Introduction and Utilization of High Priced HCV Medicines across Europe; Implications for the Future
Identifieur interne : 000536 ( Pmc/Corpus ); précédent : 000535; suivant : 000537Introduction and Utilization of High Priced HCV Medicines across Europe; Implications for the Future
Auteurs : Winnie De Bruijn ; Cristina Ibá Ez ; Pia Frisk ; Hanne Bak Pedersen ; Ali Alkan ; Patricia Vella Bonanno ; Ljiljana S. Brki I ; Anna Bucsics ; Guillaume Dedet ; Jaran Eriksen ; Joseph O. Fadare ; Jurij Fürst ; Gisselle Gallego ; Isabella P. God I ; Augusto A. Guerra Júnior ; Hakk Gürsöz ; Saira Jan ; Jan Jones ; Roberta Joppi ; Saim Kerman ; Ott Laius ; Newman Madzikwa ; Einar Magnússon ; Mojca Maticic ; Vanda Markovic-Pekovic ; Amos Massele ; Olayinka Ogunleye ; Aisling O'Leary ; Jutta Piessnegger ; Catherine Sermet ; Steven Simoens ; Celda Tiroyakgosi ; Ilse Truter ; Magnus Thyberg ; Kristina Tomekova ; Magdalena Wladysiuk ; Sotiris Vandoros ; Elif H. Vural ; Corinne Zara ; Brian GodmanSource :
- Frontiers in Pharmacology [ 1663-9812 ] ; 2016.
Abstract
Url:
DOI: 10.3389/fphar.2016.00197
PubMed: 27516740
PubMed Central: 4964878
Links to Exploration step
PMC:4964878Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Introduction and Utilization of High Priced HCV Medicines across Europe; Implications for the Future</title><author><name sortKey="De Bruijn, Winnie" sort="De Bruijn, Winnie" uniqKey="De Bruijn W" first="Winnie" last="De Bruijn">Winnie De Bruijn</name><affiliation><nlm:aff id="aff1"><institution>Department of Pharmaceutical Sciences, Utrecht University</institution><country>Utrecht, Netherlands</country></nlm:aff></affiliation></author><author><name sortKey="Iba Ez, Cristina" sort="Iba Ez, Cristina" uniqKey="Iba Ez C" first="Cristina" last="Ibá Ez">Cristina Ibá Ez</name><affiliation><nlm:aff id="aff2"><institution>Catalan Health Service - Servei Català de la Salut</institution><country>Barcelona, Spain</country></nlm:aff></affiliation></author><author><name sortKey="Frisk, Pia" sort="Frisk, Pia" uniqKey="Frisk P" first="Pia" last="Frisk">Pia Frisk</name><affiliation><nlm:aff id="aff3"><institution>Public Health Services Committee, Stockholm County Council</institution><country>Stockholm, Sweden</country></nlm:aff></affiliation></author><author><name sortKey="Bak Pedersen, Hanne" sort="Bak Pedersen, Hanne" uniqKey="Bak Pedersen H" first="Hanne" last="Bak Pedersen">Hanne Bak Pedersen</name><affiliation><nlm:aff id="aff4"><institution>Health Technologies and Pharmaceuticals, Division of Health Systems and Public Health, WHO Regional Office for Europe</institution><country>Copenhagen, Denmark</country></nlm:aff></affiliation></author><author><name sortKey="Alkan, Ali" sort="Alkan, Ali" uniqKey="Alkan A" first="Ali" last="Alkan">Ali Alkan</name><affiliation><nlm:aff id="aff5"><institution>Turkish Medicines and Medical Devices Agency, Ministry of Health</institution><country>Ankara, Turkey</country></nlm:aff></affiliation></author><author><name sortKey="Vella Bonanno, Patricia" sort="Vella Bonanno, Patricia" uniqKey="Vella Bonanno P" first="Patricia" last="Vella Bonanno">Patricia Vella Bonanno</name><affiliation><nlm:aff id="aff6"><institution>Independent Pharmaceutical Consultant</institution><country>Mellieha, Malta</country></nlm:aff></affiliation></author><author><name sortKey="Brki I, Ljiljana S" sort="Brki I, Ljiljana S" uniqKey="Brki I L" first="Ljiljana S." last="Brki I">Ljiljana S. Brki I</name><affiliation><nlm:aff id="aff7"><institution>Croatian Health Insurance Fund</institution><country>Zagreb, Croatia</country></nlm:aff></affiliation></author><author><name sortKey="Bucsics, Anna" sort="Bucsics, Anna" uniqKey="Bucsics A" first="Anna" last="Bucsics">Anna Bucsics</name><affiliation><nlm:aff id="aff8"><institution>Department of Finance, University of Vienna</institution><country>Vienna, Austria</country></nlm:aff></affiliation></author><author><name sortKey="Dedet, Guillaume" sort="Dedet, Guillaume" uniqKey="Dedet G" first="Guillaume" last="Dedet">Guillaume Dedet</name><affiliation><nlm:aff id="aff9"><institution>Ministry of Health</institution><country>Paris, France</country></nlm:aff></affiliation></author><author><name sortKey="Eriksen, Jaran" sort="Eriksen, Jaran" uniqKey="Eriksen J" first="Jaran" last="Eriksen">Jaran Eriksen</name><affiliation><nlm:aff id="aff10"><institution>Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge</institution><country>Stockholm, Sweden</country></nlm:aff></affiliation></author><author><name sortKey="Fadare, Joseph O" sort="Fadare, Joseph O" uniqKey="Fadare J" first="Joseph O." last="Fadare">Joseph O. Fadare</name><affiliation><nlm:aff id="aff11"><institution>Department of Pharmacology, Ekiti State University</institution><country>Ado-Ekiti, Nigeria</country></nlm:aff></affiliation></author><author><name sortKey="Furst, Jurij" sort="Furst, Jurij" uniqKey="Furst J" first="Jurij" last="Fürst">Jurij Fürst</name><affiliation><nlm:aff id="aff12"><institution>Health Insurance Institute</institution><country>Ljubljana, Slovenia</country></nlm:aff></affiliation></author><author><name sortKey="Gallego, Gisselle" sort="Gallego, Gisselle" uniqKey="Gallego G" first="Gisselle" last="Gallego">Gisselle Gallego</name><affiliation><nlm:aff id="aff13"><institution>School of Medicine, The University of Notre Dame Australia</institution><country>Darlinghurst, NSW, Australia</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff14"><institution>Department of Pharmacology and Clinical Neuroscience, Umea University</institution><country>Umea, Sweden</country></nlm:aff></affiliation></author><author><name sortKey="God I, Isabella P" sort="God I, Isabella P" uniqKey="God I I" first="Isabella P." last="God I">Isabella P. God I</name><affiliation><nlm:aff id="aff15"><institution>School of Pharmacy, Graduate Program in Medicines and Pharmaceutical Assistance, Federal University of Minas Gerais</institution><country>Belo Horizonte, Brazil</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff16"><institution>Department of Social Pharmacy, SUS Collaborating Centre – Health Technology Assessment and Excellence in Health, College of Pharmacy, Federal University of Minas Gerais</institution><country>Belo Horizonte, Brazil</country></nlm:aff></affiliation></author><author><name sortKey="Guerra Junior, Augusto A" sort="Guerra Junior, Augusto A" uniqKey="Guerra Junior A" first="Augusto A." last="Guerra Júnior">Augusto A. Guerra Júnior</name><affiliation><nlm:aff id="aff15"><institution>School of Pharmacy, Graduate Program in Medicines and Pharmaceutical Assistance, Federal University of Minas Gerais</institution><country>Belo Horizonte, Brazil</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff16"><institution>Department of Social Pharmacy, SUS Collaborating Centre – Health Technology Assessment and Excellence in Health, College of Pharmacy, Federal University of Minas Gerais</institution><country>Belo Horizonte, Brazil</country></nlm:aff></affiliation></author><author><name sortKey="Gursoz, Hakk" sort="Gursoz, Hakk" uniqKey="Gursoz H" first="Hakk" last="Gürsöz">Hakk Gürsöz</name><affiliation><nlm:aff id="aff5"><institution>Turkish Medicines and Medical Devices Agency, Ministry of Health</institution><country>Ankara, Turkey</country></nlm:aff></affiliation></author><author><name sortKey="Jan, Saira" sort="Jan, Saira" uniqKey="Jan S" first="Saira" last="Jan">Saira Jan</name><affiliation><nlm:aff id="aff17"><institution>Clinical Pharmacy, Rutgers State University of New Jersey</institution><country>Piscataway, NJ, USA</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff18"><institution>Horizon Blue Cross Blue Shield of New Jersey</institution><country>Newark, NJ, USA</country></nlm:aff></affiliation></author><author><name sortKey="Jones, Jan" sort="Jones, Jan" uniqKey="Jones J" first="Jan" last="Jones">Jan Jones</name><affiliation><nlm:aff id="aff19"><institution>Scottish Medicines Consortium</institution><country>Glasgow, UK</country></nlm:aff></affiliation></author><author><name sortKey="Joppi, Roberta" sort="Joppi, Roberta" uniqKey="Joppi R" first="Roberta" last="Joppi">Roberta Joppi</name><affiliation><nlm:aff id="aff20"><institution>Pharmaceutical Drug Department, Azienda Sanitaria Locale of Verona</institution><country>Verona, Italy</country></nlm:aff></affiliation></author><author><name sortKey="Kerman, Saim" sort="Kerman, Saim" uniqKey="Kerman S" first="Saim" last="Kerman">Saim Kerman</name><affiliation><nlm:aff id="aff5"><institution>Turkish Medicines and Medical Devices Agency, Ministry of Health</institution><country>Ankara, Turkey</country></nlm:aff></affiliation></author><author><name sortKey="Laius, Ott" sort="Laius, Ott" uniqKey="Laius O" first="Ott" last="Laius">Ott Laius</name><affiliation><nlm:aff id="aff21"><institution>State Agency of Medicines</institution><country>Tartu, Estonia</country></nlm:aff></affiliation></author><author><name sortKey="Madzikwa, Newman" sort="Madzikwa, Newman" uniqKey="Madzikwa N" first="Newman" last="Madzikwa">Newman Madzikwa</name><affiliation><nlm:aff id="aff22"><institution>Ministry of Health and Child Care</institution><country>Harrare, Zimbabwe</country></nlm:aff></affiliation></author><author><name sortKey="Magnusson, Einar" sort="Magnusson, Einar" uniqKey="Magnusson E" first="Einar" last="Magnússon">Einar Magnússon</name><affiliation><nlm:aff id="aff23"><institution>Department of Health Services, Ministry of Health</institution><country>Reykjavík, Iceland</country></nlm:aff></affiliation></author><author><name sortKey="Maticic, Mojca" sort="Maticic, Mojca" uniqKey="Maticic M" first="Mojca" last="Maticic">Mojca Maticic</name><affiliation><nlm:aff id="aff24"><institution>Clinic for Infectious Diseases and Febrile Illnesses, University Medical Centre Ljubljana</institution><country>Ljubljana, Slovenia</country></nlm:aff></affiliation></author><author><name sortKey="Markovic Pekovic, Vanda" sort="Markovic Pekovic, Vanda" uniqKey="Markovic Pekovic V" first="Vanda" last="Markovic-Pekovic">Vanda Markovic-Pekovic</name><affiliation><nlm:aff id="aff25"><institution>Faculty of Medicine, University of Banja Luka</institution><country>Banja Luka, Bosnia and Herzegovina</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff26"><institution>Ministry of Health and Social Welfare</institution><country>Banja Luka, Bosnia and Herzegovina</country></nlm:aff></affiliation></author><author><name sortKey="Massele, Amos" sort="Massele, Amos" uniqKey="Massele A" first="Amos" last="Massele">Amos Massele</name><affiliation><nlm:aff id="aff27"><institution>Department of Clinical Pharmacology, School of Medicine, University of Botswana</institution><country>Gaborone, Botswana</country></nlm:aff></affiliation></author><author><name sortKey="Ogunleye, Olayinka" sort="Ogunleye, Olayinka" uniqKey="Ogunleye O" first="Olayinka" last="Ogunleye">Olayinka Ogunleye</name><affiliation><nlm:aff id="aff28"><institution>Clinical Pharmacology Unit, Department of Medicine, Lagos State University Teaching Hospital</institution><country>Lagos, Nigeria</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff29"><institution>Department of Pharmacology and Therapeutics, Lagos State University College of Medicine</institution><country>Lagos, Nigeria</country></nlm:aff></affiliation></author><author><name sortKey="O Leary, Aisling" sort="O Leary, Aisling" uniqKey="O Leary A" first="Aisling" last="O'Leary">Aisling O'Leary</name><affiliation><nlm:aff id="aff30"><institution>National Centre for Pharmacoeconomics</institution><country>Dublin, Ireland</country></nlm:aff></affiliation></author><author><name sortKey="Piessnegger, Jutta" sort="Piessnegger, Jutta" uniqKey="Piessnegger J" first="Jutta" last="Piessnegger">Jutta Piessnegger</name><affiliation><nlm:aff id="aff31"><institution>Hauptverband der Österreichischen Sozialversicherungsträger</institution><country>Wien, Austria</country></nlm:aff></affiliation></author><author><name sortKey="Sermet, Catherine" sort="Sermet, Catherine" uniqKey="Sermet C" first="Catherine" last="Sermet">Catherine Sermet</name><affiliation><nlm:aff id="aff32"><institution>IRDES</institution><country>Paris, France</country></nlm:aff></affiliation></author><author><name sortKey="Simoens, Steven" sort="Simoens, Steven" uniqKey="Simoens S" first="Steven" last="Simoens">Steven Simoens</name><affiliation><nlm:aff id="aff33"><institution>Department of Pharmaceutical and Pharmacological Sciences, KU Leuven</institution><country>Leuven, Belgium</country></nlm:aff></affiliation></author><author><name sortKey="Tiroyakgosi, Celda" sort="Tiroyakgosi, Celda" uniqKey="Tiroyakgosi C" first="Celda" last="Tiroyakgosi">Celda Tiroyakgosi</name><affiliation><nlm:aff id="aff34"><institution>Ministry of Health, Nelson Mandela Drive</institution><country>Gaborone, Botswana</country></nlm:aff></affiliation></author><author><name sortKey="Truter, Ilse" sort="Truter, Ilse" uniqKey="Truter I" first="Ilse" last="Truter">Ilse Truter</name><affiliation><nlm:aff id="aff35"><institution>Drug Utilisation Research Unit, Faculty of Health Sciences, Nelson Mandela Metropolitan University</institution><country>Port Elizabeth, South Africa</country></nlm:aff></affiliation></author><author><name sortKey="Thyberg, Magnus" sort="Thyberg, Magnus" uniqKey="Thyberg M" first="Magnus" last="Thyberg">Magnus Thyberg</name><affiliation><nlm:aff id="aff36"><institution>Stockholms Läns Landsting, Hälso-och Sjukvårdsförvaltningen</institution><country>Stockholm, Sweden</country></nlm:aff></affiliation></author><author><name sortKey="Tomekova, Kristina" sort="Tomekova, Kristina" uniqKey="Tomekova K" first="Kristina" last="Tomekova">Kristina Tomekova</name><affiliation><nlm:aff id="aff37"><institution>Faculty of Management, Comenius University</institution><country>Bratislava, Slovakia</country></nlm:aff></affiliation></author><author><name sortKey="Wladysiuk, Magdalena" sort="Wladysiuk, Magdalena" uniqKey="Wladysiuk M" first="Magdalena" last="Wladysiuk">Magdalena Wladysiuk</name><affiliation><nlm:aff id="aff38"><institution>HTA Consulting</institution><country>Cracow, Poland</country></nlm:aff></affiliation></author><author><name sortKey="Vandoros, Sotiris" sort="Vandoros, Sotiris" uniqKey="Vandoros S" first="Sotiris" last="Vandoros">Sotiris Vandoros</name><affiliation><nlm:aff id="aff39"><institution>School of Management and Business, King's College London</institution><country>London, UK</country></nlm:aff></affiliation></author><author><name sortKey="Vural, Elif H" sort="Vural, Elif H" uniqKey="Vural E" first="Elif H." last="Vural">Elif H. Vural</name><affiliation><nlm:aff id="aff5"><institution>Turkish Medicines and Medical Devices Agency, Ministry of Health</institution><country>Ankara, Turkey</country></nlm:aff></affiliation></author><author><name sortKey="Zara, Corinne" sort="Zara, Corinne" uniqKey="Zara C" first="Corinne" last="Zara">Corinne Zara</name><affiliation><nlm:aff id="aff2"><institution>Catalan Health Service - Servei Català de la Salut</institution><country>Barcelona, Spain</country></nlm:aff></affiliation></author><author><name sortKey="Godman, Brian" sort="Godman, Brian" uniqKey="Godman B" first="Brian" last="Godman">Brian Godman</name><affiliation><nlm:aff id="aff10"><institution>Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge</institution><country>Stockholm, Sweden</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff40"><institution>Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde</institution><country>Glasgow, UK</country></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">27516740</idno><idno type="pmc">4964878</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4964878</idno><idno type="RBID">PMC:4964878</idno><idno type="doi">10.3389/fphar.2016.00197</idno><date when="2016">2016</date><idno type="wicri:Area/Pmc/Corpus">000536</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000536</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Introduction and Utilization of High Priced HCV Medicines across Europe; Implications for the Future</title><author><name sortKey="De Bruijn, Winnie" sort="De Bruijn, Winnie" uniqKey="De Bruijn W" first="Winnie" last="De Bruijn">Winnie De Bruijn</name><affiliation><nlm:aff id="aff1"><institution>Department of Pharmaceutical Sciences, Utrecht University</institution><country>Utrecht, Netherlands</country></nlm:aff></affiliation></author><author><name sortKey="Iba Ez, Cristina" sort="Iba Ez, Cristina" uniqKey="Iba Ez C" first="Cristina" last="Ibá Ez">Cristina Ibá Ez</name><affiliation><nlm:aff id="aff2"><institution>Catalan Health Service - Servei Català de la Salut</institution><country>Barcelona, Spain</country></nlm:aff></affiliation></author><author><name sortKey="Frisk, Pia" sort="Frisk, Pia" uniqKey="Frisk P" first="Pia" last="Frisk">Pia Frisk</name><affiliation><nlm:aff id="aff3"><institution>Public Health Services Committee, Stockholm County Council</institution><country>Stockholm, Sweden</country></nlm:aff></affiliation></author><author><name sortKey="Bak Pedersen, Hanne" sort="Bak Pedersen, Hanne" uniqKey="Bak Pedersen H" first="Hanne" last="Bak Pedersen">Hanne Bak Pedersen</name><affiliation><nlm:aff id="aff4"><institution>Health Technologies and Pharmaceuticals, Division of Health Systems and Public Health, WHO Regional Office for Europe</institution><country>Copenhagen, Denmark</country></nlm:aff></affiliation></author><author><name sortKey="Alkan, Ali" sort="Alkan, Ali" uniqKey="Alkan A" first="Ali" last="Alkan">Ali Alkan</name><affiliation><nlm:aff id="aff5"><institution>Turkish Medicines and Medical Devices Agency, Ministry of Health</institution><country>Ankara, Turkey</country></nlm:aff></affiliation></author><author><name sortKey="Vella Bonanno, Patricia" sort="Vella Bonanno, Patricia" uniqKey="Vella Bonanno P" first="Patricia" last="Vella Bonanno">Patricia Vella Bonanno</name><affiliation><nlm:aff id="aff6"><institution>Independent Pharmaceutical Consultant</institution><country>Mellieha, Malta</country></nlm:aff></affiliation></author><author><name sortKey="Brki I, Ljiljana S" sort="Brki I, Ljiljana S" uniqKey="Brki I L" first="Ljiljana S." last="Brki I">Ljiljana S. Brki I</name><affiliation><nlm:aff id="aff7"><institution>Croatian Health Insurance Fund</institution><country>Zagreb, Croatia</country></nlm:aff></affiliation></author><author><name sortKey="Bucsics, Anna" sort="Bucsics, Anna" uniqKey="Bucsics A" first="Anna" last="Bucsics">Anna Bucsics</name><affiliation><nlm:aff id="aff8"><institution>Department of Finance, University of Vienna</institution><country>Vienna, Austria</country></nlm:aff></affiliation></author><author><name sortKey="Dedet, Guillaume" sort="Dedet, Guillaume" uniqKey="Dedet