# Evaluation économique du traitement antiviral de l'hépatite B chronique en Belgique – Tome 2

KCE reports 157B

Centre fédéral d'expertise des soins de santé
Federaal Kenniscentrum voor de Gezondheidszorg
2011
## Le Centre fédéral d'expertise des soins de santé

**Présentation :** Le Centre fédéral d'expertise des soins de santé est un parastatal, créé le 24 décembre 2002 par la loi-programme (articles 262 à 266), sous tutelle du Ministre de la Santé publique et des Affaires sociales, qui est chargé de réaliser des études éclairant la décision politique dans le domaine des soins de santé et de l'assurance maladie.

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Evaluation économique du traitement antiviral de l'hépatite B chronique en Belgique

— Tome 2

KCE reports 157B

CHRISTOPH SCHWIERZ, NANCY THIRY, STEFAAN VAN DE SANDE, MOHAMED GAMIL, FREDERIK NEVENS, ISABELLE COLLE, YVES HORMANS, FRANK HULSTAERT

Centre fédéral d'expertise des soins de santé
Federaal Kenniscentrum voor de gezondheidszorg
2011
KCE reports 157B

**Titre:** Evaluation économique du traitement antiviral de l'hépatite B chronique en Belgique - Tome 2

**Auteurs:** Christoph Schwierz (KCE), Nancy Thiry (KCE), Stefaan Van de Sande (KCE), Mohamed Gamil (UZ Gasthuisberg Leuven), Frederik Nevens (UZ Gasthuisberg, Leuven), Isabelle Colle (UZ Gent), Yves Horsmans (Cliniques universitaires Saint-Luc, Bruxelles), Frank Hulstaert (KCE)

**Relecture:** Chris De Laet (KCE), Irina Cleemput (KCE), Mattias Neyt (KCE).

**Experts externes:** Michael Adler (ULB Hôpital Erasme, Bruxelles), Chantal de Galocsy (HIS, site Bracops, Bruxelles), Jean Delwaide (CHU, Liège), André Elewaut (UZ Gent), Catharina Mathei (KU Leuven), Peter Michielsen (UZ Antwerpen), Hans Orlent (AZ St Jan AV, Brugge), Geert Robays (UZ Gasthuisberg, Leuven, ZOL, Genk), et Pierre Van Damme (Universiteit Antwerpen), Marc Vandecasteele (UZ Gasthuisberg, Leuven et INAMI).

**Remerciements:** Les auteurs tiennent à remercier l'équipe de VeedaCR sa, Bruxelles, et en particulier Eva Vannieuwenhuyse, Marie-Paule Derde et Leonard Kaufman pour l'organisation des enquêtes auprès des patients. Nous exprimons également nos sentiments de gratitude envers les nombreux enquêteurs non mentionnés ci-dessus, qui ont activement participé à la réalisation de leur mission: Collins Assene, Stefan Bourgeois, Stephane de Maeght, Eric Goffin, Joannes Holvoet, Pierre Lammens, Luc Lasser, Hendrik Reynaert, Dirk Sprengers et tous les co-investigateurs. De plus, nous tenons particulièrement à remercier Anna Lok (University of Michigan, USA), Yun-Fan Liaw (University of Taipei, Taiwan), Jo Robays (KCE) et Chris De Laet (KCE), pour leurs commentaires utiles au cours du projet.

**Validateurs externes:** Heiner Wedemeyer (University Hospital Hannover), Philippe Beutels (University Antwerp), Steven Simoens (University Leuven).

**Conflits d'intérêt:** Le Prof. Horsmans déclare avoir reçu des financements de recherche de la part des entreprises pharmaceutiques Roche, Schering et GSK, des honoraires de consultation de la part de GSK, Roche, Schering, Gilead, Bayer, Novartis et BMS, et d'avoir participé comme chercheur scientifique à des études de GSK, Roche, Schering, Gilead, Novartis et BMS. Le Prof. Colle déclare que son département a reçu des financements de recherche de la part de Roche et Schering Plough. Elle a perçu des honoraires de consultation de la part de BMS, des honoraires d'orateur de la part de BMS et Schering Plough, ainsi que des indemnités de voyage de la part de Roche, Schering Plough, BMS et Gilead. Le Prof. Nevens déclare que son département a perçu des honoraires pour participation à des conférences scientifiques de Gilead et de BMS. Le Prof. Wedemeyer déclare avoir reçu des financements de recherche, des honoraires de consultation et d'orateur de la part des entreprises pharmaceutiques Roche, Gilead, BMS, Abbott, MSD et Novartis.

**Disclaimer:** Les experts externes ont été consultés sur une version (préliminaire) du rapport scientifique. Leurs remarques ont été discutées au cours des réunions. Ils ne sont pas co-auteurs du rapport scientifique et n'étaient pas nécessairement d'accord avec son contenu.

Une version (finale) a ensuite été soumise aux validateurs. La validation du rapport résulte d'un consensus ou d'un vote majoritaire entre les validateurs. Les validateurs ne sont pas co-auteurs du rapport scientifique et ils n'étaient pas nécessairement tous les trois d'accord avec son contenu.

Finalement, ce rapport a été approuvé à l'unanimité par le Conseil d'administration.
Le KCE reste seul responsable des erreurs ou omissions qui pourraient subsister de même que des recommandations faites aux autorités publiques.

Mise en Page: Ine Verhulst

Bruxelles, 14 juin 2011

Etude n° 2008-11

Domaine : Health Technology Assessment (HTA)

MeSH : Hepatitis B, Chronic ; Antiviral Agent ; Hepatitis B virus ; Cost-Benefit Analysis

Classification NLM: WC 536

Langage: français, anglais

Format : Adobe® PDF™ (A4)

Dépôt légal : D/2011/10.273/28

Ce document est disponible en téléchargement sur le site Web du Centre fédéral d'expertise des soins de santé.

Les rapports KCE sont publiés sous Licence Creative Commons « by/nc/nd » (http://creativecommons.org/licenses/by-nc-nd/2.0/be/deed.fr).

Comment citer ce rapport?

Schwierz C, Thiry N, Van de Sande S, Gamil M, Nevens F, Colle I, Horsmans Y, Hulstaert F. Evaluation économique du traitement antiviral de l'hépatite B chronique en Belgique – Tome 2. Health Technology Assessment (HTA). Bruxelles: Centre federal d'expertise des soins de santé (KCE). 2011. Reports 157B. D/2011/10.273/28

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<figure><img src="image_2.png" /></figure>
# PRÉFACE

Durant la dernière décennie, il s'est produit une petite révolution en matière de traitement des infections virales. Après les succès spectaculaires enregistrés dans les inhibiteurs du sida, nous disposons aussi aujourd'hui de plus en plus de médicaments permettant de guérir les infections virales ou du moins d'en atténuer les conséquences les plus graves.

Il est question ici de traitements médicamenteux destinés à la suppression à long terme de la prolifération du virus de l'hépatite B, dans l'espoir de réduire le risque de deux complications tardives redoutées de l'hépatite B chronique : la cirrhose et le cancer du foie.

Nous avons essayé de réduire au minimum l'incertitude au niveau des calculs du rapport coût-efficacité, en rassemblant nous-mêmes des données de patients belges. Grâce à nos propres enquêtes et à la mise à disposition d'une cohorte clinique de l'hôpital universitaire de Leuven, nous avons pu substituer nos propres chiffres aux estimations – souvent trop optimistes- issues de publications sponsorisées la plupart du temps. Ces chiffres concernent les coûts engendrés à charge de l'assurance maladie, la qualité de vie des patients chroniques et les probabilités réelles de développer des complications.

Ce rapport s'appuie sur un rapport précédent et construit un modèle exploitant les données rassemblées pour apprécier les coûts et les bénéfices d'un traitement. Compte tenu du prix actuel de ces médicaments et de la durée importante du traitement, les coûts qui en découlent sont très élevés par rapport aux gains de santé qui ne se manifesteront qu'à terme. Les surcoûts sont à mettre en balance avec le coût d'interventions alternatives, mais nous ne disposons malheureusement pas d'une situation de référence très claire en la matière. Néanmoins, les données chiffrées rassemblées devraient permettre d'y voir plus clair dans cette décision difficile.

Nous avons pu bénéficier durant ce travail de l'aide d'hépatologues, de virologues et d'autres spécialistes belges et étrangers. Nous tenons tout particulièrement à les remercier car sans eux, nous n'aurions pas pu mener ce travail à bien.

Jean Pierre CLOSON
Directeur général adjoint

Raf MERTENS
Directeur général
# Résumé

## INTRODUCTION

L'hépatite B chronique (chronic hepatitis B, CHB) est une inflammation du foie le plus souvent asymptomatique provoquée par une infection chronique due au virus de l'hépatite B (VHB). Au départ, l'hépatite B chronique se caractérise par la présence dans le sang de l'antigène e du VHB (CHBe+). L'évolution de l'hépatite B chronique présente une grande variation. Chez de nombreux patients, la réplication virale et l'inflammation hépatique sont fortement réduites après une séroconversion de l'antigène e. Ces patients deviennent alors des 'porteurs inactifs' (inactive carriers, ICAR) et peuvent atteindre une séroconversion pour l'antigène de surface du VHB (HBsAg- ou stade résolu). D'autres patients peuvent évoluer vers une forme d'hépatite active à antigène e négatif (CHBe-). Tant les patients CHBe+ que les CHBe-, non cirrhotiques, se trouvent exposés au risque de développer une cirrhose du foie (compensée : CC ou décompensée : DC). Les patients avec CHB, en particulier les cirrhotiques, courent un risque de développer un carcinome hépatocellulaire (CHC), une forme de cancer hépatique. Comparé aux patients de race blanche le risque de CHC s'est révélé plus élevé chez les Asiatiques. Il est probablement également plus haut chez les Africains d'origine subsaharienne, qui représentent une proportion croissante des patients CHB en Belgique. A moins qu'une greffe du foie puisse être pratiquée, la cirrhose décompensée (DC) et le CHC sont associés à une mortalité élevée.

Pour être remboursé tout médicament antiviral contre le VHB nécessite une prescription par un spécialiste en médecine interne et une autorisation par le médecin conseil de la mutualité. Les patients doivent entre autres présenter des taux élevés d'enzymes hépatiques (ALT) et un stade de fibrose ou d'inflammation hépatique (non précisés) sur une biopsie du foie.

En Belgique environ 10% des patients traités reçoivent des injections d'interféron-alpha pégylé pendant un an. Pour beaucoup de patients cette modalité thérapeutique n'est pas considérée comme appropriée pour des raisons diverses. En revanche, les analogues de nucléos(t)ide (AN) peuvent être utilisés plus généralement comme traitement antiviral. Les AN sont disponibles sous forme orale et sont bien tolérés mais ils peuvent nécessiter une administration tout au long de la vie. Le premier AN, la lamivudine, a obtenu un remboursement en 2001 comme traitement de première ligne. Toutefois, étant donné que le VHB développe une résistance envers la lamuvidine, entraînant très probablement l'inefficacité du traitement, ce dernier n'est plus considéré approprié comme traitement de première ligne. Adefovir a succédé à la lamuvidine, mais seulement en traitement de seconde ligne.

Depuis 2010 tenofovir et entecavir sont remboursés à 100% en traitement de première ligne à un coût annuel de respectivement 4 970 euros et 5 221 euros par patient. Les deux médicaments sont bien tolérés et empêchent la réplication virale avec une probabilité très faible d'entraîner une résistance au médicament, au moins chez les patients qui ne présentent pas encore de résistance à la lamuvidine. Il n'existe cependant pas d'études randomisées et contrôlées à long terme pour tenofovir ni pour entecavir démontrant un effet sur la progression de la maladie ni sur des critères d'évaluation cliniques durs.

Le présent rapport est le second des projets du KCE relatifs au traitement antiviral de l'hépatite B chronique. Dans cette seconde partie du rapport, nous étudions le rapport coût-efficacité du traitement antiviral. Nous nous basons sur la première partie dans laquelle nous avions couvert l'histoire naturelle et l'épidémiologie, les traitements antiviraux et les études de rapport coût-efficacité publiées. En outre, nous avons collecté prospectivement des informations cliniques et relatives à la qualité de vie chez 544 patients ayant consulté leur hépatologue en Belgique au cours du premier semestre 2009 pour une infection à VHB chronique ou une complication non aiguë de celle-ci. Les données cliniques enregistrées portent sur l'année 2009 et, lorsqu'elles étaient disponibles, aussi sur 2006. Les données cliniques de 2006 ont été liées aux coûts de 2006 de l'INAMI (Institut National Maladie-Invalidité). De surcroît, nous avons analysé la progression de la maladie au sein d'une vaste cohorte récente de patients de race blanche atteints de CHB et non traités, suivis à l'Hôpital universitaire de Leuven.
# METHODES

## STADES ET TRANSITIONS DE LA MALADIE

<figure><img src="image_3.png" /><figcaption>Figure A. Modélisation des stades et transitions de la maladie.</figcaption></figure>

### Abréviations:

CHBe+ hépatite B chronique, antigène e positif CHBe- hépatite B chronique, antigène e négatif

NC non-cirrhotique CC cirrhose compensée

ICAR porteur inactif HBsAg- hépatite B, antigène de surface négatif

DC cirrhose décompensée HCC carcinome hépatocellulaire

Notes: En utilisant un cycle d'une durée d'un an, les patients évoluent entre les stades de la maladie. Les patients peuvent rester dans un même stade avec une certaine probabilité pendant plus d'une année, sauf au stade de la transplantation hépatique, à partir duquel ils évoluent soit vers le stade post-transplantation soit vers le décès. On part de l'hypothèse selon laquelle les patients sont traités aux stades indiqués en gras : CHBe+/- NC, CHBe+/- CC, DC et HCC; Dans le modèle, les transitions blocquées, en partie, de façon directe grâce au traitement antiviral sont marquées par une croix.

L'évaluation est basée sur un modèle Markov avec des stades de la maladie et des transitions multiples (Figure A). Les probabilités de transition pour la stratégie « aucun traitement antiviral » reposent essentiellement sur la littérature et les avis d'experts. De plus, nous avons eu accès à des données non publiées relatives à 278 patients de race blanche atteints de CHB mais non traités, avec une durée moyenne de suivi de 7,8 années à l'Hôpital universitaire de Leuven. Pour au moins deux raisons, cette base de données s'est révélée très précieuse. Premièrement, elle nous a permis d'estimer les probabilités de transition vers un état cirrhotique, spécifiques à l'âge, chez des patients CHBe+ et CHBe- non traités. Ceci a permis une découverte novatrice dans ce champ de recherche, à savoir le constat d'une augmentation considérable de la probabilité de transition vers la cirrhose hépatique après l'âge de 50 ans. Cette information a fortement amélioré la précision de nos estimations dans le modèle. Deuxièmement, nous avons observé que chez les 59 patients CHBe+, qui présentaient des taux d'enzymes hépatiques (ALT) stables en l'absence de cirrhose hépatique, aucune progression de la maladie sur une période de 10 ans n'a été observée, confirmant et renforçant les constats antérieurs.
## COHORTES DE PATIENTS, STRATÉGIES THÉRAPEUTIQUES ET EFFETS

Pour nos analyses des coûts et d'efficacité, nous comparons la stratégie de traitement antiviral (avec tenofovir ou entecavir) à la stratégie de 'non-traitement antiviral'. Nous utilisons l'histoire naturelle en guise de comparateur étant donné que (1) la lamivudine n'est plus considérée comme traitement de première ligne de référence pour la CHB, (2) adefovir consiste en un traitement de seconde ligne, et (3) l'interféron-alpha pégylé n'est éligible comme traitement de première ligne que pour des patients sélectionnés.

Selon les résultats des études à court terme disponibles, l'entecavir et le tenofovir semblent présenter une efficacité équivalente pour des patients non résistant à la lamivudine. Les patients ayant une résistance à la lamivudine peuvent aussi manifester une résistance à l'entecavir. Vu que le tenofovir est moins coûteux que l'entecavir (et devrait probablement le rester), l'option tenofovir prédomine sur l'option entecavir. Autrement dit, le tenofovir présentera toujours un rapport coût-efficacité plus favorable que l'entecavir.

Comme point de départ, nous avons suivi des cohortes hypothétiques de patients européens, traités et non traités, âgés de 40 ans souffrant d'une hépatite B chronique à antigène e positif ou négatif, non cirrhotiques (CHBe+ NC et CHBe- NC). Par ailleurs, nous avons évalué une cohorte de patients de 50 ans atteints d'une cirrhose compensée (CC), cette cohorte étant constituée de 30% de patients CHBe+ CC et de 70% de patients CHBe- CC. Pour chacune de ces trois cohortes (toutes étant constituées à 70% de patients de sexe masculin), nous avons pris en compte des horizons temporels de 10 et de 20 ans, vu que l'expérience thérapeutique actuelle basée sur des études (non contrôlées) est limitée à environ 5 ans.

Dans les analyses de scénarios, nous avons évalué différents âges au début du traitement, nous avons augmenté la probabilité de transition vers un CHC telle qu'observée dans les cohortes asiatiques et nous avons varié les taux d'actualisation pour les coûts et les effets. Pour le scénario de base le taux d'actualisation des coûts et des effets a été fixée à 3% et 1,5% respectivement.

Notre modèle applique le traitement antiviral en accord étroit avec les recommandations internationales. Ceci implique que les patients CHBe- reçoivent leur traitement antiviral tout au long de leur vie ou jusqu'à une transplantation hépatique. En l'absence d'essai clinique contrôlé randomisé, nous nous basons pour la modélisation des effets du tenofovir et de l'entecavir sur des avis d'experts et sur des études à un seul bras avec un suivi maximal de 5 ans. Le traitement antiviral est supposé réduire fortement la progression vers la cirrhose hépatique et la décompensation: dès lors, nous appliquons une réduction de 75% des probabilités de transition. L'effet antiviral sur le CHC est beaucoup moins certain. Cette incertitude a été incluse dans le modèle.

## COÛTS ET SCORES D'UTILITÉ

L'analyse utilise la perspective de l'assurance maladie-invalidité qui rembourse les soins de santé. Les coûts de la prise en charge de la maladie se fondent sur les montants réels facturés pour 2006 obtenus en utilisant l'enquête belge (Partie I du rapport). Seuls les coûts pouvant être attribués à l'hépatite B chronique par un médecin spécialiste en ce domaine ont été inclus. Nous avons constaté que les données relatives aux coûts obtenues pour les plus petits groupes (DC, CHC, année de la greffe du foie) étaient en accord avec les publications de coûts internationales. Les valeurs d'utilité sont fondées sur notre enquête EQ-5D de 2009 auprès de 500 patients dans 18 centres belges d'hépatologie (Partie I du rapport), tandis que les valeurs pour les plus petits groupes ont été adaptées en se basant sur la littérature (Table A).
<table><caption>Tableau A. Nombre de patients, coûts annuels et score d'utilité par stade de la maladie</caption><thead><tr><th rowspan="2">Stade la maladie</th><th rowspan="2">Nombre de patients ayant consulté un spécialiste en Belgique en 2009 pour une CHB°</th><th colspan="2">Coûts moyens annuels par patient, liés au VHB</th><th rowspan="2">Score d'utilité moyen (95% intervalle de confiance)</th></tr><tr><th>Pas de stratégie antivirale (euros)</th><th>Stratégie Tenofovir (euros)</th></tr></thead><tbody><tr><td>ICAR</td><td>1266</td><td>115</td><td>115</td><td>0.83 (0.82-0.87)</td></tr><tr><td>CHBe+/- NC</td><td>1197</td><td>591*</td><td>591+4970**</td><td>0.82 (0.78-0.86)</td></tr><tr><td>CHBe+/- CC</td><td>383</td><td>1115*</td><td>1115+4970**</td><td>0.78 (0.73-0.84)</td></tr><tr><td>DC§</td><td>10</td><td>6814*</td><td>6814+4970**</td><td>0.49 (0.46-0.51)#</td></tr><tr><td>CHC</td><td>49</td><td>10816*</td><td>10816+4970**</td><td>0.52 (0.49-0.54)#</td></tr><tr><td>Greffe hépatique</td><td>19</td><td>99998</td><td>99998</td><td>0.71 (0.69-0.74)#</td></tr><tr><td>Post greffe hépatique</td><td>181</td><td>7518</td><td>7518</td><td>0.82 (0.75-0.88)</td></tr></tbody></table>

## RESULTATS

Pour le scénario de référence, les effets en termes de QALYs (quality-adjusted life year, années de vie ajustées pour la qualité) gagnées, de coûts supplémentaires et de rapports coût-efficacité différents (ICER) sont repris dans le tableau B. Dans le cas des patients CHBe+/- NC, les gains en QALYs sur une période de 20 ans sont faibles. Les surcoûts sont considérables, amenant à des ICER d'en moyenne plus de 100 000 euro par QALY. L'ICER est plus favorable pour les patients CHBe+/- de 50 ans et d'origine européenne, principalement en raison de gains plus élevés en QALYs sur une période de suivi de 20 ans. A un horizon d'observation de 10 ans, les ICER sont considérablement plus élevés qu'à 20 ans, en particulier pour les cohortes de patients de 40 ans CHBe+ (de 210 000 à 838 000 euro par QALY) et CHBe- (de 249 000 à 1 325 000 euro par QALY).

<table><caption>Tableau B. Analyse coût-utilité de base, horizon d'observation de 20 ans</caption><thead><tr><th>Cohorte</th><th>QALY gagnés<br>En moyenne<br>(intervalles de<br>confiance)</th><th>Moyenne des<br>coûts<br>supplémentaires<br>en Euro<br>(intervalles de<br>confiance)</th><th>Moyenne des<br>ICER en<br>euro/QALY<br>(intervalles de<br>confiance)</th></tr></thead><tbody><tr><td>CHBe+ NC<br>40 ans</td><td>0.3<br>(0.2 to 0.5)</td><td>33 000<br>(26 000 to 41 000)</td><td>110 000<br>(65 000 to 184 000)</td></tr><tr><td>CHBe- NC<br>40 ans</td><td>0.5<br>(0.3 to 0.8)</td><td>58 000<br>(53 000 to 62 000)</td><td>131 000<br>(75 000 to 240 000)</td></tr><tr><td>CHBe+/- CC<br>50 ans</td><td>1.3<br>(0.8 to 1.8)</td><td>32 000<br>(21 000 to 41 000)</td><td>29 000<br>(16 000 to 47 000)</td></tr></tbody></table>

La probabilité de considérer que le traitement par tenofovir est coût-efficace va dépendre de ce que la société est prête à payer pour un QALY supplémentaire, c'est-à-dire de la valeur seuil de l'ICER. Ceci est illustré par les courbes d'acceptabilité du rapport coût-efficacité. Par exemple, dans le scénario de référence pour un patient CHB non-cirhotique avec un suivi de 20 ans, le traitement par tenofovir ne s'avère jamais une stratégie optimale à des valeurs seuil de l'ICER allant jusqu'à 60 000 euro. Si l'on accepte un ICER de 100 000 euro par QALY la probabilité qu'un traitement par tenofovir devienne une option coût-efficace augmente à 40%. Pour les patients atteints de cirrhose, la probabilité qu'un traitement par tenofovir soit coût-efficace monte à 90% pour une valeur seuil de 40 000 euros par QALY.

<footnote>°En excluant une co-infection par le VIH ou le VHC; \*Coûts de prise en charge de la maladie liée au VHB après exclusion du coût des médicaments antiviraux; \*\*Ce coût annuel du tenofovir avait été diminué dans le modèle de 17% en 2015 et de 19% en 2018. \#En se basant sur la réduction absolue des scores d'utilité de la CHB, telle que rapportée par Levy et al. 2008. § Le nombre de patients avec cirrhose décompensée est clairement sous-estimé vu que les patients avec affection aiguë ont été exclus de la participation à l'enquête.</footnote>
<figure><img src="image_4.png" /><figcaption>Figure B. Courbes d'acceptabilité du rapport coût-efficacité pour traitement par tenofovir (versus aucun traitement antiviral) chez des patients CHBe+/- non cirrhotiques de 40 ans, pour un suivi de 20 ans.</figcaption></figure>

Pour des patients non cirrhotiques, le traitement par tenofovir diminue de manière significative les coûts du traitement (et le nombre de cas) des cirrhoses hépatiques décompensées, des CHC et des transplantations hépatiques, dans le modèle sur 20 ans (Figure C). Cependant cette amélioration engendre un coût cumulé élevé pour le tenofovir qui représente la plus grande partie du coût.

<figure><img src="image_5.png" /><figcaption>Figure C. Coûts (actualisés) par patient et par stade de la maladie: comparaison des stratégies de « non traitement » et de traitement par tenofovir chez les Européens CHBe- non cirrhotiques de 40 ans, suivis sur 20 ans.</figcaption></figure>

Le tableau C présente les résultats d'analyse par scénario. Les ICER diminuent avec l'avancement de l'âge du patient de 30 à 50 ans. Les ICER sont légèrement plus favorables pour les cohortes asiatiques que pour les Européennes.
<table><caption>Tableau C. Analyses de scenario : intervalles d'ICER pour le traitement par tenofovir de patients CHBe+ et CHBe- par âge, origine et état de cirrhose hépatique à un horizon de 20 ans (ICER exprimés en x1 000 euro/QALY)</caption><thead><tr><th>Cohorte d'âge</th><th>Origine du patient</th><th>CHBe+ NC</th><th>CHBe- NC</th><th>CHBe+/- CC</th></tr></thead><tbody><tr><td rowspan="2">30 ans</td><td>Européenne</td><td>132 - 355</td><td>143 - 461</td><td>15 - 45</td></tr><tr><td>Asiatique</td><td>85 - 212</td><td>92 - 296</td><td>14 - 46</td></tr><tr><td rowspan="2">40 ans</td><td>Européenne</td><td>65 - 184</td><td>75 - 240</td><td>15 - 47</td></tr><tr><td>Asiatique</td><td>51 - 126</td><td>58 - 157</td><td>13 - 45</td></tr><tr><td rowspan="2">50 ans</td><td>Européenne</td><td>28 - 97</td><td>38 - 145</td><td>16 - 47</td></tr><tr><td>Asiatique</td><td>23 - 75</td><td>32 - 101</td><td>15 - 46</td></tr><tr><td rowspan="2">60 ans</td><td>Européenne</td><td>31 - 110</td><td>39 - 156</td><td>16 - 52</td></tr><tr><td>Asiatique</td><td>28 - 83</td><td>37 - 119</td><td>15 - 50</td></tr></tbody></table>

## IMPACT BUDGETAIRE

En 2009, les frais remboursés pour les médicaments antiviraux contre le VHB (en excluant les patients avec des coïnfections VIH ou VHC) se sont élevés à environ 3 millions d'euros. Si l'utilisation du tenofovir devait se généraliser chez les patients CHB tel que modélisé, le coût du remboursement du tenofovir dépasseraient les 8 millions d'euros par an, ce qui représente des dépenses additionnelles de plus de 5 millions d'euros par an (dont environ 2 millions d'euros pour le traitement des patients cirrhotiques). Cet impact budgétaire serait encore plus important si les critères de traitement étaient assouplis en faveur des patients présentant des valeurs ALT normales. Le budget global de la prise en charge des maladies liées au VHB, pourrait passer 8 à 13 millions d'euros par an.

