Utility for in Utility for ac Utility for fa Utility for ca Utility for di Utility for ad a +/− 25%. b +/− 10%. Table 2 Diagnostic and Diagnostic t Sensitivity a Specificity a Sensitivity n Specificity n Screening co Pregnant wo Newborn fro Adult cluste Children clu Adult cluste Treatment e Chronic dise Acute diseas Treatment r Adults Benznidazol Nifurtimox Children Benznidazol Nifurtimox a +/− 25%. b +/− 10%. c Average of Madrid portation to caregivers of non-qua Estadística, of caregiver were estimalence among adult cluster of the positive mother 0.0724 0.05 alence among adult cluster of the negative mother 0.0141 0.01 smission 0.0435 0.01 e probability among infected newborns 0.275 0.20 because of acute disease among treated newborns 0.01 0.00 ase probability 0.182 0.13 ease probability 0.09 0.06 te disease duration (years) 52.1 39.1– ase duration (years) 24.8 18.6–31 e duration (years) 0.1 0.05–0.2 uration (years) 0.2 0.1–0.3 rocess duration (years) 0.13 0.09–0.16 ncy (years) 82.1 78–82.1 st because of cardiac disease 4.23 3.2–5.3a st because of digestive disease 3.31 2.5–4.1a st because of fatal acute disease 81 80–82 disease 1 determinate disease 0.925 0.906–0.9 ute disease 0.30 0.23–0.38 tal acute disease 0 – rdiac disease 0.72 0.65–0.79 gestive disease 0.84 0.76–0.92 verse event to drug treatment 0.80 0.7–0.9 treatment of Chagas disease. Average and range values. ests accuracy (0–1) Average Range R ntibody test 0.995 0.98–1 B Fntibody test 0.99 0.98–1 ewborn diagnostic procedure 1 0.9–1 F ewborn diagnostic procedure 1 0.9–1 F mpliance (0–1) man 0.95 0.5–1 B m positive mother 0.99 0.95–1 B r positive mother 0.65 0.49–0.81a A ster positive mother 0.9 0.75–1 A r negative mother 0.2 0.15–0.25a A fficacy (0–1) ase 0.395 0.08–0.71 G e 0.979 0.65–1 G elated adverse events probability (0–1) e Adverse events 0.59c 0.44–0.74a P (Withdrawals 0.23c 0.17–0.29a Severe adverse events Adverse events 0.975 0.73–1 J Withdrawals 0.395 0.3–0.5a Severe adverse events 0.074 0.056–0.093a e Adverse events 0.58 0.44–0.73b A Withdrawals 0.065 0.049–0.081a Severe adverse events 0.018 0.014–0.023a Adverse events 0.31 0.23–0.39a J Withdrawals 0 Severe adverse events 0 three studies. subway rates were used to estimate public trans- health centre costs (Madrid Community, 2014). The fees were estimated according to the annual income lified staff in Spain for 2011 (Instituto Nacional de 2011). Furthermore, 33% of full time equivalent (FTE) s fees for severe cardiac and 20% for digestive disease ated. The pro cardiac and costs were American re average num by the une Estadística,89 Mott et al. (1976) .0174 Mott et al. (1976) 73 Basile et al. (2011) 44a Basile et al. (2011), Rassi et al. (2010) .0125a Mandell (2010) 28a Akhavan (2000) 13a Akhavan (2000) Lee et al. (2013), Instituto Nacional de Estadistica (2015) Lee et al. (2013), Instituto Nacional de Estadistica (2015) Author’s estimation Author’s estimation Author’s estimation Instituto Nacional de Estadistica (2015) Ministerio de salud de Chile (2012) Ministerio de salud de Chile (2012) Author’s estimation Wilson et al. (2005) 44a Akhavan (2000) a Authors’ estimate Authors’ estimate b Akhavan (2000), Sicuri et al. (2011), Wilson et al. (2005) b Akhavan (2000) Authors’ estimate eferences ern et al. (2007), González-Tomé et al. (2013), lores-Chávez et al. (2007) lores-Chávez et al. (2010) lores-Chávez et al. (2010) lasco Hernández et al. (2013) lasco Hernández et al. (2013) uthors’ estimate uthors’ estimate uthors’ estimate uedes et al. (2011), Pérez-Molina et al. (2009), Wilson et al. (2005) uedes et al. (2011), Lee et al. (2013) inazo et al. (2013), Hasslocher-Moreno et al. 2012), Pinazo et al. (2010) ackson et al. (2010) ltcheh et al. (2005) ackson et al. (2010) ductivity loss was estimated to be 5 and 2.5 years for digestive disease respectively. The productivity loss calculated on the basis of the average salary of Latin sidents (Instituto Nacional de Estadística, 2011) and the ber of working hours in Spain (Grupo, 2014) weighted