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35-41, Objectives: We studied the cost-effectiveness of tenofovir and entecavir in e antigen positive (CHBe+) and negative (CHBe-) chronic hepatitis B. Methods: Using a multicenter survey including 544 patients we measured patient quality of life and attributable costs by clinical disease stage. Natural disease progression was studied in 278 patients in a single center. A Markov model was constructed to follow hypothetical cohorts of treated and untreated 40-year-old CHBe+ and CHBe- patients and 50-year-old patients with compensated cirrhosis. Results: We did not find an improvement in quality of life when viral load was reduced under treatment. Transition rates to liver cirrhosis were found to be age-dependent. Assuming equal effectiveness, tenofovir dominates the entecavir strategy because of its lower price in Belgium. The incremental cost-effectiveness ratio (ICER) of tenofovir after 20 years is more favorable for treating Caucasian cirrhotic patients (mean ICER €29,000/quality-adjusted life-year [QALY]) compared with treating non-cirrhotic patients (mean ICER €110,000 and 131,000/QALY for CHB e+ and e-, respectively). Within the non-cirrhotic patients the ICER decreases with increasing cohort starting age from 30 to 50 years. Conclusions: Results of long-term models for tenofovir or entecavir treatment of CHB need to be interpreted with caution as long-term trials with hard end points are lacking. Especially the effect on HCC remains highly uncertain. Based on cost-effectiveness considerations such antiviral treatment should be targeted at patients with cirrhosis or at risk of rapid progression to this disease stage.

GLOSSARY 2 -- 1 BACKGROUND AND OBJECTIVES 3 -- 1.1 NATURAL HISTORY AND EPIDEMIOLOGY 3 -- 1.2 TREATMENT 4 -- 1.3 OBJECTIVES AND CONTENT OF THE TWO REPORTS 5 -- 2 METHODS 7 -- 2.1 TARGET POPULATION 7 -- 2.2 MODEL STRUCTURE AND BASIC ASSUMPTIONS 7 -- 2.3 TRANSITION PROBABILITIES 9 -- 2.4 DISEASE MANAGEMENT AND TREATMENT COSTS 12 -- 2.5 UTILITIES 13 -- 2.6 ANTIVIRAL TREATMENT 14 -- 3 RESULTS 16 -- 3.1 MODEL VALIDATION: NATURAL EVOLUTION OF DISEASE WITHIN EUROPEAN -- COHORTS 17 -- 3.2 HEALTH OUTCOMES 18 -- 3.2.1 Life-years gained in the three cohorts 18 -- 3.2.2 Undiscounted life-years gained in DC and HCC 19 -- 3.2.3 Mean tenofovir treatment duration in CHB e+ vs e- cohorts 20 -- 3.3 BASE-CASE COST-UTILITY ANALYSES 20 -- 3.3.1 Overview of the results for the three base-case cohorts 20 -- 3.3.2 CHBe+ non-cirrhotic Europeans 21 -- 3.3.3 CHBe- non-cirrhotic Europeans 23 -- 3.3.4 Patient with compensated liver cirrhosis 25 -- 3.4 SCENARIO AND PROBABILISTIC SENSITIVITY ANALYSES 27 -- 3.4.1 Probabilistic sensitivity analysis 27 -- 3.4.2 ICERs in function of the time horizon 30 -- 3.4.3 Asian cohorts 31 -- 3.4.4 Variations in the discount rates 32 -- 3.5 BUDGET IMPACT 33 -- 4 DISCUSSION AND CONCLUSIONS 34 -- 5 APPENDICES 37 -- 5.1 NATURAL PROGRESSION TO LIVER CIRRHOSIS IN 278 CHRONIC HEPATITIS B -- PATIENTS OF EUROPEAN ORIGIN, THE IMPORTANCE OF AGE AND ELEVATED ALT . 37 -- 5.1.1 Introduction 37 -- 5.1.2 Aim 37 -- 5.1.3 Methods 37 -- 5.1.4 Results 38 -- 5.1.5 Discussion and Conclusion 39 -- 5.2 COMPARISON OF PUBLISHED QUALITY OF LIFE DATA 40 -- 5.2.1 Aims 40 -- 5.2.2 Methods 41 -- 5.2.3 Results 43 -- 5.3 DISEASE MANAGEMENT COSTS 46 -- 5.3.1 Data sources 48 -- 5.3.2 Primary inclusion counts 52 -- 5.3.3 Exclusions and sub grouping for cost study 53 -- 5.3.4 Extrapolations for partial lump sum remunerations 59 -- 5.3.5 Results 66 -- 5.3.6 Discussion 72 -- 6 REFERENCES 74

