A macroeconomic overview of viral hepatitis C in Germany

THE ECO-HEP REPORT A macroeconomic overview of viral hepatitis C in Germany Publisher: Leberhilfe Projekt gUG (Liver Help Project Ltd.) with support ...
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THE ECO-HEP REPORT A macroeconomic overview of viral hepatitis C in Germany

Publisher: Leberhilfe Projekt gUG (Liver Help Project Ltd.) with support from Quantify Research

Realisation of the Eco-Hep Report was supported by Gilead Sciences GmbH Germany

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CONTENTS Foreword Executive summary A

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HEPATITIS C IN GERMANY 1. What is Hepatitis C? 1.1. The hepatitis C virus (HCV), natural course and epidemiology 1.2. Extrahepatic manifestations 1.3. Distinction between prevalent and incident disease 2. Living with hepatitis C 2.1. Quality of life and stigmatisation 2.2. Occupation / work productivity 3. Medical care and treatment 3.1. 3.2.

HCV treatment yesterday and today – a success story Screening / diagnosis / identification

4. Eliminating hepatitis C in Germany – problem areas B

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THE ECO-HEP MODEL – FUNDAMENTALS AND SCENARIOS 1. 2. 3. 4. 5. 6. 7. 8.

Issue and object of investigation General principles of a health economic model Principles of calculation model for the burden of hepatitis C in Germany What data does the model use? What can the Eco-Hep model calculate? Limitations of the model What costs does the Eco-Hep model calculate? Base case scenario 8.1. Cost factor treatment costs 8.2. Cost factor HCV management without treatment 8.3. Extrahepatic manifestations 8.4. Cost factor indirect costs 8.5. Cost factor social costs 9. Elimination scenario 9.1. Basic assumption and cost factor screening 9.2. Cost factor prevention

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RESULTS

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DISCUSSION

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RECOMMENDED PROCEDURE

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Annex

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Glossary

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CONTRIBUTORS

Publisher: Leberhilfe Projekt gUG (Liver Help Project Ltd.); Babette Herder and Achim Kautz

The following companies, commissioned by the Leberhilfe Projekt gUG, contributed to development of the model and writeup of the report: Quantify Research Pfingstgraf Gesundheitskommunikation Philipp Neuerburg Economic Development Consulting

We would like to express our particular thanks for major contributions to this work to: Prof. Dr. med. Thomas Berg Director, Hepatology Section, Leipzig University Clinics, Clinic and Polyclinic for Gastroenterology & Rheumatology, Leipzig, Germany

Dipl.-Soz.päd. Joachim Herder Prof. Dr. Christian Krauth Institute for Epidemiology, Social Medicine and Healthcare System Research, MHH, Hanover, Germany

Prof. Dr. med. S. Rossol M.Sc. Chief Physician, Medical Clinic, Krankenhaus Nordwest, Frankfurt am Main, Germany

Dr. Jona Stahmeyer Institute for Epidemiology, Social Medicine and Healthcare System Research, MHH, Hanover, Germany

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SUPPORTERS

We would like to thank the following persons for their support:

Prof. Dr. med. Markus Backmund Practice Centre im Tal (pit), Ludwig Maximilian University of Munich, Germany

PD Dr. med. Philip Bruggmann Chief Physician, Internal Medicine, Arud Centres, Zurich, Switzerland

Dr. med. Peter Buggisch Physician in Charge, Hepatology Centre, ifi – Institute for interdisciplinary Medicine, Hamburg, Germany

Dr. med. Stefan Christensen CIM – Centre for Interdisciplinary Medicine, Shared Infectiology Practice, Münster, Germany

Dr. med. Christoph Niederau Medical Director and Executive Manager, Laboratory Dortmund Leopoldstraße GbR, Medical Care Centre, Dortmund, Germany

PD Dr. med. Holger Hinrichsen Gastroenterological-Hepatological Centre Kiel, Kiel, Germany

Prof. Dr. Dr. med. Michael R. Kraus Medical Director of the clinics, Chief Physician of Medical Clinic II, Regional Clinics Altötting-Burghausen, Altötting, Germany

Dr. med. Stefan Christensen Centre for HIV and Hepatogastroenterology, Düsseldorf, Germany

Homie Razavi PhD Center for Disease Analysis, CDA, Louisville CO, USA

Prof. Jürgen Rockstroh Senior Physician, Medical University Clinic and Polyclinic I, University Clinics, Bonn, Germany

Prof. Dr. med. Christoph Sarrazin Vice Director of Medical Clinic 1, Clinics of Goethe University, Frankfurt am Main, Germany

Prof. Dr. med. Martin Schäfer Director of the Clinic for Psychiatry, Psychotherapy, Psychosomatics and Addiction Medicine, Central Essen Clinics, Essen, Germany

Dr. med. K.-G. Simon FG Coordinator Hepatology bng, Drs Eisenbach/Simon/Schwarz GbR, Leverkusen, Germany

Timo Rockel IMS Health GmbH Germany, Frankfurt, Germany

Prof. Dr. med. Stefan Zeuzem Director of Medical Clinic 1, Clinics of Goethe University, Frankfurt am Main, Germany

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Foreword From a purely medical point of view we are now on track to eliminate a viral disease. This kind of success has eluded us up to now in the fight against cancer and HIV, but elimination of hepatitis C in Germany is now feasible. However, the societal obligation to treat a disease once diagnosed does impact the macroeconomic picture. Costs are generated: Costs for medical management, drugs, treatment of late complications and, not least, social and indirect costs. The question "What is the cost of a cure?" often entails a further question: "What can we afford?" This report is therefore guided by two simple questions: "What is the cost of eliminating hepatitis C in Germany?" and: "Can Germany afford the elimination of hepatitis C?" To anticipate the conclusion right at the outset: Yes, cost-effective elimination of hepatitis C in Germany is feasible. This statement is possible based on development of a macroeconomic model: the Eco-Hep model. This is a health economic model that analyses the structures of a complex reality and combines basic historical data with future interventions. Based on the data available for Germany, Eco-Hep first produces a calculated model of the macroeconomic burden of hepatitis C in the status quo scenario for 2015. Using the Eco-Hep model matrix it is also possible to describe the elimination of hepatitis C in Germany as a processual phenomenon under certain conditions. Under these conditions, described in the report as concrete measures, hepatitis C can be eliminated in Germany before 2040 by means of a short-term cost increase, disburdening all payers over the middle and long terms.