mployment rate of immigrants (Instituto Nacional de 2014). I. Imaz-Iglesia et al. / Acta Tropica 148 (2015) 77–88 83 Fig. 4. Population size and diagnosis results of the four strategies. TP: true positives; PPV: positive predictive value. Table 3 Cost of the diagnostic process. Average and range values. Outcome group Medical cost (D ) (Boletín Oficial de la Comunidad de Madrid, 2013; Oblikue, 2014) Non-medical cost (D ) (Madrid Community, 2014; Instituto Nacional de Estadística, 2011; Grupo, 2014; Instituto Nacional de Estadística, 2014) Average Range Average Range Negative mo Negative new Negative mo Positive mot .5 Positive new Positive mot .5 Positive mot .5 a +/− 25%. 2.2.3.3. Cos tial program estimated b of personne activities in Health Insti program w the “Non-sc 2.3. Analysi The strat ratio (ICUR) with the im other. The I tive. Althou technology as it was the et al., 2002) 0–5) was ap A determ the model ing th e wa ed al edica ults se ca resu es a ctive hree Table 4 Cost of pharm Benznidazol Nifurtimox f Benznidazol Nifurtimox f Adults Children a +/− 25%.ther 20 15–25a born 587 326–848 ther adult cluster 199 150–248a her 253.1 166.7–339 born 577 326–828 her adult cluster 253.1 166.7–339 her children cluster 371.1 227.7–514 t of developing the screening program. Costs of a poten- for Chagas screening to implement in the SNHS were y the investigators (Table 6). The expenses included cost l (gross salaries) and other costs needed to coordinate the regions. The costs were based on the “Carlos III” tute official rates. The costs of developing the screening ere applied to the three screening strategies but not to reening” strategy. s egies were compared using the incremental cost-utility . This indicator provides the cost of gaining one QALY out us spectiv includ non-m 3. Res 3.1. Ba The spectiv perspe other tplementation of a certain strategy in comparison with CUR was calculated for both societal and SNHS perspec- gh there is no an established ICUR threshold for health introduction in Spain, D 30,000 per QALY was assumed most quoted figure in the Spanish literature (Sacristán . An annual discount for costs and results of 3% (range plied. inistic and univariate sensitivity analysis test in all of parameters from the societal perspective was carried and less effe gies the “Ne most expen Assumin D 30,000 pe tives would mother clu in an ICUR spective the acological treatment and adverse events. Average and range values. Medical costs (D ) (Boletín Oficial de la Comunidad de Ma 2013; Oblikue, 2014; Agencia Espan˜ola de Medicamentos Disposición, 2015a; Disposición, 2015b) Treatment cost Average Range e for adults 179.4 134.5–224.2a or adults 220 165–275a e for children 178.9 134.2–223.7a or children 256.5 192.4–320.6a Adverse events 444.3 321.1–567.5 65.2 43.5–86.9 0 67.5 45.01–90.02 38.3 25.5–51.01 38.03 25.5–51.01 63.76 25.5–102.02 38.03 25.5–51.01 38.03 25.5–51.01 e range of values already described. The societal per- s used as reference for the sensitivity analyses because l variables, while the SNHS perspective excluded the l cost variables. se lts of the base case from both societal and SNHS per- re shown in Figs. 5 and 6 and Tables 7 and 8. In both s the “Non-screening” strategy was dominated by the screening strategies because resulted more expensive ctive than the others. Among the three screening strate- gative mother cluster” was the most effective while the sive. g a threshold for health technology introduction of r QALY, the most efficient strategy from both perspec- be the “Positive mother cluster”. To adopt the “Negative ster” instead of the “Positive mother cluster” resulted value higher than the threshold. From the societal per- “Negative mother cluster” would achieve an additional drid, , 2014; Non-medical costs (D ) (Madrid Community, 2014; Instituto Nacional de Estadística, 2011; Grupo, 2014; Instituto Nacional de Estadística, 2014) Average Range 137.82 103.4–172.3a 51.01 38.2–63.7a 81.7 61.3–102.1a 51.01 38.3–63.8a 39.4 27.01–51.8 22 15–29 84 