X, 77 p., ill., Depuis plusieurs années, de nouveaux médicaments sont disponibles pour traiter l'hépatite B chronique. Le coût de ce traitement s’élève à environ 5 000 euros par patient et par an. Les décideurs ont demandé au Centre fédéral d’expertise des soins de santé (KCE) d’identifier quels groupes de patients sont susceptibles de bénéficier le plus de ce traitement, et à quel prix. Le KCE conclut que le bénéfice par euro dépensé est maximal lorsque le traitement est appliqué à un stade avancé de la maladie, à savoir le stade de la cirrhose du foie. Les calculs effectués par le KCE sont basés sur une étude originale de la progression et des coûts de la maladie, menée en collaboration avec un grand nombre d’hépatologues., GLOSSARY 2 -- 1 BACKGROUND AND OBJECTIVES 3 -- 1.1 NATURAL HISTORY AND EPIDEMIOLOGY 3 -- 1.2 TREATMENT 4 -- 1.3 OBJECTIVES AND CONTENT OF THE TWO REPORTS 5 -- 2 METHODS 7 -- 2.1 TARGET POPULATION 7 -- 2.2 MODEL STRUCTURE AND BASIC ASSUMPTIONS 7 -- 2.3 TRANSITION PROBABILITIES 9 -- 2.4 DISEASE MANAGEMENT AND TREATMENT COSTS 12 -- 2.5 UTILITIES 13 -- 2.6 ANTIVIRAL TREATMENT 14 -- 3 RESULTS 16 -- 3.1 MODEL VALIDATION: NATURAL EVOLUTION OF DISEASE WITHIN EUROPEAN -- COHORTS 17 -- 3.2 HEALTH OUTCOMES 18 -- 3.2.1 Life-years gained in the three cohorts 18 -- 3.2.2 Undiscounted life-years gained in DC and HCC 19 -- 3.2.3 Mean tenofovir treatment duration in CHB e+ vs e- cohorts 20 -- 3.3 BASE-CASE COST-UTILITY ANALYSES 20 -- 3.3.1 Overview of the results for the three base-case cohorts 20 -- 3.3.2 CHBe+ non-cirrhotic Europeans 21 -- 3.3.3 CHBe- non-cirrhotic Europeans 23 -- 3.3.4 Patient with compensated liver cirrhosis 25 -- 3.4 SCENARIO AND PROBABILISTIC SENSITIVITY ANALYSES 27 -- 3.4.1 Probabilistic sensitivity analysis 27 -- 3.4.2 ICERs in function of the time horizon 30 -- 3.4.3 Asian cohorts 31 -- 3.4.4 Variations in the discount rates 32 -- 3.5 BUDGET IMPACT 33 -- 4 DISCUSSION AND CONCLUSIONS 34 -- 5 APPENDICES 37 -- 5.1 NATURAL PROGRESSION TO LIVER CIRRHOSIS IN 278 CHRONIC HEPATITIS B -- PATIENTS OF EUROPEAN ORIGIN, THE IMPORTANCE OF AGE AND ELEVATED ALT . 37 -- 5.1.1 Introduction 37 -- 5.1.2 Aim 37 -- 5.1.3 Methods 37 -- 5.1.4 Results 38 -- 5.1.5 Discussion and Conclusion 39 -- 5.2 COMPARISON OF PUBLISHED QUALITY OF LIFE DATA 40 -- 5.2.1 Aims 40 -- 5.2.2 Methods 41 -- 5.2.3 Results 43 -- 5.3 DISEASE MANAGEMENT COSTS 46 -- 5.3.1 Data sources 48 -- 5.3.2 Primary inclusion counts 52 -- 5.3.3 Exclusions and sub grouping for cost study 53 -- 5.3.4 Extrapolations for partial lump sum remunerations 59 -- 5.3.5 Results 66 -- 5.3.6 Discussion 72 -- 6 REFERENCES 74