Babette Herder and Achim Kautz, Leberhilfe Projekt gUG

ABBREVIATIONS ArbMedVV

Verordnung zur arbeitsmedizinischen Vorsorge (ordinance on preventive care in occupational medicine)

BGW

Berufsgenossenschaft für Gesundheitsdienst und Wohlfahrtspflege (Employers' Liability Insurance Association for Healthcare and Welfare Services)

BMBF

Bundesministerium für Bildung und Forschung (Federal Education and Research Ministry)

BMG

Bundesministerium für Gesundheit (Federal Ministry of Health)

DAAs

Direct acting agents

GBE

Gesundheitsberichterstattung des Bundes (Federal Health Reporting System)

GPT (ALT) Glutamate pyruvate transaminase

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HBsAG

HBV surface antigen

HBV

Hepatitis B virus

HCV

Hepatitis C virus

INHSU

International Network on Hepatitis among Substance Users

INF/R

Interferon and ribavirin therapy

IQWiG

Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (Institute for Quality and Efficiency in Healthcare

PI

Protease inhibitors

PSS

Progressive systemic sclerosis

PWID

Person who injects drugs

QALY

Quality adjusted life year

RKI

Robert Koch Institute

RNA

Ribonucleic acid

SVR

Sustained viral response

Viraemic

Detection of virus

WHA

World Health Assembly

WHO

World Health Organisation

EXECUTIVE SUMMARY

Infections with hepatitis C virus, accounting for over 130 million chronically ill persons, are among the most common infectious diseases worldwide.1 Left untreated, they are among the major causes of liver cirrhosis and hepatocellular carcinoma and cause more than 350,000-500,000 deaths globally each year.2 For Germany the number of persons affected is estimated at about 250,000 persons.3 Since the exact number is not known, experts assume between 150,000 and 385,000 HCV cases and at least 1300 deaths per year.45. For those affected, living with hepatitis C often entails a significant loss of quality of life, in many cases accompanied by exclusion and stigmatisation. In addition to these individual burdens, hepatitis C also generates costs, thus making it a factor in health economics and health policy. This makes it all the more important that Germany has now taken a major step towards elimination of HCV in just two years (2013 to 2015). More treatments are being administered annually (25,000 vs. 12,000) and the latest, most efficacious forms of therapy are being use to achieve cure rates averaging over 90% SVR6, with significantly reduced treatment time and significantly improved compatibility. However, further measures are necessary to achieve the goal - cost-effective elimination of hepatitis C disease - and these measures are described in this report as follows: Initially, the Eco-Hep model calculates a model of the macroeconomic burden of hepatitis C in Germany, based on the existing data for Germany in 20157 for the period ending in 2040 - hereinafter referred to as the "base case".

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World Health Organisation: Hepatitis C – Fact sheet N°164 Geneva: WHO; 2014 [updated Updated April 2014]. Available from: http://www.who.int/mediacentre/factsheets/fs164/en/) 2 World Health Organisation: Hepatitis C – Fact sheet N°164 Geneva: WHO; 2014 [updated Updated April 2014]. Available from: http://www.who.int/mediacentre/factsheets/fs164/en/) 3 Razavi et al.; 2014 outputs from the CDA model; JVH 2015 4 Razavi et al.; 2014 outputs from the CDA model; JVH 2015 5 Razavi et al.; 2014 outputs from the CDA model; JVH 2015 6 IMS Health, 2015 7 All Eco-Hep model calculations (base case and elimination model) are modelled and patterned after valid data. However, no valid data are available for the efficacy of prevention and screening due to lack of implementation. In the elimination model, prevention, screening and treatment allocation are calculated without drop-out rate estimates. Thus the model assumes complete efficacy wherever no data are available.

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Basic assumptions of the base case scenario

Base Case Scenario Realisation of 25,000 treatments per year with the latest generation of DAAs beginning in 2015 (depending on the capacities of the treating medical specialists)

New diagnosis of 3.5% HCV-infected persons and their allocation to treatment by medical specialists

New infection rate of 5,500 per year

No use of targeted screening and prevention measures.

What would be the consequences of maintaining the 2015 status quo? Since specific screening measures are not carried out, the goal of 25,000 annual treatments can no longer be met starting in 2024. But this also means that the number of hepatitis C infected persons will remain largely constant from 2024 in the period under review until 2040. The previously diagnosed patients have completed treatment, the rates of newly diagnosed patients and newly infected patients are approximately the same. Economically it would mean that the annual cost of treatment, and in particular the costs for the treatment of late sequelae over the investigated period would show some reduction, but then stabilise at a relatively high level, as would the indirect costs (lost productivity) and social costs (e.g. costs of early retirement, costs of hepatitis C-related accidents, rehabilitation, etc.). It can be shown for the base case scenario that costs of 13.2 billion euros would accumulate by the year 2040. For the individual infected with hepatitis C, the burden takes the form of unrecognised disease progression to cirrhosis decompensated cirrhosis, liver cancer and death, added to which is the risk of infecting other persons. The base case scenario is contrasted with the "elimination model“.

Basic assumptions of the elimination model

Elimination model Realisation of 25,000 treatments per year with the latest generation of DAAs beginning in 2015 (depending on the capacities of the treating medical specialists) Effective prevention prevents new infections and re-infections.

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Active diagnostic practice and allocation to treatment by medical specialists prevent late sequelae.

Targeted screening and prevention measures.

For the above-mentioned measures, complete efficacy is assumed here in the elimination model calculation.8. This model scenario will also generate costs of around 14.2 billion euros by 2040. There is, however, a crucial difference: In contrast to the base case scenario, hepatitis C will be eliminated and annual costs halved beginning as early as 2025. The Eco-Hep model can provide an important basis for health economic and health policy decisions. Eco-Hep, using the example of the elimination model, demonstrates the potential effects of prevention, screening and treatment of hepatitis C in Germany. Two aspects must be distinguished: On the one hand the model shows, based on the calculations, that elimination of hepatitis C is possible before 2030 with relatively low levels of additional expense. On the other hand the model shows that many late sequelae such as cirrhosis, decompensated cirrhosis, liver cancer and early death can be effectively prevented. Elimination of hepatitis C in Germany is both medically possible and economically feasible. However, the societal challenge of elimination of this disease is only possible if: Time is not lost before the relevant responsibilities and competencies are identified, effective measures introduced and all institutions, organisations and payers directly or indirectly involved actively address the elimination, prevention as well as effective diagnostics and treatment are based on international (e.g. WHO) and national recommendations with a broad consensus (for example S3 Guidance on HCV, Plan of Action for a National Strategy to Fight Viral Hepatitis, RKI).

The elimination of hepatitis C will succeed with the support of politics, payers, science, physicians and patients.

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All Eco-Hep model calculations (base case and elimination model) are modelled and patterned after valid data. However, no valid data are available for the efficacy of prevention and screening due to lack of implementation. In the elimination model, prevention, screening and treatment allocation are calculated without drop-out rate estimates. Thus the model assumes complete efficacy wherever no data are available.