I. Imaz-Iglesia et al. / Acta Tropica 148 (2015) 77–88 Table 5 Disease management costs. Average and range values (D ). Intervention Unit cost (range) Frequency × years (range) Average Range References Acute disease Medical costs Hospitalization 4275 1 4275 3206–5344 Boletín Oficial de la Comunidad de Madrid (2013) Total 4275 3206–5344 Non-medical costs Transport 6 2 (1–3) 12 6–18 Parents productivity loss due to children hospitalization 39 2 (1–3) 78 39–117 Total 90 45–135 Indeterminate disease Medical costs First medical visit 130 1 130 Boletín Oficial de la Comunidad de Madrid (2013) Follow-up medical visits 78 0.5 × 51.1 1992.9 822.9–3162.9 Boletín Oficial de la Comunidad de Madrid (2013) Electrocardiogram 16.73 0.5 × 51.1 427.4 176.5–678.4 Oblikue (2014) Total 2550 1129–3971 Non-medical costs Transport 6 0.5 × 52.1 159.3 69.3–249.3 Madrid Community (2014) Productivity loss for medical visits 39 0.25 × 52.1 517.9 225.3–810.5 Instituto Nacional de Estadística (2011), Grupo (2014), Instituto Nacional de Estadística (2014) Total 677.2 294.60–1060 Cardiac disease Medical costs First medical visit 130 1 130 Boletín Oficial de la Comunidad de Madrid (2013) Follow-up medical visits 78 [10.6 + 3 (2 − 4)] × 13.2 3915.6 2886–4945 Boletín Oficial de la Comunidad de Madrid (2013) Electrocardiogram 16.7 1 × 24.8 414.9 Sicuri et al. (2011), Oblikue (2014) Chest x-ray 13.4 1 × 24.8 333.6 Sicuri et al. (2011), Boletín Oficial de la Comunidad de Madrid (2013) Digoxin 14 0.5 (0.33––0.66) 6.9 4.6–9.2 Sicuri et al. (2011), Digoxina (2014), Enalapril (2014), Furosemida (2014) Enalapril 84.2 0.5 (0.33–0.66) 41.7 27.8–55.6 Furosemide 10.5 0.5 (0.33–0.66) 5.2 3.5–6.9 Doppler ultrasound 60.7 0.2 301.2 Sicuri et al. (2011), Oblikue (2014) Holter 170.2 0.01 1.7 Stress echocardiography 69.2 0.08 5.5 Pacemaker 10,915 (8525–13,304) 0.03 (0.02–0.04) 300.1 170.5–465.6 Sicuri et al. (2011), Boletín Oficial de la Comunidad de Madrid (2013), Basquiera et al. (2003), Schenone (1998) Automatic defibrillator 32,717 (28,112–37,323) 0.03 981.5 843.4–1120 Sicuri et al. (2011), Boletín Oficial de la Comunidad de Madrid (2013) Cardiac transplant 82,326 0.01 823.3 Heart failure hospitalization 3545 2.35 (0.33–4.38) 8344 1175–15,512 Ministerio de salud de Chile (2012), Boletín Oficial de la Comunidad de Madrid (2013) Digestive disease hospitalization 5645 0.06 (0.02–0.10) 321.8 84.7–558.9 Total 15,927 7206–24,684 Non-medical costs Transport 6 [11.6 + 3 (2–4)] × 13.2 307.2 230.4–384 Madrid Community (2014) Caregivers 5771 13.2 × 0.33 (0.166–0.666) 25,392 12,696–50,785 Instituto Nacional de Estadística (2011) Productivity loss due to medical visits 39 0.5 × 12 (9–15) 234.08 175.6–292.6 Instituto Nacional de Estadística (2011), Grupo (2014), Instituto Nacional de Estadística (2014) Productivity loss due to illness 8,269 1 × 0.3 (0–2) 2481 0–16,537 Instituto Nacional de Estadística (2011), Instituto Nacional de Estadística (2014) Total 28,414 13,102–67,999 Digestive disease Medical costs First medical visit 130 1 130 Boletín Oficial de la Comunidad de Madrid (2013) Follow-up medical visits 78 [0.5 (0.25–1) × 10.6)] + [0.5 (0.25 − 1) × 13.2] 928.2 464–1856 I. Imaz-Iglesia et al. / Acta Tropica 148 (2015) 77–88 85 Table 5 (Continued) Intervention Unit cost (range) Frequency × years (range) Average Range References Barium X-ray 13.5 0.2 2.7 Sicuri et al. (2011), Boletín Oficial de la Comunidad de Madrid (2013) Intestinal transit study 13.5 0.2 2.7 Mega-viscera surgery 8970 (6259–11,680) 0.052 (0.05–0.055) 470 313–642 Akhavan (2000), Wilson et al. (2005), Boletín Oficial de la Comunidad de Madrid (2013) Digestive disease hospitalization 5645 0.322 × 3.8 (1–6.6) 6907 1818–11,997 Castro Martín and Rosero-Bixby (2011), Ministerio de salud de Chile (2012) Heart failure disease hospitalization 3545 0.015 × 7.1 (1–13.2) 377.5 53.2–701.9 Omeprazol 37.2 0.5 (0.33–0.66) 18.4 12.3–24.5 Sicuri et al. (2011), Omeprazol (2015), Almax Forte (2015), Cleboril (2015) Antiacids 41.1 0.5 (0.33–0.66) 20.4 13.6–27.1 Prokinetic