X, 77 p., ill., Sinds enkele jaren zijn nieuwe geneesmiddelen beschikbaar voor de behandeling van chronische hepatitis B. De kostprijs van deze behandeling bedraagt zowat 5000 euro per patiënt per jaar. De beleidsmakers vroegen aan het Federaal Kenniscentrum voor de Gezondheidszorg (KCE) na te gaan welke groepen patiënten het meest baat kunnen hebben bij deze behandeling, en tegen welke prijs. Het KCE concludeerde dat het behandelen van een meer gevorderd ziektestadium, in dit geval levercirrose, gepaard gaat met de hoogste gezondheidswinst per gespendeerde euro. De berekeningen door het KCE zijn gebaseerd op een origineel onderzoek naar het ziekteverloop en de ziektekosten in samenwerking met een groot aantal leverspecialisten., GLOSSARY 2 -- 1 BACKGROUND AND OBJECTIVES 3 -- 1.1 NATURAL HISTORY AND EPIDEMIOLOGY 3 -- 1.2 TREATMENT 4 -- 1.3 OBJECTIVES AND CONTENT OF THE TWO REPORTS 5 -- 2 METHODS 7 -- 2.1 TARGET POPULATION 7 -- 2.2 MODEL STRUCTURE AND BASIC ASSUMPTIONS 7 -- 2.3 TRANSITION PROBABILITIES 9 -- 2.4 DISEASE MANAGEMENT AND TREATMENT COSTS 12 -- 2.5 UTILITIES 13 -- 2.6 ANTIVIRAL TREATMENT 14 -- 3 RESULTS 16 -- 3.1 MODEL VALIDATION: NATURAL EVOLUTION OF DISEASE WITHIN EUROPEAN -- COHORTS 17 -- 3.2 HEALTH OUTCOMES 18 -- 3.2.1 Life-years gained in the three cohorts 18 -- 3.2.2 Undiscounted life-years gained in DC and HCC 19 -- 3.2.3 Mean tenofovir treatment duration in CHB e+ vs e- cohorts 20 -- 3.3 BASE-CASE COST-UTILITY ANALYSES 20 -- 3.3.1 Overview of the results for the three base-case cohorts 20 -- 3.3.2 CHBe+ non-cirrhotic Europeans 21 -- 3.3.3 CHBe- non-cirrhotic Europeans 23 -- 3.3.4 Patient with compensated liver cirrhosis 25 -- 3.4 SCENARIO AND PROBABILISTIC SENSITIVITY ANALYSES 27 -- 3.4.1 Probabilistic sensitivity analysis 27 -- 3.4.2 ICERs in function of the time horizon 30 -- 3.4.3 Asian cohorts 31 -- 3.4.4 Variations in the discount rates 32 -- 3.5 BUDGET IMPACT 33 -- 4 DISCUSSION AND CONCLUSIONS 34 -- 5 APPENDICES 37 -- 5.1 NATURAL PROGRESSION TO LIVER CIRRHOSIS IN 278 CHRONIC HEPATITIS B -- PATIENTS OF EUROPEAN ORIGIN, THE IMPORTANCE OF AGE AND ELEVATED ALT . 37 -- 5.1.1 Introduction 37 -- 5.1.2 Aim 37 -- 5.1.3 Methods 37 -- 5.1.4 Results 38 -- 5.1.5 Discussion and Conclusion 39 -- 5.2 COMPARISON OF PUBLISHED QUALITY OF LIFE DATA 40 -- 5.2.1 Aims 40 -- 5.2.2 Methods 41 -- 5.2.3 Results 43 -- 5.3 DISEASE MANAGEMENT COSTS 46 -- 5.3.1 Data sources 48 -- 5.3.2 Primary inclusion counts 52 -- 5.3.3 Exclusions and sub grouping for cost study 53 -- 5.3.4 Extrapolations for partial lump sum remunerations 59 -- 5.3.5 Results 66 -- 5.3.6 Discussion 72 -- 6 REFERENCES 74

VIII, 111 p., ill., En collaboration avec des médecins spécialistes des maladies du foie, le Centre fédéral d’expertise des soins de santé (KCE) a réalisé une étude sur l’évolution et les possibilités de traitement de l’hépatite B chronique. Ces dernières années, de nouveaux antiviraux ont fait leur apparition sur le marché et sont remboursés depuis peu. Souvent, ces traitements doivent être pris à vie. Leur but est d’empêcher le développement de complications à long terme, tels la cirrhose ou le cancer du foie. L’efficacité et la sécurité de ces traitements ont été démontrées à court terme, mais pas encore en cas de prise prolongée. En l’absence de telles données de long terme, il est actuellement difficile d’évaluer le rapport entre le coût des ces traitements et leurs bénéfices en terme de santé, bénéfices non encore démontrés., 1 AIMS AND METHODS 5 -- 1.1 AIMS 5 -- 1.2 METHODS 5 -- 1.3 OVERVIEW OF THE REPORT, PART 1 AND PART 2 5 -- 2 NATURAL HISTORY AND EPIDEMIOLOGY 6 -- 2.1 HEPATITIS B: TRANSITION AND NATURAL EVOLUTION 6 -- 2.1.1 