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A HEPATITIS C IN GERMANY 1. What is hepatitis C9? 1.1. The hepatitis C virus, natural course and epidemiology

Hepatitis C is a liver inflammation caused by the hepatitis C virus. Minute quantities of blood are sufficient to transmit the virus. HCV is about 10 times as infectious as HIV10. The virus is highly resistant and survives outside the body for some time. The survival time in dried blood is several days, and in liquids at room temperature even a few weeks (for example as residue in a syringe)11;12. Becoming infected does not require direct contact with an infected person. Even indirect blood contact via blood on needles, razors, toothbrushes, in syringes etc. may be sufficient. The acute infection rarely causes symptoms and can clear up spontaneously in the first six months in about 20% of those affected. In most cases, however, the infection becomes chronic (up to 80%), and then remains permanently in the body. The course of chronic hepatitis C shows considerable individual variation. After an average of two to three decades, late complications such as cirrhosis and liver cancer develop in 15 to 30% of infected persons. Chronic hepatitis C also frequently leads to other, usually serious diseases, known as extrahepatic manifestations, such as diabetes, heart disease or depression. With the treatment options available today, hepatitis C is, however, curable in most cases. The epidemiology of HCV in Germany is difficult to quantify. Leading scientists and institutions report an official average prevalence of 0.3%. This is equivalent to approximately 250,000 cases of chronic viral hepatitis. Because of the high estimated underreporting rates, which cannot be quantified and insufficient consideration of high-risk groups in the corresponding prevalence studies, the real prevalence level is likely to be much higher13. In the DEGS1 study,14 a prevalence level of 0.3% was confirmed by the Robert Koch Institute, but with the restriction that "high-risk individuals" (e.g. persons who inject drugs (PWIDS) inmates of correctional facilities, resident patients of hospitals and nursing homes,

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Chronic hepatitis C Coutinho RA (1998) HIV and hepatitis C among injecting drug users. BMJ. 317:424–425 11 Doerrbecker J et al. (2011) Inactivation and survival of hepatitis C virus on inanimate surfaces; J Infect Dis 204 (12): 1830-1838 12 Paintsil E et al. (2010) Survival of hepatitis C virus in syringes: implication for transmission among injection drug users. J Infect Dis 202(7): 984-90 13 RKI Epi Bulletin 30-2015 14 RKI Epi Bulletin 302015 10

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hospital staff and persons from countries with a higher HCV prevalence) are clearly underreported. To reduce the number of unreported cases, the S3 guidelines recommend diagnostics for persons in the following categories:

HCV diagnostics are indicated in 1. People with elevated "transaminases" and / or clinical signs of hepatitis or chronic liver disease of unknown origin, 2. Recipients of blood and blood products (before 1992), 3. Transplant recipients, 4. Haemodialysis patients, 5. Active and former i.v. drug users, 6. Inmates of correctional facilities, 7. HIV and / or HBV-infected individuals, 8. Household members or sexual partners of HCV-infected persons, 9. Children of HCV-positive mothers, 10. Persons with an immigrant background from regions with raised HCV Infection rates, 11. Medical staff and 12. Blood, organ and tissue donors. In addition, HCV diagnostics including adequate counselling should be provided to anyone who explicitly wishes to undergo such an examination..

Another epidemiological field in which the data situation is not settled is the rate of diagnosed patients vs. the rate of non-diagnosed patients in Germany. The difficulty lies in the fact that, as described above, the group of persons at increased risk for HCV are highly heterogeneous. Perhaps the most recent and most reliable source is the study published in 2014 by Bruggmann et. al.15 In this study it is estimated that, of the overall prevalence of 275,000 (165000-494000) viraemic patients, 160,000 have been diagnosed. The ratio in Germany is thus ~ 60% diagnosed to ~ 40% non-diagnosed patients.

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Bruggmann et al.; Historical epidemiology of hepatitis C virus (HCV) in selected countries; Journal of Viral Hepatitis, 2014, 21, (Suppl. 1:5-33

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1.2. Extrahepatic manifestations Besides the liver damage it causes, chronic hepatitis C can also harm other organ systems and be associated with non-liver-specific complaints. These are known as "extrahepatic manifestations", that is hepatitis C-associated complications outside the liver. Among the manifestations observed are, inter alia, joint and muscle problems, depression and anxiety, neuropathy, dry mouth mucosa, kidney or thyroid disorders, heart disease and increased risk of diabetes. As many as 74% of all hepatitis C sufferers develop extrahepatic manifestations16. Distinctions are made between extrahepatic manifestations with high prevalence and confirmed pathogenesis, clear association, presumed association of suspected and casuistic description.

1.3. Distinction between prevalent and incident disease Definition of prevalence: Epidemiological prevalence is the frequency of cases of a particular disease within a population at the time of the investigation; period prevalence refers to a defined period.17 Definition of incidence: Incidence describes numbers of additional cases (incidence cases [new infections]) within a population of patients / affected persons (prevalence). The latter is thus an essential factor in the analysis and assessment of risks within a population.18 Over the past 25 years, the risk groups have shifted significantly in terms of prevalence and incidence. The largest group of affected persons in the early 1990s and 2000s were persons who had received blood or blood products before 1992 that were contaminated with the hepatitis C virus. This source of infection was effectively eliminated after the introduction of screening for HCV in blood and blood products. Since the first treatment options were developed, many persons in this group have been treated. This group is now very small due to cure or mortality (natural or HCV-related). The high-risk groups with the highest incidence and the highest prevalence since discovery of the virus are PWIDs, inmates of correctional institutions, HIV patients, medical staff and persons with a migrant background from high-prevalence regions (see page 4 - Consensus guideline). The overall conclusion is that the investigation of prevalence and incidence in this area is a difficult undertaking. Various studies have shown the importance of the discussion on valid prevalence data:

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Cacoub et al.; Extrahepatic manifestations of chronic hepatitis c virus infection; 1590-8658, 2014 Editrice Gastroenterologica 17 Roche Lexikon Medizin, 4th edition; © Urban & Fischer Verlag, Munich 1999 18 www.rki.de

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From May 2008 to September 2009, 22,038 patients were tested for anti-HCV in the emergency ward of the Charité Clinic in Berlin19. The anti-HCV prevalence was 2.4% in this group.20

A similar study between September 2009 and March 2010 in Frankfurt a.M. in the emergency ward of the Goethe University Clinic revealed an anti-HCV prevalence of 3.5% in 6,319 patients.21 Also in Frankfurt, at Northwest Hospital, a prevalence of 2.7% was observed over 2 years in 10,215 patients.22 A study conducted by general practitioners as part of the Check-up 35 study Ruhr district involving 21,008 patients showed HCV prevalence (anti-HCV) of 0.95% / 0.43% HCV RNA23 positive results.24.