## DISCUSSION ET CONCLUSION

Le modèle que nous avons développé comporte un nombre d'avantages par rapport à ceux publiés jusqu'à présent. Primo, nous avons tenu compte de la situation belge en ce qui concerne le nombre de patients, leurs caractéristiques, leur qualité de vie et les coûts attribuables par stade clinique de la maladie. Secundo, nous avons pu avoir accès aux données non publiées d'une vaste cohorte de patients CHB non traités, de race blanche, suivis par l'Hôpital universitaire de Leuven. Cela nous a permis de construire un modèle plus précis de progression de la maladie et qui tient compte de l'âge.

Un premier constat important basé sur cette cohorte est l'absence de progression mesurable de la maladie sur une période moyenne de 10 ans chez 59 patients avec des valeurs normales pour les enzymes hépatiques. Cette observation vient en support des critères actuels de remboursement qui excluent de tels patients.

L'ICER pour un traitement permanent et coûteux visant à prévenir les complications à long terme dépend d'un certain nombre de variables clés. Les principales étant le délai survenant avant les complications qu'on veut éviter, leur fréquence et le coût annuel du traitement. Ceci explique les ICER plus favorables pour la cohorte des patients cirrhotiques que pour les non cirrhotiques : ces derniers accumulent les coûts de traitement antiviral et autre durant des périodes plus longues avant que les effets cliniques de ce traitement apparaissent.

Bien que les possibilités de transplantation du foie soient relativement élevées en Belgique, les ICER que nous avons trouvés pour les cohortes CHBe+ et CHBe- sont en général considérablement plus élevés que ceux rapportés par d'autres études (sponsorisées par les firmes pharmaceutiques). En guise d'explication, le tableau D énumère quelques déterminants majeurs.
<table><caption>Tableau D. Déterminants majeurs des différences d'ICER entre les modélisations du traitement antiviral de l'hépatite B chronique</caption><thead><tr><td></td><td>Modèles publiés (ICER plus bas)</td><td>Modèle KCE (ICER plus élevé)</td></tr></thead><tbody><tr><td>Amélioration de la qualité de vie en cas de faibles taux d'ADN VHB ou de séroconversion 'e'</td><td>Oui, uniquement basé sur des suppositions</td><td>Non, basé sur des observations</td></tr><tr><td>Adhérence aux directives de traitement en cas de CHBe-</td><td>Non, traitement stoppé si faibles taux d'ADN VHB</td><td>Oui, traitement poursuivi</td></tr><tr><td>Progression naturelle vers cirrhose</td><td>Uniformément élevée pour tous âges (5% à 9%)</td><td>Dépendant le l'âge (1% à 5%)</td></tr><tr><td>Horizon temporel du modèle</td><td>Toute la vie</td><td>10 à 20 ans</td></tr><tr><td>Réduction présumée du risque de CHC sous traitement</td><td>Réduction forte, basée sur les données d'une cohorte non traitée</td><td>Réduction d'environ 50% dans des cohortes CHB, grande incertitude</td></tr></tbody></table>

Tout d'abord, de nombreux modèles partent du postulat optimiste que les scores d'utilité s'améliorent immédiatement de 0.18 lorsque la diminution de la charge virale escomptée après le traitement s'amorce. Même si le traitement coûte 5 000 euros par an, l'ICER approche ainsi facilement les 25 000 euros par QALY. En fait, nous n'avons pas mesuré de différence d'utilité chez les patients présentant des niveaux élevés ou faibles d'ADN VHB sous traitement antiviral.

Deuxièmement, nous avons trouvé chez les patients CHBe+ et CHBe- des probabilités de transition vers une cirrhose qui augmentaient avec l'âge, surtout après les 50 ans. Sans cet ajustement, on pourrait conclure qu'instaurer le traitement le plus tôt possible conduit à un rapport coût-efficacité plus favorable, tandis que notre étude indique l'inverse. En outre, des probabilités uniformément élevées de transition vers une cirrhose dans tous les groupes d'âge ne sont pas compatibles avec le taux relativement faible de patients atteints d'une cirrhose hépatique parmi les patients CHB de race blanche en Belgique.

Sur base de notre modèle les ICER s'améliorent considérablement lorsque l'horizon d'observation est prolongé. Cependant, comme l'expérience thérapeutique actuelle ne s'étend même pas à dix ans, la plus grande prudence est de mise quant à l'interprétation des projections au-delà de vingt ans.

Enfin, certains modèles partent de l'hypothèse d'effets élevés du traitement, tant pour l'évolution vers la cirrhose que vers le CHC, effets qui sont calibrés en utilisant des données de charge virale obtenues dans une cohorte de population non traitée (qui est essentiellement constituée de patients à antigène HBe négatif au Taiwan). Il reste à prouver qu'une diminution de la charge virale amenée par le traitement, entraîne une réduction à long terme de la cirrhose et de la CHC jusqu'à un niveau comparable à celui rencontré dans un état naturel de faible charge virale. La relation entre le système d'immunité, la charge virale et le stade de fibrose hépatique est plus complexe, comme cela a été rapporté dans une étude récente en Australie chez des patients CHBe+.

L'effet du traitement antiviral sur le développement du CHC est toujours peu clair et difficile à dissocier du processus de progression de la fibrose. Si l'on accepte que la présence d'une cirrhose du foie crée, en soi, un risque accru de CHC, le repoussement de l'évolution vers la cirrhose devrait également réduire le CHC. En outre, il peut y avoir un effet direct de la diminution de la charge virale sur le développement d'un CHC, ce que nous avons modélisé de manière prudente. Des données récentes du Japon semblent exclure toute réduction majeure du CHC sous traitement par entecavir. L'effet présumé du traitement sur le CHC revêt une importance essentielle pour les populations CHB asiatiques puisque ces dernières ont une incidence accrue de CHC par rapport aux cohortes de patients européennes. Le traitement des patients CHB asiatiques induit dès lors des ICER légèrement plus favorables par rapport aux cohortes de patients européennes.
Nous ne savons pas encore dans quelle mesure les données obtenues chez des
asiatiques vivant en Asie peuvent être extrapolées à des patients d'Afrique sub-
saharienne ayant émigré en Europe et qui représentent une fraction croissante de
l'ensemble de la population CHB totale en Europe.

Enfin, le coût annuel actuel de l'entecavir administré à raison de 0.5mg par jour étant plus élevé que celui du tenofovir, les résultats ne peuvent pas être extrapolés en tant que tels à l'entecavir. De plus, chez les patients infectés par le VHB résistant à la lamivudine, on a rapporté une résistance à l'entecavir, ce qui aura également un impact sur les analyses. Bien entendu, il reste toujours des situations dans lesquelles il peut être plus adéquat de recourir à une molécule spécifique. Une analyse coûts-utilité ne doit pas être interprétée comme une recommandation pour la pratique clinique.

En conclusion, il importe de souligner qu'il n'existe aucune étude randomisée et contrôlée sur le tenofovir ni l'entecavir, qui démontre un effet sur la progression de l'affection ni sur des indicateurs cliniques durs. A cet égard, toute interprétation de résultats de modélisations à long terme, comme celle développée ici, doit se faire avec prudence. Plus particulièrement, l'effet du traitement antiviral sur le cancer hépatocellulaire reste fort incertain.
## RECOMMANDATIONSª

* L'ICER du traitement par tenofovir des patients à un stade plus avancé de la maladie (cirrhotiques) est plus favorable que celui du traitement des patients non cirrhotiques. De ce fait, le traitement de l'hépatite B chronique par tenofovir devrait cibler les patients avec cirrhose hépatique ou à haut risque de la développer.

* Le remboursement de ce traitement antiviral est recommandé chez les patients cirrhotiques souffrant d'hépatite B chronique présentant des valeurs normales pour les enzymes hépatiques (ALT).

* Un traitement antiviral chez les patients souffrant d'hépatite B chronique sans cirrhose et présentant des valeurs normales pour les enzymes hépatiques (ALT) ne se justifie pas tant en termes d'efficacité que de rapport coût-efficacité.

* Partant de l'hypothèse d'une efficacité égale chez les patients non-résistants à la lamuvidine, le tenofovir constitue en général une option thérapeutique plus coût-efficace par rapport à l'entecavir et devrait donc être utilisé de préférence.

* Pour le vaste groupe de patients souffrant d'une hépatite B chronique non-cirrhotique, lancer un traitement à 30 ans est clairement moins coût-efficace que de le lancer à l'âge de 50 ans.

## AGENDA DE RECHERCHE

* Il convient d'encourager des recherches ultérieures visant à identifier les patients souffrant d'hépatite B chronique avec un risque élevé de développer une cirrhose du foie.

* Des recherches ultérieures sont nécessaires pour déterminer l'effet du traitement antiviral sur l'incidence du carcinome hépatocellulaire en cas d'hépatite B chronique.

<footnote>ª Le KCE reste seul responsable des recommandations faites aux autorités publiques</footnote>
# Scientific summary

## Table of contents

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

<table><thead><tr><td>ABBREVIATION</td><td>DEFINITION</td></tr></thead><tbody><tr><td>ALT</td><td>Alanine aminotransferase</td></tr><tr><td>CEAC</td><td>Cost-effectiveness acceptability curves</td></tr><tr><td>CC</td><td>Compensated cirrhosis</td></tr><tr><td>CHBe- NC</td><td>Chronic hepatitis B e antigen negative without cirrhosis</td></tr><tr><td>CHBe+ CC</td><td>CHBe+ with compensated cirrhosis</td></tr><tr><td>CHBe+ NC</td><td>Chronic hepatitis B e antigen positive without cirrhosis</td></tr><tr><td>CHBe-CC</td><td>CHBe- with compensated cirrhosis</td></tr><tr><td>CI</td><td>Confidence interval</td></tr><tr><td>DC</td><td>Decompensated cirrhosis</td></tr><tr><td>eSC</td><td>e antigen seroconversion</td></tr><tr><td>HAI</td><td>Histology activity index</td></tr><tr><td>HR</td><td>Hazard ratio</td></tr><tr><td>HBsAg- CC</td><td>HBsAg-with compensated cirrhosis</td></tr><tr><td>HBsAg- NC</td><td>HBsAg- without cirrhosis</td></tr><tr><td>HBV</td><td>Hepatitis B virus</td></tr><tr><td>HCC</td><td>Hepatocellular Carcinoma</td></tr><tr><td>ICAR CC</td><td>Inactive carrier with compensated cirrhosis</td></tr><tr><td>ICAR NC</td><td>Inactive carrier (low viral replication state) without cirrhosis</td></tr><tr><td>ICER</td><td>Incremental cost-effectiveness ratio</td></tr><tr><td>LR death</td><td>Liver related death</td></tr><tr><td>LT</td><td>Liver transplant</td></tr><tr><td>LY</td><td>Life year</td></tr><tr><td>LYG</td><td>Life-year gained</td></tr><tr><td>NA</td><td>Nucleos(t)ide analogues</td></tr><tr><td>NC</td><td>Non cirrhotic</td></tr><tr><td>NIHDI</td><td>National Institute for Health and Disability Insurance, INAMI/RIZIV</td></tr><tr><td>Peg-IFN</td><td>Pegylated interferon</td></tr><tr><td>QALY</td><td>Quality-adjusted life-year</td></tr><tr><td>QoL</td><td>Quality of Life</td></tr><tr><td>RCT</td><td>Randomized controlled trials</td></tr></tbody></table>
# I BACKGROUND AND OBJECTIVES

## I.1 NATURAL HISTORY AND EPIDEMIOLOGY

The hepatitis B virus is a small circular DNA virus. Chronic infections (HBsAg+) with this virus affect about 5% of the world population and causes 0.5 to 1.2 million deaths a year.¹ For Belgium, recent data are missing, but the last available estimates mention HBs antigen positivity for 0.7% of the Belgian population.² This is in line with a prevalence of 0.1-2% in Western Europe and the US. The prevalence is 2-8% in the Mediterranean countries and Eastern Europe, and 8-20% in high endemic regions such as South Asia and sub-Saharan Africa.¹ Vaccination can prevent infection but not cure it. In low endemic countries, such as Belgium, infection is usually acquired via injecting drug use, sexual contact or body piercing. In most of these cases the immune system will suppress the virus and only 5 to 10% of the infections will become chronic.³ An increasing proportion of the population chronically infected in Western Europe consists of immigrants from endemic regions. Most of these subjects have been infected from their infected mother during birth, and infections at that young age have a high probability of becoming chronic.³ During many years or decades the virus does not cause any significant symptoms and the infection is often discovered by chance during a blood examination. The presence of HBV can be detected based on its DNA (HBV DNA) or its antigens, e.g. hepatitis B surface antigen (HBsAg) and e antigen (HBeAg). The human immune response to the virus is reflected by detectable antibody levels to these antigens.

After years or decades of 'immune tolerance', the immune system starts to attack the virus and more severe inflammation and damage may occur in the liver (hepatitis), most often reflected by increased levels of liver enzymes (e.g. alanine aminotransferase, ALT). Sometimes the virus can be suppressed during this 'immune reactive phase' and after e antigen seroconversion the patient may become an 'inactive carrier' (ICAR), a state with low viral replication. Infections in patients who develop anti-HBs antibodies and who are no longer HBsAg+ are considered 'resolved'. However, many patients spontaneously develop a mutated virus that prevents HBeAg expression, resulting in 'HBeAg negative chronic hepatitis' (CHBe-). The characteristics of the major phases of the HBV infection are given below. Not all patients go through every phase (Table I).⁴ Chronic hepatitis leads to scar formation in the liver (fibrosis), sometimes resulting in compensated liver cirrhosis (CC). This process is accelerated e.g. by alcohol (ab)use. In addition, patients with CHB (and even more those with liver cirrhosis) have an increased risk of developing hepatocellular carcinoma (HCC). For patients with decompensated cirrhosis (DC) or limited forms of HCC a liver transplantation can be life saving.

<table><caption>Table I. The distinct phases of infections with the hepatitis B virus.</caption><thead><tr><th rowspan="2">Phases</th><th rowspan="2">Immune tolerance</th><th colspan="2">Immune active CHB</th><th rowspan="2">Inactive carrier (ICAR)</th><th rowspan="2">Reactivation</th><th rowspan="2">Resolved</th></tr><tr><th>HBsAg+ (wild type) Immune reactive CHBe+</th><th>HBsAg- (precore mutant) CHBe-</th></tr></thead><tbody><tr><td>HBsAg</td><td>+</td><td>+</td><td>+</td><td>+</td><td>+</td><td>-</td></tr><tr><td>HBeAg</td><td>+</td><td>+</td><td>-</td><td>-</td><td>+ or -</td><td>-</td></tr><tr><td>Anti-HBe</td><td>-</td><td>-</td><td>+</td><td>+</td><td>+ or -</td><td>+</td></tr><tr><td>ALT</td><td>Normal</td><td>Elevated</td><td>Fluctuating</td><td>Normal</td><td>Elevated or normal</td><td>Normal</td></tr><tr><td>HBV DNA</td><td>&gt; 2 Mio IU/mL</td><td>Typically &gt; 20 000 IU/mL</td><td>&gt; 2 000 IU/mL</td><td>&lt; 2 000 IU/mL</td><td>&gt; 2 000 IU/mL</td><td>&lt; 2 000 IU/mL in most</td></tr><tr><td>Histologic progression</td><td>Minimal</td><td>Yes</td><td>Yes</td><td>Minimal</td><td>Yes</td><td>No</td></tr><tr><td>Consider treatment ?</td><td>No</td><td>Yes</td><td>Yes</td><td>No</td><td>Yes</td><td>No</td></tr></tbody></table>
## 1.2 TREATMENT

The RCTs used to support marketing approval of antiviral drugs in CHB showed histologic (various scores used for inflammation and fibrosis), virologic (HBV DNA), biochemical (ALT) and serologic (HBe seroconversion in HBeAg+ CHB) improvement over placebo after one year of treatment. The long-term goal of the treatment is to prevent the development of cirrhosis and HCC. As the course of the chronic infection varies from very benign to life-threatening, identifying those patients at high risk of severe complications is important to guide the frequency of monitoring and to target treatment. It should be noted that a complete elimination of HBV is most probably not possible. It is recommended not to treat patients who are in the 'immune tolerance' phase and 'inactive carriers' (Table 1). In order to be reimbursed in Belgium, all HBV antiviral drugs require a prescription by a medical specialist in internal medicine and approval by the sickness fund.

Interferon-alpha was introduced in 1991 and pegylated interferon-alfa2a (Peg-IFN, Pegasys®) in 2007. Peg-IFN requires medical monitoring for side-effects, including depression. Depression is however seen less frequently compared with Peg-IFN treatment in chronic hepatitis C patients. It is administered subcutaneously weekly for one year and will result in HBeAg loss in about a third of HBeAg+ CHB patients and in HBsAg loss in 3% of HBeAg+⁹ and 4% of HBeAg- CHB patients.¹⁰ In Belgium about 10% of the treated patients are treated for one year with injections of (pegylated) interferon-alpha but for many other patients this is not considered an appropriate treatment option for a variety of reasons.

Antiviral nucleos(t)ide analogues (NAs) are available as pills, are generally well tolerated and may need to be taken lifelong. The first NA, i.e. lamivudine (Zeffix®), obtained reimbursement in 2001 as a first line treatment. It was followed by adefovir dipivoxil (Hepsera®), but only for second line treatment (it is not considered a recommended first line treatment). Guidelines for treatment of CHB have been updated over the last few years with the market introduction of a number of antiviral agents.⁵⁻⁸ Recently, the reimbursement criteria in Belgium have been adapted in accordance with the international guidelines. This means that lamivudine is no longer considered an appropriate first line treatment. Instead, in Belgium, tenofovir (Viread®, 300mg tenofovir disoproxil fumarate, equivalent to 245 mg tenofovir disoproxil, per day) and entecavir (Baraclude®, 0.5mg per day) obtained reimbursement for first line treatment of chronic hepatitis B (tenofovir was already reimbursed before for HIV treatment). Tenofovir and entecavir have a relatively high annual cost of about 5000 euro per year. The NA class of drugs has the potential for mitochondrial damage, leading to myopathy and neuropathy.¹¹ One NA was recently withdrawn for that reason. Adefovir and tenofovir may cause nefrotoxicity and renal tubular damage.

After 4 years of lamivudine treatment HBV will have developed mutations causing resistance to lamivudine in over half of the patients.¹², ¹³ HBV develops much less frequently resistance to tenofovir or entecavir. Therefore, these agents are more likely to lower HBV DNA for more than 5 years in most patients. However, resistance to entecavir has been detected in lamivudin-refractory patients.¹⁴⁻¹⁶ In studies with a duration up to 5 years, these newer NAs have also shown to improve liver inflammation and fibrosis scores. In about half of the HBeAg+ CHB patients HBeAg seroconversion can be induced, but this effect is frequently reverted after treatment discontinuation. The major reason for giving an antiviral treatment is that long-term lowering of HBV DNA levels will translate in fewer cases of liver cirrhosis and HCC. These assumptions are however still uncertain as there are no high-quality long-term research studies to support them. ¹⁷ Such long-term studies have not been a requirement for obtaining marketing approval nor for obtaining reimbursement.
## 1.3 OBJECTIVES AND CONTENT OF THE TWO REPORTS

This is the second report of the KCE project on health-economic aspects of antiviral treatment of chronic hepatitis B (CHB). The overall goal of the project is the study of the cost-effectiveness of the recently introduced antiviral drugs in Belgium (tenofovir and entecavir), using a model based as much as possible on Belgian data. These Belgian data allow ascertaining to a better degree the quality of our results and the possibility of drawing policy recommendations. As lamivudine is no longer considered a state-of-the-art first line treatment of CHB, as adefovir is a second line treatment, as (pegylated) interferon-alpha is an appropriate first line treatment for selected patients only, we use the natural history as comparator.

In the part I KCE report, we studied the natural history and epidemiology of chronic infections with the hepatitis B virus (HBV), and the literature on treatment efficacy and safety, as summarized above. We reviewed nine recent publications on the cost-effectiveness of the currently approved antiviral treatments for this infection and found they often model optimistic assumptions on long-term effectiveness without inclusion of an appropriate range of uncertainty.¹⁸⁻²⁶ The authors also assume a significant improvement of quality of life after a surrogate marker (HBeAg, HBV DNA) response, an assumption which is in contrast to our field assessment of quality of life (QoL) in real patients with a low HBV DNA under NA treatment. In our model we address several of the identified weaknesses.

QoL (EQ-5D form) data and clinical information were prospectively collected in 544 patients visiting their liver specialist in Belgium during the first half of 2009 for chronic HBV infection or a non-acute complication thereof. The investigators reported the disease state, laboratory values and antiviral treatment for 2009 and, if available, for 2006. The 2006 clinical data were linked to the 2006 costs for the NIHDI (National Institute for Health and Disability Insurance, INAMI/RIZIV). We estimated the HBV CHB related burden of disease for Belgium (Table 2).

<table><caption>**Table 2. Estimated number of patients by stage/complication and region of origin, visiting a liver specialist in Belgium for chronic HBV infection or its complications, situation early 2009.**</caption><thead><tr><th></th><th>Africa</th><th>Asia</th><th>Europe</th><th>Turkey</th><th>Total N</th><th>%</th></tr></thead><tbody><tr><td>Immune tolerance</td><td>70</td><td>32</td><td>16</td><td>0</td><td>119</td><td>3,6%</td></tr><tr><td>Inactive carrier</td><td>476</td><td>177</td><td>508</td><td>105</td><td>1266</td><td>38,6%</td></tr><tr><td>Immune reactive</td><td>50</td><td>123</td><td>228</td><td>61</td><td>462</td><td>14,1%</td></tr><tr><td>HBeAg neg CHB</td><td>119</td><td>124</td><td>412</td><td>79</td><td>735</td><td>22,4%</td></tr><tr><td>HBsAg neg</td><td>9</td><td>9</td><td>36</td><td>0</td><td>53</td><td>1,6%</td></tr><tr><td>Comp. Cirrhosis</td><td>68</td><td>79</td><td>210</td><td>26</td><td>383</td><td>11,7%</td></tr><tr><td>Decomp. Cirrhosis</td><td>5</td><td>5</td><td>0</td><td>0</td><td>10</td><td>0,3%</td></tr><tr><td>HCC</td><td>0</td><td>10</td><td>39</td><td>0</td><td>49</td><td>1,5%</td></tr><tr><td>Liver transplant</td><td>16</td><td>23</td><td>145</td><td>16</td><td>200</td><td>6,1%</td></tr><tr><td>Total N</td><td>813</td><td>582</td><td>1595</td><td>287</td><td>3277</td><td>100,0%</td></tr></tbody></table>

Notes: Based on KCE report I.²⁷ Co-infections with HIV or HCV are not included. The number of patients with decompensated cirrhosis was likely underestimated as patients presenting with acute disease could not participate to the survey.
Over the last years about 19 patients per year received a life saving liver transplant in Belgium, mainly for decompensated cirrhosis or also for limited forms of HCC.

The second part of the project was conducted by KCE experts in collaboration with a number of hepatologists, in particular from Leuven University Hospital, and guided by other external experts who had been involved in part 1.

In this second part, we add to the natural history literature the preliminary results on disease progression by patient age based on a large untreated cohort of Caucasian patients followed at Leuven University Hospital. We compare and complement our measured utility scores with a review of the literature on health utilities for different CHB disease states. We analyse and report Belgian HBV-related healthcare consumption data by CHB disease state.

<table><caption>Table 3. Sources of input variables for Markov model.</caption><thead><tr><th></th><th>Disease states and transitions</th><th>Costs by disease state</th><th>Utilities by disease state</th></tr></thead><tbody><tr><td>Literature review</td><td>Yes</td><td>Partly</td><td>Partly</td></tr><tr><td>Collection and analysis of Belgian data</td><td>Yes</td><td>Yes</td><td>Yes</td></tr></tbody></table>

All above mentioned data served as input for a Markov model to study the cost-effectiveness of two recently introduced antiviral agents (tenofovir and entecavir). The results of this model are presented in this report. We followed treated and untreated hypothetical cohorts of patients aged 40 years, with either e antigen positive or negative CHB, non cirrhotic (CHBe+ NC and CHB- NC). In addition, a cohort of 50 year old patients with compensated cirrhosis (CC) was evaluated, consisting of 30% CHBe+ CC and 70% CHBe- CC patients. For each of these three cohorts we considered time horizons of 10 and 20 years for the base-case. In sensitivity analyses we varied the age at start of the cohorts, the transition probabilities to HCC to reflect an Asian population, and the discounting rates for costs and effects.