Introduction 6 -- 2.1.2 Natural history of infections with the HBV 6 -- 2.1.3 Methods 8 -- 2.1.4 Results 9 -- 2.2 HBV IN BELGIUM AND SURROUNDING COUNTRIES 12 -- 2.2.1 Introduction and search strategy 12 -- 2.2.2 Epidemiology for Belgium, France, Germany and The Netherlands 12 -- 2.2.3 General Conclusion 16 -- 3 TREATMENT 17 -- 3.1 INDICATIONS FOR TREATMENT 17 -- 3.1.1 Treatment goals 17 -- 3.1.2 Definition of response 17 -- 3.1.3 Treatment options 18 -- 3.1.4 Interferon and pegylated interferon 18 -- 3.1.5 Nucleos(t)ide analogues in HBeAg-positive patients 20 -- 3.1.6 Nucleos(t)ide analogues in HBeAg-negative patients 24 -- 3.1.7 Nucleos(t)ide analogues in patients with cirrhosis or advanced fibrosis 25 -- 3.2 RECOMMENDATIONS FOR THE TREATMENT 28 -- 3.2.1 The BASL 2007 recommendations 28 -- 3.2.2 The EASL 2009 recommendations 28 -- 3.2.3 Treatment strategies 29 -- 3.2.4 Management of antiviral resistance to current NA therapy 31 -- 4 SITUATION IN BELGIUM 38 -- 4.1 HISTORY OF REIMBURSEMENT OF ANTIVIRAL DRUGS 38 -- 4.2 THE PROSPECTIVE STUDY 39 -- 4.2.1 Rationale 39 -- 4.2.2 Objectives 40 -- 4.2.3 Ethics and privacy protection 40 -- 4.2.4 Study design and schedule 41 -- 4.3 RESULTS OF THE STUDY 43 -- 4.3.1 Patient characteristics 43 -- 4.3.2 Estimation of the number of patients by disease stage, visiting a medical specialist for chronic HBV infection in Belgium. 46 -- 4.3.3 Conclusion for situation in Belgium 50 -- 4.3.4 Quality of life results 50 -- 4.3.5 Conclusion for quality of life assessment 52 -- 5 REVIEW OF THE COST-EFFECTIVENESS LITERATURE 53 -- 5.1 METHODS 53 -- 5.1.1 Literature search strategy 53 -- 5.1.2 Selection criteria 53 -- 5.1.3 Selection process 54 -- 5.2 OVERVIEW OF THE ECONOMIC EVALUATIONS - TRANSVERSAL 56 -- 5.2.1 Analytical technique 56 -- 5.2

VIII, 111 p., ill., Het Federaal Kenniscentrum voor de Gezondheidszorg (KCE) onderzocht in samenwerking met een aantal specialisten van leverziekten de evolutie en de behandelingsmogelijkheden van chronische hepatitis B. De laatste jaren zijn nieuwe virusremmers op de markt gekomen die sinds kort ook worden terugbetaald. Deze dienen dikwijls levenslang te worden ingenomen. Het doel van de behandeling is het vermijden van ernstige verwikkelingen van de infectie op langere termijn, zoals levercirrose en leverkanker. De werkzaamheid en veiligheid van deze geneesmiddelen zijn gekend op korte termijn, maar nog niet bij langdurige inname. In afwachting van deze gegevens blijft het voorlopig moeilijk om in te schatten of de kostprijs opweegt tegen de nog te behalen gezondheidswinst., 1 AIMS AND METHODS 5 -- 1.1 AIMS 5 -- 1.2 METHODS 5 -- 1.3 OVERVIEW OF THE REPORT, PART 1 AND PART 2 5 -- 2 NATURAL HISTORY AND EPIDEMIOLOGY 6 -- 2.1 HEPATITIS B: TRANSITION AND NATURAL EVOLUTION 6 -- 2.1.1 Introduction 6 -- 2.1.2 Natural history of infections with the HBV 6 -- 2.1.3 Methods 8 -- 2.1.4 Results 9 -- 2.2 HBV IN BELGIUM AND SURROUNDING COUNTRIES 12 -- 2.2.1 Introduction and search strategy 12 -- 2.2.2 Epidemiology for Belgium, France, Germany and The Netherlands 12 -- 2.2.3 General Conclusion 16 -- 3 TREATMENT 17 -- 3.1 INDICATIONS FOR TREATMENT 17 -- 3.1.1 Treatment goals 17 -- 3.1.2 Definition of response 17 -- 3.1.3 Treatment options 18 -- 3.1.4 Interferon and pegylated interferon 18 -- 3.1.5 