It is therefore likely that significant heterogeneity exists in Germany as to the assumptions of prevalence for different risk groups (0.1% - 75%) and spatial distribution. The authors of this report based their work on an assumed prevalence 0.3%, supplemented by differentiation by age group.

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Proof of virus contact, no statement as to whether this was a viraemic case. B. Schlosser, D. Domke, M. Möckel, M. Biermer, B. Fülöp, N. Haas, H. Bail, B. Wiedenmann, C. Müller, R. Tauber, K. Hensel-Wiegel, T Berg; Anti-HCV Prävalenz bei 22.038 konsekutiven Patienten einer internistischen und chirurgischen Notaufnahme in Berlin: abschließende Ergebnisse eines HCV-Screenings ; Z Gastroenterol 2010; 48 - P4_41 DOI: 10.1055/s-0029-1246533 21 S. Elanjimattom, J. Vermehren, A. Berger, I. Marzi, R. Lehmann, G. Hintereder, S. Zeuzem, C. Sarrazin; Hohe Prävalenz von Hepatitis C Virus-Antikörpern bei Patienten in der Zentralen Notaufnahme der J.W. Goethe Universitätsklinik, Frankfurt am Main; Z Gastroenterol 2011; 49 - P4_16; DOI: 10.1055/s-0030-1269671 22 F. Bert, A. Rindermann, AM. Abdelfattah, S. Rossol; Erhöhte Prävalenz der chronischen Hepatitis B und C Infektion im Patientenkollektiv einer interdisziplinären Notaufnahme in Frankfurt am Main: Ergebnisse einer prospektiven Screeninganalyse an 10.215 Patienten; Gesundheitswesen 2014; 76 - A5; DOI: 10.1055/s-00341386855 23 Viraemic proof of HCV activity in the body. 24 Ingmar Wolffram, David Petroff, Olaf Bätz, Katrin Jedrysiak, Jan Kramer, Hannelore Tenckhoff, Thomas Berg, Johannes Wiegand; Prevalence of elevated ALT values, HBsAg, and anti-HCV in the primary care setting and evaluation of guideline defined hepatitis risk scenarios; Journal of Hepatology 2015 vol. 62 j 1256–1264) 20

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2. Living with hepatitis C 2.1. Quality of life and stigmatisation The WHO defines quality of life as follows: "Quality of life is the subjective perception of a person of his position in life in relation to the culture and value systems within which that person lives and in relation to his or her goals, expectations, standards and concerns". Health is defined by the WHO as follows: "Health is a state of comprehensive physical, mental and social wellbeing and not merely the absence of disease or disability."25 According to these definitions, more than 250,000 persons in Germany are currently experiencing a deterioration of their quality of life due to their HCV disease. This number can be significantly reduced through prevention, targeted screening measures and allocation to appropriate treatments. In 2006, German Leberhilfe e.V. investigated, among other things, the quality of life in HCV patients as part of the BMBF-sponsored "Competence Network Hepatitis". "The mental and physical scores in SF12 Questionnaire were reduced among HCV-infected persons by about one standard deviation - that is significantly - compared to the general populace. Quality of life was progressively worse with increasing inflammation and fibrosis."26 It is not only the quality of life that is reduced in HCV patients. They are also exposed to significant stigmatisation in many areas of work and private life. Reports of disadvantages crop up repeatedly in the Counselling Service of Deutsche Leberhilfe e.V. and many selfhelp groups: "I cannot get dental treatment"; "I am being denied life insurance"; "I was asked not to register my child in this kindergarten"; "I was terminated during the probationary period after stating that I was an HCV patient"; "I cannot get disability insurance" - these are just a few examples of the social stigma and de facto discrimination that shadow persons infected with hepatitis C. The above study also showed that most of these sufferers feel particularly affected in their occupational surroundings and personal life planning. This phenomenon is observed worldwide (WHA 2015).27 In further studies it was found that 35 - 85% of these patients are exposed to HCV stigmatisation.28 "HCV affected persons per se are suspected of either having HIV and AIDS, being promiscuous, being gay, using illegal drugs or having been in prison". And further, "HCV infection is punishment for sins - those infected deserve their fate".29

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www.who.int Niederau, et al.: Sozio-ökonomische Charakteristika, Lebensqualität und Wissensstand bei Patienten mit Hepatitis C Virusinfektion in Germany; Z. Gastroenterol 2006; 44:305-317 27 World Hepatitis Alliance, 2015 28 Modabbernia et al. 2013; Zickmund et al. 2003; Zacks et al. 2006; Niederau et al. 2006; Niederau et al 2007 29 (Modabbernia et al. 2013; Zickmund et al. 2003; Zacks et al. 2006; Niederau et al. 2006; Niederau et al 2007 26

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The primary factor limiting patient quality of life in most cases is the virus itself. This is also the case with other chronic diseases. However, the added stigmatisation represents an additional constraint on the quality of life factor. Patient organisations and scientists therefore call for greater awareness and understanding of these problems, both in the general population and among representatives of the medical professions.

2.2. Occupation / work productivity The effects of hepatitis C on a person's occupation and productivity is a more recent topic of research, which focuses mainly on the aspects of "absenteeism" and "presenteeism". Absenteeism is defined as productivity lost due to absences and working time lost due to sick leave and doctor visits or appointments related to comprehensive treatment and management of a disease. Presenteeism describes the impairment of daily functioning on the job and the resulting loss of productivity.30.. Both aspects were recently researched specifically in HCV patients by Vietri et al (2013)31 and Younossi et al (2015)32. Lost annual productivity in an HCV-infected employee, compared to a member of a control group with a different disease amounts to ~ 3,000 euros. Compared to the healthy populace, the annual loss amounts to 7,500 euros. The reason for these much higher costs lies in the non-specific symptoms of HCV. These include above all tiredness, fatigue and impaired concentration, which are experienced even by HCV-infected persons whose degree of fibrosis is still low. The impact of HCV on the cognitive system have been confirmed in many studies33. The advanced stage of HCV is also includes the complication of hepatic encephalopathy. This is a late sequel disease that directly impacts brain performance. Another aspect is unemployment and fear of losing ones job. The above study by Niederau et al. also showed that HCV-affected persons have higher unemployment rates than the general population. On the one hand, this is attributable to the natural course of the disease. A further aspect is the fear of employers that HCV ill employees could infect their colleagues. Although this cannot be confirmed by hard figures, counselling discussions in self-help groups make it very clear that this is a real factor.