Also the budget impact for the National Institute for Health and Disability Insurance (NIHDI) of introducing these new treatments was estimated.
# 2 METHODS

## 2.1 TARGET POPULATION

The analysis was based on the following cohorts (Table 4) reflecting the heterogeneity of the CHB patients in Belgium that have been described in the KCE report part 1.²⁷

First, we distinguish between patients with versus without a European country of origin. In this document the term Caucasian is also used for patients with a European country of origin. Patients born in high endemic regions such as Asia and Central Africa are mostly infected with HBV early in life. Studies in Asia show a relatively higher incidence of HCC in CHB patients. Data from cohorts in sub-Saharan Africa are lacking so far, but it is believed the risk of HCC is also increased in these patients, who constitute a growing proportion of the CHB patients in Belgium and Europe.

Second, we also model starting antiviral treatment in patient who already developed compensated liver cirrhosis. Between 11%²⁸ of CHBe+ patients and up to 30% of CHBe- patients have cirrhosis at the first visit at a specialist for their CHB infection.

Third, we run the model for cohorts of patients aged 40 and 50 years at baseline, which roughly corresponds to the average ages of new non-cirrhotic and cirrhotic patients seen in Belgium, respectively²⁷ (CHBe- NC patients in Belgium were on average nearly three years older compared with CHBe+ NC patients). Additional results were obtained for cohorts aged 30, 50 and 60 years for the non-cirrhotic patients and 30, 40 and 60 years for cirrhotic patients.

<table><caption>Table 4. Populations modelled.</caption><thead><tr><th>Population at start of treatment</th><th>Mean age in years<br>(additional cohorts<br>studied)</th><th>Gender</th></tr></thead><tbody><tr><td><strong>European patients</strong></td><td></td><td></td></tr><tr><td>Non cirrhotic CHBe+ (CHBe+ NC)</td><td>40</td><td rowspan="3">70% men<br>and 30%<br>women</td></tr><tr><td>Non cirrhotic CHBe- (CHBe- NC)</td><td>(30, 50, 60)</td></tr><tr><td>Mixed cohort of compensated cirrhosis (CHBe+/e- CC)<br>patients (30% e+ and 70% e-)</td><td>50<br>(30, 40, 60)</td></tr><tr><td><strong>Asian population</strong></td><td></td><td></td></tr><tr><td colspan="3">As above scenarios, but with transition probabilities to HCC applying to Asians</td></tr></tbody></table>

## 2.2 MODEL STRUCTURE AND BASIC ASSUMPTIONS

We modelled disease progression as patient flows between 13 disease states, mainly based on the selection of states as defined in KCE report part 1.²⁷ Our model differs from most previously published models in the fact that we defined subgroups of patients with CHBe+, inactive carrier (ICAR) and CHBe- based on the absence (NC) or presence of compensated cirrhosis (CC), as different state transition rates have been described (see Table 5 of transition rates for references). For the states of decompensated cirrhosis (DC), HCC, liver transplant and post liver transplant, liver related death rates were applied and all-cause mortality was added; for all other states only all-cause mortality was applied. In the model we used a broad definition for DC as we did not model liver-related mortality in CC. Our DC state thus includes all non-HCC complications associated with liver related mortality, eg bleeding esophagal varices.
<figure><img src="image_6.png" /><figcaption>Figure 1. Modelled patient flow.</figcaption></figure>

Notes: Using a 1-year cycle length patients move between the disease states starting from the state according to the outlined scenarios in section 2.1. Patients may remain in the same state with a certain probability for more than one year except in the liver transplant state, from where they move either to the post-liver transplant state or to death. It is assumed that patients are treated in the bold states: CHBe+/- NC, CHBe+/- CC, DC and HCC; Abbreviations: CHBe+, chronic hepatitis B e antigen positive; CHBe-, chronic hepatitis B e antigen negative; NC, non-cirrhotic; CC, compensated cirrhosis; ICAR, inactive carrier; HBsAg-, hepatitis B surface antigen negative; DC, decompensated cirrhosis; HCC, hepatocellular carcinoma. Note that transition to ICAR is assumed to be realized when confirmed 6 months after e seroconversion, thus at a time when antiviral treatment is discontinued.

In contrast with some more recently published models, we did not define Markov states based on viral load because we do not feel confident with the data that feed such models (see also Discussion section).

## Analyses

The analysis is based on a static, probabilistic Markov model with bootstrapping (visual Basic). All calculations are done in Excel, except for the estimation of transition probabilities from the non-cirrhotic to the cirrhotic states, which have been done in STATA.

## Further basic structure of the model is defined by the following items:

* In our analyses of costs and effects we compare a strategy of antiviral treatment (using tenofovir or entecavir) with a "no antiviral treatment" strategy. We use the natural history as comparator because (1) lamivudine is no longer considered a state-of-the-art first line treatment of CHB, (2) adefovir is a second line treatment, and (3) (pegylated) interferon-alpha is an appropriate first line treatment for selected patients only.

* We used a 10 year and 20 year follow-up perspective as a base-case for the estimation of cost-effectiveness. This choice of these time horizons was driven by the insight that for some patient groups depending on age it may take long until the beneficial effects of treatment of avoiding disease complications materialize. Predictions beyond 20 years have however a high degree of uncertainty, both in terms of natural evolution of the cohort and especially treatment effects, as current treatment experience in trials is limited to about 5 years.

* Discounting. For the base-case, we utilized a discount rate of 3.0% for costs and 1.5% for outcomes according to the Belgian guidelines.²⁹
* The analysis was performed from the perspective of health care payer, which includes payments out of the government's health care budget. Patient co-payments were calculated but not included as they constituted a very low percentage of the overall expenditures: 1% for newly transplanted patients to maximum 7% for inactive carriers, and most probably even lower when restricted to HBV related costs.

* We assumed that patients move between the states on average at the half of each yearly cycle.

* We used life-years (LY) and quality-adjusted life-years (QALYs) as model outcomes.

* The following probability distributions to the input factors of the model have been applied:

* Transition probabilities between disease states: Beta distribution

* Treatment effects: Beta distribution

* Utility parameters: Beta distribution

* Disease management costs: Gamma distribution

* The parameters were drawn by use of the BETAINV and GAMMAINV functions in Excel.

## 2.3 TRANSITION PROBABILITIES

Transition probabilities were obtained from the literature review on natural history presented in part I of the report, completed with data from additionally identified references and a preliminary analysis of a large cohort of untreated CHB patients followed at Leuven University Hospital. This analysis is detailed in Appendix I. The appropriateness of the Markov model for the Belgian situation and the importance of using appropriate individual transition probabilities was tested over hundreds of cycles until a steady state for each health status was achieved. With our final selection of transition rates, a distribution of disease states was obtained that was in line with the estimates for the Belgian patient population as assessed in report part I (assuming the 2009 situation in Caucasians of age 40 and over reflects more or less a steady state situation).
<table><caption>Table 5. Summary of transition probabilities.</caption><thead><tr><th>From</th><th>To</th><th>Annual transition probability (range)#</th><th>Rationale and references</th></tr></thead><tbody><tr><td>CHBe+/- NC (age &lt; 40y)</td><td>CHBe+/- CC</td><td>1.0% (0.5 to 1.5)</td><td>Transition probabilities are based on the analysis of a large cohort of untreated Caucasian patients followed at Leuven University Hospital. Transition probability to cirrhosis varied with patient age but not with e antigen status. Others reported a transition probability 2 to 3% for clinic-based longitudinal studies, with older age, CHBe+ and high ALT as risk factors<sup>30</sup>. Studies included in the review by Liaw<sup>31</sup> report an incidence of CC in CHBe+ of 2.4% (which was higher than the overall incidence of 2.1%) to 3.5% (in CHB with persistent e+) and of 2.9% in CHBe-. Higher transition probabilities for Europe were reported by Fattovich but based on small studies: 3.7% (CHBe+, 77 patients) and 9.2% (CHBe-, 30 patients).<sup>32</sup> Importance of age for development of cirrhosis was also shown in a cohort in Taiwan.<sup>33</sup></td></tr><tr><td>CHBe+/- NC (age 40 to 50y)</td><td>CHBe+/- CC</td><td>2.0% (1.0 to 3.0)</td><td></td></tr><tr><td>CHBe+/- NC (age &gt; 50 y)</td><td>CHBe+/- CC</td><td>5.0% (2.5 to 7.5)</td><td></td></tr><tr><td>ICAR NC</td><td>ICAR CC</td><td>0.02% (0.01 to 0.03)</td><td>Fattovich<sup>32</sup> reports 0.01% and 0.07% for European and Asian patient populations. Only 1 in 184 patients developed CC after a median follow-up of 6.8 years.<sup>31</sup></td></tr><tr><td rowspan="2">CHBe+ NC</td><td>ICAR NC</td><td>11% (5.5 to 16.5)</td><td rowspan="2">During e antigen seroconversion (eSC) about 5%<sup>32</sup> or 10 to 20%<sup>30</sup> directly transit to CHBe-; this transition is 10 times more frequent in CHBe+ CC.<sup>34</sup> The others transit to ICAR where about 75% will remain.<sup>30, 32</sup></td></tr><tr><td>CHBe- NC</td><td>1.5% (0.8 to 2.3)</td></tr><tr><td rowspan="2">CHBe+ CC</td><td>ICAR CC</td><td>2% (1.0 to 3.0)</td><td rowspan="2">Spontaneous eSC in CHBe+ varies from 2% to 15%,<sup>31</sup> 8% to 12%,<sup>30</sup> or 10 to 15% per year in adults with elevated ALT.<sup>32</sup> In the cohort of 70 CHBe+ patients,<sup>28</sup> only 4/8 CHBe+ CC patients showed eSC (about 4% per year) versus 57/62 CHBe+ NC patients (about 20% per year). In Taiwan eSC was 12% for CHBe+ NC and 6% for CHBe+ CC.<sup>35</sup></td></tr><tr><td>CHBe- CC</td><td>4% (2.0 to 6.0)</td></tr><tr><td>ICAR NC/CC</td><td>CHBe+ NC/CC</td><td>1% (0.5 to 1.5)</td><td>About 20% of the patients in ICAR experience reversions back to CHBe+ and 20% will finally transit to CHBe-. It has been reported that after 16 years 25% of all eSC patients have CHBe-.<sup>36</sup> The transition from CHBe- to ICAR has been reported to be very rare and was not included.</td></tr><tr><td>ICAR NC/CC</td><td>CHBe- NC/CC</td><td>2% (1.0 to 3.0)</td><td></td></tr><tr><td>ICAR NC/CC</td><td>HBsAg- NC/CC</td><td>1.6% (0.8 to 2.4)</td><td>The annual HBsAg seroclearance rate has been reported to be 0.5% to 0.8% overall,<sup>30</sup> and 1.2% to 2.1%<sup>31</sup>, 1% to 2%<sup>32</sup> and 2.1%<sup>28</sup> in ICAR patients.</td></tr><tr><td>CHBe+ CC</td><td>CHBe+ DC</td><td>3.5% (1.75 to 5.25)</td><td>Liver decompensation in CHBe+ CC and CHBe- CC is 4 times more frequent than in ICAR CC.<sup>37</sup> Liver decompensation is seen in about 14 to 15% after 5 years.<sup>32, 36</sup> Differences in transition probabilities in e+ versus e- CC are derived from mortality which is reportedly 6 times more frequent in CC CHBe+ and 4 times higher in CC CHBe- compared with ICAR CC.<sup>36</sup> The risk of death is decreased by a factor of 2.2 when eSC occurred in CHBe+ CC<sup>38</sup> Liver-related death rates in CC are 3.3% and 2.9% in Europe and Asia,<sup>32</sup> while overall mortality at 5 and 10 years in CC is 16% and 32% (annual transition probability: 3.8%).<sup>30, 39</sup></td></tr><tr><td>ICAR CC</td><td>ICAR DC</td><td>0.75% (0.4 to 1.2)</td><td></td></tr><tr><td>CHBe- CC</td><td>CHBe- DC:</td><td>3% (1.5 to 4.5)</td><td></td></tr></tbody></table>
<table><thead><tr><th>From</th><th>To</th><th>Annual transition probability (range)#</th><th>Rationale and references</th></tr></thead><tbody><tr><td>CHBe+/- NC</td><td rowspan="6">HCC</td><td>0.12% (0.04 to 0.36)<br>0.60% (0.53 to 0.72)*</td><td rowspan="6">Transition rates to HCC in Europe are lower compared with Asia for all states, probably reflecting the importance of co-factors which are mainly present in Asia, such as aflatoxins.<sup>30</sup> The transition rates were selected as reported by Fattovich in a systematic review,<sup>32</sup> except for European CHB patients where we used the transition rate from the unpublished Leuven cohort. This rate is at the low end of the published transition rates for studies in Europe and the US (0.12% to 0.41% per year), not restricted to Caucasian patients.<sup>32</sup> Liaw<sup>31</sup> reports an annual incidence of HCC of 3 to 6% in Asian patients with cirrhosis.</td></tr><tr><td>ICAR NC</td><td>0.02% (0 to 0.05%)<br>0.20% (0.1 to 0.3)*</td></tr><tr><td>CHBe+/- CC or DC</td><td>2.15% (1.5 to 2.8)<br>3.5% (3.0 to 4.0)*</td></tr><tr><td>HBsAg- NC</td><td>0.01% (0 to 0.02)<br>0.10% (0.05 to 0.15)*</td></tr><tr><td>ICAR CC or HBsAg- CC</td><td>1.08% (0.5 to 1.6)<br>1.75% (0.9 to 2.6)*</td></tr><tr><td rowspan="2">DC</td><td>LT-DC-y1</td><td>50% (25.0 to 75.0)</td><td rowspan="2">The 5 years mortality rates in DC vary from 70-85% to 86% (transition probability of 22 to 32.5%).<sup>30, 32</sup> In Belgium relatively many patients with DC or HCC benefit from liver transplantation. Kirchner et al.<sup>40</sup> reported for HCC in Southern Germany an overall transition probability to death of 35% per year.</td></tr><tr><td>LR death</td><td>25% (12.5 to 37.5)</td></tr><tr><td rowspan="2">HCC</td><td>LT-HCC-y1</td><td>15% (7.5 to 22.5)</td><td rowspan="2"></td></tr><tr><td>LR death</td><td>35% (17.5 to 52.5)</td></tr><tr><td>LT-DC-y1</td><td rowspan="4">LR death</td><td>9% (4.5 to 13.5)</td><td rowspan="4">One year mortality after liver transplantation in Leuven, Belgium, for LT-HCC-y1 is 11% versus 9% without HCC. The 10y mortality after liver transplantation for HCC is 48% versus 24% without HCC, corresponding to transition probabilities to death after y1 of 6% and 2% per year, respectively. As the overall Belgian statistics are somewhat less favourable for survival, at least after HCC,<sup>41</sup> and also to adjust for patient age, we add the age dependent mortality (about 1% per year at age 60y) to the LR death.</td></tr><tr><td>LT-HCC-y1</td><td>11% (5.5 to 16.5)</td></tr><tr><td>LT-DC</td><td>2% (1 to 3)</td></tr><tr><td>LT-HCC</td><td>6% (3 to 9)</td></tr></tbody></table>

<footnote># Range from 50% to 150% of point estimate value, unless the 95% confidence interval based on available study results provides a more narrow range. * Transition probabilities for Asian population. Original yearly transition rates have been converted to yearly transition probabilities for inclusion in the model using the following formula: transition probability = 1 - exp(-rate); Transition probabilities have further been transformed into the standard alpha and beta distribution moments of the beta distribution. CHBe+, chronic hepatitis B e antigen positive; CHBe-, chronic hepatitis B e antigen negative; NC, non cirrhotic; CC, compensated cirrhosis; ICAR, inactive carrier; HBsAg-, hepatitis B surface antigen negative; DC, decompensated cirrhosis; HCC, hepatocellular carcinoma; LT, liver transplant; LR death, liver related death; y1, year 1.</footnote>
## 2.4 DISEASE MANAGEMENT AND TREATMENT COSTS

Disease management costs are based on actual billing records from patients collected in 18 Belgian hepatology centres for the year 2006.²⁷ Since patients with CHB frequently undergo treatments related to other diseases, billing records were – in a major effort – thoroughly sorted according to their probability to be due to CHB or not (Appendix, section 6.3). The resulting disease management costs are depicted in Table 6. One drawback of this data is the low number of patients in decompensated cirrhosis, HCC and liver transplant. However, the costs are in the range of disease management costs of hepatitis B as registered in Europe (Belgium, France, Italy, Spain and UK) and Canada.⁵ For comparison, these costs inflated to year 2009 Euros are estimated as follows: CHB e+/- NC: 1,306 – 3,463 €; compensated cirrhosis: 326 – 4,075 €; decompensated cirrhosis: 6,324 – 10,511 €; HCC: 4,459 – 13,041 €; liver transplant: 30,075 – 86,228 €. Thus, in the Belgian sample we have somewhat lower costs for CHB e+/- NC, we are in the range for compensated cirrhosis, decompensated cirrhosis and HCC, and we estimate higher costs for liver transplants.

<table><caption>Table 6. Disease management costs by disease stage (costing year 2009).</caption><thead><tr><th>Disease state</th><th>Based on # patients</th><th>Mean cost</th><th>Standard deviation</th><th>Alpha** Parameter</th><th>Beta** parameter</th></tr></thead><tbody><tr><td>Inactive carrier</td><td>71</td><td>115.22 €</td><td>29.39 €</td><td>15.4</td><td>7.5</td></tr><tr><td>Chronic hepatitis B e antigen +/-</td><td>141</td><td>591.06 €*</td><td>150.78 €</td><td>15.4</td><td>38.5</td></tr><tr><td>Compensated cirrhosis</td><td>47</td><td>1,114.90 €*</td><td>284.41 €</td><td>15.4</td><td>72.6</td></tr><tr><td>Decompensated cirrhosis</td><td>5</td><td>6,814.23 €*</td><td>1,738.32 €</td><td>15.4</td><td>443.5</td></tr><tr><td>HCC</td><td>4</td><td>10,816.24 €*</td><td>2,759.25 €</td><td>15.4</td><td>703.9</td></tr><tr><td>Liver transplant</td><td>5</td><td>99,997.52 €</td><td>25,509.57 €</td><td>15.4</td><td>6507.5</td></tr><tr><td>Post liver transplant</td><td>41</td><td>7,518.38 €</td><td>1,917.95 €</td><td>15.4</td><td>489.3</td></tr></tbody></table>

Notes: Estimates based on methodology as presented in section 6.3. Costs are inflated from year 2006 to 2009 by the using the Belgian Health Index,⁴² which corresponds to a 6.7% increase. We assumed that 10% (range 5% to 15%) of all HCC patients received Nexavar (sorafenib) for an average of 18 weeks. In 2006, Nexavar was not yet reimbursed in Belgium; it is, however, reimbursed in 2010. This inflates the estimated disease management costs for patients with HCC by an average of 1610 € (Standard deviation 357.80 €). * Excluding cost of antiviral drugs, **Based on the Gamma probability distribution, the alpha parameters values are always the same, because of the previous assumption that costs vary +/-50% within the 95% confidence interval.

Based on estimates provided by the RIZIV-INAMI, the 2009 annual price of Viread (tenofovir) up to 1st July 2015 will be 4970.6 €. On the 1st July 2015 the ex-factory price of Viread will drop by 17%, and by 19% on the 1st July 2018 with reference to today's price. We have to assume in our scenarios that no generic antiviral will arrive on the market, since the impact on price developments are not quantifiable with any certainty. Otherwise, a further price decrease of Viread would have to be taken into account. Based on these price decreases, the average annual prices of tenofovir are depicted in Table 7. Similar price decreases are envisaged for Baraclude (entecavir), however starting from an annual price of 5,221 € in 2009, remaining above the annual cost of Viread in all subsequent years. No specific costs for monitoring tenofovir or entecavir therapy were included.
<table><caption>Table 7. Annual antiviral costs of Viread (tenofovir) in Belgium (costing year 2009).</caption><thead><tr><td>Time period</td><td>Mean cost in €</td></tr></thead><tbody><tr><td>Up to 1<sup>st</sup> July 2015</td><td>4,970.6</td></tr><tr><td>From 1<sup>st</sup> July 2015</td><td>4,144.1</td></tr><tr><td>From 1<sup>st</sup> July 2018 onwards</td><td>4,046.8</td></tr></tbody></table>

Notes: based on estimated provided by RIZIV-INAMI.

## 2.5 UTILITIES

Utility values to be used in the model were derived from our EQ-5D survey on the Belgian population during the first part of this study,²⁷ provided that the number of respondents per health state was high enough for the values to be robust. In the model, mean utilities (and 95% confidence intervals) for the health states CHB, CC, post-LT (follow-up years with liver transplant) and ICAR were thus valued at 0.82 (0.78-0.86; n=127); 0.78 (0.73-0.84; n=69), 0.82 (0.75-0.88; n=60), 0.83 (0.80-0.87; n=153). Utility values for the health state CHB was applied to both HBeAg+ and HBeAg- CHB, as no differences were seen in the survey (Table 8).

Utility values for the health states DC, HCC and LT were derived from the whole patient sample of Levy et al.⁴³ However, since the health preference values reported in Levy et al.⁴³ are much lower than ours, probably due to differences in instrument (EQ-5D vs Standard Gamble) or in subjects, we did not use the absolute values reported in this study. Instead, we computed the decrement in utility values between the states DC, HCC and LT compared with CHB in Levy et al.⁴³ and we subtracted this decrement from the initial CHB value (0.82) obtained in our survey.

Our EQ-5D survey did not reveal any major difference between the utilities reported from the whole patients sample (i.e. 50.9% Europe; 8.6% Turkey; 22.4% Africa; 18% Asia) and those from patients with a European origin only. By contrast Levy et al.⁴³ found important differences in utilities between countries with lower utilities reported from China and Hong Kong (both high endemic regions) compared to utilities reported from Canada, USA, UK and Spain. Levy et al. explains that the lower ratings of even the milder health states (CHB and CC) in China and Hong Kong may reflect a greater fear of the social consequences of infection since, for example, discrimination against Chinese carriers of CHB can result in difficulties in finding employment and access to education.

<table><caption>Table 8. Utilities by disease stage.</caption><thead><tr><td>Disease states</td><td>Mean</td><td>95% CI</td><td>Source</td><td>Alpha**</td><td>Beta**</td></tr></thead><tbody><tr><td>CHBe+ NC</td><td>0.82</td><td>0.78 0.86</td><td>KCE, 2010<sup>27</sup></td><td>289.8</td><td>63.6</td></tr><tr><td>CHBe- NC</td><td>0.82</td><td>0.78 0.86</td><td>KCE, 2010<sup>27</sup></td><td>289.8</td><td>63.6</td></tr><tr><td>Inactive Carrier</td><td>0.83</td><td>0.82 0.87</td><td>KCE, 2010<sup>27</sup></td><td>719.0</td><td>147.3</td></tr><tr><td>Compensated cirrhosis</td><td>0.78</td><td>0.73 0.84</td><td>KCE, 2010<sup>27</sup></td><td>169.2</td><td>47.7</td></tr><tr><td>Decompensated cirrhosis</td><td>0.49</td><td>0.46 0.51</td><td>Levy et al., 2008<sup>43</sup> (Adapted)</td><td>752.2</td><td>782.9</td></tr><tr><td>HCC</td><td>0.52</td><td>0.49 0.54</td><td>Levy et al., 2008<sup>43</sup> (Adapted)</td><td>797.3</td><td>735.9</td></tr><tr><td>Liver transplant</td><td>0.71</td><td>0.69 0.74</td><td>Levy et al., 2008<sup>43</sup> (Adapted)</td><td>897.8</td><td>366.7</td></tr><tr><td>Post liver transplant</td><td>0.82</td><td>0.75 0.88</td><td>KCE, 2010<sup>27</sup></td><td>109.2</td><td>24.0</td></tr><tr><td>HBsAg</td><td>0.83</td><td>0.82 0.87</td><td>KCE, 2010<sup>27</sup></td><td>719.0</td><td>147.3</td></tr><tr><td>HBsAg- CC</td><td>0.78</td><td>0.73 0.84</td><td>KCE, 2010<sup>27</sup></td><td>169.2</td><td>47.7</td></tr></tbody></table>

Notes: Based on section 6.2. CHB, chronic hepatitis B; NC, non cirrhotic; HCC, hepatocellular carcinoma; HBsAg-CC, HBsAg-with compensated cirrhosis; **Based on the Beta probability distribution.
## 2.6 ANTIVIRAL TREATMENT

Recently, well tolerated and potent antiviral drugs with a high threshold for development of resistance, tenofovir (300mg tenofovir disoproxil fumarate, equivalent to 245 mg tenofovir disoproxil, per day) and entecavir (0.5mg per day), have been introduced in Belgium as in other countries. These antiviral drugs significantly advance the possibilities of treating patients with CHB during different stages of the disease.

In our analyses of costs and effects we compare a strategy of antiviral treatment (using tenofovir or entecavir) with a “no antiviral treatment” strategy. We use the natural history as comparator because (1) lamivudine is no longer considered a state-of-the-art first line treatment of CHB, (2) adefovir is a second line treatment, and (3) (pegylated) interferon-alpha is an appropriate first line treatment for selected patients only.

We however excluded quantifying the cost-effectiveness of entecavir, because it is dominated by tenofovir for the following reasons:

* Based on the available (short term) study results entecavir and tenofovir are assumed to be equally effective in patients who were not treated with lamivudine (the data are reviewed in detail in part 1).

* Patients, who are resistant to lamivudine and are then treated with entecavir as second-line treatment, are more likely to develop resistance than if treated with tenofovir

* With 5,221 € treatment costs per patient year, entecavir is around 250 € more expensive than tenofovir. The price difference is expected to remain after the planned price decreases mentioned in table 7.

