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BACKGROUND: Haemophilia is a rare hereditary haemorrhagic disease that requires regular intravenous injections of clotting factor (CF) concentrates. This study sought to estimate the health and economic burden of haemophilia in Belgium. This is the first study of its type to be conducted, and reflects the Belgian authorities' growing interest for haemophilia as part of their priority planning for rare and chronic diseases. METHODS: A probabilistic model was developed in order to estimate the lifetime haemophilia burden for the 2011 birth-year Belgian cohort. The health burden was initially expressed in terms of disability-adjusted life years (DALYs), the number of healthy life years lost due to living with disability and dying prematurely. An incidence perspective was used in line with World Health Organization recommendations. The economic burden calculated from direct and indirect haemophilia-related costs was expressed in euros. Data were drawn from the literature if none were available from federal institutions or health insurance. Disability weights for DALY calculation were derived using generic quality-of-life tools such as SF-6D from the SF-36 (36-item Short-Form Health Survey; for adults) and KINDL (generic quality-of-life instrument; for children) compared to population norms. Analyses were stratified according to haemophilia type and severity. RESULTS: In Belgium, haemophilia resulted in 145 undiscounted and unweighted DALYs in total (95% credible interval [CrI] = 90-222), which represents an average of 11 DALYs per incident case with haemophilia (95% CrI = 8-15) during his life, varying according to haemophilia severity (17 DALYs for severe haemophilia, 12 DALYs for moderate, and 4 DALYs for mild). Mean total lifetime costs reached €7.8 million per people with haemophilia, 94.3% being direct costs and 5.7% indirect costs. Clotting factors accounted for 82.5% of direct costs. CONCLUSIONS: Haemophilia represents both an economic and health burden, especial

Introduction and Objectives: Haemophilia is a rare hereditary haemorrhagic disease that requires regular intravenous injections of clotting factor (CF) concentrates. This study sought to estimate the health and economic burden of haemophilia in Belgium. This is the first study of its type to be conducted, and reflects the European and Belgian authorities’ growing interest for haemophilia as part of their planning for rare diseases. Materials and Methods: A probabilistic model was developed in order to estimate the lifetime haemophilia burden for the 2011 birth-year Belgian cohort. The health burden was initially expressed in disability-adjusted life years (DALYs) lost, this being the number of lost healthy years due to both disability and premature mortality. An incidence perspective was used in line with World Health Organization recommendations. The economic burden calculated from direct and indirect haemophilia-related costs was expressed in euro. Data were drawn from the literature if none were available from federal institutions or health insurance. Disability weights for DALY calculation were derived using generic quality-of-life tools compared to population norms. Analyses were stratified according to haemophilia type and severity. Results: In Belgium, haemophilia resulted in 145 undiscounted and unweighted DALYs in total (95% credible interval [CrI]=90-222), which represents an average of 11 DALYs per incident case with haemophilia (95% CrI=8-15) during his life, varying according to haemophilia severity (17 DALYs for severe haemophilia, 12 DALYs for moderate, and 4 DALYs for mild). Mean total lifetime costs reached €7.8 million per people with haemophilia, 94.3% being direct costs and 5.7% indirect costs. CF accounted for 82.5% of direct costs. Conclusion: Haemophilia represents both an economic and health burden, especially regarding individual health on an individual patient level. Initiatives to counteract this burden should be clearly identified and giv

Background Haemophilia is a rare hereditary haemorrhagic disease that requires regular intravenous injections of clotting factor (CF) concentrates. This study sought to estimate the health and economic burden of haemophilia in Belgium. This is the first study of its type to be conducted, and reflects the Belgian authorities’ growing interest for haemophilia as part of their priority planning for rare and chronic diseases. Methods A probabilistic model was developed in order to estimate the lifetime haemophilia burden for the 2011 birth-year Belgian cohort. The health burden was initially expressed in disability-adjusted life years (DALYs) lost, this being the number of lost healthy years due to both disability and premature mortality. An incidence perspective was used in line with World Health Organization recommendations. The economic burden calculated from direct and indirect haemophilia-related costs was expressed in euro. Data was drawn from the literature if none was available from federal institutions or health insurance. Disability weights for DALY calculation were derived using generic quality-of-life tools such as SF-36 (36-item Short-Form Health Survey; for adults) and KINDL (generic quality-of-life instrument for children) compared to population norms. Analyses were stratified according to haemophilia type and severity. Results In Belgium, haemophilia resulted in 145 healthy years lost due to morbidity, invalidity or early death (or DALYs) in total (95% credible interval [CrI]=90-222), which represents an average of 11 DALYs per incident case with haemophilia (PWH) (95% CrI=8-15) during his life, varying according to haemophilia severity (17 DALYs for severe haemophilia, 12 DALYs for moderate, and 4 DALYs for mild). Mean total lifetime costs reached 7.8 million euro per PWH, 94.3% being direct costs and 5.7% indirect costs. Clotting factors accounted for 82.5% of direct costs. Conclusions Haemophilia represents both an economic and health burden, especial

VIII, 101 p., ill., LIST OF TABLES 3-- LIST OF FIGURES 5-- GLOSSARY 6-- 1 BACKGROUND 7-- 1.1 THE SEVEN-VALENT CONJUGATE PNEUMOCOCCAL VACCINE 7-- 1.2 TWO NEW CONJUGATE PNEUMOCOCCAL VACCINES 8-- 2 OBJECTIVES AND RESEARCH QUESTIONS 9-- 3 LITERATURE SEARCHES AND METHODS 10-- 4 IMMUNOGENICITY, EFFICACY AND EFFECTIVENESS OF CURRENT-- PNEUMOCOCCAL CONJUGATE VACCINES 13-- 4.1 SEVEN VALENT PNEUMOCOCCAL CONJUGATE VACCINE (PCV7) 13-- 4.1.1 Clinical trials – efficacy of PCV7 13-- 4.1.2 Post-licensure studies – effectiveness of PCV7 14-- 4.1.3 Pathogenicity of serotypes 21-- 4.2 TEN VALENT