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M. Steinke et al.; Präsentismus (presenteeism): Ein Review zum Stand der Forschung (research status review); BAUA 2011 31 Vietri et al. BMC Gastroenterology 2013, 13:16 32 Z. Younossi et al.; Impact of eradicating hepatitis C virus on the work productivity of chronic hepatitis C (CHC) patients: an economic model from five European countries; Journal of Viral Hepatitis, 2015 33 Cacoub et al.; Extrahepatic manifestations of chronic hepatitis c virus infection; 15902014, 2014 Editrice Gastroenterologica

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3. Medical care and treatment 3.1. HCV treatment yesterday and today – a success story Following the discovery and identification of the hepatitis C virus in 1988, the first therapeutic trials began in 1990. The treatment course with interferon-alpha lasted for 24 weeks. The success rate was, however, insufficient at 6% SVR. It was decided to extend the duration of treatment to 48 weeks, but the maximum SVR reached was still only 16%34. In 1997, treatment was supplemented with ribavirin. The cure rates rose to 40%35. Although this was a sensation for the physicians, it was both a blessing and a curse for patients. Individual patients now had a realistic chance of being cured, but were subjected on the other hand to significant side effects and had to endure a stringent regimen of drug administration for an extended period: 3 x weekly injections and 3 to 5 tablet doses daily. In early 2000, interferon was modified so that patients required only 1 injection per week starting in 2001. At the same time, the SVR rate rose to an average of 50%. The side effects were reduced slightly. However, quality of life under the treatment was still impaired. Also the duration of treatment had remained the same at 48 weeks.

Figure: Development of HCV treatment

The problem with HCV treatment was that no method had yet been found of attacking the virus directly. Interferon and ribavirin act only to strengthen the immune system, thus countering the virus indirectly. A much more effective fight against this infection would have been possible if the means could have been found to penetrate the virus and stop its replication process. Initial tests of this approach were conducted in 2002, but they had to be stopped due to sometimes fatal side effects. Nevertheless, the principle of direct viral inhibition was further explored on the basis of this initial data.

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Manns M.P. et al.; TREATING VIRAL HEPATITIS C: EFFICACY, SIDE EFFECTS, AND COMPLICATIONS Gut 2006;55:1350–1359 35 Manns M.P. et al.; TREATING VIRAL HEPATITIS C: EFFICACY, SIDE EFFECTS, AND COMPLICATIONS Gut 2006;55:1350–1359

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The breakthrough came in 2011 when the so-called first generation of DAAs (direct acting agents) were approved for genotype 1. The DAAs of the first generation were protease inhibitors (PIs), which interfere directly with the cellular structure of the virus and prevent it from replicating. Cure rates rose to 75% SVR. However, the treatment regimen with this first group of DAAs was complex and placed high demands on patients and treating physicians: Precisely timed administration every 8 - 12 hours, in some cases combined with targeted fat intake. There were also significant side effects that led to an increase 36 in hospitalisations and required more interdisciplinary cooperation. In addition, treatment contraindications in many patients limited use of the new substances. 2014 then saw the "revolution" in treatment of hepatitis C - as it was often, and still is, referred to: The second generation of DAAs received market authorisation. The advantage of this new generation of drugs is that the substance has a direct antiviral effect with simplified treatment management and reduced side effects. The average success rate is over 90% with an average treatment duration of 8.5 weeks. A further advantage of the second-generation DAAs is their effectiveness against all HCV genotypes. No other medical therapeutic field has seen such a success story unfold within a period of just 15 years. The hepatitis C viral infection is the only one that can be cured within a short time without significant side effects in up to 100% of cases. Hepatitis C therapy is the current standard for maximum therapeutic efficacy. 3.2. Screening / diagnosis / identification Screening is an essential component of secondary prevention. Secondary prevention is aimed at early detection and prevention of the progression of a disease. Its purpose is to detect damage or disease at an early stage and to ensure that the course of a disease does not worsen. Studies show, however, that screening recommendations in accordance with the relevant national guidelines or international recommendations are often not, or only insufficiently, implemented. The RKI Epidemiological Bulletin 30 (July 2015) comments on this situation as follows: "Because of the often asymptomatic or unspecific course, many persons who are infected with HCV are not aware of their infection. Therefore screening programs, particularly for vulnerable groups with high prevalence, are important if we are to find these infected individuals, inform them of their status and offer them a treatment to stop the virus spreading. Studies have determined that HCV screening programs (and early therapy) are cost-effective in populations with a high HCV prevalence (such as injecting drug users and migrants)."37 38

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Stahmeyer JT et al.; Pharmacoeconomics EASL 2014 Sroczynski G, Esteban E, Conrads-Frank A, Schwarzer R, Muhlberger N, Wright D, et al.: Long-term effectiveness and cost-effectiveness of screening for hepatitis C virus infection. Eur J Public Health. 2009;19(3):245 – 53

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In its guidelines published in 2014, "Guidelines for the screening, care and treatment of persons with hepatitis C", the WHO recommends screening for hepatitis C of all persons belonging to groups with a high prevalence or with previous HCV exposure / risk behaviour as long as culturally sensitive provision of information and the voluntary nature and confidentiality of testing and allocation to treatment can be guaranteed.39 In Germany, although recommendations have been issued regarding HCV screening for groups at increased risk of hepatitis infection, e.g. healthcare staff, HIV-co-infected persons and injecting drug users 40, these recommendations are not all mandatory and are not generally reimbursed or fully implemented by health insurers. In the summer of 2013 the organisations "Aktionsbündnis Hepatitis und Drogengebrauch", "Deutsche Leberhilfe e.V." and the "Deutsche Leberstiftung" presented a plan of action for a national strategy to fight viral hepatitis in Germany at a press conference, as well as at a subsequent BMG meeting.41 The objectives of the plan of action are to reduce new infections by various measures and to recognise and treat existing acute and chronic infections. Specifically, the recommendation is to develop a strategy against hepatitis as part of a public health concept that reflects a socio-political strategy.