**Model follows current treatment guidelines**

The aim of the therapies is preventing disease progression and complications (development of cirrhosis, end-stage liver disease and HCC). However, these hard clinical endpoints take years or decades to occur and are therefore impractical targets for clinical trials. Current evidence has been reported as insufficient to assess antiviral treatment effect on hard clinical outcomes. Note that clearance of HBV is rarely, if ever, achievable.

Most patients included in phase III pivotal trials of antiviral therapy had a liver biopsy at baseline. A 2-point reduction in the modified histology activity index (HAI) score after treatment was extensively used as a primary or secondary endpoint in these trials. In 2008, it has been reported that a 2-point increase on this same scale is associated with an increased progression to liver complications.⁴⁴ No long term histological assessments are available in RCTs of NAs. Improvements from baseline liver biopsy data after 3 years of tenofovir treatment⁴⁵ or up to 6 years of (1mg) entecavir treatment⁴⁶ have been published.

As a result, surrogate markers, believed to correlate with hard clinical outcomes (loss of HBeAg, suppression of viral replication, improvement of liver biopsy), are often used to evaluate therapies. None of these surrogate markers is ideal on its own.⁴⁷ Nevertheless, currently, the most used surrogate marker is suppression of viral replication. It is assumed that significant suppression of HBV DNA replication results in lessening of the liver disease progression to cirrhosis and its complications including HCC. This surrogate endpoint is at the basis of all treatment guidelines, despite that its clinical validation is still insufficient and further research is needed. In patients who are HBeAg+, the treatment goal is HBeAg seroconversion (anti-HBe occurrence) with sustained suppression of HBV DNA, and hopefully HBsAg seroconversion. In the model, treatment is discontinued when the patient dies, is transplanted or shows e antigen seroconversion. Treatment remains discontinued as long as the patient remains in an inactive state (ICAR NC/CC or HBsAg- NC/CC). Treatment is restarted when the patient shows re-activation from ICAR NC/CC and transitions to CHBe+ or CHBe- NC or CC state.
In patients who are HBeAg-, the therapeutic goal is sustained suppressed HBV DNA and HBsAg seroconversion (anti-HBs occurrence), but this endpoint has not been reached so far in NA studies.⁴⁵ Therefore, in the model treatment in CHBe- patients is continued lifelong or until liver transplant.

Unclear effect of antiviral treatment on the development of HCC

The effect of NA on the incidence of HBV-related HCC remains a topic of discussion as there remains a lack of hard evidence based on well controlled trials.⁴⁸ Only one randomized controlled trial of NAs reported HCC as an outcome.⁴⁹ In this trial, 651 HBsAg positive Asian patients with compensated liver disease, who were HBeAg positive and/or had serum HBV DNA >700,000 gEq/mL (roughly >140,000 IU/mL), with bridging fibrosis or cirrhosis (about a third) were randomized to receive lamivudine (n=436) or placebo (n=215). This trial was terminated after a median follow-up of 32 (range 0-42) months because a statistically significant difference in the primary endpoint (increase in Child-Turcotte-Pugh score by 2 or more points or development of 1 of the following complications: HCC, spontaneous bacterial peritonitis, renal insufficiency or variceal bleeding) was observed between the two groups. At the time the trial was terminated, 17 (3.9%) lamivudine treated patients and 16 (7.4%) placebo controls had been diagnosed with HCC, hazard ratio (HR) 0.49 (95% CI 0.25-0.99) (P = 0.047) or a 47.6% reduction from 16/215 to 17/436. When the five HCC cases in year 1 (two prevalent cases in placebo group and three in lamivudine group) were excluded, HR was 0.47 and the difference between the two groups was no longer significant (P = 0.052). Data from this trial showed that patients who experienced virological breakthrough associated with lamivudine resistance did not derive as much clinical benefit as those who had maintained viral suppression. As was also suggested by a meta-analysis of nonrandomized trials the treatment effect seemed to be stronger in patients who were HBeAg positive at baseline. In HBeAg positive patients disease progression was reduced from 20% (25/124) to 6% (15/252) whereas in HBeAg negative patients the reduction was much smaller, from 14% (13/91) to 10% (19/182). It is unclear whether this suggested difference in efficacy applies similarly to HCC and liver decompensation.

A recent systematic review of published results,⁵⁰ including the above RCT and other nonrandomized studies suggests a lower HCC incidence under nucleos(t)ide treatment of 2.8% versus 6.4%. The effect seemed to be limited to patients showing a virological response.

Incorporating treatment effects in the model

We included treatment effects of tenofovir and entecavir in a very transparent way, summarized in Table 9. For the effect on fibrosis progression we assume a reduction of 75% (65% to 85%) under treatment of the transition probabilities from CHBe+ NC or CHBe- NC to CC states and from CHBe+ CC and CHBe- CC to DC states in the model. Note that this reduction in transition rates results in a much stronger reduction of over 90% in the incidence of decompensated cirrhosis cases (see results section). This strong treatment effect is based on non-controlled relatively short term efficacy data on liver histology and expert opinion and corresponds eg to a 100% response in 75% of patients and 0% in 25% of patients (or a corresponding mix of intermediate response scenario's). We assume drug resistance and drug toxicity will not become a major issue. We assume perfect long term drug adherence in over 75% of the patients who picked up the reimbursed drugs at the pharmacy. These assumptions are more likely to remain valid for shorter time horizons. Despite the fact that we assume treatment is continued in DC and HCC states, no beneficial effects of tenofovir are modelled once the patient failed treatment (entered DC or HCC state).
As the incidence of HCC is much increased in cirrhotic states, reducing the transition to cirrhosis will also result in a decrease of HCC. In addition, a smaller direct reduction of 25% with a broad range of uncertainty (0% to 50%) on the transition from treated states to HCC was included. This reflects the uncertainty there is on the effect of antiviral treatments on HCC incidence. The combination of the indirect and direct effects results in an overall reduction of HCC of about 50% in the 40 year old CHBe+/- cohorts. In the 50 year old CC cohort, the HCC reduction is much smaller as patients remain in CC for a much longer period during which they remain at moderate risk for HCC (see results section). These effects combined are in line with the short term results seen in the single RCT (lamivudine treatment) as discussed above.⁴⁹

<table><caption>**Table 9. Treatment effects.**</caption><thead><tr><th rowspan="2">Transitions</th><th colspan="5">Tenofovir</th></tr><tr><th>Mean reduction<br>of transition probability</th><th colspan="2">95% CI</th><th>Alpha*</th><th>Beta*</th></tr></thead><tbody><tr><td>From CHBe+/- NC to CHBe+/- CC</td><td rowspan="2">75%</td><td rowspan="2">65%</td><td rowspan="2">85%</td><td rowspan="2">53.3</td><td rowspan="2">17.8</td></tr><tr><td>From CHBe+/- CC to DC</td></tr><tr><td>From CHBe+/- NC to HCC</td><td rowspan="3">25%</td><td rowspan="3">0%</td><td rowspan="3">50%</td><td rowspan="3">2.6</td><td rowspan="3">7.9</td></tr><tr><td>From CHBe+/- CC to HCC</td></tr><tr><td>From DC to HCC</td></tr></tbody></table>

Notes: *Based on the Beta probability distribution.
# 3 RESULTS

## 3.1 MODEL VALIDATION: NATURAL EVOLUTION OF DISEASE WITHIN EUROPEAN COHORTS

This section aims at an intuitive (soft) evaluation of whether the model is reasonably well calibrated in terms of a comparison of life-expectancy of the modelled populations with the Belgian population. These results go beyond the 20 years horizon which we use for the cost-effectiveness analysis, and are thus more uncertain. As on average relatively few patients without cirrhosis develop complications which lead to early death, their life-expectancy could be expected (at least at lower ages) to be rather close to the Belgian average. For a mixed 40 year old cohort of 70% male and 30% female CHBe+ NC / CHBe- NC patients (representative of Belgian CHB cohorts) life-expectancy is on average 34.8 / 33.0 years, respectively. This compares to 39.5 years for the Belgian population (Table 10). The difference in life-expectancy declines with increasing age. For the cohort of 50 year old cirrhotic patients, life-expectancy is on average 20.3 years – falling thus 10 years below the Belgian average. This is due to a high incidence of life-threatening complications (DC and HCC) in this cohort.

<table><caption>Table 10. Life-expectancy of untreated cohorts compared to the Belgian population; in years.</caption><thead><tr><th>Age in years</th><th></th><th>CHBe+ non-cirrhotic patients**</th><th>CHBe- non-cirrhotic patients**</th><th>CHBe+/- cirrhotic patients**</th><th>Belgian population***</th></tr></thead><tbody><tr><td rowspan="2">30</td><td>Mean</td><td>43.4</td><td>41.0</td><td>27.7</td><td>49.0</td></tr><tr><td>95% range*</td><td>42.0 42.0</td><td>38.9 42.8</td><td>30.4 44.5</td><td></td></tr><tr><td rowspan="2">40</td><td>Mean</td><td>34.8</td><td>33.0</td><td>24.2</td><td>39.5</td></tr><tr><td>95% range</td><td>33.7 33.7</td><td>31.2 34.6</td><td>26.5 35.8</td><td></td></tr><tr><td rowspan="2">50</td><td>Mean</td><td>26.5</td><td>25.4</td><td>20.3</td><td>30.3</td></tr><tr><td>95% range</td><td>25.4 25.4</td><td>23.9 26.8</td><td>21.8 27.5</td><td></td></tr><tr><td rowspan="2">60</td><td>Mean</td><td>19.5</td><td>19.1</td><td>15.8</td><td>21.8</td></tr><tr><td>95% range</td><td>19.0 19.0</td><td>18.3 19.8</td><td>16.8 20.0</td><td></td></tr></tbody></table>

Notes: Base-line scenarios highlighted in bold. Results based on Markov model as presented in section 1. * 95% range: Interval ranging from 2.5-percentile to 97.5 percentile of the distribution of simulated results. ** Undiscounted life-years in natural evolution. ***Based on data from Statbe51 on a mixed cohort of 70% men and 30% women. CHBe+/-, chronic hepatitis B e antigen positive/ negative.
## 3.2 HEALTH OUTCOMES

### 3.2.1 Life-years gained in the three cohorts

<figure><img src="image_7.png" /><figcaption>Figure 3. Cohort evolution (undisc. LY in 40 y CHBe- NC Europe).</figcaption></figure>

<figure><img src="image_8.png" /><figcaption>Figure 4. Cohort evolution (undisc. LY in 50 y CHBe+/- CC Europe).</figcaption></figure>

<figure><img src="image_9.png" /></figure>
### 3.2.2 Cumulative undiscounted life-years gained per person in DC and HCC

<figure><img src="image_10.png" /><figcaption>Figure 6. Cumul. life-years per patient in DC and HCC (40 y CHBe- NC Europeans).</figcaption></figure>

<figure><img src="image_11.png" /><figcaption>Figure 7. Cumul. life-years per patient in DC and HCC (50 y CHBe+/- CC Europeans).</figcaption></figure>

<figure><img src="image_12.png" /></figure>

As in our model tenofovir has no impact on the life-years in DC and HCC, the above figures reflect the cumulative treatment-induced decrease in number of cases of DC and HCC as a function of patient age.
### 3.2.3 Mean tenofovir treatment duration in CHB e+ vs e- cohorts

In contrast to CHBe+ NC patients, over 20 years of follow-up CHBe- NC patients spend most of their life-years in states treated with tenofovir (mostly in CHBe- NC) (Table 11). As such, CHBe- non-cirrhotic patients are treated with antivirals for over 90% of the 20 years of follow-up. In contrast, CHBe+ NC patients spend on average somewhat more than half of years under antiviral treatment (mostly in CHBe+ NC and CHBe- NC disease states). Also cirrhotic patients are most of the time in antiviral treatment at 20 years follow-up.

<table><caption>Table 11. In contrast to CHBe+ NC patients, CHBe- NC patients spend most of their life-years in disease states treated with tenofovir (20 years time horizon).</caption><thead><tr><th rowspan="2"></th><th colspan="3">Mean cumulative undiscounted life-years spent in states with vs. without antiviral treatment</th></tr><tr><th>With</th><th>Without</th><th>Total</th></tr></thead><tbody><tr><td>40 y CHBe+ NC Europeans</td><td>9.48</td><td>7.96</td><td>17.44</td></tr><tr><td>40 y CHBe- NC Europeans</td><td>17.36</td><td>0.06</td><td>17.42</td></tr><tr><td>50 y CHBe+/- CC Europeans</td><td>12.94</td><td>1.98</td><td>14.92</td></tr></tbody></table>

Notes: Results based on Markov model as presented in section 1. 1.5% and 3.0% discount rates for outcomes and costs respectively.

## 3.3 BASE-CASE COST-UTILITY ANALYSES

### 3.3.1 Overview of the results for the three base-case cohorts

The general lines of the results are as follows. For CHBe+ NC patients (40 years old Europeans), in discounted QALYs, the treatment effect results only in 0.3 QALYs (95% CI: 0.2; 0.5) gained over a period of 20 years of treatment (Table 12). This moderate improvement in QALYs is seen despite the inclusion of a high treatment effect: a 90% reduction of life-years spent in decompensated cirrhosis and nearly a 50% reduction of life-years spent in HCC (Figure 8). For CHBe+ non-cirrhotic Europeans, antiviral treatment costs account for roughly 80% of total costs (Figure 9). At 20 years follow-up, the mean ICERs for treating patients with chronic hepatitis B with e antigen positivity are at 110,000 € per QALY gained (95% CI: 65,000; 184,000) (Table 14).

For CHBe- NC patients (40 years old Europeans), the same line of reasoning leads to slightly more unfavourable ICERs at 131,000 € per QALY gained (95% CI: 75,000; 240,000) (Table 17).

The picture is more favourable for 50 year old CHBe+/- CC Europeans, mostly due to higher gains in QALYs over 20 years of follow-up. The mean ICER is at 28,000 € per QALY gained (95% CI: 16,000; 47,000) (Table 20).
### 3.3.2 CHBe+ non-cirrhotic Europeans

<table><caption>Table 12. Up to 20 years of treatment, CHBe+ non-cirrhotic Europeans gain little in discounted QALYs when compared to no antiviral treatment.</caption><thead><tr><th rowspan="2">Age in years</th><th rowspan="2"></th><th colspan="3">10 years follow-up</th><th colspan="3">20 years follow-up</th></tr><tr><th>QALY no treatment</th><th>QALY: treated with tenofovir</th><th>QALYs gained</th><th>QALY no treatment</th><th>QALY: treated with tenofovir</th><th>QALYs gained</th></tr></thead><tbody><tr><td rowspan="2">30</td><td>Mean</td><td>8.3</td><td>8.3</td><td>0.0</td><td>14.5</td><td>14.6</td><td>0.2</td></tr><tr><td>95% range*</td><td>8.1 8.5</td><td>8.1 8.6</td><td>0.0 0.1</td><td>14.1 14.8</td><td>14.3 15.0</td><td>0.1 0.3</td></tr><tr><td rowspan="2">40</td><td>Mean</td><td>8.2</td><td>8.3</td><td>0.1</td><td>14.0</td><td>14.3</td><td>0.3</td></tr><tr><td>95% range</td><td>8.0 8.4</td><td>8.0 8.5</td><td>0.0 0.1</td><td>13.6 14.4</td><td>14.0 14.7</td><td>0.2 0.5</td></tr><tr><td rowspan="2">50</td><td>Mean</td><td>8.0</td><td>8.1</td><td>0.2</td><td>13.1</td><td>13.6</td><td>0.6</td></tr><tr><td>95% range</td><td>7.7 8.2</td><td>7.9 8.3</td><td>0.1 0.3</td><td>12.6 13.5</td><td>13.3 14.0</td><td>0.3 0.9</td></tr><tr><td rowspan="2">60</td><td>Mean</td><td>7.6</td><td>7.8</td><td>0.1</td><td>11.8</td><td>12.3</td><td>0.5</td></tr><tr><td>95% range</td><td>7.4 7.9</td><td>7.6 8.0</td><td>0.1 0.2</td><td>11.4 12.2</td><td>12.0 12.6</td><td>0.3 0.7</td></tr></tbody></table>

Notes: **Base-line scenario highlighted in bold.** Results based on Markov model as presented in section 1. 1.5% and 3.0% discount rates for outcomes and costs respectively. \* 95% range: Interval ranging from 2.5-percentile to 97.5 percentile of the distribution of simulated results. QALY: quality-adjusted life-year. CHBe+, chronic hepatitis B e antigen positive; Similarly small gains are observed, when life-years instead of QALYs are used as the outcome variable.

<figure><img src="image_13.png" /><figcaption>Figure 8. Low gains in discounted life-years under antiviral treatment with tenofovir over 20 years of follow-up albeit a high treatment efficacy.</figcaption></figure>

Notes: Results based on a cohort of 40 year old Europeans (70% male and 30% female) starting treatment in CHBe+ NC. TNF: tenofovir; CHBe+, chronic hepatitis B e antigen positive; CHBe-, chronic hepatitis B e antigen negative; NC; non cirrhotic; CC, compensated cirrhosis; ICAR, inactive carrier; HBsAg-, hepatitis B surface antigen negative; DC, decompensated cirrhosis; HCC, hepatocellular carcinoma; LT, liver transplant.
<table><caption>Table 13. Up to 20 years of treatment, CHBe+ non-cirrhotic treatment with tenofovir results in significant incremental costs when compared to no antiviral treatment.</caption><thead><tr><th rowspan="3">Age in years</th><th rowspan="3"></th><th colspan="3">10 years follow-up costs in 1,000 €/patient</th><th colspan="3">20 years follow-up costs in 1,000 €/patient</th></tr><tr><th>Costs no treatment*</th><th>Costs: treated with tenofovir**</th><th>Incremental costs</th><th>Costs no treatment*</th><th>Costs: treated with tenofovir**</th><th>Incremental costs</th></tr></thead><tbody><tr><td rowspan="2">30</td><td>Mean</td><td>5</td><td>32</td><td>27</td><td>10</td><td>45</td><td>35</td></tr><tr><td>95% range</td><td>4 8</td><td>26 38</td><td>22 32</td><td>7 13</td><td>36 55</td><td>27 43</td></tr><tr><td rowspan="2">40</td><td>Mean</td><td>6</td><td>32</td><td>26</td><td>13</td><td>46</td><td>33</td></tr><tr><td>95% range</td><td>4 9</td><td>27 39</td><td>21 31</td><td>9 17</td><td>37 55</td><td>26 41</td></tr><tr><td rowspan="2">50</td><td>Mean</td><td>9</td><td>32</td><td>24</td><td>17</td><td>45</td><td>28</td></tr><tr><td>95% range</td><td>6 12</td><td>27 38</td><td>19 29</td><td>11 24</td><td>36 55</td><td>20 37</td></tr><tr><td rowspan="2">60</td><td>Mean</td><td>8</td><td>31</td><td>23</td><td>15</td><td>42</td><td>27</td></tr><tr><td>95% range</td><td>6 11</td><td>26 37</td><td>18 28</td><td>10 21</td><td>34 50</td><td>20 34</td></tr></tbody></table>

Notes: **Base-line scenario highlighted in bold.** * Disease management costs only. **Disease management costs and antiviral treatment costs; See Table 12.

<figure><img src="image_14.png" /><figcaption>Figure 9. Over 20 years of follow-up, antiviral treatment costs with tenofovir account for over 80% of total costs within non-cirrhotic CHBe+ 40 year old Europeans; Costs in €/patient.</figcaption></figure>

Notes: See Figure 8.

<table><caption>Table 14. ICERs per QALY gained above 100,000 € and 50,000 € at 10 and 20 years of follow-up, respectively; Non-cirrhotic CHBe+ 40 year old Europeans.</caption><thead><tr><th rowspan="2">Age in years</th><th rowspan="2"></th><th colspan="2">ICER: 1,000 €/QALY gained</th></tr><tr><th>At 10 years follow-up</th><th>At 20 years follow-up</th></tr></thead><tbody><tr><td rowspan="2">30</td><td>Mean</td><td>761</td><td>212</td></tr><tr><td>95% range</td><td>368 1,413</td><td>123 355</td></tr><tr><td rowspan="2">40</td><td>Mean</td><td>411</td><td>110</td></tr><tr><td>95% range</td><td>210 838</td><td>65 184</td></tr><tr><td rowspan="2">50</td><td>Mean</td><td>178</td><td>54</td></tr><tr><td>95% range</td><td>85 354</td><td>28 97</td></tr><tr><td rowspan="2">60</td><td>Mean</td><td>178</td><td>62</td></tr><tr><td>95% range</td><td>88 366</td><td>31 110</td></tr></tbody></table>

Notes: **Base-line scenario highlighted in bold; See Table 12.**
### 3.3.3 CHBe- non-cirrhotic Europeans

<table><caption>Table 15. Up to 20 years of treatment, CHBe- non-cirrhotic Europeans gain little in discounted QALYs when compared to no antiviral treatment.</caption><thead><tr><th rowspan="2">Age in years</th><th rowspan="2"></th><th colspan="3">10 years follow-up</th><th colspan="3">20 years follow-up</th></tr><tr><th>QALY no treatment</th><th>QALY: treated with tenofovir</th><th>QALYs gained</th><th>QALY no treatment</th><th>QALY: treated with tenofovir</th><th>QALYs gained</th></tr></thead><tbody><tr><td rowspan="2">30</td><td>Mean</td><td>8.3</td><td>8.3</td><td>0.0</td><td>14.3</td><td>14.6</td><td>0.3</td></tr><tr><td>95% range</td><td>7.8 8.6</td><td>7.9 8.7</td><td>0.0 0.1</td><td>13.6 14.9</td><td>13.9 15.2</td><td>0.1 0.4</td></tr><tr><td rowspan="2">40</td><td>Mean</td><td>8.2</td><td>8.2</td><td>0.1</td><td>13.7</td><td>14.2</td><td>0.5</td></tr><tr><td>95% range</td><td>7.8 8.5</td><td>7.9 8.6</td><td>0.0 0.2</td><td>13.1 14.3</td><td>13.6 14.9</td><td>0.3 0.8</td></tr><tr><td rowspan="2">50</td><td>Mean</td><td>7.9</td><td>8.1</td><td>0.2</td><td>12.8</td><td>13.5</td><td>0.7</td></tr><tr><td>95% range</td><td>7.5 8.2</td><td>7.7 8.4</td><td>0.1 0.3</td><td>12.1 13.5</td><td>12.8 14.1</td><td>0.4 1.2</td></tr><tr><td rowspan="2">60</td><td>Mean</td><td>7.6</td><td>7.7</td><td>0.2</td><td>11.6</td><td>12.2</td><td>0.6</td></tr><tr><td>95% range</td><td>7.2 7.9</td><td>7.4 8.1</td><td>0.1 0.3</td><td>11.0 12.1</td><td>11.6 12.7</td><td>0.3 1.1</td></tr></tbody></table>

Notes: **Base-line scenario highlighted in bold.** Results based on Markov model as presented in section 1. 1.5% and 3.0% discount rates for outcomes and costs respectively. \* 95% range: Interval ranging from 2.5-percentile to 97.5 percentile of the distribution of simulated results. QALY: quality-adjusted life-year; CHBe-, chronic hepatitis B e antigen negative.

<figure><img src="image_15.png" /><figcaption>Figure 10. Low gains in discounted life-years under antiviral treatment with tenofovir over 20 years of follow-up albeit a high treatment efficacy.</figcaption></figure>

Notes: Results based on a cohort of 40 year old Europeans (70% male and 30% female) starting treatment in CHBe- NC. TNF: tenofovir; CHBe+, chronic hepatitis B e antigen positive; CHBe-, chronic hepatitis B e antigen negative; NC; non cirrhotic; CC, compensated cirrhosis; ICAR, inactive carrier; HBsAg-, hepatitis B surface antigen negative; DC, decompensated cirrhosis; HCC, hepatocellular carcinoma; LT, liver transplant.
<table><caption>Table 16. Up to 20 years of treatment, CHBe- non-cirrhotic treatment with tenofovir results in significant incremental costs when compared to no antiviral treatment.</caption><thead><tr><th rowspan="2">Age in years</th><th colspan="3">10 years follow-up costs in 1,000 €/patient</th><th colspan="3">20 years follow-up costs in 1,000 €/patient</th></tr><tr><th>Costs no treatment *</th><th>Costs: treated with tenofovir**</th><th>Incremental costs</th><th>Costs no treatment*</th><th>Costs: treated with tenofovir**</th><th>Incremental costs</th></tr></thead><tbody><tr><td rowspan="2">30</td><td>Mean</td><td>7</td><td>49</td><td>41</td><td>15</td><td>78</td><td>63</td></tr><tr><td>95% range</td><td>5 11</td><td>46 52</td><td>40 42</td><td>10 20</td><td>74 83</td><td>60 65</td></tr><tr><td rowspan="2">40</td><td>Mean</td><td>8</td><td>48</td><td>40</td><td>19</td><td>77</td><td>58</td></tr><tr><td>95% range</td><td>5 11</td><td>46 51</td><td>39 41</td><td>13 26</td><td>73 82</td><td>53 62</td></tr><tr><td rowspan="2">50</td><td>Mean</td><td>11</td><td>48</td><td>37</td><td>23</td><td>75</td><td>52</td></tr><tr><td>95% range</td><td>7 15</td><td>46 51</td><td>33 39</td><td>15 34</td><td>71 79</td><td>42 58</td></tr><tr><td rowspan="2">60</td><td>Mean</td><td>10</td><td>46</td><td>36</td><td>20</td><td>68</td><td>48</td></tr><tr><td>95% range</td><td>7 15</td><td>44 49</td><td>32 38</td><td>13 30</td><td>65 72</td><td>40 53</td></tr></tbody></table>

Notes: Base-line scenario highlighted in bold. * Disease management costs only. ** Disease management costs and antiviral treatment costs. See Table 12.

<figure><img src="image_16.png" /><figcaption>Figure 11. Over 20 years of follow-up, antiviral treatment costs with tenofovir account for over 80% of total costs within non-cirrhotic CHBe- 40 year old Europeans; Costs in €/patient.</figcaption></figure>

Notes: See Figure 8.