PNEUMOCOCCAL CONJUGATE VACCINE (PCV10) 22-- 4.2.1 Clinical trials – immunogenicity of PCV10 22-- 4.2.2 Clinical trials – efficacy of PCV10 24-- 4.3 THIRTEEN VALENT PNEUMOCOCCAL CONJUGATE VACCINE (PCV13) 25-- 4.3.1 Clinical trials – immunogenicity of PCV13 25-- 5 DISEASE BURDEN IN BELGIUM 27-- 5.1 INVASIVE PNEUMOCOCCAL DISEASE (IPD) 28-- 5.2 ACUTE OTITIS MEDIA (AOM) AND COMMUNITY ACQUIRED PNEUMONIAE (CAP) 35-- 5.3 HOSPITALISATIONS 36-- 5.3.1 Meningitis hospitalisations 36-- 5.3.2 Bacteremia and septicaemia hospitalisations 38-- 5.3.3 Pneumonia hospitalisations 39-- 5.4 DEATHS 39-- 5.4.1 Invasive pneumococcal diseases (IPD) deaths 39-- 5.4.2 (Pneumococcal) pneumonia deaths 40-- 5.4.3 Pneumococcal meningitis deaths 40-- 5.4.4 Pneumococcal septicaemia deaths 41-- 6 ECONOMIC EVALUATIONS OF PCV10 AND PCV13 42-- 6.1 MODELS STRUCTURE 42-- 6.2 MAIN ASSUMPTIONS AND RESULTS 43-- 7 MATHEMATICAL MODELS OF PNEUMOCOCCAL TRANSMISSION 46-- 8 COST-UTILITY ANALYSIS OF PCV10 AND PCV13 IN BELGIUM 48-- 8.1 STUDY DESIGN 48-- 8.1.1 General 48-- 8.1.2 Vaccination options 48-- 8.1.3 Mathematical model structure 49-- 8.2 MODEL INPUT DATA 50-- 8.2.1 Epidemiological parameters and transition probabilities 50-- 8.2.2 Vaccine efficacy estimates 52-- 8.2.3 Direct costs 61-- 8.2.4 Health-Related Quality of Life 63-- 8.3 RESULTS 64-- 8.3.1 Cost-effectiveness acceptability curves 64-- 8.3.2 Incremental costs, outcomes and cost-effectiveness ratios

X, 101 p., ill., In 2007 werd het pneumokokkenvaccin PCV7 in het Belgische vaccinatieschema van jonge kinderen opgenomen. In 2009 kwamen 2 nieuwe pneumokokkenvaccins op de markt: PCV 10 en PCV13. Onderzoekers van de Universiteit Antwerpen bekeken deze nieuwe vaccins in opdracht van het Federaal Kenniscentrum voor de Gezondheidszorg (KCE). Ze stelden vast dat de vaccins een hogere bescherming bieden dan het huidige vaccin, PCV7. Het is dus medisch aan te raden om het huidige vaccin te vervangen en een van de 2 nieuwe op te nemen in het vaccinatieprogramma. De uiteindelijke keuze hangt af van hun kostprijs en de voorkeur van de beleidsmaker. Als hij vooral eerder zeldzame, maar ernstige aandoeningen wil voorkomen, is PCV13 de meest wenselijke optie. Als hij vooral bij veel kinderen milde gevallen, zoals oorontsteking, wil voorkomen, lijkt de voorkeur naar PCV10 te gaan. Het KCE beveelt aan om een aanbestedingsprocedure uit te schrijven om betere prijzen te verkrijgen. Het huidige schema van 3 vaccinatiedosissen wordt best behouden, er wordt best geen extra 4e dosis toegediend., LIST OF TABLES 3 -- LIST OF FIGURES 5 -- GLOSSARY 6 -- 1 BACKGROUND 7 -- 1.1 THE SEVEN-VALENT CONJUGATE PNEUMOCOCCAL VACCINE 7 -- 1.2 TWO NEW CONJUGATE PNEUMOCOCCAL VACCINES 8 -- 2 OBJECTIVES AND RESEARCH QUESTIONS 9 -- 3 LITERATURE SEARCHES AND METHODS 10 -- 4 IMMUNOGENICITY, EFFICACY AND EFFECTIVENESS OF CURRENT -- PNEUMOCOCCAL CONJUGATE VACCINES 13 -- 4.1 SEVEN VALENT PNEUMOCOCCAL CONJUGATE VACCINE (PCV7) 13 -- 4.1.1 Clinical trials – efficacy of PCV7 13 -- 4.1.2 Post-licensure studies – effectiveness of PCV7 14 -- 4.1.3 Pathogenicity of serotypes 21 -- 4.2 TEN VALENT PNEUMOCOCCAL CONJUGATE VACCINE (PCV10) 22 -- 4.2.1 Clinical trials – immunogenicity of PCV10 22 -- 4.2.2 Clinical trials – efficacy of PCV10 24 -- 4.3 THIRTEEN VALENT PNEUMOCOCCAL CONJUGATE VACCINE (PCV13) 25 -- 4.3.1 