38

Hahne SJ, Veldhuijzen IK, Wiessing L, Lim TA, Salminen M, Laar M: Infection with hepatitis B and C virus in Europe: a systematic review of prevalence and cost-effectiveness of screening. BMC Infect Dis 2013;13(1):181) 39 World Health Organisation: Guidelines for the screening, care and treatment of persons with hepatitis C infection 2014 40 Sarrazin C, Berg T, Ross RS, Schirmacher P, Wedemeyer H, Neumann U, et al.: [Prophylaxis, diagnosis and therapy of hepatitis C virus (HCV) infection: the German guidelines on the management of HCV infection]. 2010;48(2):289 – 351 41 http://www.deutsche-leberstiftung.de/aktuelles/aktionsplan/aktionsplan_virushepatitis_final_web.pdf

12

The following measures are emphasised: To increase awareness of the problem of viral hepatitis and its transmission paths To integrate the strategy in a public health concept and educate the public on viral hepatitis as an element of national health programs Increased testing for hepatitis viruses under consideration and participation of specific target groups Reduction of stigmatisation of persons living with chronic viral hepatitis Adapting interventions to concrete living conditions - this applies in particular to special target groups (migrants, drug users, prison inmates, etc.) Provision of access to guideline-based treatment for all patients infected with a viral hepatitis Collection of meaningful data on the frequency of viral hepatitis and possible sequelae such as cirrhosis and hepatocellular carcinoma The measures proposed above are consistent with the recommendations prioritised at the international level by the WHO and WHA. Effects of screening on HCV: Slowing disease progression by means of a conscious lifestyle (for example reduction of toxic substance consumption, improved diet and more exercise) Prevention of transmission If the disease is detected at a readily treatable early stage a cure is more likely and requires less expense and effort Treatment at an early stage impairs quality of life to a lesser extent Treatment at an early stage generates lower costs and often prevents development of harmful sequelae.

13

4. Eliminating hepatitis C in Germany – problem areas

From a purely medical point of view we are now on track to eliminate a viral disease. This has become possible due to effective treatments. On the ground, however, the elimination process is a complex one. Various scenarios are conceivable, the effects of which are not easily foreseen. Elimination of hepatitis C will require going beyond treatment of diagnosed patients. For example, rates of diagnosis and prevention will have to be increased to prevent new cases and re-infections. Although the course is set there are barriers to complete implementation. The question of costs, and especially of calculability of the costs, arises. "What is the cost of eliminating hepatitis C in Germany?" There are so far no studies that could provide an adequate answer to this. A basis for economic decision-making in this area has not yet been established. This is where the Eco-Hep model comes in. The model was developed for the purpose of presenting the macroeconomic burden of hepatitis C on Germany.

14

B

THE ECO-HEP MODEL – Fundamentals and Scenarios

1. Issue and object of investigation What happens if we just maintain the status quo? A 2014 study published in the Journal of Viral Hepatitis (Razavi et al.) first calculated what will happen if the status quo in 2014 is maintained with respect to the treatment rate in Germany:

Figure: Berechnung der Spätfolgenwelle für Deutschland (Calculation of wave of late complications for Germany), Journal of Viral Hepatitis, 2014

It is expected that until 2030 the number of decompensated cirrhosis, primary liver cancer and liver transplants indications will show a steady increase. These consequences were analysed separately for the US and the authors arrived at the following conclusion42: The total medical expenses (medical expenses without HCV therapy, HCV therapy, late sequel treatment costs and costs for extrahepatic manifestations) will more than quintuple. HCV-related complications (for example extrahepatic manifestations) and late complications (cirrhosis and decompensated cirrhosis) will increase alarmingly. HCV-related deaths will rise sharply.

42

Razavi H. et al.; chronic hepatitis C virus (HCV) disease burden and cost in the United States; HEPATOLOGY, Vol. 57, No. 6, 2013

15

To be able to view this situation not only epidemiologically, but also holistically, it is important to develop further assumptions: What impact will this development have on society and how this can be categorised within a macroeconomic framework? Who will pay for these developments? What measures can be developed to counteract these developments? How can interventions / measures be calculated and what economic impact will they have? To answer these questions the publishers of this report have developed a macroeconomic model: The Eco-Hep model.

2. General principles of a health economic model A health economic model provides the framework for structural analysis of a complex reality, such as the progression of the disease, the impact on society and use of available resources43. It makes use of scientific resources and generates economic and epidemiological results such as prevalence and incidence of disease, mortality and qualityadjusted life years (QALYs) corrected to accommodate health economic aspects, healthcare costs, lost productivity and social burdens as well as the efficacy of interventions. Within the health economy there are different approaches to estimating the burden of a disease or the economic costs of an intervention. In many countries a variety of databases are available for calculation of prevalence, incidence and mortality. In some cases, the economic burdens to date can also be analysed. However, making forward-looking calculations requires a model that combines the historic base data with future interventions. Therefore a simulation model was developed that is capable of representing both health developments and the economic aspects.

43

16

IQWiG; allgemeine Methoden, Version 4.2.2015

Figure: Basic structure of health economic models

3. Principles of calculation model for the burden of hepatitis C in Germany In health economic models, various health states (clusters) are selected to represent the various disease stages. The stages are based on clinical scale values that express disease progression. These disease stages are economically relevant based on the notion that differing costs will arise at the different stages44. Health states in hepatitis C cases are normally defined in terms of the degree of fibrosis. Fibrosis reflects the structural changes in the liver tissue, which results in complications that may develop in patients such as cirrhosis of the liver, decompensated cirrhosis of the liver and hepatocellular carcinoma. Depending on health state (clusters), a patient in the system generates certain costs and general statements on the patient’s quality of life can be made depending on health status. The patients within such a cluster are still very heterogeneous. At an individual level, some patients in a mild stage (F0 - F1) may experience severe symptoms (for example fatigue joint or muscle pain) or extrahepatic manifestations. Other patients in the same stage may be entirely asymptomatic. This individual variability is hard to capture in a model. As per standard practice, the EcoHep model reduces the level of complexity. Costs and quality of life are illustrated for an "average patient". Individualised consideration with too much detail would increase the level of complexity, rendering adequate reproduction of a long period difficult. 44

Gordon SC, Pockros PJ, Terrault NA, Hoop RS, Buikema A, Nerenz D, et al. Impact of disease severity on healthcare costs in patients with chronic hepatitis C (CHC) virus infection. Hepatology 2012 Nov;56(5):1651-60.