<table><caption>Table 17. ICERs per QALY gained above 100,000 € and 50,000 € at 10 and 20 years of follow-up, respectively; Non-cirrhotic CHBe- 40 year old Europeans. ICER: 1,000 €/QALY gained</caption><thead><tr><th rowspan="2">Age in years</th><th rowspan="2"></th><th colspan="2">At 10 years follow-up</th><th colspan="2">At 20 years follow-up</th></tr><tr><th>Mean</th><th>95% range</th><th>Mean</th><th>95% range</th></tr></thead><tbody><tr><td rowspan="2">30</td><td>Mean</td><td>1,069</td><td>441</td><td>2,229</td><td>143</td><td>461</td></tr><tr><td>Mean</td><td>562</td><td>249</td><td>1,325</td><td>75</td><td>240</td></tr><tr><td rowspan="2">40</td><td>Mean</td><td>371</td><td>106</td><td>569</td><td>38</td><td>145</td></tr><tr><td>Mean</td><td>253</td><td>109</td><td>545</td><td>39</td><td>156</td></tr><tr><td rowspan="2">50</td><td>Mean</td><td>131</td><td>131</td><td>131</td><td>75</td><td>131</td></tr><tr><td>Mean</td><td>84</td><td>84</td><td>84</td><td>84</td><td>84</td></tr><tr><td rowspan="2">60</td><td>Mean</td><td>84</td><td>84</td><td>84</td><td>84</td><td>84</td></tr><tr><td>Mean</td><td>84</td><td>84</td><td>84</td><td>84</td><td>84</td></tr></tbody></table>

Notes: Base-line scenario highlighted in bold. See Table 12.
### 3.3.4 Patient with compensated liver cirrhosis

<table><caption>Table 18. Up to 20 years of treatment, CHBe+/- CC Europeans gain up to 1.3 QALYs on average when compared to no antiviral treatment.</caption><thead><tr><th rowspan="2">Age in years</th><th rowspan="2"></th><th colspan="3">10 years follow-up</th><th colspan="3">20 years follow-up</th></tr><tr><th>QALY no treatment</th><th>QALY: treated with tenofovir</th><th>QALYs gained</th><th>QALY no treatment</th><th>QALY: treated with tenofovir</th><th>QALYs gained</th></tr></thead><tbody><tr><td rowspan="2">30</td><td>Mean</td><td>7.0</td><td>7.4</td><td>0.5</td><td>10.9</td><td>12.2</td><td>1.3</td></tr><tr><td>95% range</td><td>6.5 7.4</td><td>6.9 7.9</td><td>0.3 0.7</td><td>10.0 11.7</td><td>11.2 13.0</td><td>0.8 1.8</td></tr><tr><td rowspan="2">40</td><td>Mean</td><td>6.9</td><td>7.4</td><td>0.5</td><td>10.9</td><td>12.2</td><td>1.3</td></tr><tr><td>95% range</td><td>6.4 7.4</td><td>6.8 7.8</td><td>0.3 0.7</td><td>10.0 11.7</td><td>11.2 13.0</td><td>0.8 1.8</td></tr><tr><td rowspan="2">50</td><td>Mean</td><td>6.8</td><td>7.2</td><td>0.4</td><td>10.9</td><td>12.2</td><td>1.3</td></tr><tr><td>95% range</td><td>6.3 7.2</td><td>6.7 7.7</td><td>0.3 0.6</td><td>10.0 11.7</td><td>11.2 13.0</td><td>0.8 1.8</td></tr><tr><td rowspan="2">60</td><td>Mean</td><td>6.5</td><td>7.0</td><td>0.4</td><td>10.9</td><td>12.2</td><td>1.3</td></tr><tr><td>95% range</td><td>6.1 7.0</td><td>6.4 7.4</td><td>0.3 0.6</td><td>10.0 11.7</td><td>11.2 13.0</td><td>0.8 1.8</td></tr></tbody></table>

Notes: **Base-case highlighted in bold.** 1.5% and 3.0% discount rates for outcomes and costs respectively. * 95% range: Interval ranging from 2.5-percentile to 97.5 percentile of the distribution of simulated results. QALY: quality-adjusted life-year; CHBe+, chronic hepatitis B e antigen positive.

<figure><img src="image_17.png" /><figcaption>Figure 12. 9% gain in discounted life-years under antiviral treatment with tenofovir over 20 years of follow-up; 50 year old CHBe+/- CC Europeans.</figcaption></figure>

Notes: Results based on a mixed cohort of 70% CHBe+ CC and 30% CHBe- CC 50 year old Europeans (70% male and 30% female). TNF: tenofovir; CHBe+, chronic hepatitis B e antigen positive; CHBe-, chronic hepatitis B e antigen negative; NC; non cirrhotic; CC, compensated cirrhosis; ICAR, inactive carrier; HBsAg-, hepatitis B surface antigen negative; DC, decompensated cirrhosis; HCC, hepatocellular carcinoma; LT, liver transplant.
<table><caption>Table 19. Up to 20 years of treatment, treatment of CHBe+/- cirrhotic Europeans with tenofovir results in significant incremental costs when compared to no antiviral treatment.</caption><thead><tr><th rowspan="2">Age in years</th><th rowspan="2"></th><th colspan="4">10 years follow-up costs in 1,000 €/patient</th><th colspan="4">20 years follow-up costs in 1,000 €/patient</th></tr><tr><th>Costs no treatment*</th><th colspan="2">Costs: treated with tenofovir**</th><th>Incremental costs</th><th>Costs no treatment*</th><th colspan="2">Costs: treated with tenofovir**</th><th>Incremental costs</th></tr></thead><tbody><tr><td rowspan="2">30</td><td>Mean</td><td>34</td><td>58</td><td>24</td><td>24</td><td>56</td><td>89</td><td>33</td><td>33</td></tr><tr><td>95% range</td><td>24</td><td>46</td><td>53</td><td>65</td><td>16</td><td>30</td><td>41</td><td>43</td></tr><tr><td rowspan="2">40</td><td>Mean</td><td>34</td><td>58</td><td>24</td><td>24</td><td>55</td><td>88</td><td>33</td><td>33</td></tr><tr><td>95% range</td><td>24</td><td>46</td><td>53</td><td>63</td><td>15</td><td>30</td><td>40</td><td>42</td></tr><tr><td rowspan="2">50</td><td>Mean</td><td>33</td><td>57</td><td>24</td><td>24</td><td>52</td><td>84</td><td>32</td><td>32</td></tr><tr><td>95% range</td><td>24</td><td>45</td><td>52</td><td>63</td><td>16</td><td>30</td><td>38</td><td>41</td></tr><tr><td rowspan="2">60</td><td>Mean</td><td>32</td><td>55</td><td>23</td><td>23</td><td>48</td><td>77</td><td>29</td><td>29</td></tr><tr><td>95% range</td><td>23</td><td>44</td><td>50</td><td>60</td><td>15</td><td>29</td><td>35</td><td>38</td></tr></tbody></table>

Notes: Base-line scenario highlighted in bold; *Disease management costs only; **Disease management costs and antiviral treatment costs; See Table 12.

<figure><img src="image_18.png" /><figcaption>Figure 13. Over 20 years of follow-up, antiviral treatment costs with tenofovir account for over 65% of total costs within CHBe+/- cirrhotic 50 year old Europeans; Costs in €/patient.</figcaption></figure>

Notes: See Figure 8.

<table><caption>Table 20. ICERs per QALY gained around 57,000 € and 29,000 € at 10 and 20 years of follow-up, respectively; CHBe+/- CC Europeans.</caption><thead><tr><th rowspan="2">Age in years</th><th rowspan="2"></th><th colspan="2">ICER: 1,000 €/QALY gained</th></tr><tr><th>At 10 years follow-up</th><th>At 20 years follow-up</th></tr></thead><tbody><tr><td rowspan="2">30</td><td>Mean</td><td>55</td><td>28</td></tr><tr><td>95% range</td><td>30</td><td>90</td><td>15</td><td>45</td></tr><tr><td rowspan="2">40</td><td>Mean</td><td>56</td><td>28</td></tr><tr><td>95% range</td><td>29</td><td>96</td><td>15</td><td>47</td></tr><tr><td rowspan="2">50</td><td>Mean</td><td>57</td><td>29</td></tr><tr><td>95% range</td><td>30</td><td>96</td><td>16</td><td>47</td></tr><tr><td rowspan="2">60</td><td>Mean</td><td>57</td><td>31</td></tr><tr><td>95% range</td><td>29</td><td>98</td><td>16</td><td>52</td></tr></tbody></table>

Notes: See Table 12.
## 3.4 SCENARIO AND PROBABILISTIC SENSITIVITY ANALYSES

### 3.4.1 Probabilistic sensitivity analysis

#### 3.4.1.1 Tornado diagrams

In order to assess the impact of the model input variables on the ICER, we have estimated how much the ICER changes, if the mean value of a specific input variable is increased by 1%, e.g. a 1% increase of the annual cost of tenofovir from 4,971 to 5,020 €. For both the CHBe+ NC and the CHBe- cohorts, the ICER is most sensitive to changes in the cost of tenofovir, as well as to changes in utilities, such as utility in CC (Figure 14 and 15). Now consider the sensitivity of some of the most elastic parameters. In the base case scenario for CHBe+ NC patients, in order for the ICER to decrease from 110,000 to 30,000€/QALY, the current price of tenofovir should decrease by 65% to around 1,750€. Within the CHBe- NC model, a 65% decrease in the price of tenofovir entails a drop of the ICER from 131,000 to 40,000€/QALY. Applying a relatively low utility for CC of 0.68 instead of 0.78, such as in the UK population in Levy et al. 2008, the mean ICERs decrease to 75,000€/QALY and 86,000€/QALY for the CHBe+NC and CHBe-NC cohorts, respectively. Finally, assuming a doubling of the age dependent transition probabilities from CHBe+/- NC to CHBe+/-CC, the ICER decreases to 54,000€/QALY and to 66,000€/QALY for the CHBe+NC and CHBe-NC cohorts, respectively.

<table><caption>Figure 14. Tornado diagram for CHBe+ NC European cohort aged 40 years at 20 years of follow-up.</caption><caption>Elasticities of ICER w.r.t 1% increase in mean parameter values</caption><tbody><tr><td colspan="2">TRANSITION PROBABILITY</td></tr><tr><td>CHBe+ NC to CHBe- NC</td><td>0.07%</td></tr><tr><td>CHBe+ NC to ICAR NC</td><td>-0.05%</td></tr><tr><td>CHBe+ NC to CHBe+ CC</td><td>-0.21%</td></tr><tr><td>CHBe+ NC to HCC</td><td>-0.02%</td></tr><tr><td>CHBe+ CC to DC</td><td>-0.29%</td></tr><tr><td>CHBe+ CC to HCC</td><td>-0.27%</td></tr><tr><td>CHBe- CC to DC</td><td>-0.10%</td></tr><tr><td>CHBe- CC to HCC</td><td>-0.10%</td></tr><tr><td>DC to LT</td><td>0.11%</td></tr><tr><td>DC to Death</td><td>-0.07%</td></tr><tr><td>HCC to Death</td><td>-0.05%</td></tr><tr><td>LTDC to Death</td><td>-0.32%</td></tr><tr><td colspan="2">COSTS</td></tr><tr><td>tenofovir</td><td>2.85%</td></tr><tr><td colspan="2">UTILITY IN STATE</td></tr><tr><td>CHBe+ NC</td><td>-1.64%</td></tr><tr><td>CHBe- NC</td><td>-1.25%</td></tr><tr><td>Inactive Carrier</td><td>-1.08%</td></tr><tr><td>CC</td><td>2.77%</td></tr><tr><td colspan="2">TREATMENT EFFECT</td></tr><tr><td>CHBe+ NC to CHBe+ CC</td><td>-0.85%</td></tr><tr><td>CHBe+ NC to HCC</td><td>-0.03%</td></tr></tbody><tfoot><tr><td colspan="2">% change in ICER due to a 1% increase in parameter</td></tr></tfoot></table>

Notes: The results show only those effects which were significant at the 5% statistical significance level; * Individual elasticity extrapolated to the confidence interval of each parameter. Cost of tenofovir was decreased up to 20%.
<table><caption>Figure 15. Tornado diagram for CHBe- NC European cohort aged 40 years at 20 years of follow-up.</caption><caption>Elasticities of ICER w.r.t 1% increase in mean parameter values</caption><tbody><tr><td colspan="2">TRANSITION PROBABILITY</td></tr><tr><td>-0.26%</td><td>CHBe+ NC to CHBe+ CC</td></tr><tr><td>-0.02%</td><td>CHBe- NC to HCC</td></tr><tr><td>0.04%</td><td>CC INCA to CC-HBS</td></tr><tr><td>0.05%</td><td>CHBe+ CC to CHBe- CC</td></tr><tr><td>-0.37%</td><td>CHBe- CC to DC</td></tr><tr><td>-0.35%</td><td>CHBe- CC to HCC</td></tr><tr><td>0.04%</td><td>DC to LT</td></tr><tr><td>-0.12%</td><td>DC to Death</td></tr><tr><td>-0.10%</td><td>HCC to Death</td></tr><tr><td colspan="2">COSTS</td></tr><tr><td>-0.05%</td><td>tenofovir</td></tr><tr><td>-0.06%</td><td>DM cost in state DC</td></tr><tr><td></td><td>DM cost in state LT-DC</td></tr><tr><td colspan="2">UTILITY IN STATE</td></tr><tr><td>-5.38%</td><td>CHBe- NC</td></tr><tr><td>3.63%</td><td>CC</td></tr><tr><td colspan="2">TREATMENT EFFECT</td></tr><tr><td>-0.61%</td><td>CHBe+ NC to CHBe+ CC</td></tr><tr><td>-0.05%</td><td>CHBe+ NC to HCC</td></tr><tr><td>-0.14%</td><td>CHBe- CC to DC</td></tr></tbody><tfoot><tr><td colspan="2">% change in ICER due to a 1% increase in parameter</td></tr></tfoot></table>

Notes: The results show only those effects which were significant at the 5% statistical significance level; * Individual elasticity extrapolated to the confidence interval of each parameter. Cost of tenofovir was decreased up to 20%.

### 3.4.1.2 Cost-effectiveness acceptability curves

For a decision-maker it may be valuable to know, how the probability that treatment with tenofovir is cost-effective, changes with his valuation of QALYs gained. One way to illustrate this link is cost-effectiveness acceptability curves (CEAC). These curves show the probability that a specific treatment is optimal, for a range of threshold values per QALY gained.⁵² For instance, at 10 years follow-up for CHBe+ non-cirrhotic Europeans, the probability that the treatment with tenofovir is cost-effective is always 0, at least up to the threshold value of 100,000 € per QALY (Figure 16). At 20 years follow-up tenofovir treatment is never an optimal strategy at threshold QALY values up to 60,000 €. The probability that tenofovir becomes a cost-effective option increases to 40% at a value of 100,000 € per QALY.
<table><caption>Figure 16. At 20 years follow-up, very low probability that treatment with tenofovir is cost-effective when QALY is valued below 80,000€; Comparator is no antiviral treatment; Non-cirrhotic CHBe+/- 40 year old Europeans.</caption><thead><tr><th>Non-cirrhotic CHBe+ 40 year old Europeans.</th><th>Non-cirrhotic CHBe- 40 year old Europeans.</th></tr></thead><tbody><tr><td>Probability cost-effective</td><td>Probability cost-effective</td></tr><tr><td>10 years</td><td>10 years</td></tr><tr><td>20 years</td><td>20 years</td></tr><tr><td>Value per QALY in €</td><td>Value per QALY in €</td></tr></tbody></table>

<figure><img src="image_19.png" /></figure>

<figure><img src="image_20.png" /></figure>

Notes: Cost-effectiveness acceptability curves (CEAC). These curves show the probability that a specific treatment is optimal for a range of threshold values per QALY.⁵²

<figure><img src="image_21.png" /><figcaption>Figure 17. At 20 years follow-up, 50% probability that treatment with tenofovir is cost-effective when QALY is valued around 28,000€; Comparator is no antiviral treatment; Cirrhotic CHBe+/- 50 year old Europeans.</figcaption></figure>

Notes: Cost-effectiveness acceptability curves (CEAC). These curves show the probability that a specific treatment is optimal for a range of threshold values per QALY.⁵²
### 3.4.2 ICERs in function of the time horizon

<figure><img src="image_22.png" /><figcaption>Figure 19. Steep decrease in ICERs from 10 to 20 years of follow-up, (unpredictable) uncertainty thereafter; CHBe+/- CC Europeans.</figcaption></figure>

<figure><img src="image_23.png" /></figure>
### 3.4.3 Asian cohorts

For the Asian cohorts, the ICERs are in general more favorable than for the European cohorts, as they have a higher probability to develop HCC under natural evolution. Accordingly, the gain of avoiding HCC under antiviral treatment with tenofovir is in general higher.

<table><caption>Table 21. ICERs per QALY gained around 273,000 € and 80,000 € at 10 and 20 years of follow-up, respectively; CHBe+ NC Asians.</caption><thead><tr><th rowspan="2">Age</th><th rowspan="2"></th><th colspan="4">ICER: 1,000 €/QALY gained</th></tr><tr><th>At 10 years follow-up</th><th>At 20 years follow-up</th><th>At 30 years follow-up</th><th>At 40 years follow-up</th></tr></thead><tbody><tr><td rowspan="2">30</td><td>Mean</td><td>422</td><td></td><td>138</td><td></td></tr><tr><td>95% range</td><td>240</td><td>758</td><td>85</td><td>212</td></tr><tr><td rowspan="2">40</td><td>Mean</td><td>273</td><td></td><td>80</td><td></td></tr><tr><td>95% range</td><td>150</td><td>501</td><td>51</td><td>126</td></tr><tr><td rowspan="2">50</td><td>Mean</td><td>135</td><td></td><td>43</td><td></td></tr><tr><td>95% range</td><td>70</td><td>242</td><td>23</td><td>75</td></tr><tr><td rowspan="2">60</td><td>Mean</td><td>137</td><td></td><td>50</td><td></td></tr><tr><td>95% range</td><td>73</td><td>246</td><td>28</td><td>83</td></tr></tbody></table>

Notes: **Base-line scenario highlighted in bold.** Results based on Markov model as presented in section 1. 1.5% and 3.0% discount rates for outcomes and costs respectively. * 95% range: Interval ranging from 2.5-percentile to 97.5 percentile of the distribution of simulated results. QALY: quality-adjusted life-year; CHBe+, chronic hepatitis B e antigen positive.

<table><caption>Table 22. ICERs per QALY gained around 358,000 € and 96,000 € at 10 and 20 years of follow-up, respectively; CHBe- NC Asians.</caption><thead><tr><th rowspan="2">Age</th><th rowspan="2"></th><th colspan="4">ICER: 1,000 €/QALY gained</th></tr><tr><th>At 10 years follow-up</th><th>At 20 years follow-up</th><th>At 30 years follow-up</th><th>At 40 years follow-up</th></tr></thead><tbody><tr><td rowspan="2">30</td><td>Mean</td><td>541</td><td></td><td>167</td><td></td></tr><tr><td>95% range</td><td>261</td><td>1,211</td><td>92</td><td>296</td></tr><tr><td rowspan="2">40</td><td>Mean</td><td>358</td><td></td><td>96</td><td></td></tr><tr><td>95% range</td><td>175</td><td>685</td><td>58</td><td>157</td></tr><tr><td rowspan="2">50</td><td>Mean</td><td>218</td><td></td><td>58</td><td></td></tr><tr><td>95% range</td><td>167</td><td>219</td><td>32</td><td>101</td></tr><tr><td rowspan="2">60</td><td>Mean</td><td>140</td><td></td><td>66</td><td></td></tr><tr><td>95% range</td><td>135</td><td>207</td><td>37</td><td>119</td></tr></tbody></table>

Notes: **Base-line scenario highlighted in bold.** See Table 21.
<table><caption>Table 23. ICERs per QALY gained around 50,000 € and 27,000 € at 10 and 20 years of follow-up, respectively; CHBe+/- CC Asians.</caption><thead><tr><th rowspan="2">Age</th><th rowspan="2"></th><th colspan="2">ICER: 1,000 €/QALY gained</th></tr><tr><th>At 10 years follow-up</th><th>At 20 years follow-up</th></tr></thead><tbody><tr><td rowspan="2">30</td><td>Mean</td><td>50</td><td>27</td></tr><tr><td>95% range</td><td>26</td><td>88</td><td>14</td><td>46</td></tr><tr><td rowspan="2">40</td><td>Mean</td><td>51</td><td>26</td></tr><tr><td>95% range</td><td>25</td><td>88</td><td>13</td><td>45</td></tr><tr><td rowspan="2">50</td><td>Mean</td><td>50</td><td>27</td></tr><tr><td>95% range</td><td>26</td><td>82</td><td>15</td><td>46</td></tr><tr><td rowspan="2">60</td><td>Mean</td><td>52</td><td>29</td></tr><tr><td>95% range</td><td>28</td><td>88</td><td>15</td><td>50</td></tr></tbody></table>

Notes: Base-line scenario highlighted in bold. See Table 21.

### 3.4.4 Variations in the discount rates

<table><caption>Table 24. Variations in discount rates do not significantly impact on ICERs per QALY gained; CHBe+ NC European and Asian cohorts aged 40 years at 20 years of follow-up.</caption><thead><tr><th rowspan="2">Discount rates</th><th rowspan="2"></th><th colspan="2">ICER: 1,000 €/QALY gained</th></tr><tr><th>Europeans</th><th>Asians</th></tr></thead><tbody><tr><td>Cost: 0.0%</td><td>Mean</td><td>105</td><td>78</td></tr><tr><td>Outcome: 0.0%</td><td>95% range</td><td>60</td><td>176</td><td>50</td><td>122</td></tr><tr><td>Cost: 3.0%</td><td>Mean</td><td>110</td><td>80</td></tr><tr><td>Outcome: 1.5%</td><td>95% range</td><td>65</td><td>184</td><td>51</td><td>126</td></tr><tr><td>Cost: 3.0%</td><td>Mean</td><td>133</td><td>98</td></tr><tr><td>Outcome: 3.0%</td><td>95% range</td><td>77</td><td>208</td><td>60</td><td>151</td></tr><tr><td>Cost: 5.0%</td><td>Mean</td><td>157</td><td>114</td></tr><tr><td>Outcome: 5.0%</td><td>95% range</td><td>92</td><td>258</td><td>73</td><td>177</td></tr></tbody></table>

<table><caption>Table 25. Variations in discount rates do not significantly impact on ICERs per QALY gained; CHBe- NC European and Asian cohorts aged 40 years at 20 years of follow-up.</caption><thead><tr><th rowspan="2">Discount rates</th><th rowspan="2"></th><th colspan="2">ICER: 1,000 €/QALY gained</th></tr><tr><th>Europeans</th><th>Asians</th></tr></thead><tbody><tr><td>Cost: 0.0%</td><td>Mean</td><td>161</td><td>101</td></tr><tr><td>Outcome: 0.0%</td><td>95% range</td><td>115</td><td>163</td><td>60</td><td>161</td></tr><tr><td>Cost: 3.0%</td><td>Mean</td><td>131</td><td>96</td></tr><tr><td>Outcome: 1.5%</td><td>95% range</td><td>75</td><td>240</td><td>58</td><td>157</td></tr><tr><td>Cost: 3.0%</td><td>Mean</td><td>161</td><td>119</td></tr><tr><td>Outcome: 3.0%</td><td>95% range</td><td>124</td><td>161</td><td>70</td><td>191</td></tr><tr><td>Cost: 5.0%</td><td>Mean</td><td>120</td><td>134</td></tr><tr><td>Outcome: 5.0%</td><td>95% range</td><td>117</td><td>185</td><td>80</td><td>218</td></tr></tbody></table>
<table><caption>Table 26. Variations in discount rates do not significantly impact on ICERs per QALY gained; CHBe+/- CC European and Asian cohorts aged 40 years at 20 years of follow-up.</caption><thead><tr><th rowspan="2">Discount rates</th><th rowspan="2"></th><th colspan="2">ICER: 1,000 €/QALY gained</th></tr><tr><th>Europeans</th><th>Asians</th></tr></thead><tbody><tr><td>Cost: 0.0%</td><td>Mean</td><td>29</td><td>27</td></tr><tr><td>Outcome: 0.0%</td><td>95% range</td><td>15</td><td>47</td><td>14</td><td>46</td></tr><tr><td>Cost: 3.0%</td><td>Mean</td><td>28</td><td>26</td></tr><tr><td>Outcome: 1.5%</td><td>95% range</td><td>15</td><td>47</td><td>13</td><td>45</td></tr><tr><td>Cost: 3.0%</td><td>Mean</td><td>34</td><td>32</td></tr><tr><td>Outcome: 3.0%</td><td>95% range</td><td>17</td><td>55</td><td>17</td><td>53</td></tr><tr><td>Cost: 5.0%</td><td>Mean</td><td>37</td><td>36</td></tr><tr><td>Outcome: 5.0%</td><td>95% range</td><td>19</td><td>62</td><td>19</td><td>60</td></tr></tbody></table>

## 3.5 BUDGET IMPACT

A comparison of the current costs of treatment of the CHB Belgian population with a situation of generalized treatment with tenofovir shows that total annual costs increase from 8.2 to 13.5 million €, i.e. an increase of around 5.3 million € (Table 25). On average and per patient, the annual costs increase from 2,642 to 4,340 €, i.e. a 64% increase in mean costs per patient. Note that patients co-infected with HIV or HCV are not included in the estimates.