G" first="Guillaume" last="Dedet">Guillaume Dedet</name><affiliation><nlm:aff id="aff9"><institution>Ministry of Health</institution><country>Paris, France</country></nlm:aff></affiliation></author><author><name sortKey="Eriksen, Jaran" sort="Eriksen, Jaran" uniqKey="Eriksen J" first="Jaran" last="Eriksen">Jaran Eriksen</name><affiliation><nlm:aff id="aff10"><institution>Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge</institution><country>Stockholm, Sweden</country></nlm:aff></affiliation></author><author><name sortKey="Fadare, Joseph O" sort="Fadare, Joseph O" uniqKey="Fadare J" first="Joseph O." last="Fadare">Joseph O. Fadare</name><affiliation><nlm:aff id="aff11"><institution>Department of Pharmacology, Ekiti State University</institution><country>Ado-Ekiti, Nigeria</country></nlm:aff></affiliation></author><author><name sortKey="Furst, Jurij" sort="Furst, Jurij" uniqKey="Furst J" first="Jurij" last="Fürst">Jurij Fürst</name><affiliation><nlm:aff id="aff12"><institution>Health Insurance Institute</institution><country>Ljubljana, Slovenia</country></nlm:aff></affiliation></author><author><name sortKey="Gallego, Gisselle" sort="Gallego, Gisselle" uniqKey="Gallego G" first="Gisselle" last="Gallego">Gisselle Gallego</name><affiliation><nlm:aff id="aff13"><institution>School of Medicine, The University of Notre Dame Australia</institution><country>Darlinghurst, NSW, Australia</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff14"><institution>Department of Pharmacology and Clinical Neuroscience, Umea University</institution><country>Umea, Sweden</country></nlm:aff></affiliation></author><author><name sortKey="God I, Isabella P" sort="God I, Isabella P" uniqKey="God I I" first="Isabella P." last="God I">Isabella P. God I</name><affiliation><nlm:aff id="aff15"><institution>School of Pharmacy, Graduate Program in Medicines and Pharmaceutical Assistance, Federal University of Minas Gerais</institution><country>Belo Horizonte, Brazil</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff16"><institution>Department of Social Pharmacy, SUS Collaborating Centre – Health Technology Assessment and Excellence in Health, College of Pharmacy, Federal University of Minas Gerais</institution><country>Belo Horizonte, Brazil</country></nlm:aff></affiliation></author><author><name sortKey="Guerra Junior, Augusto A" sort="Guerra Junior, Augusto A" uniqKey="Guerra Junior A" first="Augusto A." last="Guerra Júnior">Augusto A. Guerra Júnior</name><affiliation><nlm:aff id="aff15"><institution>School of Pharmacy, Graduate Program in Medicines and Pharmaceutical Assistance, Federal University of Minas Gerais</institution><country>Belo Horizonte, Brazil</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff16"><institution>Department of Social Pharmacy, SUS Collaborating Centre – Health Technology Assessment and Excellence in Health, College of Pharmacy, Federal University of Minas Gerais</institution><country>Belo Horizonte, Brazil</country></nlm:aff></affiliation></author><author><name sortKey="Gursoz, Hakk" sort="Gursoz, Hakk" uniqKey="Gursoz H" first="Hakk" last="Gürsöz">Hakk Gürsöz</name><affiliation><nlm:aff id="aff5"><institution>Turkish Medicines and Medical Devices Agency, Ministry of Health</institution><country>Ankara, Turkey</country></nlm:aff></affiliation></author><author><name sortKey="Jan, Saira" sort="Jan, Saira" uniqKey="Jan S" first="Saira" last="Jan">Saira Jan</name><affiliation><nlm:aff id="aff17"><institution>Clinical Pharmacy, Rutgers State University of New Jersey</institution><country>Piscataway, NJ, USA</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff18"><institution>Horizon Blue Cross Blue Shield of New Jersey</institution><country>Newark, NJ, USA</country></nlm:aff></affiliation></author><author><name sortKey="Jones, Jan" sort="Jones, Jan" uniqKey="Jones J" first="Jan" last="Jones">Jan Jones</name><affiliation><nlm:aff id="aff19"><institution>Scottish Medicines Consortium</institution><country>Glasgow, UK</country></nlm:aff></affiliation></author><author><name sortKey="Joppi, Roberta" sort="Joppi, Roberta" uniqKey="Joppi R" first="Roberta" last="Joppi">Roberta Joppi</name><affiliation><nlm:aff id="aff20"><institution>Pharmaceutical Drug Department, Azienda Sanitaria Locale of Verona</institution><country>Verona, Italy</country></nlm:aff></affiliation></author><author><name sortKey="Kerman, Saim" sort="Kerman, Saim" uniqKey="Kerman S" first="Saim" last="Kerman">Saim Kerman</name><affiliation><nlm:aff id="aff5"><institution>Turkish Medicines and Medical Devices Agency, Ministry of Health</institution><country>Ankara, Turkey</country></nlm:aff></affiliation></author><author><name sortKey="Laius, Ott" sort="Laius, Ott" uniqKey="Laius O" first="Ott" last="Laius">Ott Laius</name><affiliation><nlm:aff id="aff21"><institution>State Agency of Medicines</institution><country>Tartu, Estonia</country></nlm:aff></affiliation></author><author><name sortKey="Madzikwa, Newman" sort="Madzikwa, Newman" uniqKey="Madzikwa N" first="Newman" last="Madzikwa">Newman Madzikwa</name><affiliation><nlm:aff id="aff22"><institution>Ministry of Health and Child Care</institution><country>Harrare, Zimbabwe</country></nlm:aff></affiliation></author><author><name sortKey="Magnusson, Einar" sort="Magnusson, Einar" uniqKey="Magnusson E" first="Einar" last="Magnússon">Einar Magnússon</name><affiliation><nlm:aff id="aff23"><institution>Department of Health Services, Ministry of Health</institution><country>Reykjavík, Iceland</country></nlm:aff></affiliation></author><author><name sortKey="Maticic, Mojca" sort="Maticic, Mojca" uniqKey="Maticic M" first="Mojca" last="Maticic">Mojca Maticic</name><affiliation><nlm:aff id="aff24"><institution>Clinic for Infectious Diseases and Febrile Illnesses, University Medical Centre Ljubljana</institution><country>Ljubljana, Slovenia</country></nlm:aff></affiliation></author><author><name sortKey="Markovic Pekovic, Vanda" sort="Markovic Pekovic, Vanda" uniqKey="Markovic Pekovic V" first="Vanda" last="Markovic-Pekovic">Vanda Markovic-Pekovic</name><affiliation><nlm:aff id="aff25"><institution>Faculty of Medicine, University of Banja Luka</institution><country>Banja Luka, Bosnia and Herzegovina</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff26"><institution>Ministry of Health and Social Welfare</institution><country>Banja Luka, Bosnia and Herzegovina</country></nlm:aff></affiliation></author><author><name sortKey="Massele, Amos" sort="Massele, Amos" uniqKey="Massele A" first="Amos" last="Massele">Amos Massele</name><affiliation><nlm:aff id="aff27"><institution>Department of Clinical Pharmacology, School of Medicine, University of Botswana</institution><country>Gaborone, Botswana</country></nlm:aff></affiliation></author><author><name sortKey="Ogunleye, Olayinka" sort="Ogunleye, Olayinka" uniqKey="Ogunleye O" first="Olayinka" last="Ogunleye">Olayinka Ogunleye</name><affiliation><nlm:aff id="aff28"><institution>Clinical Pharmacology Unit, Department of Medicine, Lagos State University Teaching Hospital</institution><country>Lagos, Nigeria</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff29"><institution>Department of Pharmacology and Therapeutics, Lagos State University College of Medicine</institution><country>Lagos, Nigeria</country></nlm:aff></affiliation></author><author><name sortKey="O Leary, Aisling" sort="O Leary, Aisling" uniqKey="O Leary A" first="Aisling" last="O'Leary">Aisling O'Leary</name><affiliation><nlm:aff id="aff30"><institution>National Centre for Pharmacoeconomics</institution><country>Dublin, Ireland</country></nlm:aff></affiliation></author><author><name sortKey="Piessnegger, Jutta" sort="Piessnegger, Jutta" uniqKey="Piessnegger J" first="Jutta" last="Piessnegger">Jutta Piessnegger</name><affiliation><nlm:aff id="aff31"><institution>Hauptverband der Österreichischen Sozialversicherungsträger</institution><country>Wien, Austria</country></nlm:aff></affiliation></author><author><name sortKey="Sermet, Catherine" sort="Sermet, Catherine" uniqKey="Sermet C" first="Catherine" last="Sermet">Catherine Sermet</name><affiliation><nlm:aff id="aff32"><institution>IRDES</institution><country>Paris, France</country></nlm:aff></affiliation></author><author><name sortKey="Simoens, Steven" sort="Simoens, Steven" uniqKey="Simoens S" first="Steven" last="Simoens">Steven Simoens</name><affiliation><nlm:aff id="aff33"><institution>Department of Pharmaceutical and Pharmacological Sciences, KU Leuven</institution><country>Leuven, Belgium</country></nlm:aff></affiliation></author><author><name sortKey="Tiroyakgosi, Celda" sort="Tiroyakgosi, Celda" uniqKey="Tiroyakgosi C" first="Celda" last="Tiroyakgosi">Celda Tiroyakgosi</name><affiliation><nlm:aff id="aff34"><institution>Ministry of Health, Nelson Mandela Drive</institution><country>Gaborone, Botswana</country></nlm:aff></affiliation></author><author><name sortKey="Truter, Ilse" sort="Truter, Ilse" uniqKey="Truter I" first="Ilse" last="Truter">Ilse Truter</name><affiliation><nlm:aff id="aff35"><institution>Drug Utilisation Research Unit, Faculty of Health Sciences, Nelson Mandela Metropolitan University</institution><country>Port Elizabeth, South Africa</country></nlm:aff></affiliation></author><author><name sortKey="Thyberg, Magnus" sort="Thyberg, Magnus" uniqKey="Thyberg M" first="Magnus" last="Thyberg">Magnus Thyberg</name><affiliation><nlm:aff id="aff36"><institution>Stockholms Läns Landsting, Hälso-och Sjukvårdsförvaltningen</institution><country>Stockholm, Sweden</country></nlm:aff></affiliation></author><author><name sortKey="Tomekova, Kristina" sort="Tomekova, Kristina" uniqKey="Tomekova K" first="Kristina" last="Tomekova">Kristina Tomekova</name><affiliation><nlm:aff id="aff37"><institution>Faculty of Management, Comenius University</institution><country>Bratislava, Slovakia</country></nlm:aff></affiliation></author><author><name sortKey="Wladysiuk, Magdalena" sort="Wladysiuk, Magdalena" uniqKey="Wladysiuk M" first="Magdalena" last="Wladysiuk">Magdalena Wladysiuk</name><affiliation><nlm:aff id="aff38"><institution>HTA Consulting</institution><country>Cracow, Poland</country></nlm:aff></affiliation></author><author><name sortKey="Vandoros, Sotiris" sort="Vandoros, Sotiris" uniqKey="Vandoros S" first="Sotiris" last="Vandoros">Sotiris Vandoros</name><affiliation><nlm:aff id="aff39"><institution>School of Management and Business, King's College London</institution><country>London, UK</country></nlm:aff></affiliation></author><author><name sortKey="Vural, Elif H" sort="Vural, Elif H" uniqKey="Vural E" first="Elif H." last="Vural">Elif H. Vural</name><affiliation><nlm:aff id="aff5"><institution>Turkish Medicines and Medical Devices Agency, Ministry of Health</institution><country>Ankara, Turkey</country></nlm:aff></affiliation></author><author><name sortKey="Zara, Corinne" sort="Zara, Corinne" uniqKey="Zara C" first="Corinne" last="Zara">Corinne Zara</name><affiliation><nlm:aff id="aff2"><institution>Catalan Health Service - Servei Català de la Salut</institution><country>Barcelona, Spain</country></nlm:aff></affiliation></author><author><name sortKey="Godman, Brian" sort="Godman, Brian" uniqKey="Godman B" first="Brian" last="Godman">Brian Godman</name><affiliation><nlm:aff id="aff10"><institution>Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge</institution><country>Stockholm, Sweden</country></nlm:aff></affiliation><affiliation><nlm:aff id="aff40"><institution>Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde</institution><country>Glasgow, UK</country></nlm:aff></affiliation></author></analytic><series><title level="j">Frontiers in Pharmacology</title><idno type="eISSN">1663-9812</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p><bold>Background:</bold> Infection with the Hepatitis C Virus (HCV) is a widespread transmittable disease with a diagnosed prevalence of 2.0%. Fortunately, it is now curable in most patients. Sales of medicines to treat HCV infection grew 2.7% per year between 2004 and 2011, enhanced by the launch of the protease inhibitors (PIs) boceprevir (BCV) and telaprevir (TVR) in addition to ribavirin and pegylated interferon (pegIFN). Costs will continue to rise with new treatments including sofosbuvir, which now include interferon free regimens.</p><p><bold>Objective:</bold> Assess the uptake of BCV and TVR across Europe from a health authority perspective to offer future guidance on dealing with new high cost medicines.</p><p><bold>Methods:</bold> Cross-sectional descriptive study of medicines to treat HCV (pegIFN, ribavirin, BCV and TVR) among European countries from 2008 to 2013. Utilization measured in defined daily doses (DDDs)/1000 patients/quarter (DIQs) and expenditure in Euros/DDD. Health authority activities to influence treatments categorized using the 4E methodology (Education, Engineering, Economics and Enforcement).</p><p><bold>Results:</bold> Similar uptake of BCV and TVR among European countries and regions, ranging from 0.5 DIQ in Denmark, Netherlands and Slovenia to 1.5 DIQ in Tayside and Catalonia in 2013. However, different utilization of the new PIs vs. ribavirin indicates differences in dual vs. triple therapy, which is down to factors including physician preference and genotypes. Reimbursed prices for BCV and TVR were comparable across countries.</p><p><bold>Conclusion:</bold> There was reasonable consistency in the utilization of BCV and TVR among European countries in comparison with other high priced medicines. This may reflect the social demand to limit the transmission of HCV. However, the situation is changing with new curative medicines for HCV genotype 1 (GT1) with potentially an appreciable budget impact. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Front Pharmacol</journal-id><journal-id journal-id-type="iso-abbrev">Front Pharmacol</journal-id><journal-id journal-id-type="publisher-id">Front. Pharmacol.</journal-id><journal-title-group><journal-title>Frontiers in Pharmacology</journal-title></journal-title-group><issn pub-type="epub">1663-9812</issn><publisher><publisher-name>Frontiers Media S.A.</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">27516740</article-id><article-id pub-id-type="pmc">4964878</article-id><article-id pub-id-type="doi">10.3389/fphar.2016.00197</article-id><article-categories><subj-group subj-group-type="heading"><subject>Pharmacology</subject><subj-group><subject>Original Research</subject></subj-group></subj-group></article-categories><title-group><article-title>Introduction and Utilization of High Priced HCV Medicines across Europe; Implications for the Future</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>de Bruijn</surname><given-names>Winnie</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><uri xlink:type="simple" xlink:href="http://loop.frontiersin.org/people/351480/overview"></uri></contrib><contrib contrib-type="author"><name><surname>Ibáñez</surname><given-names>Cristina</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref><uri xlink:type="simple" xlink:href="http://loop.frontiersin.org/people/347701/overview"></uri></contrib><contrib contrib-type="author"><name><surname>Frisk</surname><given-names>Pia</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref><uri xlink:type="simple" xlink:href="http://loop.frontiersin.org/people/351466/overview"></uri></contrib><contrib contrib-type="author"><name><surname>Bak Pedersen</surname><given-names>Hanne</given-names></name><xref ref-type="aff" rid="aff4"><sup>4</sup></xref><uri xlink:type="simple" xlink:href="http://loop.frontiersin.org/people/139264/overview"></uri></contrib><contrib contrib-type="author"><name><surname>Alkan</surname><given-names>Ali</given-names></name><xref ref-type="aff" rid="aff5"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Vella Bonanno</surname><given-names>Patricia</given-names></name><xref ref-type="aff" rid="aff6"><sup>6</sup></xref></contrib><contrib contrib-type="author"><name><surname>Brkičić</surname><given-names>Ljiljana S.</given-names></name><xref ref-type="aff" rid="aff7"><sup>7</sup></xref></contrib><contrib contrib-type="author"><name><surname>Bucsics</surname><given-names>Anna</given-names></name><xref ref-type="aff" rid="aff8"><sup>8</sup></xref><uri xlink:type="simple" xlink:href="http://loop.frontiersin.org/people/66208/overview"></uri></contrib><contrib contrib-type="author"><name><surname>Dedet</surname><given-names>Guillaume</given-names></name><xref ref-type="aff" rid="aff9"><sup>9</sup></xref></contrib><contrib contrib-type="author"><name><surname>Eriksen</surname><given-names>Jaran</given-names></name><xref ref-type="aff" rid="aff10"><sup>10</sup></xref></contrib><contrib contrib-type="author"><name><surname>Fadare</surname><given-names>Joseph O.</given-names></name><xref ref-type="aff" rid="aff11"><sup>11</sup></xref></contrib><contrib contrib-type="author"><name><surname>Fürst</surname><given-names>Jurij</given-names></name><xref ref-type="aff" rid="aff12"><sup>12</sup></xref></contrib><contrib contrib-type="author"><name><surname>Gallego</surname><given-names>Gisselle</given-names></name><xref ref-type="aff" rid="aff13"><sup>13</sup></xref><xref ref-type="aff" rid="aff14"><sup>14</sup></xref></contrib><contrib contrib-type="author"><name><surname>Godói</surname><given-names>Isabella P.</given-names></name><xref ref-type="aff" rid="aff15"><sup>15</sup></xref><xref ref-type="aff" rid="aff16"><sup>16</sup></xref></contrib><contrib contrib-type="author"><name><surname>Guerra Júnior</surname><given-names>Augusto A.