Nucleos(t)ide analogues in HBeAg-positive patients 20 -- 3.1.6 Nucleos(t)ide analogues in HBeAg-negative patients 24 -- 3.1.7 Nucleos(t)ide analogues in patients with cirrhosis or advanced fibrosis 25 -- 3.2 RECOMMENDATIONS FOR THE TREATMENT 28 -- 3.2.1 The BASL 2007 recommendations 28 -- 3.2.2 The EASL 2009 recommendations 28 -- 3.2.3 Treatment strategies 29 -- 3.2.4 Management of antiviral resistance to current NA therapy 31 -- 4 SITUATION IN BELGIUM 38 -- 4.1 HISTORY OF REIMBURSEMENT OF ANTIVIRAL DRUGS 38 -- 4.2 THE PROSPECTIVE STUDY 39 -- 4.2.1 Rationale 39 -- 4.2.2 Objectives 40 -- 4.2.3 Ethics and privacy protection 40 -- 4.2.4 Study design and schedule 41 -- 4.3 RESULTS OF THE STUDY 43 -- 4.3.1 Patient characteristics 43 -- 4.3.2 Estimation of the number of patients by disease stage, visiting a medical specialist for chronic HBV infection in Belgium. 46 -- 4.3.3 Conclusion for situation in Belgium 50 -- 4.3.4 Quality of life results 50 -- 4.3.5 Conclusion for quality of life assessment 52 -- 5 REVIEW OF THE COST-EFFECTIVENESS LITERATURE 53 -- 5.1 METHODS 53 -- 5.1.1 Literature search strategy 53 -- 5.1.2 Selection criteria 53 -- 5.1.3 Selection process 54 -- 5.2 OVERVIEW OF THE ECONOMIC EVALUATIONS - TRANSVERSAL 56 -- 5.2.1 Analytical technique 56 -- 5.2

VI, 111 p., ill., 1 AIMS AND METHODS 5 -- 1.1 AIMS 5 -- 1.2 METHODS 5 -- 1.3 OVERVIEW OF THE REPORT, PART 1 AND PART 2 5 -- 2 NATURAL HISTORY AND EPIDEMIOLOGY 6 -- 2.1 HEPATITIS B: TRANSITION AND NATURAL EVOLUTION 6 -- 2.1.1 Introduction 6 -- 2.1.2 Natural history of infections with the HBV 6 -- 2.1.3 Methods 8 -- 2.1.4 Results 9 -- 2.2 HBV IN BELGIUM AND SURROUNDING COUNTRIES 12 -- 2.2.1 Introduction and search strategy 12 -- 2.2.2 Epidemiology for Belgium, France, Germany and The Netherlands 12 -- 2.2.3 General Conclusion 16 -- 3 TREATMENT 17 -- 3.1 INDICATIONS FOR TREATMENT 17 -- 3.1.1 Treatment goals 17 -- 3.1.2 Definition of response 17 -- 3.1.3 Treatment options 18 -- 3.1.4 Interferon and pegylated interferon 18 -- 3.1.5 Nucleos(t)ide analogues in HBeAg-positive patients 20 -- 3.1.6 Nucleos(t)ide analogues in HBeAg-negative patients 24 -- 3.1.7 Nucleos(t)ide analogues in patients with cirrhosis or advanced fibrosis 25 -- 3.2 RECOMMENDATIONS FOR THE TREATMENT 28 -- 3.2.1 The BASL 2007 recommendations 28 -- 3.2.2 The EASL 2009 recommendations 28 -- 3.2.3 Treatment strategies 29 -- 3.2.4 Management of antiviral resistance to current NA therapy 31 -- 4 SITUATION IN BELGIUM 38 -- 4.1 HISTORY OF REIMBURSEMENT OF ANTIVIRAL DRUGS 38 -- 4.2 THE PROSPECTIVE STUDY 39 -- 4.2.1 Rationale 39 -- 4.2.2 Objectives 40 -- 4.2.3 Ethics and privacy protection 40 -- 4.2.4 Study design and schedule 41 -- 4.3 RESULTS OF THE STUDY 43 -- 4.3.1 Patient characteristics 43 -- 4.3.2 Estimation of the number of patients by disease stage, visiting a medical specialist for chronic HBV infection in Belgium. 46 -- 4.3.3 Conclusion for situation in Belgium 50 -- 4.3.4 Quality of life results 50 -- 4.3.5 Conclusion for quality of life assessment 52 -- 5 REVIEW OF THE COST-EFFECTIVENESS LITERATURE 53 -- 5.1 METHODS 53 -- 5.1.1 Literature search strategy 53 -- 5.1.2 Selection criteria 53 -- 5.1.3 Selection process 54 -- 5.2 OVERVIEW OF THE ECONOMIC EVALUATIONS - TRANSVERSAL 56 -- 5.2.1 Analytical technique 56 -- 5.2