<table><caption>Table 27. Compared to current antiviral treatment, generalized treating with tenofovir increases the annual costs by an estimated total of 5.3 million €; in €.</caption><thead><tr><th rowspan="2">Disease state</th><th rowspan="2">Belgian patients</th><th colspan="2">HBV related DMC* incl. antiviral costs</th><th colspan="2">HBV related DMC* excl. antiviral costs for CHB, CC, DC and HCC</th><th colspan="2">HBV related DMC* incl. tenofovir cost in CHB, CC, DC and HCC</th></tr><tr><th>Mean</th><th>Total</th><th>Mean</th><th>Total</th><th>Total (tenofovir)</th><th>Total (tenofovir and DM costs)</th></tr></thead><tbody><tr><td>ICAR</td><td>1,266</td><td>115</td><td>145,685</td><td>115</td><td>145,685</td><td>-</td><td>145,685</td></tr><tr><td>CHB</td><td>1,200</td><td>2,493</td><td>2,991,028</td><td>591</td><td>708,629</td><td>5,965,200</td><td>6,673,829</td></tr><tr><td>CC</td><td>383</td><td>2,560</td><td>980,629</td><td>1,115</td><td>426,909</td><td>1,903,893</td><td>2,330,802</td></tr><tr><td>DC</td><td>10</td><td>8,406</td><td>84,055</td><td>6,814</td><td>68,143</td><td>49,710</td><td>117,853</td></tr><tr><td>HCC</td><td>49</td><td>11,518</td><td>564,392</td><td>10,816</td><td>529,977</td><td>243,579</td><td>773,556</td></tr><tr><td>LTy1</td><td>19</td><td>102,752</td><td>1,952,284</td><td>102,752</td><td>1,952,284</td><td>-</td><td>1,952,284</td></tr><tr><td>Ltpost</td><td>180</td><td>8,279</td><td>1,490,137</td><td>8,279</td><td>1,490,137</td><td>-</td><td>1,490,137</td></tr><tr><td>Total</td><td>3,107</td><td>2,642</td><td>8,208,209</td><td>1,713</td><td>5,321,763</td><td>8,162,382</td><td>13,484,145</td></tr><tr><td colspan="8"><strong>Costs under treatment with tenofovir in €</strong></td></tr><tr><td colspan="8">Total annual cost increase</td><td>5,275,936</td></tr><tr><td colspan="8">Mean annual cost per patient</td><td>4,340</td></tr><tr><td colspan="8">Annual cost increase per patient</td><td>1,698</td></tr><tr><td colspan="8">% cost increase per patient</td><td>64%</td></tr></tbody></table>

Notes: *Disease management costs; Number of Belgian patients based on survey estimates from part I of the publication, the number of patients with decompensated cirrhosis is likely underestimated as patients with acute disease could not participate to the survey.
## 4 DISCUSSION AND CONCLUSIONS

Decision makers should be aware that there are no long term randomized controlled trials available for tenofovir or entecavir showing an effect on disease progression and hard clinical endpoints. Therefore results of long term models need to be interpreted with caution. Especially the effect of antiviral treatment on hepatocellular carcinoma remains highly uncertain. We opted to not model (pegylated) interferon-alpha treatment, as this treatment option is appropriate only for selected patients.

We believe our study has many advantages over previous research. First, we carefully collected and analyzed data on the Belgian situation in treatment centres for CHB, including patient numbers, characteristics, quality of life and HBV related costs by clinical disease stage. Second, we accessed an unpublished large cohort of untreated Caucasian CHB patients at Leuven University Hospital, which allowed us to more accurately model disease progression as a function of patient age.

A first important finding concerns the absence of measurable disease progression over a mean period of 10 years in 59 Caucasian CHBe+ patients with normal ALT levels during the first three years of follow-up at Leuven University Hospital (Appendix 6.1). In such patients antiviral treatment cannot be justified based on these observations.

<table><caption>Table 28. Estimated ICER ranges for tenofovir treatment of CHBe+ and CHBe- patients by age, origin and liver cirrhosis status (based on 20 years time horizon).</caption><thead><tr><th>Age cohort</th><th>Patient origin</th><th>CHBe+ NC</th><th>CHBe- NC</th><th>CHBe+/- CC</th></tr></thead><tbody><tr><td rowspan="2">30 y</td><td>European</td><td>132 - 355</td><td>143 - 461</td><td>15 - 45</td></tr><tr><td>Asian</td><td>85 - 212</td><td>92 - 296</td><td>14 - 46</td></tr><tr><td rowspan="2">40 y</td><td>European</td><td>65 - 184</td><td>75 - 240</td><td>15 - 47</td></tr><tr><td>Asian</td><td>51 - 126</td><td>58 - 157</td><td>13 - 45</td></tr><tr><td rowspan="2">50 y</td><td>European</td><td>28 - 97</td><td>38 - 145</td><td>16 - 47</td></tr><tr><td>Asian</td><td>23 - 75</td><td>32 - 101</td><td>15 - 46</td></tr><tr><td rowspan="2">60 y</td><td>European</td><td>31 - 110</td><td>39 - 156</td><td>16 - 52</td></tr><tr><td>Asian</td><td>28 - 83</td><td>37 - 119</td><td>15 - 50</td></tr></tbody></table>

In the modelled CHBe+ and CHBe- cohorts, tenofovir treatment nearly completely eliminates the occurrence of liver decompensation and roughly halves the incidence of HCC. Despite these dramatic clinical effects we find that the treatment is most probably not cost-effective over 10 or 20 years (Table 28) of follow-up, although the ICERs decrease with increasing time horizon. This contrasts with a more favourable ICER for antiviral treatment of patients with compensated liver cirrhosis (Table 26), where the clinical effects of treatment may be less dramatic but occur more in the short term. It seems to be of use to continue the research to identify CHB patients at high risk of disease progression who would benefit most from antiviral treatment. Variables that should be considered are the fibrosis stage, ALT, viral load and genotype.

The ICER of a continued and expensive treatment for the prevention of complications in the long term depends on a number of key variables. Chief are the time to complications which can be prevented, their frequency and cost as well as the annual cost of treatment. These considerations underline the importance of the selected transition probability to liver cirrhosis as an input variable for the Markov model.

The ICERs for CHBe+ and CHBe- cohorts are in general much higher than those reported in the literature thus far. We identified multiple variables in our model that may explain differences in reported ICERs.

We identified two variables in our base-case model that result in a lower ICER:

* For models with ongoing costs and benefits only in the long term the Belgian rules for discounting costs at 3% and effects at 1.5% result in more favourable ICERs when compared to discounting cost and effects equally at 3.5%, as is the case for the UK,⁵³ and as used in the publications we reviewed in the part I report.¹⁸⁻²⁶
* The cost induced by the management of complications (DC, HCC) depends mainly on the access to and cost of liver transplantation. Both are high in Belgium when compared to transition probabilities and costs used in models for other countries.

More variables in our base-case model result in a higher ICER:

* The annual cost of tenofovir (and entecavir) is high as compared with less expensive NAs studied in some previous models.

* All studies reviewed in part I assume a QoI improvement after treatment-induced HBeAg seroconversion or after a low level of HBV DNA. These assumptions were not based on any assessments in real patients. The utility values used for CHB and treatment-induced response are 0.69 and 0.78 in the model by Lacey et al.;²⁵ 0.95 and 1.00 in the model by Veenstra et al.;²⁴ 0.81 and 0.99 in the models using the study by Levy et al.¹⁸, ¹⁹, ⁴³ Dakin et al.⁵³ includes a utility improvement after e seroconversion (from 0.77 to 0.85) but not based on viral suppression. In that study, CHBe+ patients were not reported separately and constituted 44% of the CHB cohort.⁵³ It seems important to mention that to our knowledge no measurements of health utility in treatment responders have been reported to date, also not in the study of Levy et al.⁴³ One does not need a calculator to see that any antiviral treatment that costs 5000 euro per year will turn out to be cost-effective if such assumed improvement in utility of 0.18 is used for all patients who show a viral load decrease, independent of any long term effects. This assumption is however in contrast with the utility values we measured in patients with low and high HBV DNA levels under NA treatment.²⁷ Our findings restrict utility gains in our model to the reduction of disease complications.

* Point estimates of ICERs become more favourable if the time horizon is extended beyond 20 years, as done in a recent model on tenofovir.⁵³ Despite our efforts the documentation of the natural disease evolution of chronic hepatitis B is far from perfect to build a Markov model that covers the rest of the patient's life. Even more uncertain is the prediction of cost-effectiveness if one uses time horizons that are more than double the clinical treatment experience available today.

* Many published models use rather high transition probabilities to cirrhosis for CHBe+ and CHBe- and apply these uniformly across all age groups. The natural transition rates included in the models vary considerably between studies. For example, the natural transition rates from CHB to CC modelled for CHBe+ vary from 2.6%²⁵ to 4.4%¹⁸ or 5%.⁵³ In CHBe-, the rate varies from under 2%²⁰⁻²² or 2.9%¹⁹ based on REVEAL,⁵⁴, ⁵⁵ up to 9%.²⁴, ²⁵, ⁵³ Uniform high transition rates result in a higher proportion (about half) of CHB patients having liver cirrhosis compared with the situation observed in clinical practice, and as documented in the part I report. High transition rates also result in a higher frequency of complications and lower accumulated drug costs to prevent these. The net effect is a more favourable ICER, but such models do not reflect the reality of disease progression we measured. We were fortunate to get access to a large unpublished data set of 278 untreated Caucasian CHB patients with a mean follow-up of 7.8 years. The at risk person-years in our data set contributing to the estimation of transition rate to cirrhosis in Caucasians was 2.5 times higher for active CHBe+ patients (890 versus 347 person-years) and 7.5 times higher for CHBe- patients (672 versus 90 person-years) compared with the data sets included in a systematic review on natural disease progression.³² As a consequence of this rich data, our model is the first that includes age-specific transition probabilities for the development of liver cirrhosis in untreated CHB patients. This adjustment for patient age may seem obvious for hepatologists, but robust epidemiologic data were lacking so far. This adjustment also has additional implications: starting treatment at a more early age is no longer more cost-effective, whereas one would conclude the contrary without this adjustment, as was suggested recently in a US study recently.⁵⁶
* As we concluded in the part I report, many published Markov models of CHBe- disease do not follow international clinical guidelines as they do not continue NA treatment until liver transplant or lifelong. In these models treatment is discontinued in CHBe- when a low viral load is achieved for one year.⁵⁶ Some models in CHBe+ assume no disease reactivation (or no re-treatment after reactivation) after treatment-induced e seroconversion, and assume no additional liver related mortality once e seroconversion has been observed²³, ⁵⁷, ⁵⁸ in CHBe+ or a low DNA value is achieved in CHBe-.

* Some models assume very high treatment effects both for progression to cirrhosis and HCC calibrated using baseline viral load data obtained in the untreated REVEAL community cohort.⁵⁴, ⁵⁵ which mainly consisted of e antigen negative patients in Taiwan. It remains to be demonstrated that treatment induced lowering of viral load results in a long term HCC incidence reduction to a level that is identical to a natural state of low viral load. Extrapolating the reduction in progression to cirrhosis to the CHBe+ situation, as done in these models is even more questionable as in e positive CHB patients an inverse association between Metavir fibrosis stage and viral load was more recently reported in a hospital based study in Australia.⁵⁹

The effect of antiviral treatment on the development of HCC in CHB is still unclear and difficult to unravel from the fibrosis progression process. If one accepts that the presence of liver cirrhosis itself creates an increased risk of HCC, avoiding progression towards cirrhosis should also reduce HCC. In addition, there may be a direct effect of lowering viral load on HCC development, which we modelled in a conservative way. In contrast with some more recently published models, we did not define Markov states based on viral load because we do not feel confident with the data that feed such models, as discussed above. A recent report from Japan showed a similar high incidence of HCC under lamivudin or entecavir treatment of about 1% per year in 194 CHB NC patients and about 8% per year in 62 CHB CC patients, followed for an average of 4.25 years.⁶⁰ These data suggest that the HCC reduction (if any) due to antiviral treatment is minimal.

The assumed effect of antiviral treatment on HCC is of high importance for the Asian CHB populations which has reportedly a higher incidence of HCC compared with European patient cohorts. Treating Asian CHB patients thus results in slightly more favourable ICERs compared with European patient cohorts. It remains unclear to what extent data obtained in Asians living in Asia can be extrapolated to sub-Saharan African patients who migrated to Europe, and who constitute a growing proportion of the overall CHB patient population in Europe.

Finally, as the current annual cost of entecavir 0.5mg daily is higher compared with tenofovir, and the price decrease for tenofovir is expected earlier, the results cannot be extrapolated to entecavir. In addition, in patients infected with lamivudin resistant HBV, development of resistance to entecavir has been reported and this will also impact on the analyses. Of course, there are also other conditions whereby it may be more appropriate to use a specific NA. A cost-utility analysis should never be interpreted as a clinical practice guideline.
# 5 APPENDICES

## 5.1 NATURAL PROGRESSION TO LIVER CIRRHOSIS IN 278 CHRONIC HEPATITIS B PATIENTS OF EUROPEAN ORIGIN, THE IMPORTANCE OF AGE AND ELEVATED ALT

### 5.1.1 Introduction

In absence of robust data showing the extent to which complications of chronic hepatitis B (CHB) are reduced after antiviral treatment, cost-effectiveness models comparing antiviral treatment with a “do nothing” strategy may provide a look into the future but need to be interpreted with caution. In the case of chronic infections with the hepatitis B virus (HBV) the natural evolution of the disease is not perfectly documented, despite its relatively high prevalence. This natural history is important as model input. It defines the burden of disease under the “do nothing” strategy.

Natural disease progression data based on large cohorts of chronic hepatitis B patients have been reported only for regions in Asia.32 Higher natural annual transition rates to cirrhosis were reported for Europe but were based on very small patient numbers (3.8% for CHBe+, n=77, mean follow-up 4.5y; 9.7% for CHBe-, n=30, mean follow-up 3y).32

McMahon reported an overall transition probability from CHB to liver cirrhosis of 2 to 3% for clinic-based longitudinal studies, with older age, CHBe+ and high ALT as risk factors.30 To our knowledge no separate transition rates have been published based on age or ALT. The most detailed data documenting a steep increase of cirrhosis incidence after age 40 were reported for a cohort in Taiwan and obtained during the years following spontaneous e seroconversion.33

Hepatitis B e antigen positivity as a marker for an increased progression rate to liver cirrhosis is supported by some studies¹ but seems to be contradicted by the results of a systematic review.32

### 5.1.2 Aim

The aim of the study was to document the natural disease progression to liver cirrhosis and HCC in patients of European origin with e antigen positive or negative chronic hepatitis B.

### 5.1.3 Methods

Patient dossiers of the Hepatology department of the University Hospital of Leuven were manually screened for patients chronically infected with HBV.

Baseline data recorded included year of birth, gender, country of origin, year of diagnosis of CHB, ALT levels for the first three years after diagnosis, baseline liver ultrasound and biopsy results (Metavir coding was introduced more recently and was not performed for most, re-analysis is ongoing), HB e antigen status. Viral load and genotype data became available more recently, and these data have not yet been analyzed.

Dossiers of patients without liver cirrhosis at baseline and diagnosed as CHBe+ or CHBe- were checked for the year of occurrence of liver cirrhosis. A subgroup of these CHBe+ patients had normal ALT values for the first three years after diagnosis and was coded as CHBe+ with low activity. The year of start of antiviral treatment, diagnosis of HCC (without cirrhosis), death or lost to follow-up were also recorded as these data are used for censoring. CHBe+ patients who showed spontaneous e seroconversion (and transition to an inactive state) were not included in the dataset currently available for analysis.
Data were entered into Stata for calculation of transition rates. Note that for inclusion into a Markov model the here reported yearly transition rates are converted to yearly transition probabilities, using the following formula: transition probability = 1 - exp(-rate).

Separate analyses were performed for CHBe-, CHBe+ and CHBe+ normal ALT patients, and also based on patient age.

### 5.1.4 Results

<table><caption>Table 27. Patient characteristics at baseline, by patient group.</caption><thead><tr><th>Group</th><th>Patients (male/ female)</th><th>Mean age (y) at CHB diagnosis</th><th>Mean calendar year at CHB diagnosis</th></tr></thead><tbody><tr><td>CHBe+ normal ALT</td><td>59 (37/22)</td><td>34.5</td><td>1993</td></tr><tr><td>CHBe+</td><td>137(103/34)</td><td>41.6</td><td>1992</td></tr><tr><td>CHBe-</td><td>82(58/24)</td><td>39.2</td><td>1989</td></tr><tr><td>All</td><td>278 (198/80)</td><td>39.4</td><td>1991</td></tr></tbody></table>

<table><caption>Table 28. Observation period and cases of liver cirrhosis by patient group.</caption><thead><tr><th>Group</th><th>Patients</th><th>Mean follow-up in years for patients</th><th>Cases of liver cirrhosis</th><th>Mean time from CHB diagnosis to cirrhosis for cases (range)</th></tr></thead><tbody><tr><td>CHBe+ normal ALT</td><td>59</td><td>10.2</td><td>0</td><td>NA</td></tr><tr><td>CHBe+</td><td>137</td><td>6.5</td><td>23</td><td>7.8</td></tr><tr><td>CHBe-</td><td>82</td><td>8.2</td><td>29</td><td>7.4</td></tr><tr><td>All</td><td>278</td><td>7.8</td><td>52</td><td>7.4</td></tr></tbody></table>

<table><caption>Table 29. Reasons for censoring, analysis for progression from CHB to cirrhosis, by patient group.</caption><thead><tr><th rowspan="3">Group</th><th rowspan="3">Patients</th><th colspan="4">Observation period</th><th rowspan="3">Uncensored</th></tr><tr><th colspan="4">Censored because of</th></tr><tr><th>HCC</th><th>Death</th><th>Loss of follow-up</th><th>Start antiviral</th></tr></thead><tbody><tr><td>CHBe+ normal ALT</td><td>59</td><td>0</td><td>0</td><td>59</td><td>0</td><td>0</td></tr><tr><td>CHBe+</td><td>137</td><td>1</td><td>0</td><td>40</td><td>73</td><td>23</td></tr><tr><td>CHBe-</td><td>82</td><td>2</td><td>0</td><td>22</td><td>29</td><td>29</td></tr><tr><td>All</td><td>278</td><td>3</td><td>0</td><td>121</td><td>102</td><td>52</td></tr></tbody></table>

An overall transition rate of 2.4% per year from CHB to cirrhosis was found when all patients were grouped. Major differences are observed in the incidence of cirrhosis between CHBe+ patients with normal ALT (not a single case of progression to cirrhosis was seen) versus the two other 'active' CHB groups, where CHBe+ and CHBe- patients showed highly similar progression rates to liver cirrhosis.

Further analyses were performed based on patient age (below 40y, 40 to 49y, 50y+). For this analysis, transition rates are based on observation periods restricted to the age category being analyzed. A patient followed from age 44 to age 53 will thus contribute 5 observation years to the 40-49y category and 4 years to the 50+ category.
<table><caption>Table 30. Transition rate from CHB to cirrhosis by patient age (active CHBe+/- and normal ALT CHBe+ groups pooled).</caption><thead><tr><th>Age group in years</th><th>Observational periods</th><th>Time at risk in median years</th><th>Mean hazard rate in % (95% CI)</th></tr></thead><tbody><tr><td>Below 40</td><td>136</td><td>6.5</td><td>0.95 (0.51; 1.78)</td></tr><tr><td>40 to 49</td><td>112</td><td>4</td><td>1.86 (1.00; 3.43)</td></tr><tr><td>50 plus</td><td>131</td><td>4</td><td>4.84 (3.46; 6.77)</td></tr><tr><td>All</td><td>379*</td><td>6</td><td>2.40 (1.83; 3.13)</td></tr></tbody></table>

Note: *There are 192 patients falling into only one observational period, 71 patients being split into two periods and 15 patients being split into 3 periods. This totals 379 observational periods based on 278 patients.

The analysis clearly shows progression rates to cirrhosis that increase with patient age, and similar but somewhat higher progression rates were obtained when the normal ALT patient group was excluded from the analysis.

<table><caption>Table 31. Transition rates from CHB to cirrhosis by patient age, with or without inclusion of CHBe+ patients with normal ALT.</caption><thead><tr><th rowspan="2">Age group in years</th><th>CHBe+/ CHBe- group to cirrhosis excluding normal ALT patients</th><th>CHBe+/ CHBe- and CHBe+ with normal ALT to cirrhosis</th></tr><tr><th>Transition rate (95% CI)</th><th>Transition rate (95% CI)</th></tr></thead><tbody><tr><td>Below 40</td><td>1.41% (0.76; 2.62)</td><td>0.95% (0.51; 1.78)</td></tr><tr><td>40 to 49</td><td>2.49% (1.35; 4.58)</td><td>1.86% (1.00; 3.43)</td></tr><tr><td>50 plus</td><td>6.29% (4.49; 8.79)</td><td>4.84% (3.46; 6.77)</td></tr><tr><td>All</td><td>3.32% (2.55; 4.34%)</td><td>2.40% (1.83; 3.13)</td></tr></tbody></table>

In addition, using the same data set an overall transition rate of 0.115% (0.037% to 0.355%) per year to HCC was found in CHB patients.

### 5.1.5 Discussion and Conclusion

To our knowledge this is the largest data set of untreated Caucasian CHB patients monitored for disease progression. The at risk person-years in our data set contributing to the estimation of transition rate to cirrhosis in Caucasians was 2.5 times higher for active CHBe+ patients (890 versus 347 person-years) and 7.5 times higher for CHBe-patients (672 versus 90 person-years) compared with the data sets included in a systematic review on natural disease progression.³²

We show that 59 CHBe+ patients with normal ALT for at least three years do not show any measurable progression to cirrhosis and HCC within a mean follow-up period of 10 years.

Progression rates in persistent CHBe+ and CHBe- patients with elevated ALT were found to be virtually identical (3.3%) and lower than the rates reported in the systematic review (3.8% for CHBe+, 9.7% for CHBe-) and used in Markov models.

Our results represent however overestimations of the real transition rates as we only start the observation period the moment of the first visit to a university hospital, at a time the CHB was already ongoing for an unknown period. For our CHBe+ dataset patients who showed spontaneous seroconversion were not included. Inclusion of the CHBe+ period of these patients in the analysis would most probably have resulted in lower transition rates for CHBe+ patients.

Patient age was identified as a major determinant of progression rate to cirrhosis. The effect was nonlinear with a major increase in transition rate after age 50. Based on the results found and best available evidence we included in the model the following transition probabilities to cirrhosis for CHBe+ and CHBe-: 1% (0.5-1.5) per year if age < 40, 2% (1-3) for 40-49y, and 5%(2.5-7.5) for age>=50.
The observed transition rate of 0.115% (0.037% to 0.355%) to HCC in CHB patients was used in the model. It is at the low end of the published transition rates for studies in Europe and the US (0.12% to 0.41% per year). These studies were not restricted to Caucasian patients.³²

Further analysis of this unique data set based on baseline fibrosis stage, ALT, viral load and genotype could be of help to identify those patients at high risk of disease progression.

## 5.2 COMPARISON OF PUBLISHED QUALITY OF LIFE DATA

### 5.2.1 Aims

In the first part of this Hepatitis B project, prospective quality of life (QoL) data were collected in patients visiting their liver specialist in Belgium during the first half of 2009 for chronic HBV infection or a non-acute complication thereof. Five-hundred and twenty-seven (527) patients completed the EQ-5D QoL questionnaire. About two third of the patients were male and the mean age was 46 years. Half of the patients had a European origin (50.9%), 22.4% originated from Africa, 18.0% from Asia and 8.6% from Turkey.²⁷

QoL weights were computed based on social preference data collected in Flanders with the EQ-Visual Analogue Scale.⁶¹ Mean utility scores are reported in Table 32 below:

<table><caption>Table 32. Mean EQ-5D utility scores for CHB infection in Belgium (2009).</caption><thead><tr><td>Hepatitis B infection phase or complication</td><td>Mean utility score (Range 0-1)</td><td>95% confidence limit</td><td>Number of patients</td><td>Mean age (years)</td></tr></thead><tbody><tr><td>Immune tolerance phase</td><td>0.81</td><td>0.72 - 0.90</td><td>22</td><td>36.09</td></tr><tr><td>Inactive carrier phase</td><td>0.83</td><td>0.80 - 0.87</td><td>153</td><td>40.58</td></tr><tr><td>Immune reactive phase (HBeAg+)</td><td>0.82</td><td>0.77 - 0.87</td><td>78</td><td>43.10</td></tr><tr><td>HBeAg- chronic hepatitis B</td><td>0.82</td><td>0.78 - 0.86</td><td>127</td><td>45.70</td></tr><tr><td>Resolved phase (HBsAg-)</td><td>0.74</td><td>0.40 - 1.00</td><td>6</td><td>53.50</td></tr><tr><td>Compensated cirrhosis (CC)</td><td>0.78</td><td>0.73 - 0.84</td><td>69</td><td>53.36</td></tr><tr><td>Decompensated cirrhosis (DC)</td><td>0.70</td><td>0.17 - 1.00</td><td>2</td><td>45.50</td></tr><tr><td>Hepatocellular carcinoma (HCC)</td><td>0.67</td><td>0.44 - 0.90</td><td>10</td><td>60.60</td></tr><tr><td>Post-liver transplant (LT)</td><td>0.82</td><td>0.75 - 0.88</td><td>60</td><td>59.10</td></tr></tbody></table>

Mean utility scores for patients in the phases of immune tolerance, inactive carrier, immune reactive and HBeAg- CHB were very similar, in the 0.81 to 0.83 range. Also patients having received a LT had on average a utility score of 0.82. Average utility scores were slightly lower in CC (0.78), in DC (n=2: 0.66 and 0.75) and in HCC (0.67). The mean utility score was only 0.74 in 6 HBsAg- patients without cirrhosis. It was 0.80 in the subgroup analysis of 102 patients without cirrhosis responding to NA antiviral treatment with a DNA level under 2000 IU/mL. No major differences were seen between the overall results and those for patients of European origin.