</given-names></name><xref ref-type="aff" rid="aff15"><sup>15</sup></xref><xref ref-type="aff" rid="aff16"><sup>16</sup></xref></contrib><contrib contrib-type="author"><name><surname>Gürsöz</surname><given-names>Hakkı</given-names></name><xref ref-type="aff" rid="aff5"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Jan</surname><given-names>Saira</given-names></name><xref ref-type="aff" rid="aff17"><sup>17</sup></xref><xref ref-type="aff" rid="aff18"><sup>18</sup></xref></contrib><contrib contrib-type="author"><name><surname>Jones</surname><given-names>Jan</given-names></name><xref ref-type="aff" rid="aff19"><sup>19</sup></xref></contrib><contrib contrib-type="author"><name><surname>Joppi</surname><given-names>Roberta</given-names></name><xref ref-type="aff" rid="aff20"><sup>20</sup></xref><uri xlink:type="simple" xlink:href="http://loop.frontiersin.org/people/158660/overview"></uri></contrib><contrib contrib-type="author"><name><surname>Kerman</surname><given-names>Saim</given-names></name><xref ref-type="aff" rid="aff5"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Laius</surname><given-names>Ott</given-names></name><xref ref-type="aff" rid="aff21"><sup>21</sup></xref></contrib><contrib contrib-type="author"><name><surname>Madzikwa</surname><given-names>Newman</given-names></name><xref ref-type="aff" rid="aff22"><sup>22</sup></xref><uri xlink:type="simple" xlink:href="http://loop.frontiersin.org/people/345832/overview"></uri></contrib><contrib contrib-type="author"><name><surname>Magnússon</surname><given-names>Einar</given-names></name><xref ref-type="aff" rid="aff23"><sup>23</sup></xref><uri xlink:type="simple" xlink:href="http://loop.frontiersin.org/people/359044/overview"></uri></contrib><contrib contrib-type="author"><name><surname>Maticic</surname><given-names>Mojca</given-names></name><xref ref-type="aff" rid="aff24"><sup>24</sup></xref></contrib><contrib contrib-type="author"><name><surname>Markovic-Pekovic</surname><given-names>Vanda</given-names></name><xref ref-type="aff" rid="aff25"><sup>25</sup></xref><xref ref-type="aff" rid="aff26"><sup>26</sup></xref></contrib><contrib contrib-type="author"><name><surname>Massele</surname><given-names>Amos</given-names></name><xref ref-type="aff" rid="aff27"><sup>27</sup></xref><uri xlink:type="simple" xlink:href="http://loop.frontiersin.org/people/351418/overview"></uri></contrib><contrib contrib-type="author"><name><surname>Ogunleye</surname><given-names>Olayinka</given-names></name><xref ref-type="aff" rid="aff28"><sup>28</sup></xref><xref ref-type="aff" rid="aff29"><sup>29</sup></xref></contrib><contrib contrib-type="author"><name><surname>O'Leary</surname><given-names>Aisling</given-names></name><xref ref-type="aff" rid="aff30"><sup>30</sup></xref><uri xlink:type="simple" xlink:href="http://loop.frontiersin.org/people/351392/overview"></uri></contrib><contrib contrib-type="author"><name><surname>Piessnegger</surname><given-names>Jutta</given-names></name><xref ref-type="aff" rid="aff31"><sup>31</sup></xref></contrib><contrib contrib-type="author"><name><surname>Sermet</surname><given-names>Catherine</given-names></name><xref ref-type="aff" rid="aff32"><sup>32</sup></xref><uri xlink:type="simple" xlink:href="http://loop.frontiersin.org/people/91670/overview"></uri></contrib><contrib contrib-type="author"><name><surname>Simoens</surname><given-names>Steven</given-names></name><xref ref-type="aff" rid="aff33"><sup>33</sup></xref><uri xlink:type="simple" xlink:href="http://loop.frontiersin.org/people/14301/overview"></uri></contrib><contrib contrib-type="author"><name><surname>Tiroyakgosi</surname><given-names>Celda</given-names></name><xref ref-type="aff" rid="aff34"><sup>34</sup></xref></contrib><contrib contrib-type="author"><name><surname>Truter</surname><given-names>Ilse</given-names></name><xref ref-type="aff" rid="aff35"><sup>35</sup></xref></contrib><contrib contrib-type="author"><name><surname>Thyberg</surname><given-names>Magnus</given-names></name><xref ref-type="aff" rid="aff36"><sup>36</sup></xref></contrib><contrib contrib-type="author"><name><surname>Tomekova</surname><given-names>Kristina</given-names></name><xref ref-type="aff" rid="aff37"><sup>37</sup></xref></contrib><contrib contrib-type="author"><name><surname>Wladysiuk</surname><given-names>Magdalena</given-names></name><xref ref-type="aff" rid="aff38"><sup>38</sup></xref></contrib><contrib contrib-type="author"><name><surname>Vandoros</surname><given-names>Sotiris</given-names></name><xref ref-type="aff" rid="aff39"><sup>39</sup></xref></contrib><contrib contrib-type="author"><name><surname>Vural</surname><given-names>Elif H.</given-names></name><xref ref-type="aff" rid="aff5"><sup>5</sup></xref><uri xlink:type="simple" xlink:href="http://loop.frontiersin.org/people/354548/overview"></uri></contrib><contrib contrib-type="author"><name><surname>Zara</surname><given-names>Corinne</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref><uri xlink:type="simple" xlink:href="http://loop.frontiersin.org/people/90535/overview"></uri></contrib><contrib contrib-type="author"><name><surname>Godman</surname><given-names>Brian</given-names></name><xref ref-type="aff" rid="aff10"><sup>10</sup></xref><xref ref-type="aff" rid="aff40"><sup>40</sup></xref><xref ref-type="author-notes" rid="fn001"><sup>*</sup></xref><uri xlink:type="simple" xlink:href="http://loop.frontiersin.org/people/14310/overview"></uri></contrib></contrib-group><aff id="aff1"><sup>1</sup><institution>Department of Pharmaceutical Sciences, Utrecht University</institution><country>Utrecht, Netherlands</country></aff><aff id="aff2"><sup>2</sup><institution>Catalan Health Service - Servei Català de la Salut</institution><country>Barcelona, Spain</country></aff><aff id="aff3"><sup>3</sup><institution>Public Health Services Committee, Stockholm County Council</institution><country>Stockholm, Sweden</country></aff><aff id="aff4"><sup>4</sup><institution>Health Technologies and Pharmaceuticals, Division of Health Systems and Public Health, WHO Regional Office for Europe</institution><country>Copenhagen, Denmark</country></aff><aff id="aff5"><sup>5</sup><institution>Turkish Medicines and Medical Devices Agency, Ministry of Health</institution><country>Ankara, Turkey</country></aff><aff id="aff6"><sup>6</sup><institution>Independent Pharmaceutical Consultant</institution><country>Mellieha, Malta</country></aff><aff id="aff7"><sup>7</sup><institution>Croatian Health Insurance Fund</institution><country>Zagreb, Croatia</country></aff><aff id="aff8"><sup>8</sup><institution>Department of Finance, University of Vienna</institution><country>Vienna, Austria</country></aff><aff id="aff9"><sup>9</sup><institution>Ministry of Health</institution><country>Paris, France</country></aff><aff id="aff10"><sup>10</sup><institution>Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge</institution><country>Stockholm, Sweden</country></aff><aff id="aff11"><sup>11</sup><institution>Department of Pharmacology, Ekiti State University</institution><country>Ado-Ekiti, Nigeria</country></aff><aff id="aff12"><sup>12</sup><institution>Health Insurance Institute</institution><country>Ljubljana, Slovenia</country></aff><aff id="aff13"><sup>13</sup><institution>School of Medicine, The University of Notre Dame Australia</institution><country>Darlinghurst, NSW, Australia</country></aff><aff id="aff14"><sup>14</sup><institution>Department of Pharmacology and Clinical Neuroscience, Umea University</institution><country>Umea, Sweden</country></aff><aff id="aff15"><sup>15</sup><institution>School of Pharmacy, Graduate Program in Medicines and Pharmaceutical Assistance, Federal University of Minas Gerais</institution><country>Belo Horizonte, Brazil</country></aff><aff id="aff16"><sup>16</sup><institution>Department of Social Pharmacy, SUS Collaborating Centre – Health Technology Assessment and Excellence in Health, College of Pharmacy, Federal University of Minas Gerais</institution><country>Belo Horizonte, Brazil</country></aff><aff id="aff17"><sup>17</sup><institution>Clinical Pharmacy, Rutgers State University of New Jersey</institution><country>Piscataway, NJ, USA</country></aff><aff id="aff18"><sup>18</sup><institution>Horizon Blue Cross Blue Shield of New Jersey</institution><country>Newark, NJ, USA</country></aff><aff id="aff19"><sup>19</sup><institution>Scottish Medicines Consortium</institution><country>Glasgow, UK</country></aff><aff id="aff20"><sup>20</sup><institution>Pharmaceutical Drug Department, Azienda Sanitaria Locale of Verona</institution><country>Verona, Italy</country></aff><aff id="aff21"><sup>21</sup><institution>State Agency of Medicines</institution><country>Tartu, Estonia</country></aff><aff id="aff22"><sup>22</sup><institution>Ministry of Health and Child Care</institution><country>Harrare, Zimbabwe</country></aff><aff id="aff23"><sup>23</sup><institution>Department of Health Services, Ministry of Health</institution><country>Reykjavík, Iceland</country></aff><aff id="aff24"><sup>24</sup><institution>Clinic for Infectious Diseases and Febrile Illnesses, University Medical Centre Ljubljana</institution><country>Ljubljana, Slovenia</country></aff><aff id="aff25"><sup>25</sup><institution>Faculty of Medicine, University of Banja Luka</institution><country>Banja Luka, Bosnia and Herzegovina</country></aff><aff id="aff26"><sup>26</sup><institution>Ministry of Health and Social Welfare</institution><country>Banja Luka, Bosnia and Herzegovina</country></aff><aff id="aff27"><sup>27</sup><institution>Department of Clinical Pharmacology, School of Medicine, University of Botswana</institution><country>Gaborone, Botswana</country></aff><aff id="aff28"><sup>28</sup><institution>Clinical Pharmacology Unit, Department of Medicine, Lagos State University Teaching Hospital</institution><country>Lagos, Nigeria</country></aff><aff id="aff29"><sup>29</sup><institution>Department of Pharmacology and Therapeutics, Lagos State University College of Medicine</institution><country>Lagos, Nigeria</country></aff><aff id="aff30"><sup>30</sup><institution>National Centre for Pharmacoeconomics</institution><country>Dublin, Ireland</country></aff><aff id="aff31"><sup>31</sup><institution>Hauptverband der Österreichischen Sozialversicherungsträger</institution><country>Wien, Austria</country></aff><aff id="aff32"><sup>32</sup><institution>IRDES</institution><country>Paris, France</country></aff><aff id="aff33"><sup>33</sup><institution>Department of Pharmaceutical and Pharmacological Sciences, KU Leuven</institution><country>Leuven, Belgium</country></aff><aff id="aff34"><sup>34</sup><institution>Ministry of Health, Nelson Mandela Drive</institution><country>Gaborone, Botswana</country></aff><aff id="aff35"><sup>35</sup><institution>Drug Utilisation Research Unit, Faculty of Health Sciences, Nelson Mandela Metropolitan University</institution><country>Port Elizabeth, South Africa</country></aff><aff id="aff36"><sup>36</sup><institution>Stockholms Läns Landsting, Hälso-och Sjukvårdsförvaltningen</institution><country>Stockholm, Sweden</country></aff><aff id="aff37"><sup>37</sup><institution>Faculty of Management, Comenius University</institution><country>Bratislava, Slovakia</country></aff><aff id="aff38"><sup>38</sup><institution>HTA Consulting</institution><country>Cracow, Poland</country></aff><aff id="aff39"><sup>39</sup><institution>School of Management and Business, King's College London</institution><country>London, UK</country></aff><aff id="aff40"><sup>40</sup><institution>Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde</institution><country>Glasgow, UK</country></aff><author-notes><fn fn-type="edited-by"><p>Edited by: Dominique J. Dubois, Université Libre de Bruxelles, Belgium</p></fn><fn fn-type="edited-by"><p>Reviewed by: Domenico Criscuolo, Genovax, Italy; Michael Hans Thiede, Health Economics and Policy, Germany</p></fn><corresp id="fn001">*Correspondence: Brian Godman <email xlink:type="simple">brian.godman@ki.se</email></corresp><fn fn-type="other" id="fn002"><p>This article was submitted to Pharmaceutical Medicine and Outcomes Research, a section of the journal Frontiers in Pharmacology</p></fn></author-notes><pub-date pub-type="epub"><day>22</day><month>7</month><year>2016</year></pub-date><pub-date pub-type="collection"><year>2016</year></pub-date><volume>7</volume><elocation-id>197</elocation-id><history><date date-type="received"><day>29</day><month>4</month><year>2016</year></date><date date-type="accepted"><day>21</day><month>6</month><year>2016</year></date></history><permissions><copyright-statement>Copyright © 2016 de Bruijn, Ibáñez, Frisk, Bak Pedersen, Alkan, Vella Bonanno, Brkičić, Bucsics, Dedet, Eriksen, Fadare, Fürst, Gallego, Godói, Guerra Júnior, Gürsöz, Jan, Jones, Joppi, Kerman, Laius, Madzikwa, Magnússon, Maticic, Markovic-Pekovic, Massele, Ogunleye, O'Leary, Piessnegger, Sermet, Simoens, Tiroyakgosi, Truter, Thyberg, Tomekova, Wladysiuk, Vandoros, Vural, Zara and Godman.</copyright-statement><copyright-year>2016</copyright-year><copyright-holder>de Bruijn, Ibáñez, Frisk, Bak Pedersen, Alkan, Vella Bonanno, Brkičić, Bucsics, Dedet, Eriksen, Fadare, Fürst, Gallego, Godói, Guerra Júnior, Gürsöz, Jan, Jones, Joppi, Kerman, Laius, Madzikwa, Magnússon, Maticic, Markovic-Pekovic, Massele, Ogunleye, O'Leary, Piessnegger, Sermet, Simoens, Tiroyakgosi, Truter, Thyberg, Tomekova, Wladysiuk, Vandoros, Vural, Zara and Godman</copyright-holder><license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</license-p></license></permissions><abstract><p><bold>Background:</bold> Infection with the Hepatitis C Virus (HCV) is a widespread transmittable disease with a diagnosed prevalence of 2.0%. Fortunately, it is now curable in most patients. Sales of medicines to treat HCV infection grew 2.7% per year between 2004 and 2011, enhanced by the launch of the protease inhibitors (PIs) boceprevir (BCV) and telaprevir (TVR) in addition to ribavirin and pegylated interferon (pegIFN). Costs will continue to rise with new treatments including sofosbuvir, which now include interferon free regimens.</p><p><bold>Objective:</bold> Assess the uptake of BCV and TVR across Europe from a health authority perspective to offer future guidance on dealing with new high cost medicines.</p><p><bold>Methods:</bold> Cross-sectional descriptive study of medicines to treat HCV (pegIFN, ribavirin, BCV and TVR) among European countries from 2008 to 2013. Utilization measured in defined daily doses (DDDs)/1000 patients/quarter (DIQs) and expenditure in Euros/DDD. Health authority activities to influence treatments categorized using the 4E methodology (Education, Engineering, Economics and Enforcement).</p><p><bold>Results:</bold> Similar uptake of BCV and TVR among European countries and regions, ranging from 0.5 DIQ in Denmark, Netherlands and Slovenia to 1.5 DIQ in Tayside and Catalonia in 2013. However, different utilization of the new PIs vs. ribavirin indicates differences in dual vs. triple therapy, which is down to factors including physician preference and genotypes. Reimbursed prices for BCV and TVR were comparable across countries.</p><p><bold>Conclusion:</bold> There was reasonable consistency in the utilization of BCV and TVR among European countries in comparison with other high priced medicines. This may reflect the social demand to limit the transmission of HCV. However, the situation is changing with new curative medicines for HCV genotype 1 (GT1) with potentially an appreciable budget impact. These concerns have resulted in different prices across countries, with their impact on budgets and patient outcomes monitored in the future to provide additional guidance.</p></abstract><kwd-group><kwd>boceprevir</kwd><kwd>cross national drug utilization study</kwd><kwd>demand-side measures</kwd><kwd>Hepatitis C</kwd><kwd>introduction new medicines</kwd><kwd>sofosbuvir</kwd><kwd>telaprevir</kwd></kwd-group><counts><fig-count count="4"></fig-count><table-count count="8"></table-count><equation-count count="0"></equation-count><ref-count count="97"></ref-count><page-count count="18"></page-count><word-count count="13691"></word-count></counts></article-meta></front><body><sec sec-type="intro" id="s1"><title>Introduction</title><p>The incidence and prevalence of patients with hepatitis C virus (HCV) infection is growing. However, the true worldwide incidence remains unknown due to heterogeneous registration and case definitions (European Centre for Desease Prevention Control, <xref rid="B26" ref-type="bibr">2010</xref>). Overall, it is believed that the diagnosed global prevalence of HCV is approximately 2.0% (1.7–2.3%) for adults, which corresponds to approximately 104 (87–124) million persons world-wide (Table <xref ref-type="table" rid="T1">1</xref>; McGowan et al., <xref rid="B66" ref-type="bibr">2013</xref>; Mohd Hanafiah et al., <xref rid="B72" ref-type="bibr">2013</xref>; European Association for the Study of the Liver, <xref rid="B25" ref-type="bibr">2014</xref>; Hope et al., <xref rid="B50" ref-type="bibr">2014</xref>; Wedemeyer et al., <xref rid="B92" ref-type="bibr">2015</xref>). Others have suggested higher figures at 2.8% globally (Lemoine and Asia, <xref rid="B57" ref-type="bibr">2014</xref>), leading to estimated prevalence rates of 150–184 million world-wide (Ramachandran et al., <xref rid="B82" ref-type="bibr">2012</xref>; Mohd Hanafiah et al., <xref rid="B72" ref-type="bibr">2013</xref>; Lemoine and Asia, <xref rid="B57" ref-type="bibr">2014</xref>; Phelan and Cook, <xref rid="B79" ref-type="bibr">2014</xref>; Barua et al., <xref rid="B5" ref-type="bibr">2015</xref>; Cure et al., <xref rid="B21" ref-type="bibr">2015</xref>; Norton, <xref rid="B76" ref-type="bibr">2015</xref>; Fraser et al., <xref rid="B31" ref-type="bibr">2016</xref>), with approximately 85% of patients living in low to middle income (LMIC) countries (Phelan and Cook, <xref rid="B79" ref-type="bibr">2014</xref>). However, estimated figures for South Africa are lower at 0.1–1.7% (Fraser et al., <xref rid="B31" ref-type="bibr">2016</xref>). In 2013, diagnosis rates vs. the estimated prevalence rates varied from 81% in Sweden and 43% in Belgium to just 16% in Turkey (Table <xref ref-type="table" rid="T1">1</xref>; Dore et al., <xref rid="B23" ref-type="bibr">2014</xref>; Wedemeyer et al., <xref rid="B92" ref-type="bibr">2015</xref>).</p><table-wrap id="T1" position="float"><label>Table 1</label><caption><p><bold>Reported anti-HCV prevalence rates (adjusted for the adult population), genotype 1 (GT1) distribution and estimated diagnose and treatment rate (Dore et al., <xref rid="B23" ref-type="bibr">2014</xref>; Gower et al., <xref rid="B42" ref-type="bibr">2014</xref>; Hope et al., <xref rid="B50" ref-type="bibr">2014</xref>; Wedemeyer et al., <xref rid="B92" ref-type="bibr">2015</xref>)</bold>.