17

Sustained virological response (SVR)

F0-F1 diagnosed

F2-F3 diagnosed

costs

costs

F4 (cirrhosis) diagnosed costs

diagnosed by screening F0-F1 Nondiagnosed

New infections

decompensated Cirrhosis

Livertransplantation

Post-Transplantation

costs

costs

costs

Hepatozelluläres Karzinom

F2-F3

F4 (cirrhosis)

Non-diagnosed

Non-diagnosed

HCV-related mortality

costs

It is the first time a model has been produced and used in order to combine medical costs, indirect costs and social costs. It is based on scientific and health economic studies of HCV .

time

Figure: Basis of the Eco-Hep model

In the model shown each box represents a health state. Varying numbers of patients are in each of these health states. Whether, and if so at what intervals, a given patient will transition to the next respective health state depends on the probability given in the literature. The model calculates in annual intervals. Each year, a patient thus either remains in the current health state or moves into another health state or advanced disease state. When a hepatitis C-infected patient is, for example, freshly infected, this is the first phase of the model, that is the patient has a mild infection. If the patient does not undergo treatment, he or she shifts, after a defined period, to the next phase of the model - the next health state. If the patient undergoes successful treatment (SVR) and is cured, he or she then leaves the model and returns to the group of non-infected persons (model environment). Depending on risk behaviour, overall HCV prevalence and incidence, a re-infection is possible. In this case the patient will start again in the cluster "new infected". Patients with mild HCV, moderate HCV and in the cirrhosis stage are classified using the METAVIR score that uses medical parameters to determine the degree of fibrosis. Starting at the cirrhosis stage, the patient is also considered to be at risk for developing hepatocellular carcinoma (HCC). Antiviral hepatitis C treatment is no longer an option in cases of advanced hepatocellular carcinoma. Surgical intervention (e.g. partial resection or liver transplant) is then the only remaining option. If the intervention is successful, the patient still remains within the model. In principle, all patients who have reached the stage of cirrhosis have a higher mortality risk. 18

The time horizon of the underlying assumptions was extended to 2040 to improve observation of short, middle and long term changes.

4. What data does the model use? The basic data used for the underlying calculations and assumptions were determined and selected by means of classic medical literature research (publicly accessible scientific literature sources, e.g. PubMed). The quality criteria for positive selection were publication in a recognised scientific journal (e.g. Journal of Hepatology) and authors whose expertise is scientifically confirmed (criterion for meta-analyses). In cases of unpublished data the authors have referenced the opinions of recognised national or international scientists and experts. The central criterion applied in such cases was that the figures used must reflect the situation in Germany and that the data used for calculation must have been collected in Germany. Data on the social / indirect costs were based mainly on data collected in Germany (e.g. online database of the German Federal Health Reporting System GBE) and data from scientific institutions or established market research institutes (e.g. IMS Health Germany). In addition to this, a number of payers made their own data available (e.g. BGW – Employers' Liability Insurance Association for Healthcare and Welfare Services). Drug costs were factored in based on data provided by IMS Health. The figures used were average costs of one week of INF-free HCV treatment. It should be mentioned here that in some cases the information used / available data do not sufficiently account for the actual number of HCV patients to whom various direct costs must be ascribed. For example, the expense figures reported for continued pay and sick pay are very conservative. The actual outlays revealed by more accurate investigations by the payers themselves are presumably much higher. This also applies to payments for reduced earning capacity pensions and compensatory payments by the BGW in cases of HCV infection.

Loss of productivity - classified in the categories presenteeism and absenteeism - should be made an object of future scientific study since the valid data available to date are insufficient and reflect a multiplicity of methods. The authors feel obliged to mention that specifically the social / indirect costs reported reflect highly conservative estimates. The actual costs are presumably much higher. Hepatitis C generates costs that are not recorded within the hepatitis C context. For example, in most cases the statistics register only the primary diagnosis (e.g. cirrhosis or HCC), but not the underlying causal diagnosis HCV.

19

5. What can the Eco-Hep model calculate? In principle, the model can be used to calculate a wide variety of scenarios and their impacts on the disease processes. The resulting economic data are then factored in as well. In an initial step, reflected in the present report, the authors concentrate on two scenarios. Firstly a "Base Case" – extrapolation of the calculated 2015 status quo. Secondly the "Elimination Scenario". These two basic scenarios define, so to speak, the "interval of possibilities". These scenarios differ regarding: Treatment options / medication Different prevention procedures Different screening procedures Differing assumptions regarding annual new infections Specific consideration of risk groups All of the above aspects can be combined and considered in terms of different time intervals. An important aspect of the underlying assumptions of the "elimination scenario" was taking cognizance of the national and international recommendations. The main sources used were the "Aktionsplan für eine nationale Strategie gegen Virushepatitis in Deutschland" (plan of action for a national strategy to fight viral hepatitis in Germany) and the recommendations of the European scientific and patient associations "Hepatitis B and C – an action plan for saving lives in Europe".

20

6. Limitations of the model At this junction the authors would like to direct readers' attention explicitly to limitations arising either from the general character of the model or applying specifically to the EcoHep model. General model limitations: As is the case with all models, the Eco-Hep model functions based on a reduction of complexity. This reduction per se thus also affects the validity of the results. Using the model, tendencies can be delineated and relationships presented. Specific Eco-Hep model limitations: The validity of the Eco-Hep model is basically influenced by various factors, e.g. the quality of the date fed into the model: Although the validity of the basic data is given high priority, relevant data are not available for all model-relevant factors. Particular attention is paid to using only data that are relevant to the situation in Germany. However, there are gaps in the required data on the German situation. For instance, the number of studies conducted to date on loss of productivity among HCV patients in Germany is very small. Public data, such as the reports of the federal government (GBE) or the payers themselves, also show limits. The available medical data are also limited. For instance, good studies have been published on the occurrence of extrahepatic manifestations, but not on the actual prevalence and expenses (management and treatment costs) generated by these conditions. The Eco-Hep model also uses the averaged valued generated by studies. This applies in particular to the path taken by patients through the various health states. The range figures reflecting the uncertainties are literature-based. This is true, for example of the screening measures used in the elimination model (see also section 9.1. Screening).

7. What costs does the Eco-Hep model calculate? The aim of the authors is to present a macroeconomic analysis of hepatitis C using the Eco-Hep model. The focus in the past was mainly on treatment costs. The medical costs that accrue even if the hepatitis C itself is not treated, as well as the "social" costs / indirect costs have not been sufficiently studied to date. The present model facilitates a macroeconomic viewpoint because it integrates these cost areas as well. Thus the EcoHep model differs from other models that feature either a solely epidemiological approach or an isolated focus on cost-effectiveness. In principle, it is possible to differentiate between the medical effort and expenditure (HCV management, HCV treatment costs and costs of HCV-caused late sequelae and complications) and the indirect / social costs. The IQWiG defines indirect costs as "costs 21

reflecting loss of productivity, work incapacitation, occupational disability (in cases of longterm disease or disability) or premature death".45 The Eco-Hep model uses loss of productivity due to absenteeism and presenteeism as an indirect cost factor. The following are considered to be social costs in this model: HCV-caused reduced earning capacity pensions and full pensions, HCV-associated accidents, wage continuation, rehabilitation costs, tax shortfalls, sick pay, etc. The question was also investigated as to which payers are currently burdened with which costs and over what periods of time the costs in teach case can be reduced by targeted measures.