drugs 27.7 0.5 (0.33–0.66) 13.7 9.1–18.3 Total 8872 2818–15,403 Non-medical costs Transport 6 [0.5 (0.25 − 1) × 11.6)] + [(1 (0.5 − 2) × 13.2] 77.4 38.7–154.8 Caregivers 5771 13.2 × 0.2 (0.1–0.4) 15,235 7618–30,471 Instituto Nacional de Estadística (2011) Productivity loss due to medical visits 39 11.1 × 0.5 (0.25–1) 108 54–217 Instituto Nacional de Estadística (2011), Grupo (2014), Instituto Nacional de Estadística (2014) Productivity loss due to illness 8268.7 0.1 [0–2] 827 0–8269 Instituto Nacional de Estadística (2011), Instituto Nacional de Estadística (2014) Total 16,248 7711–39,111 AE: Adverse events. Table 6 Cost of developing the screening program. Average and range values. Intervention Unit cost (D ) Frequency Average (D ) Range (D ) Personnel (Coordinator) 37,524 5 years 187,620 140,715–234,525 Personnel (Technical) 31,110 5 years, 2 people 311,100 233,325–388,875 Subsistence costs 8000 5 years 40,000 30,000–50,000 Travel 15,000 5 years 75,000 56,250–93,750 Computer equipment 2000 3 equipment 6,000 4,500–7500 Office equipment 1500 5 years 7,500 5,625–9375 Meetings 7900 5 years 39,500 29,625–49,375 Sub-total 666,720 500,040–833,400 Carlos III (15%) overheads 100,008 75,006–125,010 Total 766,728 575,046–958,410 Table 7 Base case results of the four screening strategies from the societal perspective. Strategy Average Cost (D ) Incremental Cost (D ) Average Utility (QALY) Incremental Utility (QALY) Average Cost-Utility ICURa (D /QALY) Mother and newborn 130.035872 – 17.507259 – 7.427540 Positive mother cluster 130.082152 0.046281 17.507375 0.000116 7.430135 399 Negative mother cluster 130.603294 0.521142 17.507389 0.000014 7.459896 38,013 Non-screening 133.359859 2.756565 17.505714 −0.001675 7.618076 Dominated a ICUR: Incremental Cost-Utility Ratio comparing each strategy with the previous one. Table 8 Base case results of the four screening strategies from the SNHS perspective. Strategy Average Cost (D ) Incremental Cost (D ) Average Utility (QALY) Incremental Utility (QALY) Average Cost-Utility ICURa (D /QALY) Mother and newborn 112.196073 – 17.507259 – 6.408546 Positive mother cluster 112.231032 0.034958 17.507375 0.000116 6.410500 301 Negative mother cluster 112.653892 0.422860 17.507389 0.000014 6.434648 30,844 Non-screening 115.168853 2.514962 17.505714 −0.001675 6.578929 Dominated a ICUR: Incremental Cost-Utility Ratio comparing each strategy with the previous one. 86 I. Imaz-Iglesia et al. / Acta Tropica 148 (2015) 77–88 Fig. 5. Cost-utility analysis results of the base case from the societal perspective. QALY in comparison with the “Mother and newborn” strategy at a cost of 38,013 D per patient. The average utility of the base case from the SNHS perspective was similar to the societal perspective, but the average costs were reduced. From the SNHS perspective to adopt the “Negative mother cluster” instead of the “Positive mother cluster” would achieve an additional QALY at a cost of 30,844 D per patient. 3.2. Sensitivity analysis The test of all the variables through sensitivity analysis pro- duced important changes on the ICUR values in ten of the variables (Table 9). The reduction of the values of two variables (“Chronic Fig. 6. Cost-utility analysis results of the base case from the SNHS perspective. treatment efficacy” and “Chagas prevalence”) made the “Non- screening” the most efficient strategy. Value changes in other eight variables made “Negative mother cluster” into the most efficient strategy. A reduction in the “Chronic treatment efficacy” from 39.5% (base case) to 8% turned the “Non-screening” into the cheapest and the most effective strategy, and therefore dominates the three screening strategies. However, an increase of the “Chronic treat- ment efficacy” to 71% converts the “Negative mother cluster” into the most efficient strategy. An increase in the Chagas prevalence of the screened population made the “Negative mother cluster” the most efficient strategy. However, if we screened population with a prevalence of 0.005 Table 9 Sensitivity