</p></caption><table frame="hsides" rules="groups"><thead><tr><th rowspan="1" colspan="1"></th><th valign="top" align="center" rowspan="1" colspan="1"><bold>AU</bold></th><th valign="top" align="center" rowspan="1" colspan="1"><bold>BE</bold></th><th valign="top" align="center" rowspan="1" colspan="1"><bold>DK</bold></th><th valign="top" align="center" rowspan="1" colspan="1"><bold>EE</bold></th><th valign="top" align="center" rowspan="1" colspan="1"><bold>ES</bold></th><th valign="top" align="center" rowspan="1" colspan="1"><bold>FR</bold></th><th valign="top" align="center" rowspan="1" colspan="1"><bold>HR</bold></th><th valign="top" align="center" rowspan="1" colspan="1"><bold>IT</bold></th><th valign="top" align="center" rowspan="1" colspan="1"><bold>NL</bold></th><th valign="top" align="center" rowspan="1" colspan="1"><bold>SE</bold></th><th valign="top" align="center" rowspan="1" colspan="1"><bold>TR</bold></th><th valign="top" align="center" rowspan="1" colspan="1"><bold>UK</bold></th></tr></thead><tbody><tr><td valign="top" align="left" rowspan="1" colspan="1">Adult anti-HCV</td><td valign="top" align="center" rowspan="1" colspan="1">0.5%</td><td valign="top" align="center" rowspan="1" colspan="1">0.9%</td><td valign="top" align="center" rowspan="1" colspan="1">0.7%</td><td valign="top" align="center" rowspan="1" colspan="1">–</td><td valign="top" align="center" rowspan="1" colspan="1">1.7%</td><td valign="top" align="center" rowspan="1" colspan="1">0.6%</td><td valign="top" align="center" rowspan="1" colspan="1">–</td><td valign="top" align="center" rowspan="1" colspan="1">2.0%</td><td valign="top" align="center" rowspan="1" colspan="1">0.2%</td><td valign="top" align="center" rowspan="1" colspan="1">0.7%</td><td valign="top" align="center" rowspan="1" colspan="1">1.0%</td><td valign="top" align="center" rowspan="1" colspan="1">0.6%</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">prevalence</td><td valign="top" align="center" rowspan="1" colspan="1">(0.1–0.7%)</td><td valign="top" align="center" rowspan="1" colspan="1">(0.1–1.2%)</td><td valign="top" align="center" rowspan="1" colspan="1">(0.5–0.7%)</td><td rowspan="1" colspan="1"></td><td valign="top" align="center" rowspan="1" colspan="1">(0.4–2.6%)</td><td valign="top" align="center" rowspan="1" colspan="1">(0.4–1.1%)</td><td rowspan="1" colspan="1"></td><td valign="top" align="center" rowspan="1" colspan="1">(1.6–7.3%)</td><td valign="top" align="center" rowspan="1" colspan="1">(0.1–0.4%)</td><td valign="top" align="center" rowspan="1" colspan="1">(0.5–0.7%)</td><td valign="top" align="center" rowspan="1" colspan="1">(0.6–2.1%)</td><td valign="top" align="center" rowspan="1" colspan="1">(0.4–1.2%)</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Genotype 1a</td><td valign="top" align="center" rowspan="1" colspan="1">20.3%</td><td valign="top" align="center" rowspan="1" colspan="1">–</td><td valign="top" align="center" rowspan="1" colspan="1">34.0%</td><td valign="top" align="center" rowspan="1" colspan="1">1.0%</td><td valign="top" align="center" rowspan="1" colspan="1">25.5%</td><td valign="top" align="center" rowspan="1" colspan="1">14.8%</td><td valign="top" align="center" rowspan="1" colspan="1">13.1%</td><td valign="top" align="center" rowspan="1" colspan="1">4.2%</td><td valign="top" align="center" rowspan="1" colspan="1">14.8%</td><td valign="top" align="center" rowspan="1" colspan="1">38.2%</td><td valign="top" align="center" rowspan="1" colspan="1">8.1%</td><td valign="top" align="center" rowspan="1" colspan="1">24.4%</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Genotype 1b</td><td valign="top" align="center" rowspan="1" colspan="1">51.6%</td><td valign="top" align="center" rowspan="1" colspan="1">50.4%</td><td valign="top" align="center" rowspan="1" colspan="1">12.0%</td><td valign="top" align="center" rowspan="1" colspan="1">71.0%</td><td valign="top" align="center" rowspan="1" colspan="1">43.8%</td><td valign="top" align="center" rowspan="1" colspan="1">29.7%</td><td valign="top" align="center" rowspan="1" colspan="1">37.4%</td><td valign="top" align="center" rowspan="1" colspan="1">57.5%</td><td valign="top" align="center" rowspan="1" colspan="1">15.7%</td><td valign="top" align="center" rowspan="1" colspan="1">7.0%</td><td valign="top" align="center" rowspan="1" colspan="1">83.7%</td><td valign="top" align="center" rowspan="1" colspan="1">11.9%</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Genotype 1c</td><td valign="top" align="center" rowspan="1" colspan="1">–</td><td valign="top" align="center" rowspan="1" colspan="1">8.6%</td><td valign="top" align="center" rowspan="1" colspan="1">–</td><td valign="top" align="center" rowspan="1" colspan="1">–</td><td valign="top" align="center" rowspan="1" colspan="1">–</td><td valign="top" align="center" rowspan="1" colspan="1">–</td><td valign="top" align="center" rowspan="1" colspan="1">–</td><td valign="top" align="center" rowspan="1" colspan="1">–</td><td valign="top" align="center" rowspan="1" colspan="1">–</td><td valign="top" align="center" rowspan="1" colspan="1">–</td><td valign="top" align="center" rowspan="1" colspan="1">–</td><td valign="top" align="center" rowspan="1" colspan="1">–</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Estimated diagnosed rate (2013)</td><td valign="top" align="center" rowspan="1" colspan="1">37%</td><td valign="top" align="center" rowspan="1" colspan="1">43%</td><td valign="top" align="center" rowspan="1" colspan="1">59%</td><td valign="top" align="center" rowspan="1" colspan="1">–</td><td valign="top" align="center" rowspan="1" colspan="1">40%</td><td valign="top" align="center" rowspan="1" colspan="1">69%</td><td valign="top" align="center" rowspan="1" colspan="1">–</td><td valign="top" align="center" rowspan="1" colspan="1">–</td><td valign="top" align="center" rowspan="1" colspan="1">61%</td><td valign="top" align="center" rowspan="1" colspan="1">81%</td><td valign="top" align="center" rowspan="1" colspan="1">16%</td><td valign="top" align="center" rowspan="1" colspan="1">35%</td></tr></tbody></table><table-wrap-foot><p>NB: AU, Austria; BE, Belgium; DK, Denmark; EE, Estonia; ES, Spain; FR, France; HR, Croatia; IT, Italy; NL, the Netherlands; SE, Sweden; TR, Turkey; UK, United Kingdom.</p></table-wrap-foot></table-wrap><p>Annually up to 0.5 million people die from the consequences of chronic hepatitis C infection, mainly in Africa, Asia and Eastern Europe (Lozano et al., <xref rid="B60" ref-type="bibr">2012</xref>). Most people are unaware of their HCV infection due to the slow progress of the disease (Yehia et al., <xref rid="B96" ref-type="bibr">2014</xref>), with sequelae of chronic hepatitis potentially appearing up to 20–30 years later. These include liver cirrhosis, which occurs in 10–20% of patients with hepatitis C, and develops into a 1–5% annual risk of hepatocellular carcinoma and 3–6% annual risk of hepatic decompensation (Thein et al., <xref rid="B87" ref-type="bibr">2008</xref>; Westbrook and Dusheiko, <xref rid="B93" ref-type="bibr">2014</xref>). In 2012, cirrhosis of the liver was the tenth leading cause of death in LMIC countries (globally the twelfth leading cause), with liver cancer the ninth leading cause of death in upper-middle-income countries (globally the sixteenth leading cause) (World Health Organisation, <xref rid="B95" ref-type="bibr">2012</xref>; Lemoine and Asia, <xref rid="B57" ref-type="bibr">2014</xref>).</p><p>Until 2011, treatment choices and their effectiveness were limited, especially for patients with genotype 1 (GT1). GT1 HCV-patients account for up to 60% of HCV infections worldwide, and predominate in Eastern, Northern and Southern Europe as well as North America and Japan (Schalm et al., <xref rid="B84" ref-type="bibr">1997</xref>; McHutchison et al., <xref rid="B68" ref-type="bibr">1998</xref>; Poynard et al., <xref rid="B80" ref-type="bibr">1998</xref>; Cebolla and Björnberg, <xref rid="B12" ref-type="bibr">2012</xref>; Messina et al., <xref rid="B69" ref-type="bibr">2014</xref>). Cure rates, defined as sustained virological response (SVR), were typically only seen in 35–43% of patients with GT1 following dual therapy with ribavirin and pegylated interferons (pegIFNs) (Schalm et al., <xref rid="B84" ref-type="bibr">1997</xref>; McHutchison et al., <xref rid="B68" ref-type="bibr">1998</xref>; Poynard et al., <xref rid="B80" ref-type="bibr">1998</xref>; Manns et al., <xref rid="B62" ref-type="bibr">2013</xref>; Mathurin, <xref rid="B64" ref-type="bibr">2013</xref>; Chou et al., <xref rid="B15" ref-type="bibr">2014</xref>; Kohli et al., <xref rid="B55" ref-type="bibr">2014</xref>). However, the serious side-effects associated with these treatments, coupled with complex regimens, resulted in problems with adherence. This led to less than 50% of patients typically completing their treatment course (McHutchison et al., <xref rid="B67" ref-type="bibr">2002</xref>; Lo Re et al., <xref rid="B59" ref-type="bibr">2011</xref>; Brennan and Shrank, <xref rid="B7" ref-type="bibr">2014</xref>).</p><p>In 2011, the direct acting antivirals (DAAs) boceprevir (BCV), and telaprevir (TVR) became available (Chou et al., <xref rid="B15" ref-type="bibr">2014</xref>)<xref ref-type="fn" rid="fn0001"><sup>1</sup></xref><sup>,</sup><xref ref-type="fn" rid="fn0002"><sup>2</sup></xref>. BCV and TVR are only licensed for GT1. Consequently physicians need to test for genotypes before starting treatment<sup>1, 2</sup>. BCV and TVR improved SVR (RR, 2.05; 95% CI 1.70–2.48) when combined with ribavirin and pegIFNs (triple therapy) (Chou et al., <xref rid="B15" ref-type="bibr">2014</xref>; Kohli et al., <xref rid="B55" ref-type="bibr">2014</xref>; Manzano-Robleda et al., <xref rid="B63" ref-type="bibr">2015</xref>)<xref ref-type="fn" rid="fn0003"><sup>3</sup></xref>; however, there were more adverse events (RR, 1.05; 1–1.03; NNH 77.59) (Manzano-Robleda et al., <xref rid="B63" ref-type="bibr">2015</xref>). In recent years, second generation DAAs have become available with encouraging cure rates up to 90–95% of patients, potentially providing shorter treatment courses and less side effects than previous treatment approaches (Kohli et al., <xref rid="B55" ref-type="bibr">2014</xref>; Childs-Kean and Hand, <xref rid="B14" ref-type="bibr">2015</xref>)<sup>3</sup>. These were sofosbuvir, simeprevir, daclatasvir and ledipasvir approved by the European Medicine Agency (EMA) in late 2013 and 2014<xref ref-type="fn" rid="fn0004"><sup>4</sup></xref><sup>,</sup><xref ref-type="fn" rid="fn0005"><sup>5</sup></xref><sup>,</sup><xref ref-type="fn" rid="fn0006"><sup>6</sup></xref><sup>,</sup><xref ref-type="fn" rid="fn0007"><sup>7</sup></xref>. More recently, combinations of DAAs have also been approved by EMA providing further options for highly effective, safe and well tolerated treatment of HCV GT1 patients (Kohli et al., <xref rid="B55" ref-type="bibr">2014</xref>)<xref ref-type="fn" rid="fn0008"><sup>8</sup></xref>.</p><p>These developments resulted in the anti HCV therapeutics market expanding at a compounded annual growth rate (CAGR) of 2.7% between 2004 and 2011<xref ref-type="fn" rid="fn0009"><sup>9</sup></xref><sup>,</sup><xref ref-type="fn" rid="fn0010"><sup>10</sup></xref>, with growth rates appreciably higher after this<sup>10</sup>. This has resulted in worldwide sales of sofosbuvir already at US$12.4 billion in 2014 (Trooskin et al., <xref rid="B88" ref-type="bibr">2015</xref>). In the US, treatments for hepatitis C became the fourth most expensive speciality medicine class in 2014 with sofosbuvir already capturing 37.5% of the HCV market<xref ref-type="fn" rid="fn0011"><sup>11</sup></xref>. These growth rates in expenditure are due not only to the price of these new treatments at over US$50,000/patient/course in some countries, but also the effectiveness and limited side-effects of the second generation DAAs (Mohd Hanafiah et al., <xref rid="B72" ref-type="bibr">2013</xref>; Brennan and Shrank, <xref rid="B7" ref-type="bibr">2014</xref>; Senior, <xref rid="B85" ref-type="bibr">2014</xref>). In addition, these new treatments are being used in patients with advanced liver disease, such as those with decompensated cirrhosis awaiting transplantation, appreciably increasing the pool of eligible patients.</p><p>We are already seeing that some European health authorities are unable to fund new high priced medicines, exacerbated by their continual launch (Experts in Chronic Myeloid Leukemia, <xref rid="B27" ref-type="bibr">2013</xref>; Kantarjian et al., <xref rid="B54" ref-type="bibr">2013</xref>; Godman et al., <xref rid="B37" ref-type="bibr">2015</xref>)<xref ref-type="fn" rid="fn0012"><sup>12</sup></xref>. This will impact on available funding for new treatments for HCV despite their undoubted effectiveness (Brennan and Shrank, <xref rid="B7" ref-type="bibr">2014</xref>; Lemoine and Asia, <xref rid="B57" ref-type="bibr">2014</xref>; Trooskin et al., <xref rid="B88" ref-type="bibr">2015</xref>; Norton, <xref rid="B76" ref-type="bibr">2015</xref>). The arrival of cost-effective second generation DAAs has fuelled the debate over pricing and reimbursement decisions across Europe given typically reimbursement for new expensive cancer treatments and those for orphan diseases despite often limited health gain, as well as whether there should be a greater focus on the budget impact of new medicines rather than just their cost-effectiveness (Kantarjian et al., <xref rid="B54" ref-type="bibr">2013</xref>; Simoens et al., <xref rid="B86" ref-type="bibr">2013</xref>; Cohen and Felix, <xref rid="B18" ref-type="bibr">2014</xref>; Godman et al., <xref rid="B37" ref-type="bibr">2015</xref>; Messori, <xref rid="B70" ref-type="bibr">2015a</xref>)<xref ref-type="fn" rid="fn0013"><sup>13</sup></xref>.</p><p>Consequently, the aim of this initial study is to compare the uptake of BCV and TVR among European countries from a health authority perspective alongside implemented activities to influence their prescribing. We will subsequently build on the findings, including current activities among health authorities regarding second generation DAAs including price negotiations, to provide future direction and guidance to health authorities (Civaner, <xref rid="B17" ref-type="bibr">2012</xref>; Lemoine and Asia, <xref rid="B57" ref-type="bibr">2014</xref>)<sup>10</sup>. This will involve specific studies to ascertain utilization and expenditure of second generation DAAs alongside negotiated prices.</p></sec><sec sec-type="methods" id="s2"><title>Methods</title><p>This was a retrospective cross sectional descriptive observational study involving twelve countries and regions from across Europe. Health authorities were contacted to provide aggregated data on the utilization and expenditure of BCV and TVR. This was purely voluntary as there was no funding for them and no funding to purchase utilization data from commercial sources. We have used this approach before when analysing the influence of different health authority measures to enhance the prescribing of generic atypical antipsychotics, proton-pump inhibitors, renin-angiotensin inhibitors, selective serotonin re-uptake inhibitors and statins across Europe (Godman et al., <xref rid="B40" ref-type="bibr">2010a</xref>, <xref rid="B39" ref-type="bibr">2014a</xref>; Vonèina et al., <xref rid="B91" ref-type="bibr">2011</xref>; Moon et al., <xref rid="B74" ref-type="bibr">2014</xref>).</p><p>The European countries and regions that provided utilization and expenditure data typically cover 100% of their population. However, there are differences in their geography, i.e., central, eastern, and western European countries, epidemiology, and financing of as well as available resources for healthcare (Table <xref ref-type="table" rid="T2">2</xref>). This is important given the heterogeneity of European healthcare systems and suggested approaches when conducting cross national studies (Cacace et al., <xref rid="B9" ref-type="bibr">2013</xref>). The only exception to health authority data is Turkey, where data from the Ministry of Health were sourced from Intercontinental Marketing Services (IMS).</p><table-wrap id="T2" position="float"><label>Table 2</label><caption><p><bold>Details of methods of financing healthcare, GDP spent on health and data providers (Godman et al., <xref rid="B40" ref-type="bibr">2010a</xref>, <xref rid="B36" ref-type="bibr">2013a</xref>; Atun et al., <xref rid="B3" ref-type="bibr">2013</xref>; Hesse et al., <xref rid="B44" ref-type="bibr">2013</xref>)<xref ref-type="fn" rid="fn0014"><sup>14</sup></xref></bold>.</p></caption><table frame="hsides" rules="groups"><thead><tr><th valign="top" align="left" rowspan="1" colspan="1"><bold>Country/region</bold></th><th valign="top" align="left" rowspan="1" colspan="1"><bold>Taxation/health insurance</bold></th><th valign="top" align="center" rowspan="1" colspan="1"><bold>GDP/capita (PPP in US $)</bold></th><th valign="top" align="center" rowspan="1" colspan="1"><bold>% GDP spent on health (2010–2014)</bold></th><th valign="top" align="left" rowspan="1" colspan="1"><bold>Data providers (100% coverage of population unless otherwise stated)</bold></th></tr></thead><tbody><tr><td valign="top" align="left" rowspan="1" colspan="1">Austria (AT)</td><td valign="top" align="left" rowspan="1" colspan="1">Health Insurance</td><td valign="top" align="center" rowspan="1" colspan="1">43,390</td><td valign="top" align="center" rowspan="1" colspan="1">11.0</td><td valign="top" align="left" rowspan="1" colspan="1">Data Warehouse of the Federation of Austrian Social Insurance Institutions—covers 98% of the population</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Belgium (BE)</td><td valign="top" align="left" rowspan="1" colspan="1">Health Insurance</td><td valign="top" align="center" rowspan="1" colspan="1">39,860</td><td valign="top" align="center" rowspan="1" colspan="1">11.2</td><td valign="top" align="left" rowspan="1" colspan="1">National Institute for Health and Disability Insurance (INAMI-RIZIV)</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Croatia (HR)</td><td valign="top" align="left" rowspan="1" colspan="1">Health Insurance</td><td valign="top" align="center" rowspan="1" colspan="1">18,760</td><td valign="top" align="center" rowspan="1" colspan="1">7.3</td><td valign="top" align="left" rowspan="1" colspan="1">Croatian Health Insurance Fund covering over 99% of the population. HCV treatments funded from a separate budget for expensive medicines</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Denmark (DK)</td><td valign="top" align="left" rowspan="1" colspan="1">Taxation</td><td valign="top" align="center" rowspan="1" colspan="1">43,430</td><td valign="top" align="center" rowspan="1" colspan="1">10.6</td><td valign="top" align="left" rowspan="1" colspan="1">Danish Prescription Registry</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Estonia (EE)</td><td valign="top" align="left" rowspan="1" colspan="1">Health Insurance</td><td valign="top" align="center" rowspan="1" colspan="1">22,500</td><td valign="top" align="center" rowspan="1" colspan="1">5.7</td><td valign="top" align="left" rowspan="1" colspan="1">Estonian Health Insurance Fund</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">France</td><td valign="top" align="left" rowspan="1" colspan="1">Health Insurance</td><td valign="top" align="center" rowspan="1" colspan="1">38,847</td><td valign="top" align="center" rowspan="1" colspan="1">11.8</td><td valign="top" align="left" rowspan="1" colspan="1">SNIIRAM (The National Information System of public Health Insurances)</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Italy (IT)</td><td valign="top" align="left" rowspan="1" colspan="1">Taxation</td><td