The aim of this section is to identify QOL weights for different health states associated with CHB in the literature and to compare them with our findings. This comparison should allow to identify the most appropriate and robust QoL data to feed our economic model.
## 5.2.2 Methods

### 5.2.2.1 Literature search strategy

Electronic databases were consulted for original publications on the quality of life estimates for each health state associated with chronic hepatitis B. Systematic searches were carried out up to October 2010 in the following databases: Medline(OVID), Embase and PsycINFO. Searches using various qualifier for "quality of life" were used as Subject heading or as text word (See tables below).

<table><caption>Table 33. Search strategy and results for Medline(OVID).</caption><tr><td>Date</td><td colspan="3">6/10/2010</td></tr><tr><td>Database</td><td colspan="3">Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations and Ovid MEDLINE(R)</td></tr><tr><td>Date covered</td><td colspan="3">1950 to Present</td></tr><tr><td>Search strategy</td><td>#</td><td>Searches</td><td>Results</td></tr><tr><td></td><td>1</td><td>"Quality of Life"/</td><td>85819</td></tr><tr><td></td><td>2</td><td>"Value of Life"/</td><td>5147</td></tr><tr><td></td><td>3</td><td>Quality-Adjusted Life Years/</td><td>4630</td></tr><tr><td></td><td>4</td><td>qol$.tw.</td><td>12361</td></tr><tr><td></td><td>5</td><td>hrqol$.tw.</td><td>4275</td></tr><tr><td></td><td>6</td><td>qaly$.tw.</td><td>3224</td></tr><tr><td></td><td>7</td><td>(quality adj 1 life).tw.</td><td>2661</td></tr><tr><td></td><td>8</td><td>1 or 2 or 3 or 4 or 5 or 6 or 7</td><td>98319</td></tr><tr><td></td><td>9</td><td>exp Hepatitis B/</td><td>39236</td></tr><tr><td></td><td>10</td><td>8 and 9</td><td>114</td></tr></table>

<table><caption>Table 34. Search strategy and results for Embase.</caption><tr><td>Date</td><td colspan="3">06/10/2010</td></tr><tr><td>Database</td><td colspan="3">Embase</td></tr><tr><td>Date covered</td><td colspan="3">No restrictions</td></tr><tr><td>Search strategy</td><td>#</td><td>Searches</td><td>Results</td></tr><tr><td></td><td>#1</td><td>'quality of life'/exp</td><td>159850</td></tr><tr><td></td><td>#2</td><td>qol$:ab,ti</td><td>15854</td></tr><tr><td></td><td>#3</td><td>qaly$:ab,ti</td><td>3241</td></tr><tr><td></td><td>#4</td><td>hrqol$:ab,ti</td><td>5055</td></tr><tr><td></td><td>#5</td><td>'hepatitis b'/exp/mj</td><td>33904</td></tr><tr><td></td><td>#6</td><td>'hepatitis b virus'/exp/mj</td><td>15458</td></tr><tr><td></td><td>#7</td><td>#1 OR #2 OR #3 OR #4</td><td>161906</td></tr><tr><td></td><td>#8</td><td>#5 OR #6</td><td>45353</td></tr><tr><td></td><td>#9</td><td>#7 AND #8</td><td>173</td></tr></table>
<table><caption>Table 35. Search strategy and results for PsycINFO(OVID).</caption><thead><tr><th>Date</th><td colspan="3">6/10/2010</td></tr><tr><th>Database</th><td colspan="3">PsycINFO</td></tr><tr><th>Date covered</th><td colspan="3">1806 to September Week 4 2010</td></tr><tr><th>Search strategy</th><th>#</th><th>Searches</th><th>Results</th></tr></thead><tbody><tr><td></td><td>1</td><td>"Quality of Life"/</td><td>18091</td></tr><tr><td></td><td>2</td><td>"Value of Life"/</td><td>0</td></tr><tr><td></td><td>3</td><td>Quality-Adjusted Life Years/</td><td>0</td></tr><tr><td></td><td>4</td><td>qol$.tw.</td><td>3922</td></tr><tr><td></td><td>5</td><td>hrqol$.tw.</td><td>1324</td></tr><tr><td></td><td>6</td><td>qaly$.tw.</td><td>384</td></tr><tr><td></td><td>7</td><td>(quality adj 1 life).tw.</td><td>889</td></tr><tr><td></td><td>8</td><td>1 or 2 or 3 or 4 or 5 or 6 or 7</td><td>18997</td></tr><tr><td></td><td>9</td><td>exp *hepatitis/</td><td>1104</td></tr><tr><td></td><td>10</td><td>8 and 9</td><td>50</td></tr><tr><td></td><td>11</td><td>(hepatitis adj c).ti.</td><td>559</td></tr><tr><td></td><td>12</td><td>10 NOT 11</td><td>5</td></tr></tbody></table>

### 5.2.2.2 Selection criteria

Identified references were assessed against pre-defined selection criteria (in terms of population, intervention, outcome and design - Table 36) in a two-step procedure: initial assessment of the title, abstract and keywords; followed by full-text assessment of the selected references. When no abstract was available and the citation was unclear or ambiguous, the citation was assessed on the basis of keywords and full-text assessments. Reference lists of the selected studies were checked for additional relevant citations.

<table><caption>Table 36. Article selection criteria.</caption><thead><tr><th></th><th>Inclusion criteria</th><th>Exclusion criteria</th></tr></thead><tbody><tr><th>Population</th><td>Hepatitis B patients</td><td>Hepatitis C patients...</td></tr><tr><th>Intervention</th><td>Medical therapy, vaccination, screening...</td><td>Not applicable</td></tr><tr><th>Outcome</th><td>Unique QoL utility values per health states</td><td>Multi-dimensions HRQoL scores, DALYs...</td></tr><tr><th>Design</th><td>Direct (TTO, SG...) or indirect (generic instruments) valuation methods in primary studies or in cost-utility analyses</td><td>Letters...</td></tr></tbody></table>

### 5.2.2.3 Selection process

The flowchart of the selection process is presented below. The searches on the databases and local HTA websites returned 292 citations. After exclusion of 94 duplicates, 198 unique citations were left. A study identified on the early e-publications of a journal was further added,⁵³ summing up to a total of 199 unique citations. Ninety-six (96) references were discarded based on their title and abstract, leaving 103 references for full-text evaluations. Another 93 references were excluded at this stage, mostly because the unmet design criteria. Many excluded studies were cost-utility analyses of interventions against hepatitis B (screening, medication, vaccination), in which utility values were not calculated as such but selected from the literature. Ten studies were left that analysed QoL utilities for chronic hepatitis B patients.⁴³, ⁶²-⁷⁰
<figure><img src="image_24.png" /><figcaption>Figure 20. Flowchart of the selection process for QoL studies.</figcaption></figure>

### 5.2.3 Results

Utility values computed for different chronic hepatitis B health stages are reported in Table 37 below. There appear to be great diversity in the values reported per health state. The most recent studies derived utilities from the patients themselves.
<table><caption>Table 37. Quality of life of CHB patients: review of the literature (Primary studies).</caption><thead><tr><th>Study</th><th>Country</th><th>Tool</th><th>Population</th><th>Mean age (SD)</th><th>N</th><th>Value</th><th>CHB</th><th>CC</th><th>DC</th><th>HCC</th><th>LT</th><th>PLT</th><th>ICAR</th></tr></thead><tbody><tr><td rowspan="3">KCE, 2010</td><td rowspan="3">Belgium¹</td><td rowspan="3">EQ-5D</td><td rowspan="3">CHB patients</td><td rowspan="3">46</td><td rowspan="3">421</td><td>Mean</td><td>0.82</td><td>0.78</td><td>0.70</td><td>0.67</td><td>-</td><td>0.82</td><td>0.83</td></tr><tr><td>95% CI</td><td>0.78-0.86</td><td>0.73-0.84</td><td>0.17-1</td><td>0.44-0.90</td><td>-</td><td>0.75-0.88</td><td>0.80-0.87</td></tr><tr><td>N</td><td>127</td><td>69</td><td>2</td><td>10</td><td>-</td><td>60</td><td>153</td></tr><tr><td rowspan="3">Lam et al., 2009<sup>66</sup></td><td rowspan="3">China</td><td rowspan="3">SF-6D</td><td rowspan="3">CHB patients</td><td rowspan="3">50.4 (12.3)</td><td rowspan="3">520</td><td>Mean</td><td>0.75</td><td>0.70<sup>7</sup></td><td></td><td>0.72</td><td>-</td><td>-</td><td>0.75</td></tr><tr><td>SD</td><td>0.15</td><td>0.15<sup>7</sup></td><td></td><td>0.16</td><td>-</td><td>-</td><td>0.14</td></tr><tr><td>N</td><td>102</td><td>139<sup>7</sup></td><td></td><td>123</td><td>-</td><td>-</td><td>156</td></tr><tr><td rowspan="3">Ong et al., 2008<sup>67</sup></td><td rowspan="3">China</td><td rowspan="3">EQ-5D</td><td rowspan="3">CHB patients</td><td rowspan="3">46.2 (12.9)</td><td rowspan="3">432</td><td>Median</td><td>1</td><td>1</td><td>0.85</td><td>0.83</td><td>-</td><td>0.85</td><td>1</td></tr><tr><td>25-75<sup>th</sup> %</td><td>0.85-1</td><td>0.85-1</td><td>0.76-1</td><td>0.73-1</td><td>-</td><td>0.77-1</td><td>1-1</td></tr><tr><td>N</td><td>142</td><td>66</td><td>24</td><td>22</td><td>-</td><td>22</td><td>156</td></tr><tr><td rowspan="3">Levy et al., 2008<sup>43</sup></td><td rowspan="3">ALL</td><td rowspan="3">SG</td><td rowspan="3">CHB patients</td><td rowspan="3">45.5 (13.1)</td><td rowspan="3">534</td><td>Mean</td><td>0.68</td><td>0.69</td><td>0.35</td><td>0.38</td><td>0.57</td><td>0.67</td><td>-</td></tr><tr><td>95% CI</td><td>0.66-0.70</td><td>0.66-0.71</td><td>0.32-0.37</td><td>0.36-0.41</td><td>0.54-0.60</td><td>0.64-0.69</td><td>-</td></tr><tr><td>N</td><td>225</td><td>98</td><td>49</td><td>56</td><td>50</td><td>39</td><td>-</td></tr><tr><td rowspan="6">Bondini et al., 2007<sup>63</sup></td><td rowspan="6">USA<sup>2</sup></td><td rowspan="6">HUI Mark-2</td><td rowspan="6">CHB patients</td><td rowspan="6">44,2 (12.9)</td><td rowspan="6">68</td><td>Mean</td><td>0.52</td><td>0.57</td><td>0.26</td><td>0.31</td><td>0.41</td><td>0.55</td><td>-</td></tr><tr><td>SD</td><td>0.60</td><td>0.64</td><td>0.30</td><td>0.38</td><td>0.56</td><td>0.64</td><td>-</td></tr><tr><td>N</td><td>0.66</td><td>0.65</td><td>0.44</td><td>0.46</td><td>0.58</td><td>0.64</td><td>-</td></tr><tr><td>Mean</td><td>0.67</td><td>0.66</td><td>0.37</td><td>0.43</td><td>0.57</td><td>0.64</td><td>-</td></tr><tr><td>SD</td><td>0.20</td><td>0.10<sup>7</sup></td><td></td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td>N</td><td>0.78</td><td>0.81<sup>7</sup></td><td></td><td>-</td><td>-</td><td>-</td><td>-</td></tr><tr><td rowspan="3">Pwu et al., 2002<sup>69</sup></td><td rowspan="3">Taiwan</td><td rowspan="3">TTO</td><td>Clinicians</td><td>-</td><td>12</td><td>Median</td><td>0.95</td><td>0.90</td><td>0.65</td><td>0.50</td><td>-</td><td>-</td><td>1</td></tr><tr><td rowspan="2">CHB patients</td><td rowspan="2">Not stated</td><td rowspan="2">53</td><td>Range</td><td>0.9-1</td><td>0.8-0.95</td><td>0.50-0.8</td><td>0.33-0.75</td><td>-</td><td>-</td><td>0.95-1</td></tr><tr><td>N</td><td>20</td><td>20<sup>7</sup></td><td></td><td>1</td><td>-</td><td>-</td><td>12</td></tr><tr><td>Aggrawal et al., 2002<sup>62</sup></td><td>India</td><td>Expert opinion</td><td>Clinicians</td><td>-</td><td>-</td><td>Estimate</td><td>0.95</td><td>0.90</td><td>0.50</td><td>0.50</td><td>-</td><td>-</td><td>-</td></tr><tr><td>Crowley et al., 2000<sup>64</sup></td><td>Australia</td><td>AQOL</td><td>Clinicians</td><td>-</td><td>4</td><td>Estimate</td><td>0.69</td><td>0.56</td><td>0.15</td><td>0.12</td><td>-</td><td>-</td><td>0.78</td></tr><tr><td>Owens et al., 1997<sup>68</sup></td><td>USA</td><td>TTO</td><td>Clinicians</td><td>-</td><td>128</td><td>Mean</td><td>0.812 (SD=0,021)</td><td>HBV asymptomatic state<sup>4</sup></td><td>0.670 (SD=0,023)</td><td>HBV mildly symptomatic state<sup>5</sup></td><td></td><td></td><td></td></tr></tbody></table>
<table><thead><tr><th>Study</th><th>Country</th><th>Tool</th><th>Population</th><th>Mean age (SD)</th><th>N</th><th>Value</th><th>CHB</th><th>CC</th><th>DC</th><th>HCC</th><th>LT</th><th>PLT</th><th>ICAR</th></tr></thead><tbody><tr><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td colspan="6">0.218 (SD=0,021) HBV severely symptomatic state <sup>6</sup></td></tr><tr><td>Wong et al., 1995<sup>70</sup></td><td>USA</td><td>TTO & SG</td><td>Clinicians</td><td>-</td><td>7</td><td>Mean</td><td>0.94</td><td>0.92</td><td>0.54</td><td>0.49</td><td>-</td><td>-</td><td>0.99</td></tr><tr><td>Dusheiko et al., 1995<sup>65</sup></td><td>UK</td><td>Expert opinion</td><td>Clinicians</td><td>-</td><td>-</td><td>Estimate</td><td>0.80</td><td>0.50</td><td>0.20</td><td>0.20</td><td>-</td><td>-</td><td>0.90</td></tr></tbody></table>

CHB=Chronic hepatitis B; CC=Compensated cirrhosis; DC=Decompensated cirrhosis; HCC=Hepatocellular carcinoma; LT=Liver transplant; PLT=Post-liver transplant; ICAR=Inactive carrier; AQOL=Assessment of quality of life; SG=Standard gamble, TTO=Time trade-off.

I=50,9% Europe; 8,6% Turkey; 22,4% Africa; 18% Asia. 2=59% Asian American; 16% White; 25% Other. 3=Self computation. 4=defined as being asymptomatic, but with the potential to transmit the disease. 5=defined as mild fatigue and malaise that did not interfere with work. 6=defined as cirrhosis, ascites and gastrointestinal bleeding. 7= there is no distinction between compensated and decompensated cirrhoses.
## 5.3 DISEASE MANAGEMENT COSTS

### LIST OF ABBREVIATIONS

<table><thead><tr><td>Abbreviation</td><td>Description English</td><td>Dutch</td><td>Dutch description</td><td>French</td><td>French description</td></tr></thead><tbody><tr><td>ATC</td><td>Anatomical Therapeutic Chemical Classification System used for the classification of drugs</td><td>ATC</td><td>Anatomisch Therapeutisch Chemisch Classificatie Systeem voor geneesmiddelen</td><td>ATC</td><td>Système de Classification Anatomique, Thérapeutique et Chimique</td></tr><tr><td>BCPI</td><td>Belgian Centre for Pharmaceutical Information</td><td>BCFI</td><td>Belgisch Centrum voor Farmacotherapeutische Informatie</td><td>CBIP</td><td>Centre Belge d'Information Pharmacothérapeutique</td></tr><tr><td>BFM</td><td>Budget Financial Means (for hospitals)</td><td>BFM</td><td>Budget Fianciële Middelen voor de ziekenhuizen</td><td>BMF</td><td>Budget Moyens Financiers des hôpitaux</td></tr><tr><td>CBSS</td><td>Crossroads Bank for Social Security</td><td>KSZ</td><td>Kruispunt bank Sociale Zekerheid</td><td>BCSS</td><td>Banque Carrefour Sécurité Sociale</td></tr><tr><td>CNK</td><td>National (unique) code for pharmaceuticals</td><td>CNK</td><td>Nationale (unieke) kode voor geneesmiddelen</td><td>CNK</td><td>Code national (unique) pour les produits pharmaceutiques</td></tr><tr><td>DDD</td><td>Defined Daily Dose for an average adult of 70 Kgs.</td><td>DDD</td><td>Gedefinieerde dagdoses voor een gemiddelde volwassene van 70 Kg.</td><td>DDD</td><td>Dose quotidienne définie pour un adulte moyen pesant 70 kilos</td></tr><tr><td>DPP</td><td>DDD per package</td><td>DPP</td><td>Aantal DDD per farmaceutische verpakking-</td><td>DPP</td><td>Nombre de DDD par conditionnement pharmaceutique</td></tr><tr><td>EF</td><td>Extrapolation Factor</td><td>EF</td><td>Extrapolatie Factor</td><td>FE</td><td>Facteur d'extrapolation</td></tr><tr><td>ETL</td><td>Extraction, Transformation and Loading (of data)</td><td>ETL</td><td>Extractie, transformation en inladen van database gegevens</td><td>ETL</td><td>Extraction, transformation et intégration de données dans une base de données commune</td></tr><tr><td>EXC</td><td>Cost class excluded for cost study</td><td>EXC</td><td>Kostencategorie uitgesloten voor kostenstudie</td><td>EXC</td><td>Catégorie de dépenses exclue de l'étude coût</td></tr><tr><td>FAMHP</td><td>Federal Agency for Medicines and Health Products</td><td>FAGG</td><td>Federaal Agentschap voor Geneesmiddelen en Gezondheidsproducten</td><td>AFMPS</td><td>Agence Fédérale des Médicaments et des Produits de Santé</td></tr><tr><td>FTU</td><td>Full Time (personel) Units</td><td>VTE</td><td>Voltijdse Eenheid</td><td>UTP</td><td>Unité Temps Plein</td></tr><tr><td>GP</td><td>General practitioner</td><td>HA</td><td>Huisarts</td><td>MG</td><td>Médecin généraliste</td></tr><tr><td>HBc</td><td>Hepatitis B core antigen</td><td>HBc</td><td>Hepatitis B kern antigen</td><td>HBc</td><td>L'antigène du noyau du virus de l'hépatite B</td></tr><tr><td>HBe</td><td>Hepatitis B e-antigen, associated with the viral nucleocapsid</td><td>Hbe</td><td>Hepatitis B e-antigeen, geassocieerd met het virale nucleocapside</td><td>Hbe</td><td>Antigène 'e' de l'hépatite B, associé au nucléocapside viral</td></tr></tbody></table>
<table><thead><tr><td>Abbreviation</td><td>Description English</td><td>Dutch</td><td>Dutch description</td><td>French</td><td>French description</td></tr></thead><tbody><tr><td>HBs</td><td>Hepatitis B surface (antigen / antibodies)</td><td>HBs</td><td>Hepatitis B oppervlakte (virale membraan) antigen</td><td>HBs</td><td>L'antigène de surface (membrane virale) de l'hépatite B</td></tr><tr><td>HBV</td><td>Hepatitis B virus related disease</td><td>HBV</td><td>Hepatitis B virus geassocieerd lijden</td><td>VHB</td><td>Maladie associée au virus de l'hépatite B</td></tr><tr><td>HCC</td><td>Hepatocellular Carcinoma</td><td>HCC</td><td>Hepatocellular carcinoma</td><td>CHC</td><td>Carcinome hépatocellulaire</td></tr><tr><td>HDI</td><td>Health and Disability Insurance</td><td>ZIV</td><td>Ziekte- en InvaliditeitsVerzekering</td><td>AMI</td><td>Assurance Maladie Invalidité</td></tr><tr><td>HIC</td><td>Health insurance company (7 national)</td><td>VI</td><td>Verzekeringsinstelling en (7 nationaal)</td><td>OA</td><td>Organismes assureurs (7 sur le plan national)</td></tr><tr><td>HIV</td><td>Human Immunodeficiency Virus (associated with AIDS = acquired immunodeficiency syndrome)</td><td>HIV</td><td>Humaan Immunodeficiëntie Virus (geassocieerd met AIDS = verworven immunodeficiëntie syndroom)</td><td>VIH</td><td>Virus de l'immunodéficience humaine (associé au SIDA = syndrome de l'immunodéficience acquise)</td></tr><tr><td>IMA</td><td>Intermutualistic Agency</td><td>IMA</td><td>Intermutualistisch agentschap</td><td>AIM</td><td>Agence Inter mutualiste</td></tr><tr><td>MCR</td><td>Minimal Clinical records</td><td>MKG</td><td>Minimale Klinische Gegevens</td><td>RCM</td><td>Résumé Clinique Minimum</td></tr><tr><td>MI</td><td>Medical imaging</td><td>MBV</td><td>Medische BeeldVorming</td><td>IM</td><td>Imagerie Médicale</td></tr><tr><td>nHBV</td><td>Not Hepatitis B virus related disease</td><td>nHBV</td><td>Niet hepatitis B virus geassocieerd lijden</td><td>nVHB</td><td>Maladie non associée au virus de l'hépatite B</td></tr><tr><td>NIHDI</td><td>National Institute for Health and Disability Insurance</td><td>RIZIV</td><td>Rijksinstituut voor ziekte- en invaliditeitsverzekerings</td><td>INAMI</td><td>Institut National d'Assurance Maladie et Invalidité</td></tr><tr><td>PAT</td><td>Costs related to 'compulsory patient contribution' regulations (paid by the patient himself)</td><td>PAT</td><td>Officiële remgelden voor de patiënt</td><td>PAT</td><td>Coûts patients de ticket modérateur</td></tr><tr><td>PH</td><td>Pharmanet data</td><td>PH</td><td>Farmanet gegevens</td><td>PH</td><td>Données Pharmanet</td></tr><tr><td>POP</td><td>Population data (demographic and concerning social security status of patients)</td><td>POP</td><td>Demografische en sociale zekerheidsgegevens van de patiënt</td><td>POP</td><td>Données démographiques et du statut sécurité sociale du patient</td></tr><tr><td>SOC</td><td>Social security compensations for families with low tax income</td><td>SOC</td><td>Compensaties in de sociale zekerheid voor lage gezinsinkomens (MAF)</td><td>SOC</td><td>Compensations de la sécurité sociale pour familles à bas revenu net imposable (MAF)</td></tr><tr><td>SS</td><td>Data of health care services delivered to patients (IMA)</td><td>SS</td><td>Gezondheidszorggegevens van de patiënt (IMA)</td><td>SS</td><td>Données des soins de santé du patient (AIM)</td></tr><tr><td>SSN</td><td>Social security number</td><td>INSZ</td><td>Inschrijvingsnummer sociale zekerheid</td><td>NISS</td><td>Numéro d'inscription sécurité sociale</td></tr></tbody></table>
<table><thead><tr><td>Abbreviation</td><td>Description English</td><td>Dutch</td><td>Dutch description</td><td>French</td><td>French description</td></tr></thead><tbody><tr><td>SWOT</td><td>Strengths, Weaknesses, Opportunities, Threats</td><td>SWOT</td><td>Sterktezwakteanalyse (een bedrijfskundig model)</td><td>AFOM</td><td>Atouts, Faiblesses, Opportunités, Menaces</td></tr><tr><td>TTP</td><td>Trusted Third Party</td><td>TTP</td><td>Intermédiaire vertrouwensorganisation</td><td>TTP</td><td>Organisation intermédiaire de confiance</td></tr><tr><td>UD</td><td>Unit dose (for hospital pharmaceuticals)</td><td>UD</td><td>Eenheidsdosis (ziekenhuismedicatie)</td><td>DU</td><td>Dose unité (conditionnements pharmaceutiques en milieu hospitalier)</td></tr></tbody></table>

## 5.3.1 Data sources

### 5.3.1.1 Field survey by Belgian hepatologists

Pre-specified data from 554 patients were collected in 18 Belgian hepatology centres, during a routinely planned visit within a six months study period (January 2009 to end of June 2009). Three patients were found to be not eligible and their data were excluded from the study, leaving the remaining 551 patients for inclusion. If available at the centre, the 2006 data were collected from the medical records.

No direct identification data were collected except for the patient's social security number (INSZ-NISS), whenever available. Data, with a unique patient number assigned to each patient, were entered in a MS Access database (Table 38) by the contracted TTPª (Trusted Third Party). Social security numbers (INSZ-NISS) were enciphered and a list of the original numbers was transferred to the TTPᵇ of the national Intermutualistic Agency (IMA) for linkage to individual healthcare consumption data of 2006 (compulsory health and disability insurance, governed by NIHDI).