Clinical trials – immunogenicity of PCV13 25 -- 5 DISEASE BURDEN IN BELGIUM 27 -- 5.1 INVASIVE PNEUMOCOCCAL DISEASE (IPD) 28 -- 5.2 ACUTE OTITIS MEDIA (AOM) AND COMMUNITY ACQUIRED PNEUMONIAE (CAP) 35 -- 5.3 HOSPITALISATIONS 36 -- 5.3.1 Meningitis hospitalisations 36 -- 5.3.2 Bacteremia and septicaemia hospitalisations 38 -- 5.3.3 Pneumonia hospitalisations 39 -- 5.4 DEATHS 39 -- 5.4.1 Invasive pneumococcal diseases (IPD) deaths 39 -- 5.4.2 (Pneumococcal) pneumonia deaths 40 -- 5.4.3 Pneumococcal meningitis deaths 40 -- 5.4.4 Pneumococcal septicaemia deaths 41 -- 6 ECONOMIC EVALUATIONS OF PCV10 AND PCV13 42 -- 6.1 MODELS STRUCTURE 42 -- 6.2 MAIN ASSUMPTIONS AND RESULTS 43 -- 7 MATHEMATICAL MODELS OF PNEUMOCOCCAL TRANSMISSION 46 -- 8 COST-UTILITY ANALYSIS OF PCV10 AND PCV13 IN BELGIUM 48 -- 8.1 STUDY DESIGN 48 -- 8.1.1 General 48 -- 8.1.2 Vaccination options 48 -- 8.1.3 Mathematical model structure 49 -- 8.2 MODEL INPUT DATA 50 -- 8.2.1 Epidemiological parameters and transition probabilities 50 -- 8.2.2 Vaccine efficacy estimates 52 -- 8.2.3 Direct costs 61 -- 8.2.4 Health-Related Quality of Life 63 -- 8.3 RESULTS 64 -- 8.3.1 Cost-effectiveness acceptability curves 64 -- 8.3.2 Incrementa

X, 101 p., ill., En 2007, le vaccin anti-pneumococcique PCV7 a été introduit dans le calendrier vaccinal des enfants en Belgique. En 2009, deux nouveaux vaccins on fait leur entrée sur le marché: le PCV10 et le PCV13. A la demande du Centre fédéral d’expertise des soins de santé (KCE), des chercheurs de l’Université d’Anvers ont évalué ces deux nouveaux vaccins. Ils estiment que ces vaccins offrent une plus grande protection que le vaccin actuel. Il est donc justifié pour des raisons médicales de remplacer le PCV7 dans le calendrier vaccinal par un des deux nouveaux vaccins. Le choix entre ces deux vaccins dépend de leur prix et des préférences du décideur politique. Si ce dernier a pour objectif de prévenir des maladies plus rares mais plus sévères, le PCV13 est l’option la plus favorable. Si il a plutôt pour objectif de prévenir des pathologies moins graves telles les otites, chez un grand nombre d’enfants, alors le PCV10 remporte la palme. Le KCE recommande de procéder à un appel d’offres afin de faire baisser le prix des nouveaux vaccins. Il recommande en outre de maintenir le schéma actuel de vaccination avec 3 doses, sans administration d’une 4è dose., LIST OF TABLES 3-- LIST OF FIGURES 5-- GLOSSARY 6-- 1 BACKGROUND 7-- 1.1 THE SEVEN-VALENT CONJUGATE PNEUMOCOCCAL VACCINE 7-- 1.2 TWO NEW CONJUGATE PNEUMOCOCCAL VACCINES 8-- 2 OBJECTIVES AND RESEARCH QUESTIONS 9-- 3 LITERATURE SEARCHES AND METHODS 10-- 4 IMMUNOGENICITY, EFFICACY AND EFFECTIVENESS OF CURRENT-- PNEUMOCOCCAL CONJUGATE VACCINES 13-- 4.1 SEVEN VALENT PNEUMOCOCCAL CONJUGATE VACCINE (PCV7) 13-- 4.1.1 Clinical trials – efficacy of PCV7 13-- 4.1.2 Post-licensure studies – effectiveness of PCV7 14-- 4.1.3 Pathogenicity of serotypes 21-- 4.2 TEN VALENT PNEUMOCOCCAL CONJUGATE VACCINE (PCV10) 22-- 4.2.1 Clinical trials – immunogenicity of PCV10 22-- 4.2.2 Clinical trials – efficacy of PCV10 24-- 4.3 THIRTEEN VALENT PNEUMOCOCCAL CONJUGATE VACCINE (PCV13) 25-- 4.3.1 Clinical trials – immunogenicity of PCV13 25-- 5 DISEASE BURDEN IN BELGIUM 27-- 5.1 INVASIVE PNEUMOCOCCAL DISEASE (IPD) 28-- 5.2 ACUTE OTITIS MEDIA (AOM) AND COMMUNITY