valign="top" align="center" rowspan="1" colspan="1">32,920</td><td valign="top" align="center" rowspan="1" colspan="1">9.1</td><td valign="top" align="left" rowspan="1" colspan="1">Medicines Utilization Unit's elaboration of data from Osmed Database and Tracciabilità del farmaco</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">The Netherlands (NL)</td><td valign="top" align="left" rowspan="1" colspan="1">Health Insurance</td><td valign="top" align="center" rowspan="1" colspan="1">43,510</td><td valign="top" align="center" rowspan="1" colspan="1">12.9</td><td valign="top" align="left" rowspan="1" colspan="1">The Drug Information System of Dutch National Health Care Institute</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Slovenia (SI)</td><td valign="top" align="left" rowspan="1" colspan="1">Health Insurance</td><td valign="top" align="center" rowspan="1" colspan="1">27,240</td><td valign="top" align="center" rowspan="1" colspan="1">9.2</td><td valign="top" align="left" rowspan="1" colspan="1">The National Institute of Public Health and Health Insurance Institute Prescription database</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Spain—Catalonia (ES—CT)</td><td valign="top" align="left" rowspan="1" colspan="1">Taxation</td><td valign="top" align="center" rowspan="1" colspan="1">31,670</td><td valign="top" align="center" rowspan="1" colspan="1">8.9</td><td valign="top" align="left" rowspan="1" colspan="1">Catalan Health Service drug prescription database (DATAMART)</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Sweden (SE)</td><td valign="top" align="left" rowspan="1" colspan="1">Taxation</td><td valign="top" align="center" rowspan="1" colspan="1">43,980</td><td valign="top" align="center" rowspan="1" colspan="1">9.7</td><td valign="top" align="left" rowspan="1" colspan="1">National Swedish Prescribed Drug Register</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Turkey (TR)</td><td valign="top" align="left" rowspan="1" colspan="1">Health Insurance</td><td valign="top" align="center" rowspan="1" colspan="1">18,020</td><td valign="top" align="center" rowspan="1" colspan="1">5.6</td><td valign="top" align="left" rowspan="1" colspan="1">Utilization information from the Ministry of Health sourced from IMS</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">UK—Scotland</td><td valign="top" align="left" rowspan="1" colspan="1">Taxation</td><td valign="top" align="center" rowspan="1" colspan="1">37,340</td><td valign="top" align="center" rowspan="1" colspan="1">9.1</td><td valign="top" align="left" rowspan="1" colspan="1">Prescribing Information Systems (PIS) from NHS National Services Scotland Corporate Warehouse</td></tr></tbody></table></table-wrap><p>The region of Catalonia is included as it is difficult to obtain comprehensive drug utilization data from across Spain, and Catalonia is one of the principal autonomous communities in Spain, which has been active over a number of years with initiatives to improve the quality and efficiency of prescribing (Coma et al., <xref rid="B19" ref-type="bibr">2009</xref>; Björkhem-Bergman et al., <xref rid="B6" ref-type="bibr">2013</xref>). Tayside was also included, representing a region in Scotland, since at the time it was difficult to obtain drug utilization data from across Scotland.</p><sec><title>Utilization data</title><p>Utilization data were collected in Defined Daily Doses (DDD)<xref ref-type="fn" rid="fn0016"><sup>16</sup></xref>, with Table <xref ref-type="table" rid="T3">3</xref> providing details of the DDDs used.</p><table-wrap id="T3" position="float"><label>Table 3</label><caption><p><bold>DDDs for medicines to treat Hepatitis C<xref ref-type="fn" rid="fn0015"><sup>15</sup></xref></bold>.</p></caption><table frame="hsides" rules="groups"><thead><tr><th valign="top" align="left" rowspan="1" colspan="1"><bold>Medicine</bold></th><th valign="top" align="left" rowspan="1" colspan="1"><bold>ATC</bold></th><th valign="top" align="left" rowspan="1" colspan="1"><bold>DDD</bold></th></tr></thead><tbody><tr><td valign="top" align="left" rowspan="1" colspan="1">Bocepravir (BCV)</td><td valign="top" align="left" rowspan="1" colspan="1">J05AE11</td><td valign="top" align="left" rowspan="1" colspan="1">2.4 g (oral)</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Peg-interferon alfa-2a</td><td valign="top" align="left" rowspan="1" colspan="1">L03AB11</td><td valign="top" align="left" rowspan="1" colspan="1">26 mcg (parenteral)</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Peg-interferon alfa-2b</td><td valign="top" align="left" rowspan="1" colspan="1">L03AB10</td><td valign="top" align="left" rowspan="1" colspan="1">7.5 mcg (parenteral)</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Ribavirin</td><td valign="top" align="left" rowspan="1" colspan="1">J05AB04</td><td valign="top" align="left" rowspan="1" colspan="1">1 gm (oral)</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Telaprevir (TVR)</td><td valign="top" align="left" rowspan="1" colspan="1">J05AE11</td><td valign="top" align="left" rowspan="1" colspan="1">2.25 gm (oral)</td></tr></tbody></table></table-wrap><p>Population data from Eurostat were used to calculate DDDs per 1000 inhabitants per quarter (DIQs)<xref ref-type="fn" rid="fn0017"><sup>17</sup></xref>. Calculations were performed using the quarterly time period since the treatment period for HCV treatments is at least 12 weeks, and mostly 24 or 48 weeks, thereby providing a realistic denominator.</p><p>Results were calculated using two approaches. Firstly, the utilization of BCV and TVR was calculated separately to compare their uptake across countries. Due to the lack of patient specific data and different algorithms for BCV and TVR, their utilization was not combined. The second approach was an estimation of percentages of treated patients with triple therapy (ribavirin + pegIFN + TVR + BCV) vs. dual-therapy (ribavirin + pegIFN). This was again because we did not have access to individual patient data nor to prevalence rates. The percentage of treated patients was estimated through assessing the utilization of BCV and TVR in relation to ribavirin. Ribavirin is used as a proxy for dual-therapy because it is typically administered with pegIFNs, although we are aware that some patients with GT3 may be administered ribavirin without pegIFN. We acknowledge that there are differences in GT1 prevalence rates among European countries (Cornberg et al., <xref rid="B20" ref-type="bibr">2011</xref>; Deuffic-Burban et al., <xref rid="B22" ref-type="bibr">2012</xref>), that treatment algorithm data are not always available and there are different opinions and barriers to care (McGowan et al., <xref rid="B66" ref-type="bibr">2013</xref>). Differences in GT1 prevalence rates and current treatment approaches are the most important uncertainties in this analysis. Consequently, we made a number of caveats to give a more realistic approach.</p><p>Estimates for GT1 is between 35 and 75% (Cornberg et al., <xref rid="B20" ref-type="bibr">2011</xref>; Deuffic-Burban et al., <xref rid="B22" ref-type="bibr">2012</xref>) of patients with chronic HCV (Table <xref ref-type="table" rid="T1">1</xref>). In our approach, we used 45–65% to give a reasonable perspective. TVR treatment length varies between 12 of 48 weeks (25%) for patients with cirrhosis to 12 of 24 weeks (50%) for patients without cirrhosis and early SVR responses. For BCV, treatment length varies between 32 of 48 (67%) weeks for some treatment naïve patient without cirrhosis, mainly relapsers and partial responders, and 44 of 48 (92%) weeks for patients with cirrhosis (Christensen et al., <xref rid="B16" ref-type="bibr">2012</xref>; Hofmann et al., <xref rid="B49" ref-type="bibr">2012</xref>; Lagging et al., <xref rid="B56" ref-type="bibr">2012</xref>; Leroy et al., <xref rid="B58" ref-type="bibr">2012</xref>; Orlent et al., <xref rid="B77" ref-type="bibr">2012</xref>; Ramachandran et al., <xref rid="B82" ref-type="bibr">2012</xref>)<sup>1, 2</sup>. Sixty five and forty five percent GT1 prevalence rates were combined with percentages of treatment length, e.g., for TVR this was 25% use and 45% GT1 prevalence (25% of 45%) equating to 11.25%. Subsequently, the numbers used to estimate the potential for triple therapy are between 11.3 and 32.5% utilization for TVR and 30.2 and 59.7% utilization for BCV (Table <xref ref-type="table" rid="T4">4</xref>). These findings define the second approach in an attempt to estimate the number of patients receiving triple therapy as a percentage of all HCV treated patients.</p><table-wrap id="T4" position="float"><label>Table 4</label><caption><p><bold>Calculated percentages for triple therapy vs. all HCV treated patients</bold>.</p></caption><table frame="hsides" rules="groups"><thead><tr><th valign="top" align="left" rowspan="1" colspan="1"><bold>GT1 prevalence</bold></th><th valign="top" align="center" rowspan="1" colspan="1"><bold>Treatment length for TVR between 25 and 50% of full treatment</bold></th><th valign="top" align="center" rowspan="1" colspan="1"><bold>Treatment length for BCV between 67 and 92% of full treatment</bold></th></tr></thead><tbody><tr><td valign="top" align="left" rowspan="1" colspan="1">45% GT1 prevalence</td><td valign="top" align="center" rowspan="1" colspan="1">11.3–22.5%</td><td valign="top" align="center" rowspan="1" colspan="1">30.2–41.4%</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">65% GT1 prevalence</td><td valign="top" align="center" rowspan="1" colspan="1">16.2–32.5%</td><td valign="top" align="center" rowspan="1" colspan="1">43.5–59.7%</td></tr></tbody></table></table-wrap></sec><sec><title>Reimbursement expenditure data</title><p>Reimbursement expenditure was calculated in Euros per DDD (EUR/DDD). Exchange rates for Croatia, Denmark, Poland, Sweden and Switzerland where pertinent were calculated using the following conversion rates (conversion date 1-January 2008 as this was the start of the data collection period): 1 EUR = 7.6 HRK (Croatian Kuna), 7.46 DKK (Danish Krone), 9.44 SEK (Swedish krona), 1.65 CHF (Swiss franc), and 3.60 PLN (Polish zloty)<xref ref-type="fn" rid="fn0018"><sup>18</sup></xref>.</p></sec><sec><title>Descriptive review of national and regional health authority demand-side activities regarding HCV drug treatment for BCV and TVR</title><p>Measures undertaken by health authorities to potentially influence the subsequent utilization of BCV and TVR were collected and collated using the 4E—Education, Engineering, Economics, and Enforcement (Wettermark et al., <xref rid="B94" ref-type="bibr">2009</xref>) methodology. This method was developed in order to make it easier to understand and compare the complexity and multiplicity of healthcare policies across countries and their potential impact and/or influence (Coma et al., <xref rid="B19" ref-type="bibr">2009</xref>; Wettermark et al., <xref rid="B94" ref-type="bibr">2009</xref>; Godman et al., <xref rid="B40" ref-type="bibr">2010a</xref>,<xref rid="B41" ref-type="bibr">b</xref>; Godman et al., <xref rid="B35" ref-type="bibr">2013b</xref>, <xref rid="B39" ref-type="bibr">2014a</xref>; Garuoliene et al., <xref rid="B33" ref-type="bibr">2011</xref>; Vonèina et al., <xref rid="B91" ref-type="bibr">2011</xref>; Malmström et al., <xref rid="B61" ref-type="bibr">2013</xref>). Table <xref ref-type="table" rid="T5">5</xref> shows definitions and gives some examples of the four dimensions.</p><table-wrap id="T5" position="float"><label>Table 5</label><caption><p><bold>Description 4E method—Education, Engineering, Economics, and Enforcement (Garuoliene et al., <xref rid="B32" ref-type="bibr">2010</xref>; Godman et al., <xref rid="B40" ref-type="bibr">2010a</xref>,<xref rid="B41" ref-type="bibr">b</xref>, <xref rid="B38" ref-type="bibr">2014b</xref>, <xref rid="B37" ref-type="bibr">2015</xref>; Maticic, <xref rid="B65" ref-type="bibr">2014</xref>; Moon et al., <xref rid="B74" ref-type="bibr">2014</xref>; Putrik et al., <xref rid="B81" ref-type="bibr">2014</xref>; Campbell et al., <xref rid="B10" ref-type="bibr">2015</xref>)</bold>.</p></caption><table frame="hsides" rules="groups"><thead><tr><th valign="top" align="left" rowspan="1" colspan="1"><bold>Approach</bold></th><th valign="top" align="left" rowspan="1" colspan="1"><bold>Description and examples</bold></th></tr></thead><tbody><tr><td valign="top" align="left" rowspan="1" colspan="1">Education</td><td valign="top" align="left" rowspan="1" colspan="1">• Activities include educational programmes that influence prescribing: e.g., national and regional guidelines with inclusion criteria, monitoring requirements, EBM initiatives (rational prescribing), and benchmarking (quality control), e.g., monitoring of prescribing against agreed guidance coupled with feedback, e.g., “Wise list” in Stockholm, Sweden</td></tr><tr style="border-bottom: thin solid #000000;"><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• Activities also include education for patients including public awareness through campaigns, world hepatitis day, flyers/printed material, as well as prescribing guidance for patients to enhance patient-doctor communication</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Engineering</td><td valign="top" align="left" rowspan="1" colspan="1">• This refers to organizational or managerial interventions</td></tr><tr><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• Activities include programs and interventions to optimize prescribing: e.g., structured programmes to optimize the entry of new medicines, price: volume agreements, capping budgets, and prescribing targets</td></tr><tr style="border-bottom: thin solid #000000;"><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• In addition any disease management programmes to optimize treatment including potential quality targets</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Economics</td><td valign="top" align="left" rowspan="1" colspan="1">• Activities include positive and negative financial initiatives for all key stakeholder groups</td></tr><tr style="border-bottom: thin solid #000000;"><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• Examples include percentage reimbursement/patient co-payment levels as well as financial incentives for physicians</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Enforcement</td><td valign="top" align="left" rowspan="1" colspan="1">• Activities include regulations such as those enforced by law; e.g., prescribing restrictions including designated signatures on prescription forms, prior authorization schemes and compulsory agreements such as compulsory international non-proprietary name (INN) prescribing and compulsory generic substitution</td></tr></tbody></table></table-wrap><p>Country data were collected through an interactive and iterative process. Answers to the developed questionnaire were provided in written format by the co-authors, and subsequently checked for accuracy. Alternatively, country profiles were provided by one of the co-authors (Winnie De Bruijn) based on published sources as well as web-based articles. As a result, more European countries were included in the country profiles of ongoing activities regarding BCV and TVR than provided utilization data. Subsequent answers were re-checked and re-confirmed with the co-authors to enhance the robustness of the country profiles. This method has been used in previous publications involving health authority personnel (Garuoliene et al., <xref rid="B32" ref-type="bibr">2010</xref>, <xref rid="B33" ref-type="bibr">2011</xref>; Godman et al., <xref rid="B40" ref-type="bibr">2010a</xref>,<xref rid="B41" ref-type="bibr">b</xref>, <xref rid="B35" ref-type="bibr">2013b</xref>, <xref rid="B39" ref-type="bibr">2014a</xref>,<xref rid="B38" ref-type="bibr">b</xref>; Vonèina et al., <xref rid="B91" ref-type="bibr">2011</xref>; Malmström et al., <xref rid="B61" ref-type="bibr">2013</xref>); consequently, applied in this research project.</p><p>All country profiles were supplemented with data from the WHO Hepatitis report<xref ref-type="fn" rid="fn0019"><sup>19</sup></xref> and Euro Hepatitis Index 2012 report (Cebolla and Björnberg, <xref rid="B12" ref-type="bibr">2012</xref>).</p><p>Patient consent as well as ethics approval was not required as aggregate utilization and expenditure data were obtained from anonymised health authority databases (Table <xref ref-type="table" rid="T2">2</xref>). This is in line with previous publications involving anonymised aggregated health authority data Europe (Godman et al., <xref rid="B40" ref-type="bibr">2010a</xref>, <xref rid="B39" ref-type="bibr">2014a</xref>; Vonèina et al., <xref rid="B91" ref-type="bibr">2011</xref>; Moon et al., <xref rid="B74" ref-type="bibr">2014</xref>).</p></sec></sec><sec sec-type="results" id="s3"><title>Results</title><sec><title>General</title><p>In the majority of countries studied, both BCV and TVR were reimbursed. Exceptions included Bosnia and Herzegovina as well as Estonia (Table <xref ref-type="table" rid="T6">6</xref>). Technically in Sweden only TVR is included in the national reimbursement scheme. However, in practice, both BCV and TVR are free for patients as both medicines are free for infectious diseases under the Infectious Disease Act.</p><table-wrap id="T6" position="float"><label>Table 6</label><caption><p><bold>Summary of most important demand side measures among European countries to influence the prescribing of BCV and TVR post-launch</bold>.</p></caption><table frame="hsides" rules="groups"><thead><tr><th valign="top" align="left" rowspan="1" colspan="1"><bold>Country</bold></th><th valign="top" align="left" rowspan="1" colspan="1"><bold>4E</bold></th><th valign="top" align="left" rowspan="1" colspan="1"><bold>Approach</bold></th></tr></thead><tbody><tr><td valign="top" align="left" rowspan="1" colspan="1">Austria</td><td valign="top" align="left" rowspan="1" colspan="1">Enforcement</td><td valign="top" align="left" rowspan="1" colspan="1">• Prior authorization scheme with cost-sharing for TVR</td></tr><tr><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">Engineering</td><td valign="top" align="left" rowspan="1" colspan="1">• PIs are reimbursed according to the published “limitations of prescription”—as long as a patient meets the criteria defined in the “limitations of prescription” his/her treatment will be approved and thus reimbursed</td></tr><tr style="border-bottom: thin solid #000000;"><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• No reimbursement of BCV for null responders</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Belgium</td><td valign="top" align="left" rowspan="1" colspan="1">Enforcement</td><td valign="top" align="left" rowspan="1" colspan="1">• Need prior approval from the Health Insurance companies according to agreed criteria (chapter IV medicine) before PIs can be used.