An Variable ther cl Chronic treatment efficacy Chagas prevalence Specificity Indetermina disease utili Cardiac dise probability Risk decreas infected for negative mo Relatives component Digestive disease probability Adverse eve utility Treatment duration * Dominatedalysis for the societal perspective. Value ICUR (D /QALY) Negative mother cluster Positive mo Higher value 0.71 1,120 Base case 0.395 38,013 Lower value 0.08 Dom Higher value 0.1875 0 Base case 0.0322 38,013 Lower value 0.005 Dom Higher value 1 3,814 Base case 0.99 38,013 Lower value 0.98 Dom te Higher value 0.94375 5,954 ty Base case 0.925 38,013 Lower value 0.91 Dom ase Higher value 0.2275 7,109 Base case 0.182 38,013 Lower value 0.1365 Dom e of being cluster of ther Higher value 0.55 10,195 Base case 0.44 38,013 Lower value 0.33 Dom Higher value 0.75 205,778 Base case 0.5 38,013 Lower value 0.25 11,031 Higher value 0.1125 13,699 Base case 0.09 38,013 Lower value 0.0675 Dom nts Higher value 0.9 Dom Base case 0.8 38,013 Lower value 0.7 16,504 Higher value 0.3 16,503 Base case 0.2 38,013 Lower value 0.1 Dom .uster Mother and newborn No screening 0 Dom* Dom 399 0 Dom Dom Dom 0 Dom Dom Dom 399 0 Dom Dom Dom 0 272 0 Dom 399 0 Dom 650 0 Dom 261 0 Dom 399 0 Dom 688 0 Dom 0 Dom Dom 399 0 Dom 2972 0 Dom 399 0 Dom 399 0 Dom 399 0 Dom 399 0 Dom 399 0 Dom 398 0 Dom 119 0 Dom 399 0 Dom 882 0 Dom 396 0 Dom 399 0 Dom 401 0 Dom 401 0 Dom 399 0 Dom 396 0 Dom I. Imaz-Iglesia et al. / Acta Tropica 148 (2015) 77–88 87 none of the screening strategies would be efficient and the “Non- screening” strategy would dominate the others. For the rest of the variables changes in their values reduced the ICUR (38,013 D /QALY) more than a half, turning the “Negative mother clus mother clus 4. Discussi Accordin for Chagas strategy wo healthcare most efficie of the Latin mother (str relatives of variables w In that s tant factors to higher pr to the mos cluster”. Th people com vians are th immigrants Mun˜oz et a fer significa American p heterogene gest that th would be th Latin Amer be the “Pos We foun with Chaga chronic dis review has wide. More sitological c results a lo thy any scr American p On the o American p ity as the m of immigra Our model account mi travels back or transplan The calc fertile wom throughout Requena an that the SN indefinitely limited rece screening p probably it about Chag The cos uncertain. health and moment of values did not produced sensitive variations on the cost-utility ratio. As far as we know, this study is the first to assess the exten- sion of Chagas screening to others than Latin American pregnant n and tion sed t in scre ost-e our an p e tha oul nose stud akin onal e de s on coun ies b rd th umm t to in are s exte es. T rns h se p o ot indi st e eir n tive vian ogram nces Espan˜ n 201 , D., 2 hagas Forte. icame J., Bia ase: e ntina ., Jans . Cha em. Eu a, A.L al., 20 sex a . Soc. Mont ., 2007 ematic ernán ncia d rid. SE /SEMT 13.pd Oficia iembr por la ed de ://ww rnet].ter” into the most efficient strategy instead of “Positive ter”. on g to our results, implementing a screening strategy disease in Spain is cost-effective. The non-screening uld not be acceptable under both the societal and the system perspectives. Among the tested strategies, the nt strategy would be to extent the antenatal screening American mothers to the relatives of the positive ategy “Positive mother cluster”). The screening to the the negative mother would not be efficient unless some ere modified. ense, the Chagas prevalence is one of the more impor- . The sensitivity analysis has shown that the screening evalence populations would increase the efficiency up t extensive program, which is the “Negative mother e prevalence of Chagas disease is very different among ing from different Latin-American countries. The Boli- e most affected people with a prevalence of 18.75% in living in Europe (Basile et al., 2011; Ramos et al., 2014; l., 2009; Roca et al., 2011), while the rest do not dif- ntly from base case. Bolivians