ACQUIRED PNEUMONIAE (CAP) 35-- 5.3 HOSPITALISATIONS 36-- 5.3.1 Meningitis hospitalisations 36-- 5.3.2 Bacteremia and septicaemia hospitalisations 38-- 5.3.3 Pneumonia hospitalisations 39-- 5.4 DEATHS 39-- 5.4.1 Invasive pneumococcal diseases (IPD) deaths 39-- 5.4.2 (Pneumococcal) pneumonia deaths 40-- 5.4.3 Pneumococcal meningitis deaths 40-- 5.4.4 Pneumococcal septicaemia deaths 41-- 6 ECONOMIC EVALUATIONS OF PCV10 AND PCV13 42-- 6.1 MODELS STRUCTURE 42-- 6.2 MAIN ASSUMPTIONS AND RESULTS 43-- 7 MATHEMATICAL MODELS OF PNEUMOCOCCAL TRANSMISSION 46-- 8 COST-UTILITY ANALYSIS OF PCV10 AND PCV13 IN BELGIUM 48-- 8.1 STUDY DESIGN 48-- 8.1.1 General 48-- 8.1.2 Vaccination options 48-- 8.1.3 Mathematical model structure 49-- 8.2 MODEL INPUT DATA 50-- 8.2.1 Epidemiological parameters and transition probabilities 50-- 8.2.2 Vaccine efficacy estimates 52-- 8.2.3 Direct costs 61-- 8.2.4 Health-Related Quality of Life 63-- 8.3 RESULTS 64-- 8.3.1 Cost-effectiveness acceptability curves 64-- 8.3.2 Incremental costs, outcomes and cost-effectiveness ratios

VII, 134 p., ill., Quels seraient les coûts et les bénéfices associés à des programmes de vaccination contre la varicelle chez les enfants et contre le zona chez les adultes ? Le Centre d’évaluation économique et de modélisation des maladies infectieuses de l’Université d’Anvers (CHERMID) a examiné ces questions pour le compte du Centre fédéral d’expertise des soins de santé (KCE). L’étude révèle qu’un programme de vaccination contre la varicelle n’est souhaitable que si l’on est certain qu’il n’engendrera pas d’augmentation trop importante du nombre de zonas. Les résultats, non encore disponibles, d’autres pays où la vaccination a déjà lieu devraient nous permettre d’en savoir plus. Les avantages de la vaccination des personnes âgées contre le zona ne sont pas clairs non plus à cause du manque actuel de données fiables., 1 GENERAL BACKGROUND 3 -- 1.1 CLINICAL MANIFESTATIONS 3 -- 1.2 TRANSMISSION 3 -- 2 DATA SOURCES AND INTERMEDIARY DATA ANALYSES 5 -- 2.1 DATA SOURCES 5 -- 2.1.1 MCD-HBD 5 -- 2.1.2 Carenet 5 -- 2.1.3 Surveys amongst NCSF members 6 -- 2.1.4 Child & Family survey 7 -- 2.1.5 Social contact patterns 7 -- 2.1.6 Serological surveys 7 -- 2.1.7 Flemish Agency for Care and Health 8 -- 2.1.8 Scientific Institute of Public Health (SIPH) 9 -- 2.1.9 Scott et al (2006) data 9 -- 2.1.10 Scientific literature 9 -- 2.2 HOSPITALISATIONS, PHYSICIAN CONSULTATIONS AND DEATHS DUE TO -- CHICKENPOX AND HERPES ZOSTER 10 -- 2.2.1 Hospitalisations due to CP and HZ 10 -- 2.2.2 Physician consultations due to CP and HZ 21 -- 2.2.3 Total number of people with CP and HZ 24 -- 2.2.4 Deaths due to CP and HZ 25 -- 2.2.5 Postherpetic neuralgia (PHN) 28 -- 2.2.6 HZ related burden-of-illness (BOI) 29 -- 2.3 COSTS RELATED TO CHICKENPOX AND HERPES ZOSTER 36 -- 2.3.1 Costs for people hospitalised for CP and HZ 36 -- 2.3.2 Cost for ambulatory care related to CP and HZ 42 -- 2.4 CP AND HZ RELATED LOSS IN QOL 48 -- 2.4.1 CP related loss in QoL 48 -- 2.4.2 HZ related loss in QoL 50 -- 2.5 BURDEN OF BREAKTHROUGH CP 52 -- 2.6 HZ IN IMMUNOCOMPETENT POPULATION 52 -- 2.7 USE OF ANTIVIRAL MEDICATION FOR HZ 54 -- 2.8 VACCINE RELATED CHARACTERISTICS 54 -- 2.8.1 Childhood VZV vaccination (“chickenpox” vaccination) 54 -- 2.8.2 Adult VZV booster vaccination (“herpes zoster” vaccination) 55 -- 3 COST-UTILITY ANALYSIS: METHODS 70 -- 3.1 VACCINATION OF ADULTS TO PREVENT HERPES ZOSTER 70 -- 3.1.1 Main outcome 70 -- 3.1.2 Mathematical model structure. 