</td></tr><tr style="border-bottom: thin solid #000000;"><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• Otherwise, 100% patient co-payment if prescribing does not follow agreed criteria</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Bosnia and Herzegovina (Republic of Srpska)</td><td valign="top" align="left" rowspan="1" colspan="1">Education</td><td valign="top" align="left" rowspan="1" colspan="1">• Guidelines available for the diagnosis and treatment of chronic hepatitis C</td></tr><tr><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• Increasing public awareness as well as campaigns stating that there is free, voluntarily, anonymous testing and counseling for patients with suspected HCV. Alongside this, distribution of educational materials—helped by establishing counseling centers for hepatitis and HIV</td></tr><tr><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">Economics</td><td valign="top" align="left" rowspan="1" colspan="1">• Therapy initiated only in specialist centers for patients with hepatitis</td></tr><tr><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">Engineering</td><td valign="top" align="left" rowspan="1" colspan="1">• Health Insurance Fund purchases medicines for patients with HCV under a 1-year (centralized tender) with defined reimbursement conditions; otherwise 100% co-payment</td></tr><tr><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">Enforcement</td><td valign="top" align="left" rowspan="1" colspan="1">• However, neither BCV (market authorization in B&H in 2012) or TVR (no application so far submitted in B&H) are currently reimbursed (100% co-payment); so far (March 2016) there have been no requests for a refund sent to the Health Insurance Fund</td></tr><tr style="border-bottom: thin solid #000000;"><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• Proposed wholesale price by the manufacturer within the market authorization process was €4720/package</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Croatia</td><td valign="top" align="left" rowspan="1" colspan="1">Engineering<break></break> Enforcement</td><td valign="top" align="left" rowspan="1" colspan="1">• Incidence and prevalence of HCV has been declining in Croatia in recent years through preventative measures. These include ensuring safety of blood products, reducing drug abuse as well as programs to reduce infection rates among intravenous drug users</td></tr><tr><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• Both BCV and TVR are reimbursed and on the list of expensive products since 2013 (BCV in Official Gazette 49/2013 and for TVR in Official Gazette 67/2013)</td></tr><tr style="border-bottom: thin solid #000000;"><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• They are both reimbursed for triple therapy but with defined guidance for use for reimbursement. Treatment is reimbursed only in hospitals to ensure prescribing is in line with current guidelines/guidance</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">France</td><td valign="top" align="left" rowspan="2" colspan="1">Education<break></break> Engineering<break></break> Enforcement</td><td valign="top" align="left" rowspan="1" colspan="1">• The prevention and management of HCV has been on the public health agenda in France since the early 1990s, with an extensive network of hepatologists and reference centers</td></tr><tr><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• The authorities through the referral centers also research outcomes from current treatment approaches</td></tr><tr style="border-bottom: thin solid #000000;"><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• Only physicians specialized in hepatology, internal medicine or infectious diseases are allowed to initiate treatment with DAAs including BCV and TVR</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Iceland</td><td valign="top" align="left" rowspan="1" colspan="1">Education</td><td valign="top" align="left" rowspan="1" colspan="1">• Both BCV and TVR are reimbursed</td></tr><tr><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• Guidelines are available but currently no health authority activities directing prescribing</td></tr><tr><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• More recently a nationwide treatment-project where all HCV infected patients are being offered the second generation DDA's over a 2–3 years period.</td></tr><tr style="border-bottom: thin solid #000000;"><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• Alongside this, a large scale epidemiological study is ongoing to ascertain whether it is possible eliminate HCV from a small, relatively confined population such as Iceland</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Ireland</td><td valign="top" align="left" rowspan="2" colspan="1">Education<break></break> Engineering<break></break> Economics<break></break> Enforcement</td><td valign="top" align="left" rowspan="1" colspan="1">• Surveillance system in place to collect effectiveness, safety, tolerability and economic outcomes from current treatments including BCV and TVR</td></tr><tr><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• All patients prescribed triple therapy are obliged to be registered with the Irish Hepatitis C Outcome and Research Network (ICORN) treatment database which captures longitudinal data</td></tr><tr style="border-bottom: thin solid #000000;"><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• Dispensing of BCV and TPR is restricted to hospitals only to ensure appropriate governance of treatment</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Italy</td><td valign="top" align="left" rowspan="2" colspan="1">Education<break></break> Engineering<break></break> Economics<break></break> Enforcement</td><td valign="top" align="left" rowspan="1" colspan="1">• Italian Horizon Scanning group issuing information on medicines for patients with chronic HCV to national and regional authorities</td></tr><tr><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• Price volume agreements - if expenditure on BCV and TVR exceeds pre-set thresholds, manufacturers payback any differences to the Italian National Health Service</td></tr><tr><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• As a result, BCV has a patient cap of 6000 patients for 2 years and a sales cap of €120 million/year and 5% discount with pegIFN. TVR has a patient cap of 2000 patients the first year, 3000 patients for the second year and re-negotiation above 4000 patients. Sales cap of €100 million/per year. Re-negotiation above €80 million per year<xref ref-type="fn" rid="fn0021"><sup>21</sup></xref></td></tr><tr><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• Physicians need to be validated by the Italian Medicines Agency with only selected centers and physicians allowed to prescribe treatment.</td></tr><tr><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• In the Veneto Region, a special network of centers exists to administer HCV medicines</td></tr><tr style="border-bottom: thin solid #000000;"><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• Patient registers are in place for patients receiving PI to monitor their use according to agreed guidance (and increasingly monitor outcomes in the future). Patient entry encouraged as part of the payment system for hospitals; otherwise hospitals will not reimbursed for the medicines costs for patients with HCV</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Malta</td><td valign="top" align="left" rowspan="1" colspan="1">Economics, Enforcement</td><td valign="top" align="left" rowspan="1" colspan="1">• Treatments initially were not reimbursed by the National Health Service. Some patients bought their treatment privately or were supported through NGOs. Alpha interferon was originally used and later pegylated interferon and ribavirin became standard treatments in Malta (Brincat et al., <xref rid="B8" ref-type="bibr">2013</xref>)</td></tr><tr><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• Subsequently, a one-time donation of medicines was undertaken by pharmaceutical companies enabling some patients to be initiated with ledipasvir/sofosbuvir</td></tr><tr style="border-bottom: thin solid #000000;"><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• Recently, newer treatments including sofosbuvir were included in the National Formulary List to be provided free of charge through the National Health Service. Their use is regulated by protocols approved by the HCV Patient Management Committee</td></tr><tr style="border-bottom: thin solid #000000;"><td valign="top" align="left" rowspan="1" colspan="1">Netherlands</td><td valign="top" align="left" rowspan="1" colspan="1">Enforcement</td><td valign="top" align="left" rowspan="1" colspan="1">• Need prior approval according to agreed guidance before a PI can be dispended</td></tr><tr style="border-bottom: thin solid #000000;"><td valign="top" align="left" rowspan="1" colspan="1">Slovakia</td><td valign="top" align="left" rowspan="1" colspan="1">Enforcement</td><td valign="top" align="left" rowspan="1" colspan="1">• To be eligible for reimbursement, a psychiatrist must make a statement that drug abusers are abstinent for at least 1 year</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Slovenia</td><td valign="top" align="left" rowspan="2" colspan="1">Education<break></break> Engineering<break></break> Enforcement</td><td valign="top" align="left" rowspan="1" colspan="1">• Detailed patient register schemes which include additional data for prescribing a PI: fibrosis stage, IL28B type, prior HCV treatment, type of PI included in treatment, lead-in phase and rapid virological response</td></tr><tr><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• When patients with HCV are treated, data is added according to the national protocol for the management of HCV in patients with HCV. The registry was established in 2007</td></tr><tr><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• Slovenia has a National Viral Hepatitis Expert Group since 1997, established to develop national treatment guidelines and evaluate the efficacy and safety of different treatment approaches in clinical practice</td></tr><tr><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• Since 1997, there is a national network of a named list of infectologists and hepatologists in 5 reference centers for treatment of viral hepatitis. These are the only physicians who can prescribe HCV therapy (in accordance with the national guidelines)</td></tr><tr><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• Since 2007, there is an interdisciplinary National healthcare network across the country for the treatment of HCV in patients who inject themselves with drugs</td></tr><tr style="border-bottom: thin solid #000000;"><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• The Health Insurance Institute of Slovenia (ZZZS) has a possibility to control physician prescribing where regulations exist. When prescribing is not in line with prescribing restrictions, the provider physician/hospital has to pay a fine</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Spain—Catalonia</td><td valign="top" align="left" rowspan="2" colspan="1">Education<break></break> Engineering<break></break> Economics</td><td valign="top" align="left" rowspan="1" colspan="1">• Available algorithms of chronic HCV treatment at a national and regional level, including IL28B testing as well as selection of dual or triple therapy in naïve/relapsers/non-responder patients</td></tr><tr><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• Register of prevalence and treatment outcomes ongoing</td></tr><tr><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• Data from surveillance systems are used to regularly monitor expenditure and benchmarking among hospitals. Also monitoring of erythropoiesis factor requirements (management and impact of side effects)</td></tr><tr><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• PI related data incorporated into the surveillance system. This includes the numbers of patients treated for HCV treated with a PI, which PI and PegIFN is selected as well as co-infected patients with HIV and organ transplanted patients treated with a PI</td></tr><tr><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• It is recommended a multidisciplinary treatment approach is undertaken to improve care including for instance a gastroenterologist/infectious disease physician, psychiatrist, pharmacist and laboratory testing personnel</td></tr><tr><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• Annual budgets for outpatient drug treatments are allocated to Catalan public hospitals (including drugs for cancer, HCV, multiple sclerosis, etc.) to help control costs</td></tr><tr style="border-bottom: thin solid #000000;"><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• There are currently no patient co-payments for HCV medicines in Catalan public hospitals</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Sweden</td><td valign="top" align="left" rowspan="2" colspan="1">Education<break></break> Engineering<break></break> Economics</td><td valign="top" align="left" rowspan="1" colspan="1">• National treatment guidelines available to guide treatment</td></tr><tr><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• BCV is currently not reimbursed by the TLV (Dental and Pharmaceutical Benefits Agency - reimbursement authority in Sweden) but TVR is. However, all drugs for HCV infection, including TVR and BCV, are free for the patient since medicines for infectious diseases including Hepatitis C are free under the Infectious Diseases Act</td></tr><tr style="border-bottom: thin solid #000000;"><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• TVR is currently reimbursed without restriction</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Turkey (Aygen et al., <xref rid="B4" ref-type="bibr">2015</xref>)</td><td valign="top" align="left" rowspan="1" colspan="1">Engineering<break></break> Enforcement</td><td valign="top" align="left" rowspan="1" colspan="1">• BCV and TVR are reimbursed with restricted indications, e.g., triple therapy is reimbursed in combination with TVR in patients infected with HCV genotype 1 who have compensated liver disease and who have previously received PegIFN/RBV therapy and relapsed</td></tr><tr><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• In patients with compensated liver disease, total treatment duration is 48 weeks with 12 weeks of TVR therapy, provided that the liver biopsy Ishak score is stage ≥4, the platelet count is below 100,000/mm<sup>3</sup>, or the prothrombin time is over 3 seconds</td></tr><tr style="border-bottom: thin solid #000000;"><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• In relapsed patients, total treatment duration is 24 weeks, including 12 weeks of TVR therapy if HCV RNA is negative at week 4 of treatment, and 48 weeks if HCV RNA is positive at week 4 of treatment</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">UK—Scotland</td><td valign="top" align="left" rowspan="1" colspan="1">Engineering</td><td valign="top" align="left" rowspan="1" colspan="1">• Pro-active approach to the introduction of triple therapy including BCV and TCR</td></tr><tr><td rowspan="1" colspan="1"></td><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• Patient numbers are tracked to check they agree with original predictions and the case for funding (in Tayside)</td></tr></tbody></table><table-wrap-foot><p>NB. BCV, Boceprevir; DAAs, direct acting antivirals; pegIFN, pegylated interferon; PI, Protease inhibitor; TVR, Telaprevir. Estonia is not included in the Table as the pharmaceutical companies were providing first generations DAAs free of charge until recently.</p></table-wrap-foot></table-wrap></sec><sec><title>Activities among by health authorities to influence the prescribing of BCV and TVR</title><p>Table <xref ref-type="table" rid="T6">6</xref> summarizes the variety of measures broken down by the 4E method (Table <xref ref-type="table" rid="T5">5</xref>) implemented by the various European countries to improve the management of patients with HCV. This includes any measures regarding subsequent utilization of BCV and TVR.</p><p>All European countries studied had a national strategy plan to manage patients with HCV, which typically included prevention and control programmes and/or guidelines<sup>19</sup>. All clinical guidelines available in English typically followed the strict EMA recommendations, e.g., besides SVR monitoring, there were also clear starting and stopping rules prior to initiating treatment and continuing treatment (European Association for the Study of the Liver, <xref rid="B24" ref-type="bibr">2011</xref>; Hofmann et al., <xref rid="B49" ref-type="bibr">2012</xref>; Lagging et al., <xref rid="B56" ref-type="bibr">2012</xref>; Leroy et al., <xref rid="B58" ref-type="bibr">2012</xref>; Orlent et al., <xref rid="B77" ref-type="bibr">2012</xref>; Ramachandran et al., <xref rid="B82" ref-type="bibr">2012</xref>)<sup>1, 2</sup>. Where countries mostly differed was their opinion regarding genotyping interleukin 28B (IL28B) polymorphism. Some countries and regions recommend routine testing, e.g., Catalonia, whilst others currently do not test.</p><p>All countries studied had a surveillance system for either acute and/or chronic HCV infections. Unfortunately current registries are heterogeneous and differ mostly in case definition (European Centre for Desease Prevention Control, <xref rid="B26" ref-type="bibr">2010</xref>; Cornberg et al., <xref rid="B20" ref-type="bibr">2011</xref>; Yehia et al., <xref rid="B96" ref-type="bibr">2014</xref>)<xref ref-type="fn" rid="fn0020"><sup>20</sup></xref>. The EMA Committee for Medicinal Products for Human Use (CHMP) emphasized that the prescribing of BCV and TVR must be undertaken by professionals with knowledge and experience of HCV, including testing and treatment<sup>1, 2</sup>. Consequently, triple therapy must be prescribed by doctors who specialize in HCV management<sup>1, 2</sup>. This is typically the case for BCV and TVR, which are only licensed for GT1. This means physicians are obliged to test for genotypes before starting treatment.