<table><caption>Table 38. Layout of VEEDACR database</caption><thead><tr><td>Field name</td><td>Description</td><td>Values</td></tr></thead><tbody><tr><td>ADEF1</td><td>Adefovir in 2006</td><td>1=ticked</td></tr><tr><td>ADEF2</td><td>Adefovir in 2009</td><td>1=ticked</td></tr><tr><td>Age</td><td>Age in years</td><td></td></tr><tr><td>Antivir06</td><td>Antiviral pharmaceuticals in 2006</td><td></td></tr><tr><td>Antivir09</td><td>Antiviral pharmaceuticals in 2009</td><td></td></tr><tr><td>Avir09</td><td></td><td></td></tr><tr><td>AVMEDO1</td><td>Other medication in 2006</td><td></td></tr><tr><td>AVMEDO2</td><td>Other medication in 2009</td><td></td></tr><tr><td>B</td><td>Belgian citizenship</td><td></td></tr><tr><td>CCIRR1</td><td>Compensated cirrhosis in 2006</td><td>1=ongoing; 2=new diagnosis</td></tr><tr><td>CCIRR2</td><td>Compensated cirrhosis in 2009</td><td>1=ongoing; 2=new diagnosis</td></tr><tr><td>ChepB</td><td>Patient_ID</td><td></td></tr><tr><td>CHEPB1</td><td>Chronic hepatitis B in 2006</td><td>1=ongoing; 2=new diagnosis</td></tr><tr><td>CHEPB2</td><td>Chronic hepatitis B in 2009</td><td>1=ongoing; 2=new diagnosis</td></tr><tr><td>COUNTRY</td><td>Country of origin</td><td></td></tr><tr><td>CVIS</td><td>Current visit</td><td>1=yes; 0=no</td></tr><tr><td>DATAI</td><td>2006 data available</td><td>1=yes; 0=no</td></tr><tr><td>DBY</td><td>Birth year</td><td></td></tr><tr><td>DCIRR1</td><td>Decompensated cirrhosis in 2006</td><td>1=ongoing; 2=new diagnosis</td></tr><tr><td>DCIRR2</td><td>Decompensated cirrhosis in 2009</td><td>1=ongoing; 2=new diagnosis</td></tr><tr><td>DCOMPD</td><td>IC & QoL completed, day</td><td></td></tr><tr><td>DCOMPM</td><td>IC & QoL completed, month</td><td></td></tr><tr><td>DCOMPY</td><td>IC & QoL completed, year</td><td></td></tr></tbody></table>

<footnote>a VeedaCR nv/sa, Brussels, a contract research organisation</footnote>

<footnote>b At that time: IBM Belgium nv/sa</footnote>
<table><thead><tr><td>Field name</td><td>Description</td><td>Values</td></tr></thead><tbody><tr><td>DFSY</td><td>Fibro scan score, year tested</td><td>(-1=unknown)</td></tr><tr><td>DHBVY</td><td>HBV genotype, year tested</td><td>(-1=unknown)</td></tr><tr><td>DMFSY</td><td>Liver biopsy Metavir fibrosis score, year tested</td><td>(-1=unknown)</td></tr><tr><td>DNA06</td><td>DNA quantity in 2006</td><td></td></tr><tr><td>DNA09</td><td>DNA quantity in 2009</td><td></td></tr><tr><td>DNAA1</td><td>DNA > 10 000 copies/ml or 2 000 IU/ml in 2006</td><td>1; 0=negative; -1=unknown</td></tr><tr><td>DNAA2</td><td>DNA > 10 000 copies/ml or 2 000 IU/ml in 2009</td><td>1= pos; 0=negative; -1=unknown</td></tr><tr><td>DNAB1</td><td>DNA > 100 000 copies/ml or 20 000 IU/ml in 2006</td><td>1= pos; 0=negative; -1=unknown</td></tr><tr><td>DNAB2</td><td>DNA > 100 000 copies/ml or 20 000 IU/ml in 2009</td><td>1= pos; 0=negative; -1=unknown</td></tr><tr><td>ENTEC1</td><td>Entecavir in 2006</td><td>1=ticked</td></tr><tr><td>ENTEC2</td><td>Entecavir in 2009</td><td>1=ticked</td></tr><tr><td>EU</td><td>Other EU citizenship</td><td></td></tr><tr><td>flag</td><td>VEEDACR internal flag</td><td></td></tr><tr><td>FS</td><td>Fibroscan score</td><td>Range 0-99</td></tr><tr><td>GCOM1</td><td>General comment1</td><td></td></tr><tr><td>GCOM2</td><td>General comment2</td><td></td></tr><tr><td>GCOM3</td><td>General comment3</td><td></td></tr><tr><td>HBEAB1</td><td>HBE Antibody in 2006</td><td>1= pos; 0=negative; -1=unknown</td></tr><tr><td>HBEAB2</td><td>HBE Antibody in 2009</td><td>1= pos; 0=negative; -1=unknown</td></tr><tr><td>HBEAG1</td><td>HBE Antigen in 2006</td><td>1= pos; 0=negative; -1=unknown</td></tr><tr><td>HBEAG2</td><td>HBE Antigen in 2009</td><td>1= pos; 0=negative; -1=unknown</td></tr><tr><td>HBSAB1</td><td>HBS Antibody in 2006</td><td>1= pos; 0=negative; -1=unknown</td></tr><tr><td>HBSAB2</td><td>HBS Antibody in 2009</td><td>1= pos; 0=negative; -1=unknown</td></tr><tr><td>HBSAG1</td><td>HBS Antigen in 2006</td><td>1= pos; 0=negative; -1=unknown</td></tr><tr><td>HBSAG2</td><td>HBS Antigen in 2009</td><td>1= pos; 0=negative; -1=unknown</td></tr><tr><td>HBV</td><td>HBV genotype</td><td></td></tr><tr><td>HCC1</td><td>Hepatocellular CA in 2006</td><td>1=ongoing; 2=new diagnosis</td></tr><tr><td>HCC2</td><td>Hepatocellular CA in 2009</td><td>1=ongoing; 2=new diagnosis</td></tr><tr><td>IA1</td><td>Interferon alpha in 2006</td><td>1=ticked</td></tr><tr><td>IA2</td><td>Interferon alpha in 2009</td><td>1=ticked</td></tr><tr><td>ICAR1</td><td>Inactive carrier in 2006</td><td>1=ongoing; 2=new diagnosis</td></tr><tr><td>ICAR2</td><td>Inactive carrier in 2009</td><td>1=ongoing; 2=new diagnosis</td></tr><tr><td>INSZ</td><td>INSZ / NISS</td><td></td></tr><tr><td>ITOL1</td><td>Immune intolerance in 2006</td><td>1=ongoing; 2=new diagnosis</td></tr><tr><td>ITOL2</td><td>Immune intolerance in 2009</td><td>1=ongoing; 2=new diagnosis</td></tr><tr><td>LAMIV1</td><td>Lamuvidin in 2006</td><td>1=ticked</td></tr><tr><td>LAMIV2</td><td>Lamuvidin in 2009</td><td>1=ticked</td></tr><tr><td>LTR1</td><td>Liver transplant in 2006</td><td>1=ongoing; 2=new diagnosis</td></tr><tr><td>LTR2</td><td>Liver transplant in 2009</td><td>1=ongoing; 2=new diagnosis</td></tr><tr><td>MFS</td><td>Liver biopsy Metavir fibrosis score</td><td>Range 0-4</td></tr><tr><td>NOINS</td><td>No other insurance</td><td></td></tr><tr><td>NONE1</td><td>No antiviral medication in 2006</td><td>1=ticked</td></tr><tr><td>NONE2</td><td>No antiviral medication in 2009</td><td></td></tr><tr><td>NONEU</td><td>Non EU citizenship</td><td></td></tr><tr><td>OINS</td><td>Other insurance</td><td></td></tr><tr><td>Orig</td><td>Continent of origin</td><td></td></tr><tr><td>PEGIA1</td><td>PEG Interferon alpha in 2006</td><td>1=ticked</td></tr><tr><td>PEGIA2</td><td>PEG Interferon alpha in 2009</td><td>1=ticked</td></tr><tr><td>SEX</td><td>Sex</td><td>1=Male / 2=Female</td></tr><tr><td>Sex01</td><td>Sex code</td><td>0 = female; 1 = male</td></tr><tr><td>SexLabel</td><td>Label sex code</td><td></td></tr><tr><td>SIGN</td><td>Signed</td><td>1=OK</td></tr><tr><td>TENOF1</td><td>Tenofovir in 2006</td><td>1=ticked</td></tr><tr><td>TENOF2</td><td>Tenofovir in 2009</td><td>1=ticked</td></tr><tr><td>VISIT1</td><td>Visit number for HBV in 2006</td><td></td></tr><tr><td>VISIT2</td><td>Visit number in current year, incl. planned</td><td></td></tr></tbody></table>
<table><thead><tr><td>Field name</td><td>Description</td><td>Values</td></tr></thead><tbody><tr><td>VRECID</td><td>VEEDACR doc_ID</td><td></td></tr><tr><td>Weight2</td><td>Body weight in 2009</td><td></td></tr></tbody></table>

### 5.3.1.2 IMA data

On a sequential base all (new) accountancy data on reimbursements in the field of compulsory health and disability insurance (HDI) are transmitted by the 7 national health insurance companies (HIC) to the legally instituted Intermutualistic Agency (IMA), along with data concerning social security status and population registry characteristics of the patients. This process integrates 3 data collection circuits: health care services (SS), Pharmanet (PH) and population data (POP), the latter from the Crossroads Bank for Social Security (CBSS). From the resulting extensive database only a selection of variables was requested for (Table 39).

<table><caption>Table 39. Specifications of requested IMA data</caption><thead><tr><td>IMA zone</td><td>Description</td><td>Field type</td><td>Fieldname after ETL</td><td>Source (*)</td></tr></thead><tbody><tr><td>SS00010<br>PP0010</td><td>Patient number (enciphered)</td><td>Alphanumeric</td><td>Pat_ID</td><td>S/F<br>P</td></tr><tr><td rowspan="2">SS00015</td><td>Start date service delivered</td><td>Date</td><td>Date_first</td><td>S</td></tr><tr><td>Delivery date</td><td>Date</td><td>Date_first</td><td>F</td></tr><tr><td>SS00020</td><td>NIHDI code</td><td>Alphanumeric</td><td>NIHDI_code</td><td>S</td></tr><tr><td>SS00020</td><td>Code category</td><td>Alphanumeric</td><td>Cat_code</td><td>F</td></tr><tr><td>SS00045</td><td>N-group of NIHDI code</td><td>Alphanumeric</td><td>N_grp</td><td>S/F</td></tr><tr><td rowspan="2">SS00050</td><td>Number of billings</td><td>Numeric, integer</td><td>N cases</td><td>S</td></tr><tr><td>Quantity</td><td>Numeric, decimal</td><td>N_units</td><td>F</td></tr><tr><td>SS00055</td><td>Number of days</td><td>Numeric, integer</td><td>N_days</td><td>S</td></tr><tr><td>SS00060</td><td>Reimbursement amount</td><td>Numeric, Euro</td><td>N_reimb</td><td>S/F</td></tr><tr><td>SS00065A</td><td>Identification health care professional (HCP)</td><td>Alphanumeric</td><td>Disp_ID</td><td>S</td></tr><tr><td>SS00065B</td><td>Qualification health care professional (HCP)</td><td>Alphanumeric</td><td>Disp_Q</td><td>S</td></tr><tr><td>SS00070A</td><td>Identification health care prescriber (PRESC)</td><td>Alphanumeric</td><td>Presc_ID</td><td>S/F</td></tr><tr><td>SS00070B</td><td>Qualification health care prescriber (PRESC)</td><td>Alphanumeric</td><td>Pres_Q</td><td>S/F</td></tr><tr><td>SS00075</td><td>ID number of health care institution (HCI)</td><td>Alphanumeric</td><td>Inst-ID</td><td>S</td></tr><tr><td>SS00080</td><td>Department of HCI</td><td>Alphanumeric</td><td>Inst_dept</td><td>S</td></tr><tr><td>SS00085</td><td>ID number of place of service delivered</td><td>Alphanumeric</td><td>Prest_place</td><td>S</td></tr><tr><td>SS00110</td><td>Admission date</td><td>Date</td><td>Date_admission</td><td>S</td></tr><tr><td>SS00115</td><td>Discharge date</td><td>Date</td><td>Date_discharge</td><td>S</td></tr><tr><td>SS00125</td><td>End date prestation (serial services)</td><td>Date</td><td>Date_last</td><td>S/F</td></tr><tr><td>SS00130</td><td>Related NIHDI code</td><td>Alphanumeric</td><td>Relative_code</td><td>S</td></tr><tr><td>SS00135</td><td>Number product</td><td>Alphanumeric</td><td>Prod_ID</td><td>S/F</td></tr><tr><td>SS00140</td><td>Normcode service delivered</td><td>Alphanumeric</td><td>Norm_prest</td><td>S</td></tr><tr><td>SS00145</td><td>Night/WE-tariff or not</td><td>Alphanumeric</td><td>N_WE</td><td>S</td></tr><tr><td>SS00150</td><td>Billed NIHDI code</td><td>Alphanumeric</td><td>Billed_code</td><td>S</td></tr><tr><td>SS00160</td><td>Patient's contribution</td><td>Numeric, Euro</td><td>QQP</td><td>S/F</td></tr><tr><td>SS00165</td><td>Supplement payed by patient</td><td>Numeric, Euro</td><td>Suppl</td><td>S</td></tr><tr><td>SS00170</td><td>Number implant</td><td>Alphanumeric</td><td>Impl_ID</td><td>S</td></tr><tr><td>SS00180</td><td>Reduced reimbursement amount</td><td>Numeric, Euro</td><td>Red_reimb</td><td>F</td></tr></tbody></table>

<footnote>c http://www.ksz-bcss.fgov.be/en/international/home/index.html</footnote>
<table><thead><tr><td>IMA zone</td><td>Description</td><td>Field type</td><td>Fieldname after ETL</td><td>Source (*)</td></tr></thead><tbody><tr><td>PP0040A</td><td>Year of death</td><td>Discriminant</td><td>Death_year</td><td>P</td></tr><tr><td>PP0040B</td><td>Month of death</td><td>Discriminant</td><td>Death_month</td><td>P</td></tr><tr><td>PP0015</td><td>Birth year</td><td>Discriminant</td><td>Birth_year</td><td>P</td></tr></tbody></table>

### 5.3.1.3 Study database

Extensive ETL (Extraction, Transformation and Loading) on VEEDACR and IMA data resulted in the creation of 4 main tables, called matrices, including some newly created variables (Table 40 and 41) Figure 21 represents relationships between main tables.

<table><caption>Table 40. Main data matrices in study database</caption><thead><tr><td>Nr</td><td>Matrix Name</td><td>Contents</td></tr></thead><tbody><tr><td>1</td><td>MatrixPatients</td><td>Patients' characteristics & HBV clinical stage based on VEEDACR data</td></tr><tr><td>2</td><td>Matrix SS</td><td>HC reimbursement data</td></tr><tr><td>3</td><td>Matrix PH</td><td>Pharmanet reimbursement data</td></tr><tr><td>4</td><td>Matrix costs</td><td>2 and 3 integrated with cost sub groupings & extrapolations</td></tr></tbody></table>

<table><caption>Table 41. Newly created variables in study database</caption><thead><tr><td>New variables</td><td>Description</td><td>Matrix nr</td></tr></thead><tbody><tr><td>Origin</td><td>Continent of patient's origin</td><td>1</td></tr><tr><td>Pat_excl</td><td>Inclusion (0) or exclusion (1) flag for patient</td><td>1</td></tr><tr><td>VEEDACR_2006</td><td>Flag indicating presence (1) or absence (0) of 2006 data in VEEDACR database</td><td>1</td></tr><tr><td>AorH</td><td>Indicates outpatient (A) or inpatient (H) care or accountancy pseudo code (T)</td><td>2/4</td></tr><tr><td>InPt_stay_ID</td><td>Chronological stay number for inpatient and 'one day' hospital stays</td><td>2/4</td></tr><tr><td>Inst_6d</td><td>ID number of health care institution (HCI) stripped to its leading 6 digit root</td><td>2</td></tr><tr><td>Pres_pl_6d</td><td>ID number of place of service delivered stripped to its leading 6 digit root</td><td>2</td></tr><tr><td>SS_ID</td><td>Unique record number in Matrix SS</td><td>2</td></tr><tr><td>PH_ID</td><td>Unique record number in Matrix PH</td><td>3</td></tr><tr><td>Prim_cost_class</td><td>Primary cost sub group of record based on NIHDI billing code</td><td>4</td></tr><tr><td>Final_cost_grp</td><td>Final cost sub group of records (HBV, nHBV, SOC, PAT or EXC) after integration</td><td>4</td></tr><tr><td>Stay_incl</td><td>Flag indicating if hospital stay is positively included (value 1); affirmatively excluded (value 0) or not (value -1)</td><td>2/4</td></tr><tr><td>FI_AV</td><td>Flag indicating HBV antiviral record (for substitution simulations)</td><td>4</td></tr><tr><td>Source</td><td>Indicates source of record (SS = matrix SS or PH = Matrix PH)</td><td>4</td></tr><tr><td>Source_ID</td><td>Unique record number of source record (connects Matrix_costs records with their source records in either Matrix SS or Matrix PH)</td><td>4</td></tr></tbody></table>

<footnote>(*) S: dataset SS = health care services & deliveries for inpatients and outpatients. F: dataset Pharmanet = medical / paramedical prescriptions carried out in 'extra muros' pharmacies (outpatients). P: dataset POP = data concerning social security status and population registry characteristics of all patients</footnote>
<figure><img src="image_25.png" /><figcaption>Figure 21. Relationships between main tables in study database</figcaption></figure>

### 5.3.2 Primary inclusion counts

Table 42 gives an overview of patient counts in both hepatologists' field survey VEEDACR database and in IMA database after linkage. Not all records in VEEDACR database could be linked to IMA patient records. However, loss was minimal and mainly restricted to the two 'lesser' clinical stages, '10 Not Active' and '11 Active'. Overall linkage percentage was 96.64%.

Two patients labelled <24 HCC> in hepatologists' data turned out to have had a liver transplant in 2006. For this cost study they were transferred to the <26 Liver transplant> group.

For rather obvious reasons (cost heterogeneity) the liver transplant group was subdivided in actual liver transplant in 2006 and post transplantation group (transplantation before 01/01/2006).

<table><caption>Table 42. Patient counts before and after linkage
Hepatologists' field survey Linkage IMA data for patients 2006</caption><thead><tr><th>Clinical stage group</th><th>Patient count</th><th>Clinical stage group</th><th>Patient count</th></tr></thead><tbody><tr><td>10 Not active</td><td>82</td><td>10 Not active</td><td>76</td></tr><tr><td>11 Active</td><td>160</td><td>11 Active</td><td>150</td></tr><tr><td>22 Comp. Cirrhosis</td><td>53</td><td>22 Comp. Cirrhosis</td><td>49</td></tr><tr><td>23 Decomp. Cirrhosis</td><td>5</td><td>23 Decomp. Cirrhosis</td><td>5</td></tr><tr><td>24 HCC</td><td>11</td><td>24 HCC (*)</td><td>6</td></tr><tr><td rowspan="2">26 Liver transplant</td><td rowspan="2">46</td><td>25 Liver transplant</td><td>6</td></tr><tr><td>26 Post transpl.</td><td>41</td></tr><tr><td><strong>2006 data</strong></td><td><strong>357</strong></td><td><strong>96.64 % linkage</strong></td><td><strong>345</strong></td></tr><tr><td><strong>No 2006 data</strong></td><td><strong>194</strong></td><td></td><td><strong>173</strong></td></tr><tr><td><strong>Total</strong></td><td><strong>551</strong></td><td></td><td></td></tr></tbody></table>

<footnote>(*) Two patients (1055 and 1311) labelled <24 HCC> in hepatologists' data had liver transplant in 2006. For this cost study they were transferred to the <26 Liver transplant> group.</footnote>
### 5.3.3 Exclusions and sub grouping for cost study

Since HBV infections frequently occur as an epiphenomenon with other pre-existing or concurrent disease(s) or treatment(s) (e.g. coagulation disorders needing multiple blood transfusions, haemodialysis, HIV ...) taking 'include-exclude' and 'cost sub grouping' decisions was ineluctable. This process was undertaken in three mutually independent layers: the patient, all his/her hospital stays (inpatient and 'one day') in 2006 and the individual fee-for-service reimbursements in both in- and outpatient settings, services and supplies delivered as well as pharmaceuticals. At the end, integration of all three layers resulted in final cost class aggregations per patient: HBV related (HBV), not HBV related (nHBV) and costs related to social security 'low income compensation' regulations (SOC), permitting a diversified cost balancing.

#### 5.3.3.1 Hospital stays identification

273 hospital stays were identified, 206 inpatient stays and 67 'one day stays'. Their admission and discharge dates were established, as well as their chronology (addendum 1). All billings related to a same stay were bundled by attributing them the unique identification code of the corresponding stay obtained through concatenation of patient number, stay order number and a suffix code indicating "H" for inpatient stay, "O" for 'one day stay', eventually followed by an extra "i" for incomplete (inpatient) stay.

#### 5.3.3.2 High level: patient exclusions

Some, luckily few patients proved having had a discharge in January of the year 2006 with an (irretrievable) admission date in 2005, since IMA data extraction did not retrograde to charges claimed in 2005. Those patients had an incomplete 'stay record' and consequently were discarded for the cost study (Table 43). With two exceptions (a patient with HCC and one with Liver transplant) losses were restricted to the 'lesser HBV stage' and at the same time most numerous patient groups.

One patient in the '11 Active group' proved to have been a psychiatric inpatient with only 134 stay days and no other services whatsoever charged by his hospital. All HBV and other medication were recorded via the outpatient pharmacy's circuit. Consequently, we decided to exclude the inpatient part of his records, but not the medication records.

<table><caption>**Table 43. Patient exclusions in IMA data**</caption><thead><tr><td>Clinical stage</td><td>Excluded patients (incomplete stay at begin 2006)</td><td>Remaining patients</td></tr></thead><tbody><tr><td>10 Not active</td><td>1</td><td>78</td></tr><tr><td>11 Active</td><td>4</td><td>151</td></tr><tr><td>22 Comp. Cirrhosis</td><td>1</td><td>50</td></tr><tr><td>23 Decomp. Cirrhosis</td><td>0</td><td>5</td></tr><tr><td>24 HCC</td><td>1</td><td>6</td></tr><tr><td>25 Liver transplant</td><td>1</td><td>6</td></tr><tr><td>26 Post transpl.</td><td>0</td><td>41</td></tr></tbody></table>
### 5.3.3.3 Medium level: stay exclusions

Since we did not have at our disposal the clinical records<sup>d</sup> of all hospital stays, we had to fall back on an in depth analysis of all billing records in order to indirectly reveal the (main) reason of each admission. Judging was mainly based on 3 axes:

1. the presence of NIHDI billing codes for diagnostic or therapeutic interventions that manifestly had no causal connection whatsoever with HBV infection status (see addendum 2);

2. obviously weighing of exclusion criteria for the other NIHDI codes had to be done separately for each clinical stage group: exclusion criteria were most severely applied to the 'non active' group and they gradually had to become more lenient with increasing severity of illness (SOI): non active' > 'active' > compensated cirrhosis > decompensated cirrhosis > HCC, liver transplant and post transplantation groups, aiming at not to exclude interventions related to HBV clinical stage or treatment complications.

3. Frequency and reimbursement total of a given billing code: the higher the frequency within a given clinical stage group the higher the likelihood of being related to HBV; however - and especially for the low number 'higher SOI' stages - with notorious exceptions (e.g. complications).

A filter was applied eliminating all billing codes not suitable for stay exclusion (e.g. laboratory tests, medical imaging, anaesthesiology...). For this purpose a preparatory 'suitable - not suitable' flagging of the NIHDI N-group classification of billing codes was used (Table 44). As a consequence, any billing code in any N-group labelled as 'not suitable' could not be eligible for stay exclusion.

<table><caption>**Table 44. Flagging of the N-groups of NIHDI billing codes for stay exclusion exercise**</caption><thead><tr><td>N-group</td><td>Label N-group</td><td>Filter parameter</td></tr></thead><tbody><tr><td>N00</td><td>Surveillance fees for hospitalized patients</td><td>NOT SUITABLE</td></tr><tr><td>N01</td><td>Consultations, home visits and medical advice</td><td>NOT SUITABLE</td></tr><tr><td>N02</td><td>General procedures (GP level)</td><td>NOT SUITABLE</td></tr><tr><td>N04</td><td>Dental care</td><td>SUITABLE</td></tr><tr><td>N05</td><td>Physical therapy by paramedics ('Kinesitherapy')</td><td>NOT SUITABLE</td></tr><tr><td>N06</td><td>Paramedical care</td><td>NOT SUITABLE</td></tr><tr><td>N08</td><td>Clinical biology - accessible for general practitioners</td><td>NOT SUITABLE</td></tr><tr><td>N10</td><td>Assistance with childbirth</td><td>SUITABLE</td></tr><tr><td>N11</td><td>Gynaecology - obstetrics</td><td>NOT SUITABLE</td></tr><tr><td>N12</td><td>Reanimation</td><td>SUITABLE</td></tr><tr><td>N13</td><td>General procedures and functions, accessible for all medical specialists</td><td>NOT SUITABLE</td></tr><tr><td>N14</td><td>Anaesthesiology (aspecific coding)</td><td>SUITABLE</td></tr><tr><td>N15</td><td>Operative assistance</td><td>NOT SUITABLE</td></tr><tr><td>N16</td><td>Stomatology</td><td>SUITABLE</td></tr><tr><td>N18</td><td>Ophthalmology</td><td>SUITABLE</td></tr><tr><td>N19</td><td>Urgency surcharges</td><td>SUITABLE</td></tr><tr><td>N20</td><td>General surgery</td><td>SUITABLE</td></tr><tr><td>N21</td><td>Neurosurgery</td><td>SUITABLE</td></tr><tr><td>N22</td><td>Plastic and reconstructive surgery</td><td>SUITABLE</td></tr><tr><td>N23</td><td>Abdominal surgery</td><td>SUITABLE</td></tr><tr><td>N25</td><td>Thoracic surgery</td><td>SUITABLE</td></tr><tr><td>N26</td><td>Vascular surgery</td><td>SUITABLE</td></tr><tr><td>N28</td><td>Otorhinolaryngology</td><td>SUITABLE</td></tr><tr><td>N30</td><td>Urology</td><td>SUITABLE</td></tr><tr><td>N32</td><td>Orthopaedics</td><td>SUITABLE</td></tr></tbody></table>

<footnote><sup>d</sup> National Minimal Clinical Records (MCR) registry of the Federal Ministry of Health</footnote>