represents 14% of Latin opulation living in Spain (INEbase, 2015), distributed ously throughout the country. The results would sug- e implementation of the “Negative mother cluster” e most efficient strategy to Bolivians while for the rest of ican immigrants the most efficient intervention would itive mother cluster”. d also other uncertainties in the parameters related s disease that could affect our results. The efficacy of ease treatment is not well established. The literature not provided consistent results and the variation is very over, an accurate biological marker to determine para- ure after treatment is still unavailable. According to our w treatment efficacy value (8%) would make not wor- eening intervention regarding Chagas disease on Latin opulation living in Spain. ther hand the official data on the population of Latin eople living in Spain may not correspond with the real- igration balance is currently negative and a percentage nts have obtained Spanish nationality (INEbase, 2015). used a static cohort until the end of life, no taking into gratory movements or future infection risks because of to origin countries for holidays. Similarly, transfusion t risk was not considered. ulation of the number of newborns and clusters from en of the cohort are based on studies that may vary the period (Castro Martín and Rosero-Bixby, 2011; d Sánchez-Domínguez, 2011). Our model assumed HS would cover the immigrants’ healthcare necessities , but their access to healthcare has been considerably ntly (Boletín Oficial del Estado, 2012). Adherence to the rogram was estimated according to current data, but will be increased in the future due to a rising concern as disease in society (Blasco Hernández et al., 2013). ts of developing the screening program are also Although they were designed by experts on public tropical medicine, it could have modifications at the implementation. Anyway, important changes in their wome evalua gies ba residen that to more c pares f Americ indicat borns w undiag Our sion m of nati ever th depend Some priorit standa 2004). In s efficien disease There fer in variabl newbo for the gram t would the mo ers, th a posi as Boli the pr ers. Refere Agencia 16 Ju Akhavan de C Almax med Altcheh, dise Arge Basile, L 2011 syst Basquier J., et male Card Bern, C., et al syst Blasco H Vive Mad com 2020 Boletín sept cos la R 〈http [Inte their newborns in a developed country. The economic published by Sicuri et al. (2011) evaluated three strate- on two models, one for the Latin American women Spain and another one for their newborns. They found en both Latin American women and their newborns is ffective than non-screening. Our study, however, com- strategies based on a unique model including all Latin opulation that is estimated living in Spain. Our results t to carry out the screening only in mothers and new- d imply that most of the affected people would remain d. y aims to provide useful information to support deci- g in Spain regarding the design and implementation strategies for prevention and treating Chagas. How- cision to incorporate a new program or technology the Public Health priorities and economy of the nation. tries use explicit cost-effective thresholds to establish ut it is not the case of Spain, where there is no a reshold for technology incorporation (Vicente Ortún, ary, our results indicate that in Spain it would be implement a screening program to control Chagas the Latin American population living in the country. everal possibilities for those programs, which can dif- nsion, adherence or target population, among other he population of Latin American mothers and their as been at the moment the most targeted population rograms. However, the efficiency to extend the pro- her populations had not been evaluated. Our results cate that for the general Latin American immigrants fficient would be to screen the Latin American moth- ewborns and the close relatives of the mothers with serology. 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