</p><p>All European countries that reimbursed triple therapy typically had no patient co-payment. We are aware that risk sharing agreements and discounts are used by health authorities to control budgets, enabling patients to have access to new high priced medicines (Adamski et al., <xref rid="B1" ref-type="bibr">2010</xref>; Ferrario and Kanavos, <xref rid="B28" ref-type="bibr">2013</xref>). However, data on the extent of any discounts are typically lacking as such arrangements are confidential. As a result, we were unable to document any cost/DDD data for BCV and TVR in Scotland (Tayside). Reimbursement for HIV co-infection and treatment before and after liver transplantation currently exists in a number of European countries including Austria, Ireland, Catalonia, Scotland, Slovakia, Slovenia and Sweden.</p></sec><sec><title>Utilization</title><p>The uptake of BCV and TVR varied between the countries and over time (Figures <xref ref-type="fig" rid="F1">1A,B</xref>). The highest uptake for TVR was in Tayside (Scotland) in the second quarter of 2012 at 2.4 DIQs. The highest uptake of BCV was in Belgium at 1.32 DIQs. Subsequently all countries showed a decrease of HCV medicines between approximately 6 months after triple therapy reimbursement, e.g., the Netherlands, Belgium, and Slovenia, and 12 months after triple therapy reimbursement, e.g., Austria, Denmark, Catalonia and Sweden. Utilization of BCV was highest in Belgium with 38% in third quarter after reimbursement (Q1 2013) and lowest in Italy and Estonia.</p><fig id="F1" position="float"><label>Figure 1</label><caption><p><bold>Uptake BCV and TVR across European countries from the month first reimbursed</bold>. Each Bar represents a 3 month period. Only the first quarter of 2012 and 2013 is displayed in the legend to include all countries. <bold>(A)</bold> Included countries are: AU, Austria; BE, Belgium; DK, Denmark; EE, Estonia; ES (CT), Catalonia (Spain). <bold>(B)</bold> Included countries are: IT, Italy; NL, the Netherlands; UK-Scot (TS), Tayside (Scotland); SI, Slovenia; SE, Sweden; TR, Turkey.</p></caption><graphic xlink:href="fphar-07-00197-g0001"></graphic></fig><p>The upper and lower range (dotted lines in Figures <xref ref-type="fig" rid="F2">2</xref>, <xref ref-type="fig" rid="F3">3</xref>) illustrate the utilization of BCV and TVR if all potential patients with GT1 prevalence of 45–65% were treated (see comments in Table <xref ref-type="table" rid="T4">4</xref>). For TVR, only Sweden meets the upper limit, which equates to the 65% GT1 prevalence and greatest percentage of therapy containing TVR. Only Austria, Estonia, Italy, and Catalonia do not meet the lower limit, indicating that even in a hypothetical situation with low GT1 prevalence and a short DAA treatment length, not all patients who should receive triple therapy actually receive it. For BCV, Belgium touches the lower limit with lowest GT1 prevalence and a lowest percentage of treatment containing BCV. Due to lack of patient specific data, prevalence data and different algorithms, the utilization of BCV and TVR are not consolidated. However, after adding BCV and TVR together, Belgium, Denmark, the Netherlands and Sweden appear to have the highest uptake of triple therapy vs. dual therapy.</p><fig id="F2" position="float"><label>Figure 2</label><caption><p><bold>Percentage utilization of TVR vs. ribavirin in quarters following reimbursement</bold>. NB: Upper range genotype 1 prevalence (=GT1) is 65% and highest percentages (50%) triple therapy containing TVR (mostly non-cirrhotic patients). Lower range GT1 prevalence is only 45% and lowest percentages (25%) triple therapy containing TVR (mostly cirrhotic patients).</p></caption><graphic xlink:href="fphar-07-00197-g0002"></graphic></fig><fig id="F3" position="float"><label>Figure 3</label><caption><p><bold>Percentage utilization of BCV vs. ribavirin in quarters following reimbursement</bold>. Upper range genotype 1 prevalence (=GT1) is 65% and highest percentages (92%) triple therapy containing BVC (mostly cirrhotic patients). Lower range GT1 prevalence is only 45% and lowest percentages (67%) triple therapy containing BVC (mostly naïve non-cirrhotic patients).</p></caption><graphic xlink:href="fphar-07-00197-g0003"></graphic></fig></sec><sec><title>Expenditure data</title><p>Table <xref ref-type="table" rid="T7">7</xref> contains reimbursed expenditure/DDD data for both BCV and TVR up to May 2013. Turkey was excluded as only IMS data were available. Estonia was excluded as these medicines have only recently been reimbursed, and Scotland (Tayside) was excluded as reimbursed data included confidential discounts; consequently unavailable for analysis. There were no differences in the documented prices between medicines dispensed in hospital pharmacies for out-patients or community pharmacies. However, this did not include any confidential discounts as part of risk sharing or other agreements (Adamski et al., <xref rid="B1" ref-type="bibr">2010</xref>; Ferrario and Kanavos, <xref rid="B28" ref-type="bibr">2013</xref>; Vogler et al., <xref rid="B90" ref-type="bibr">2013</xref>).</p><table-wrap id="T7" position="float"><label>Table 7</label><caption><p><bold>Reimbursed Euro per DDD (EUR/DDD) from the time of reimbursement until the latest available data (May 2013) of TVR and BCV</bold>.</p></caption><table frame="hsides" rules="groups"><thead><tr><th rowspan="1" colspan="1"></th><th valign="top" align="center" colspan="2" style="border-bottom: thin solid #000000;" rowspan="1"><bold>Telaprevir (TVR)</bold></th><th valign="top" align="center" colspan="2" style="border-bottom: thin solid #000000;" rowspan="1"><bold>Boceprevir (BCV)</bold></th></tr><tr><th rowspan="1" colspan="1"></th><th valign="top" align="center" rowspan="1" colspan="1"><bold>EUR/DDD when reimbursed</bold></th><th valign="top" align="center" rowspan="1" colspan="1"><bold>EUR/DDD 05-2013</bold></th><th valign="top" align="center" rowspan="1" colspan="1"><bold>EUR/DDD when reimbursed</bold></th><th valign="top" align="center" rowspan="1" colspan="1"><bold>EUR/DDD 05-2013</bold></th></tr></thead><tbody><tr><td valign="top" align="left" rowspan="1" colspan="1">Austria<xref ref-type="table-fn" rid="TN1"><sup>*</sup></xref></td><td valign="top" align="center" rowspan="1" colspan="1">321.48</td><td valign="top" align="center" rowspan="1" colspan="1">310.44</td><td valign="top" align="center" rowspan="1" colspan="1">146.60</td><td valign="top" align="center" rowspan="1" colspan="1">116.11</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Belgium<xref ref-type="table-fn" rid="TN1"><sup>*</sup></xref></td><td valign="top" align="center" rowspan="1" colspan="1">324.58</td><td valign="top" align="center" rowspan="1" colspan="1">324.54</td><td valign="top" align="center" rowspan="1" colspan="1">116.66</td><td valign="top" align="center" rowspan="1" colspan="1">116.66</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Belgium<xref ref-type="table-fn" rid="TN2"><sup>**</sup></xref></td><td valign="top" align="center" rowspan="1" colspan="1">315.29</td><td valign="top" align="center" rowspan="1" colspan="1">–</td><td valign="top" align="center" rowspan="1" colspan="1">113.31</td><td valign="top" align="center" rowspan="1" colspan="1">–</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Croatia<xref ref-type="table-fn" rid="TN2"><sup>**</sup></xref>/<xref ref-type="table-fn" rid="TN3"><sup>***</sup></xref></td><td valign="top" align="center" rowspan="1" colspan="1">331.97</td><td valign="top" align="center" rowspan="1" colspan="1">331.97</td><td valign="top" align="center" rowspan="1" colspan="1">123.46</td><td valign="top" align="center" rowspan="1" colspan="1">123.46</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Denmark<xref ref-type="table-fn" rid="TN2"><sup>**</sup></xref></td><td valign="top" align="center" rowspan="1" colspan="1">394.65</td><td valign="top" align="center" rowspan="1" colspan="1">384.53</td><td valign="top" align="center" rowspan="1" colspan="1">145.53</td><td valign="top" align="center" rowspan="1" colspan="1">131.62</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Netherlands<xref ref-type="table-fn" rid="TN1"><sup>*</sup></xref></td><td valign="top" align="center" rowspan="1" colspan="1">300.23</td><td valign="top" align="center" rowspan="1" colspan="1">302.66</td><td valign="top" align="center" rowspan="1" colspan="1">114.51</td><td valign="top" align="center" rowspan="1" colspan="1">114.05</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Slovenia<xref ref-type="table-fn" rid="TN1"><sup>*</sup></xref></td><td valign="top" align="center" rowspan="1" colspan="1">302.31</td><td valign="top" align="center" rowspan="1" colspan="1">291.64</td><td valign="top" align="center" rowspan="1" colspan="1">113.10</td><td valign="top" align="center" rowspan="1" colspan="1">113.10</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Spain-Catalonia<xref ref-type="table-fn" rid="TN2"><sup>**</sup></xref></td><td valign="top" align="center" rowspan="1" colspan="1">304.74</td><td valign="top" align="center" rowspan="1" colspan="1">304.74</td><td valign="top" align="center" rowspan="1" colspan="1">103.92</td><td valign="top" align="center" rowspan="1" colspan="1">103.92</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Sweden<xref ref-type="table-fn" rid="TN1"><sup>*</sup></xref></td><td valign="top" align="center" rowspan="1" colspan="1">329.49</td><td valign="top" align="center" rowspan="1" colspan="1">294.82</td><td valign="top" align="center" rowspan="1" colspan="1">117.69</td><td valign="top" align="center" rowspan="1" colspan="1">118.52</td></tr></tbody></table><table-wrap-foot><p>NB:</p><fn id="TN1"><label>*</label><p>Dispensed in community pharmacy;</p></fn><fn id="TN2"><label>**</label><p>Dispensed in hospital pharmacy;</p></fn><fn id="TN3"><label>***</label><p>Price from basic list and price from expensive product list (same prices). Reimbursed prices of BCV and TVR should not be compared as different treatment paradigms.</p></fn></table-wrap-foot></table-wrap><p>For both BCV and TVR, Denmark appeared to pay the highest reimbursed price at 131.52 and 384.53 EUR/DDD respectively. Catalonia (Spain) appeared to pay the lowest reimbursed price at 103.92 EUR/DDD for BCV and Slovenia the lowest reimbursed price for TVR at 291.64 EUR/DDD. Only Austria had a major price decrease from EUR 146.60 to EUR 116.1 per DDD during the course of the study following agreements.</p><p>Total expenditure for HCV treatments was decreasing in all countries before the reimbursement of BCV and TVR, especially in Catalonia and Austria (Figure <xref ref-type="fig" rid="F4">4</xref>), and again prior to the availability of the newer second generation DAAs, at the end of 2012 and beginning of 2013. Denmark and Slovenia had the lowest increase in EUR/1000 inhabitants/3 months after the reimbursement of BCV and TVR. This was 99 and 89% respectively between the lowest and highest EUR/1000 inhabitants/3 months from just before impending reimbursement of these two medicines to just after. This compares with a rise of 385% in Catalonia.</p><fig id="F4" position="float"><label>Figure 4</label><caption><p><bold>Expenditure on treatments for HCV (Euro/1000 inhabitants/quarter) from 2008 to 2013</bold>. NB: ◯ = reimbursement agreed BVC. Sweden and Denmark first quarter after EMA approval are included.</p></caption><graphic xlink:href="fphar-07-00197-g0004"></graphic></fig></sec></sec><sec sec-type="discussion" id="s4"><title>Discussion</title><p>Our analysis showed reasonable consistency in the uptake of BCV and TVR among the European countries studied (Figure <xref ref-type="fig" rid="F1">1</xref>) compared with appreciable differences that have been seen in the utilization of new high priced medicines to treat patients with rheumatoid arthritis, type 2 diabetes and cancer across Europe (Hoebert et al., <xref rid="B48" ref-type="bibr">2012</xref>; Jönsson et al., <xref rid="B53" ref-type="bibr">2014</xref>; Putrik et al., <xref rid="B81" ref-type="bibr">2014</xref>; Nolte and Corbett). This is despite appreciable differences among the participating countries in their level of spending on healthcare as well as the percentage of GDP they spend on health (Table <xref ref-type="table" rid="T1">1</xref>). This might be explained firstly by the fact that all European countries followed EMA labeled indications with strict regulations for clear genotyping and SVR monitoring. Secondly, there were relatively few measures implemented among European health authorities to influence physician prescribing of either BCV or TVR apart from directing prescribing to specialists and specialist centers and entering patients into registries. Thirdly, both treatments were typically 100% reimbursed although there are exceptions (Table <xref ref-type="table" rid="T6">6</xref>).</p><p>The rapid uptake of BCV and TVR across countries (Figure <xref ref-type="fig" rid="F1">1</xref>) may be explained by expectancy among professionals and patients regarding the increased efficacy of these first generation DAAs vs. previous regimens. This resulted in countries placing patients on waiting lists to receive triple therapy soon after BCV and TVR were reimbursed. Whilst we cannot say this with certainty, this is in line with decreasing costs of ribavirin and pegIFNs before reimbursement of the new PIs (Figure <xref ref-type="fig" rid="F4">4</xref>). Additionally, European guidelines advised postponing HCV treatment until the new DAAs including sofosbuvir became available in view of their greater efficacy and tolerability as well as reduced length of treatment (European Association for the Study of the Liver, <xref rid="B24" ref-type="bibr">2011</xref>; Hatzakis et al., <xref rid="B43" ref-type="bibr">2011</xref>).</p><p>The consistency in the utilization of BCV and TVR across Europe appears promising, especially considering a desire to reduce infection rates whilst attempting to keep the budgets for these medicines manageable. Any differences in utilization rates of BCV and TVR between countries (Figure <xref ref-type="fig" rid="F1">1</xref>) could potentially be explained by differences in HCV and GT1 prevalence variations as well as local physician preferences and knowledge rather than any specific health authority interventions (Table <xref ref-type="table" rid="T6">6</xref>). However, we cannot comment further as we did not have access to patient level data. In addition, we did not explore key issues among specialist physicians involved in the management of patients with HCV.</p><p>Reimbursed prices for BCV and TVR (EUR/DDD) also appeared comparable among the European countries studied. This did not include risk-sharing agreements including rebates and discounts as information about these agreements is limited, with the exception of Italy. This is because such measures are typically confidential.</p><p>The upper and lower ranges identified in Figures <xref ref-type="fig" rid="F2">2</xref>, <xref ref-type="fig" rid="F3">3</xref> suggest that the uptake of triple therapy appears reasonable in a number of the studied countries based on the assumptions of GT1 prevalence and treatment algorithms (Table <xref ref-type="table" rid="T4">4</xref>); although, lower in some countries. However, there needs to be caution when interpreting these results as a number of assumptions were made (Table <xref ref-type="table" rid="T4">4</xref>), and we are aware of the concerns with current estimated prevalence rates for HCV GT1 (Table <xref ref-type="table" rid="T1">1</xref>). Utilization data can also be complicated by other factors, which include patients being selected for dual therapy if they have a low HCV RNA viral load after 4 weeks or ILB28B favorable CC polymorphism. Analysis of subsequently available patient level data in Stockholm, Sweden, showed that among patients initiated on treatment in 2012, total (TVR+BCV)/ribavirin was approximately 64% in 2012, which corresponds to Figures <xref ref-type="fig" rid="F2">2</xref>, <xref ref-type="fig" rid="F3">3</xref> (Frisk, Personal Communication). However, in Catalonia, TVR+BCV/ribavirin was used in approximately 18.6% of patients, which is higher than in our study (Ibáñez, Personal Communication). In a recent report involving Italy, France, Germany, Spain and UK, most gastroenterologists stated that triple therapy would be prescribed more for non-responders in the first year of its availability. By 2014, 60% of treatment-naïve patients were expected to be treated with triple therapy<xref ref-type="fn" rid="fn0022"><sup>22</sup></xref>. This wide predicted variation in the prescribing of DAAs was not seen in practice (Figures <xref ref-type="fig" rid="F1">1A,B</xref>), with the utilization of BCV and TVR (Figures <xref ref-type="fig" rid="F1">1A,B</xref>) appearing more similar compared with the appreciable differences in the utilization of other high priced medicines, e.g., TNF alpha inhibitors and those to treat patients with cancer or Type 2 diabetes (Hoebert et al., <xref rid="B48" ref-type="bibr">2012</xref>; Jönsson et al., <xref rid="B53" ref-type="bibr">2014</xref>; Putrik et al., <xref rid="B81" ref-type="bibr">2014</xref>; Nolte and Corbett).</p><p>One reason for the lower than expected surge in the use of triple therapy in Europe could be that efficacy and safety data from clinical trials are not always replicated in clinical practice and side effects can be more frequent and severe. This is especially the case in treatment-experienced HCV patients as observed in the French cohort reported by Hézode et al. (<xref rid="B45" ref-type="bibr">2013</xref>, <xref rid="B46" ref-type="bibr">2014</xref>). The same phenomenon has been seen in Ireland where the effectiveness in patients entered into the registry (Table <xref ref-type="table" rid="T6">6</xref>) was considerably lower than those seen from the clinical trials (O'Leary, Personal Communication). Published studies in the US have shown that the uptake of triple therapy was also relatively low, although TVR (INCIVEK®) reached 1 US$ billion within a short time and US$1.6 billion after the first year<xref ref-type="fn" rid="fn0023"><sup>23</sup></xref>. In a small study (487 GT1 patients), only 18.7% of patients received triple therapy in the first year after FDA approval (Chen et al., <xref rid="B13" ref-type="bibr">2013</xref>). Reasons not to start triple therapy were principally contraindications (50%). Of all the patients who started triple therapy, 21% discontinued it. This was mostly because of side effects (Chen et al., <xref rid="B13" ref-type="bibr">2013</xref>). Other studies have also concluded that side effects are the most frequent barrier for chronic HCV treatment (McGowan et al., <xref rid="B66" ref-type="bibr">2013</xref>)<sup>.