70 -- 3.1.3 Uncertainty and sensitivity analysis 71 -- 3.1.4 Overview tables of the estimated and assumed input parameters for the HZ model 72 -- 3.2 VACCINATION OF CHILDREN AGAINST PRIMARY VZV INFECTION 78 -- 3.2.1 Main outcome 78 -- 3.2.2 Mathematical model structure. 78 -- 3.2.3 Fitting to Belgian data 80 -- 3.2.4 Options for childhood VZV (CP) vaccination 82 -- 3.2.5 Overview

VII, 134 p., ill., Een vaccinatieprogramma van kinderen tegen windpokken, en van ouderen tegen zona, wat zouden de kosten en baten hiervan zijn? Deze vraag onderzocht het Centrum voor Gezondheidseconomie en Modellering van Infectieziekten (Universiteit Antwerpen) in opdracht van het Federaal Kenniscentrum voor de Gezondheidszorg (KCE). Een vaccinatieprogramma tegen windpokken kan best pas opgestart worden als men zeker is dat daardoor het aantal gevallen van zona niet tegelijkertijd te sterk toeneemt. Daarvoor moeten de resultaten in een aantal landen, die reeds met vaccinatie zijn gestart, worden afgewacht. Voor vaccinatie tegen zona van zestig plussers zijn er te weinig betrouwbare gegevens beschikbaar om de baten eenduidig in te schatten., 1 GENERAL BACKGROUND 3 -- 1.1 CLINICAL MANIFESTATIONS 3 -- 1.2 TRANSMISSION 3 -- 2 DATA SOURCES AND INTERMEDIARY DATA ANALYSES 5 -- 2.1 DATA SOURCES 5 -- 2.1.1 MCD-HBD 5 -- 2.1.2 Carenet 5 -- 2.1.3 Surveys amongst NCSF members 6 -- 2.1.4 Child & Family survey 7 -- 2.1.5 Social contact patterns 7 -- 2.1.6 Serological surveys 7 -- 2.1.7 Flemish Agency for Care and Health 8 -- 2.1.8 Scientific Institute of Public Health (SIPH) 9 -- 2.1.9 Scott et al (2006) data 9 -- 2.1.10 Scientific literature 9 -- 2.2 HOSPITALISATIONS, PHYSICIAN CONSULTATIONS AND DEATHS DUE TO -- CHICKENPOX AND HERPES ZOSTER 10 -- 2.2.1 Hospitalisations due to CP and HZ 10 -- 2.2.2 Physician consultations due to CP and HZ 21 -- 2.2.3 Total number of people with CP and HZ 24 -- 2.2.4 Deaths due to CP and HZ 25 -- 2.2.5 Postherpetic neuralgia (PHN) 28 -- 2.2.6 HZ related burden-of-illness (BOI) 29 -- 2.3 COSTS RELATED TO CHICKENPOX AND HERPES ZOSTER 36 -- 2.3.1 Costs for people hospitalised for CP and HZ 36 -- 2.3.2 Cost for ambulatory care related to CP and HZ 42 -- 2.4 CP AND HZ RELATED LOSS IN QOL 48 -- 2.4.1 CP related loss in QoL 48 -- 2.4.2 HZ related loss in QoL 50 -- 2.5 BURDEN OF BREAKTHROUGH CP 52 -- 2.6 HZ IN IMMUNOCOMPETENT POPULATION 52 -- 2.7 USE OF ANTIVIRAL MEDICATION FOR HZ 54 -- 2.8 VACCINE RELATED CHARACTERISTICS 54 -- 2.8.1 Childhood VZV vaccination (“chickenpox” vaccination) 54 -- 2.8.2 Adult VZV booster vaccination (“herpes zoster” vaccination) 55 -- 3 COST-UTILITY ANALYSIS: METHODS 70 -- 3.1 VACCINATION OF ADULTS TO PREVENT HERPES ZOSTER 70 -- 3.1.1 Main outcome 70 -- 3.1.2 Mathematical model structure. 70 -- 3.1.3 Uncertainty and sensitivity analysis 71 -- 3.1.4 Overview tables of the estimated and assumed input parameters for the HZ model 72 -- 3.2 VACCINATION OF CHILDREN AGAINST PRIMARY VZV INFECTION 78 -- 3.2.1 Main outcome 78 -- 3.2.2 Mathematical model structure. 78 -- 3.2.3 Fitting to Belgian data 80 -- 3.2.4 Options for childhood VZV (CP) vaccination 82 -- 3.2.5 Overview