</sup></p><p>Consequently, side effects and complexity of drug treatment posology of PIs may explain the decrease in utilization and expenditure of BCV and TVR in recent years among European countries (Figures <xref ref-type="fig" rid="F1">1</xref>, <xref ref-type="fig" rid="F4">4</xref>) coupled with the anticipation of the new second generation DAAs, with less side effects, shorter treatment durations, the potential for interferon free regimens and the potential for cures (Brennan and Shrank, <xref rid="B7" ref-type="bibr">2014</xref>; Kohli et al., <xref rid="B55" ref-type="bibr">2014</xref>)<sup>3</sup>. We are aware for instance that in Catalonia, France and Sweden, a number of potentially eligible patients for BCV and TVR were put on waiting lists until the launch of the second generation DAAs, and probably in other countries as well.</p><p>This observation is strengthened by recent findings showing that sofosbuvir, after TVR, was the fastest growing prescribed medicine in the US with sales of US$2.27 billion in the first quarter of 2014<xref ref-type="fn" rid="fn0024"><sup>24</sup></xref> reaching, as mentioned, US$12.4 billion worldwide in 2014. This accounted for 37.5% of expenditure on HCV medicines among managed care organizations in 2014 (Trooskin et al., <xref rid="B88" ref-type="bibr">2015</xref>)<sup>11</sup>. This expenditure is helped by the cost of a standard 12-week course of sofosbuvir and simeprevir being initially at US$84 000 and US$66,000 in the US respectively, with sofosbuvir initially priced at between Euro 50,000 and 60,000 per 12-week course among Eurozone countries, although U$54,000 (€44,000) in the UK and €41,000 in France (Brennan and Shrank, <xref rid="B7" ref-type="bibr">2014</xref>; Lemoine and Asia, <xref rid="B57" ref-type="bibr">2014</xref>; Phelan and Cook, <xref rid="B79" ref-type="bibr">2014</xref>; van de Ven et al., <xref rid="B89" ref-type="bibr">2014</xref>; Trooskin et al., <xref rid="B88" ref-type="bibr">2015</xref>; Iyengar et al., <xref rid="B52" ref-type="bibr">2016</xref>). These prices, coupled with the prevalence of HCV, have already resulted in activities among countries to control costs through price negotiations and other strategies. This is not surprising with potential sales of US$15 trillion if an estimated 180 million people worldwide with HCV were treated with sofosbuvir (Montazerhodjat et al., <xref rid="B73" ref-type="bibr">2016</xref>). Table <xref ref-type="table" rid="T8">8</xref> summarizes some of the activities, exacerbated for instance by the authorities in France initially being charged sofosbuvir at 756 times the cost of its production in France (Phelan and Cook, <xref rid="B79" ref-type="bibr">2014</xref>).</p><table-wrap id="T8" position="float"><label>Table 8</label><caption><p><bold>Price negotiations and other strategies across countries to reduce the expenditure burden of second generation DAAs</bold>.</p></caption><table frame="hsides" rules="groups"><thead><tr><th valign="top" align="left" rowspan="1" colspan="1"><bold>Country</bold></th><th valign="top" align="left" rowspan="1" colspan="1"><bold>Summary of ongoing pricing negotiations across countries</bold></th></tr></thead><tbody><tr style="border-bottom: thin solid #000000;"><td valign="top" align="left" rowspan="1" colspan="1">Australia</td><td valign="top" align="left" rowspan="1" colspan="1">• Ongoing schemes in Australia to enable access to new effective DAAs, including potential pricing policies, as the proposed budget impact of over Australian $3 billion over a 5 year period is considered unaffordable<xref ref-type="fn" rid="fn0025"><sup>25</sup></xref></td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Brazil</td><td valign="top" align="left" rowspan="1" colspan="1">• Negotiated prices for sofosbuvir are as low as US$7000/12-weeks treatment course<xref ref-type="fn" rid="fn0026"><sup>26</sup></xref></td></tr><tr><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• Negotiated price for a bottle (28 capsules) of simeprevir in Brazil is US$1000 (Andrieux-Meyer et al., <xref rid="B2" ref-type="bibr">2015</xref>)</td></tr><tr style="border-bottom: thin solid #000000;"><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• BCV and TVR now removed from the public funded (SUS) treatment programmes in view of their lower effectiveness and greater side-effects compared with the second generation DAAs</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Egypt and India (Brennan and Shrank, <xref rid="B7" ref-type="bibr">2014</xref>; Phelan and Cook, <xref rid="B79" ref-type="bibr">2014</xref>; Trooskin et al., <xref rid="B88" ref-type="bibr">2015</xref>)</td><td valign="top" align="left" rowspan="1" colspan="1">• Egyptian authorities negotiated a 99% discount of the US price—bringing its price in Egypt down to US $900 per 12-week course</td></tr><tr style="border-bottom: thin solid #000000;"><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• Sofosbuvir is being manufactured in India at a cost of < US$250/course as Gilead was denied a patent in India</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">France</td><td valign="top" align="left" rowspan="1" colspan="1">• Second generation DAAs were initially only reimbursed for advanced liver fibrosis (F2-F4) (Dedet, Personal Communication)</td></tr><tr><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• More recently, the government in France introduced a new tax using a “progressive contribution scheme”</td></tr><tr><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• As a result, the Economic Committee for Health Products agreed a price of €13,667 per 28-tablet pack for sosfobuvir alone, i.e., approximately €5000 lower than the initial list price, at an overall negotiated price of €41,000 (US$51,000) for a 12-week course</td></tr><tr style="border-bottom: thin solid #000000;"><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• Prices are likely to fall further with the launch of additional DAAs to help cure patients with HCV<xref ref-type="fn" rid="fn0027"><sup>27</sup></xref>, including the combination of sofosobuvir and ledipasvir leading to a potential cure initially at €48,000/treatment course<xref ref-type="fn" rid="fn0028"><sup>28</sup></xref>. The negotiated price for sofosbuvir+ ledipasvir was finally set at €547.619 per tablet, i.e., €46,000/treatment course<xref ref-type="fn" rid="fn0029"><sup>29</sup></xref></td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Georgia<xref ref-type="fn" rid="fn0030"><sup>30</sup></xref></td><td valign="top" align="left" rowspan="1" colspan="1">• The minister of health, labor and social affairs in Georgia emailed Gilead to say they had a fund of US$5 million to help eradicate HCV with an infection rate of almost 7%</td></tr><tr style="border-bottom: thin solid #000000;"><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• Gilead subsequently agreed to provide sofosbuvir free of charge to help eliminate the disease within 10 years</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Italy</td><td valign="top" align="left" rowspan="1" colspan="1">• The Italian Reimbursement Agency (AIFA) negotiated a price reduction scheme with the reimbursed price for “initial patients” at €37,000/patient/course dropping to €4000 for the “last” patients, averaging €18,000 per patient (Messori, <xref rid="B70" ref-type="bibr">2015a</xref>)<xref ref-type="fn" rid="fn0031"><sup>31</sup></xref></td></tr><tr style="border-bottom: thin solid #000000;"><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• As a result, overall expenditure for sofosbuvir in Italy is expected to be less than €500 million per year initially, which was acceptable to all<sup>30</sup></td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">South Africa<xref ref-type="fn" rid="fn0032"><sup>32</sup></xref></td><td valign="top" align="left" rowspan="1" colspan="1">• Access to hepatitis treatment in South Africa remains limited due to a combination of patent, registration and cost barriers</td></tr><tr style="border-bottom: thin solid #000000;"><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• More recently, Gilead is allowing the importation of the fixed-dose combination treatment, HARVONI, with a preferential pricing for the public sector at just one one-hundredth of the US price, i.e., approximately R17,000 for a 12-week course</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Spain</td><td valign="top" align="left" rowspan="1" colspan="1">• The negotiated price per course is approximately US$25,000 per course (EU 20,500) or lower, with the ministries of Health and Finance agreeing with the regional health ministries to establish a funding plan to ensure all eligible patients will be treated with the second generation DAAs for at least 12 weeks</td></tr><tr style="border-bottom: thin solid #000000;"><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• In addition, the health outcomes of patients will be assessed (Trooskin et al., <xref rid="B88" ref-type="bibr">2015</xref>)<xref ref-type="fn" rid="fn0033"><sup>33</sup></xref>. Overall, a national expenditure ceiling of Euro727 million euros has been established to fund these new treatments for patients with HCV in Spain<sup>32</sup></td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">Sweden</td><td valign="top" align="left" rowspan="1" colspan="1">• Risk sharing arrangements to lower prices has resulted in improved access among the County Councils (Regions—budget holders)</td></tr><tr style="border-bottom: thin solid #000000;"><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• Alongside this, the authorities in Sweden are currently monitoring the effectiveness (viral load) and safety of second generation DAAs in routine clinical care</td></tr><tr><td valign="top" align="left" rowspan="1" colspan="1">USA</td><td valign="top" align="left" rowspan="1" colspan="1">• Private Insurance Plans (Managed Care Organizations—MCOs) have included sofosbuvir in their formularies although a number of MCOs have included coverage alongside prior authorization (PA) to conserve resources</td></tr><tr><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• Encouraging the use of second generation DAAs irrespective of the METAVIR score, along with PA schemes to encourage 8 weeks of treatment, has resulted in a plateau or fall in usage, endorsing this approach</td></tr><tr><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• MCOs alongside pharmacy benefit management (PBM) schemes have also established data registries to track patient outcomes in terms of relapses and/or reinfection rates</td></tr><tr><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• Among most State Medicaid schemes, patients must have a METAVIR score of F3 or F4, indicative of severe liver disease, to receive sofosbuvir</td></tr><tr><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• 30 States also require sofosbuvir to be prescribed by, or in consultation with, a specialist such as a hepatologist, gastroenterologist, or infectious disease physician before funding, and some States have introduced a sobriety requirement (Canary et al., <xref rid="B11" ref-type="bibr">2015</xref>; Rein, <xref rid="B83" ref-type="bibr">2015</xref>; Trooskin et al., <xref rid="B88" ref-type="bibr">2015</xref>).</td></tr><tr><td rowspan="1" colspan="1"></td><td valign="top" align="left" rowspan="1" colspan="1">• Proposals for new methods to finance such transformative therapies through healthcare loans and securitization (Montazerhodjat et al., <xref rid="B73" ref-type="bibr">2016</xref>)</td></tr></tbody></table></table-wrap><p>There are also ongoing activities among other African countries including Botswana and Zimbabwe given the higher prevalence of HCV in developing countries and the potential for generic agreements. These differences in policies for the second generation DAAs is already leading to considerable differences in their utilization rates in Europe<xref ref-type="fn" rid="fn0034"><sup>34</sup></xref>.</p><p>Recent analysis has shown there is still appreciable variation in the price of second generation DAAs across countries (Andrieux-Meyer et al., <xref rid="B2" ref-type="bibr">2015</xref>). For instance, the price per bottle of sofosbuvir (28 tablets) ranges from $300 (India and Pakistan) and $402 (Nigeria—current market survey) to $20,590 in Switzerland, and for daclatasvir from $175 in Egypt and $252 in Nigeria (current market survey) to $14,899 in Germany (Andrieux-Meyer et al., <xref rid="B2" ref-type="bibr">2015</xref>). Overall, prices are generally substantially lower in LMIC countries although there are outliers, with little correlation between prices and per capita income levels among higher income countries, e.g., the price for a bottle of simeprevir ranges from U$9166 in Spain to US$14,865 in Australia (Andrieux-Meyer et al., <xref rid="B2" ref-type="bibr">2015</xref>).</p><p>It is likely that prices of second generation DAAs will continue falling across countries with estimates of manufacturing for 12-week courses at US$10-$30 for daclatasvir, US$68–$136 for sofosbuvir, US$100–$210 for faldaprevir and US$130–$270 for simeprevir (Hill et al., <xref rid="B47" ref-type="bibr">2014</xref>) coupled with increased competition. This should also help the management of patients with genotypes 4, 5, and 6 that are mainly present in Africa, the Middle East and Asia, where resources are more limited (Papastergiou and Karatapanis, <xref rid="B78" ref-type="bibr">2015</xref>). Their availability as oral therapies coupled with the potential of avoiding genotyping with its associated facilities and costs should further help with increased usage and price negotiations (Ford et al., <xref rid="B30" ref-type="bibr">2014</xref>; Younossi et al., <xref rid="B97" ref-type="bibr">2015</xref>).</p><p>Prices should also fall further following the inclusion of sofosbuvir, simeprevir dasabuvir and daclatasvir in the 19th edition of the WHO Model List of Essential Medicines along with comments to negotiate affordable prices<xref ref-type="fn" rid="fn0035"><sup>35</sup></xref>. This alongside the formation of consortia, which is already happening in the US with State Medicaid schemes, following the example of ARVs where prices reduced substantially following strong pressure from multiple stakeholders (Lemoine and Asia, <xref rid="B57" ref-type="bibr">2014</xref>). In addition, the potential development of a Global Fund for treatments for patients with HCV or other mechanisms (Phelan and Cook, <xref rid="B79" ref-type="bibr">2014</xref>).</p><p>The undoubted effectiveness of the second generation DAAs is making European and other health authorities re-think their approaches to valuing new high priced medicines. This includes new medicines for patients with cancer, as well as those for orphan diseases, which are being reimbursed at high prices despite often very limited health gain in view of patient pressure and other factors (Fojo and Grady, <xref rid="B29" ref-type="bibr">2009</xref>; Hughes-Wilson et al., <xref rid="B51" ref-type="bibr">2012</xref>; Experts in Chronic Myeloid Leukemia, <xref rid="B27" ref-type="bibr">2013</xref>; Kantarjian et al., <xref rid="B54" ref-type="bibr">2013</xref>; Simoens et al., <xref rid="B86" ref-type="bibr">2013</xref>; Cohen and Felix, <xref rid="B18" ref-type="bibr">2014</xref>; <xref rid="B34" ref-type="bibr">Ghinea et al.</xref>). This will continue and be the subject of future research projects among the co-authors. Future research will also include assessing the utilization and expenditure on second generation DAAs in clinical practice among European countries as they become standards of care (Childs-Kean and Hand, <xref rid="B14" ref-type="bibr">2015</xref>), building on early analysis by the French authorities and others<sup>33</sup>.</p></sec><sec sec-type="conclusions" id="s5"><title>Conclusion</title><p>There appears to be reasonable consistency in the uptake and utilization of BCV and TVR among the studied European countries in comparison with other new high priced medicines. This may reflect the high social impact of chronic HCV treatment, especially with few health authority measures implemented to influence physician prescribing. However, using ribavirin as a benchmark hints at differences in the utilization of BCV and TVR. This may indicate that the prescribing of dual vs. triple therapy differs across countries. This cannot be explained by looking at health authority activities for these two treatments and may just reflect physician preference. Consequently, more information including GT1 prevalence data and data on treatment algorithms (including treatment length and treatment period containing PI) is needed to explain this.</p><p>There are also ongoing activities with the second generation DAAs across countries to reduce their costs in view of their undoubted effectiveness and tolerability alongside their considerable budget impact. This will be the subject of future research to provide additional guidance to authorities in the face of continuing resource pressures.</p></sec><sec id="s6"><title>Author contributions</title><p>WdB, CI, PF, HBP, and BG contributed to the design of the paper and the methodology. They also produced the first and subsequent drafts. AA, PVB, AB, LB, GD, JE, JOF, JF, GG, IG, AG, HG, SJ, JJ, RJ, SK, OL, NM, EM, MM, VM-P, AM, OO, AO'L, JP, CS, SS, CT, IT, MT, KT, MW, SV, EV, and CZ provided data on the utilization of BCV and TVR and/or ongoing measures within their own countries to improve the prevention and/or management of HCV. They also critiqued successive drafts of the paper. All authors read and approved the final manuscript.</p><sec><title>Conflict of interest statement</title><p>The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.</p></sec></sec></body><back><ack><p>We acknowledge the help of Paolo Siviero, ex AIFA in Italy, for his help with providing data and information from Italy. We wish to thank Theresa Bucsics, Department of Gastroenterology and Hepatology, Medical University of Vienna, for her helpful comments. This work was in part supported by grants from the World Health Organization and the Karolinska Institutet, Sweden. The write-up was in part supported by a Newton Advanced Fellowship awarded to Professor Augusto Afonso Guerra Junior by the Academy of Medical Sciences, through the UK Government's Newton Fund programme. It was also in part supported by a VR-Link grant from Swedish Research Council (VR-Link 2013-6710) to AM. GG has been supported by the Swedish Research Council Carl Wilhelm Scheeles Guest Professorship.</p></ack><fn-group><fn id="fn0001"><p><sup>1</sup>European Medicine Agency. Incivo - telaprevir [Internet]. 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