8. Base case scenario How can future macroeconomic development be characterised assuming the 2015 status quo were to be maintained? The base case scenario is based on the following basic assumptions:

Base Case Scenario Realisation of 25,000 treatments per year with the latest generation of DAAs beginning in 2015 (depending on the capacities of the treating medical specialists)

New diagnosis of 3.5% HCV-infected persons and their allocation to treatment by medical specialists

New infection rate of 5,500 per year

No use of targeted screening and prevention measures.

8.1. Cost factor treatment costs The IMS data were used as the basis for the treatment costs, which reveal how high the average weekly cost was and the average duration of treatment in 2015. All future costs in the report are discounted at an annual rate of 3% as per the IQWiG recommendation. A future reduction of treatment costs by 30% was also calculated into the treatment costs over the next 10 years.

45

22

IQWiG (Allgemeine Methoden - General Methods, Version 4.2 of 22.04.2015)

8.2. Cost factor HCV management without treatment The basis used here comprised the costs described in the literature per disease phase (F0 – F4, cirrhosis, decompensated cirrhosis, HCC, liver transplant, post liver transplant) 46;47;48. All of these factors refer to calculations done in Germany.

8.3. Cost factor extrahepatic manifestations A selection of extrahepatic manifestations was made for the model to make it clear that non-treatment of hepatitis C generates further costs that are not normally listed in such calculations. The selection was also took account of the fact that a number of extrahepatic manifestations are cured after successful hepatitis C treatment (e.g. PSS / sicca syndrome), while others persist and in some cases require lifelong treatment and monitoring (e.g. heart diseases and diabetes). A calculation done for the USA by Younoussi et al49 demonstrated that the annual expenses come to at least 1.44 billion US dollars, whereby costly diseases such as B-cell non-Hodgkin's lymphoma or cardiovascular diseases were not included in the calculation. Extrapolation of these data to the German situation presents difficulties of methodology. It can, however, be assumed that the annual burden is high in this country as well. The data situation regarding the actual expenses for extrahepatic manifestations in Germany is insufficient to facilitate feeding these costs into the model. Additional research is required here to facilitate exact calculation of the total expenditures for extrahepatic manifestations. 8.4. Cost factor indirect costs The indirect costs were calculated to take into account the costs resulting from presenteeism and absenteeism. These costs were calculated only for the working population and based on the literature and data from IMS. For technical reasons related to the model, the publishers assume that no differentiation applies between diagnosed and non-diagnosed patients, although we are well aware that the group of non-diagnosed infected persons presumably contains a smaller proportion of employees in obligatory social insurance plans and that the degree of manifestation of hepatitis C is likely to be mild. On the other hand, the indirect costs in the group of patients suffering from late sequelae, and the loss of productivity due to mortality, were not factored in due to insufficient data. The assumption is justified that the indirect costs factored into the calculation are too low.

46

Müllhaupt, B., Bruggmann, P., Bihl, F., Blach, S., Lavanchy, D., Razavi, H., … Negro, F. (2015) Modeling the Health and Economic Burden of Hepatitis C Virus in Switzerland. PloS One, 10(6), e0125214. 47 Stahmeyer JT et al. 2013 48 Wasem J et al. 2006 49 DIRECT MEDICAL COSTS ASSOCIATED WITH THE EXTRAHEPATIC MANIFESTATIONS OF HEPATITIS C INFECTION IN THE UNITED STATES; EASL LiverTree™. Younossi Z. Apr 24, 2015; 95844

23

8.5. Cost factor social costs The following cost types were investigated in the area of social costs: Reduced earning capacity pension Invalidity payments to officials Sick pay Wage continuation in case of illness Compensatory payments by occupational insurance associations resulting from HCV infections Rehabilitation services Further: Nursing costs Housing allowances Taxation shortfalls and reduced premium payments into unemployment insurance, nursing care insurance and pension plans

Based on the valid data in some areas, and in order to achieve a conservative approach to this cost area, the calculation includes only reduced earning capacity pensions, invalidity payments to officials, sick pay, wage continuation in case of illness, compensatory payments by occupational insurance associations resulting from HCV infections and rehabilitation services. The costs of nursing care, housing allowances, taxation shortfalls and reduced premium payment into unemployment insurance and pension plans were not included in the overall Eco-Hep model calculations due to the low levels of data validity.

24

9. Elimination scenario How can future macroeconomic development be characterised assuming the following?:

Elimination model Realisation of 25,000 treatments per year with the latest generation of DAAs beginning in 2015 (depending on the capacities of the treating medical specialists) Effective prevention prevents new infections and re-infections.

Active diagnostic practice and allocation to treatment by medical specialists prevent late sequelae.

Targeted screening and prevention measures.

Assumed costs for treatments, HCV management without treatment, extrahepatic manifestations, indirect costs and social costs from the base case scenario used as they were. Newly added: Screening costs. 9.1. Basic assumption and cost factor screening The ratio of HCV-positive patients diagnosed to date to non-diagnosed patients is approximately 60:40 (Bruggmann, 2014). Assuming for Germany a steady incident and uniform treatment rate of 25,000 treatments annually, this would mean that, if new diagnoses continue at the same rate, most diagnosed patients would be cured in a few years. Starting in approx. 2020/2021, the annual treatment rate would then be clearly reduced due to the small number of new patients presenting clinically. Without screening measures there will continue to be non-diagnosed patients, the numbers of which are currently difficult to estimate. This group of non-diagnosed patients harbour the following risks and cost factors for the "overall system": Expensive late sequelae: Non-diagnosed patients may develop extrahepatic manifestations and late sequelae. This results in higher medical and financial effort and expenditure if patients with hepatitis C are not identified until the later stages.

25

Transmission: Non-diagnosed patients and diagnosed patients that are as yet untreated can transmit the virus to other persons. This results in new cases of HCV infection and repeated expenditure for treatment of the new infections. Non-diagnosed continue to generate social / indirect costs. Screening must be factored in to calculate an elimination scenario. Selection of the screening methods and risk groups in which screening is to be done is based on the recommendations of the Hepatitis C Guideline50.

Screening groups Screening a: Medical staff (incl. indirect medical personnel) Screening b: Pregnant women Screening c: PWIDs undergoing replacement therapy Screening d: PWIDs, tested in the “Community” Screening e: HIV-infected persons Screening f: Check up 35 Screening g: Immigrants

Screening a: Medical staff (incl. indirect medical personnel) In keeping with the recommendation of the Robert Koch Institute, all medical staffers (both directly and indirectly employed in this field) should undergo periodic HCV testing. "All persons in Germany who have contact with patients or patient material must be tested to determine their HCV serostatus acc. to ArbMedVV before beginning with their professional activities. This test must be repeated at regular intervals and upon termination of the employment."51 This RKI recommendation is also reflected in EU Directive 2010/32/EU, stringent implementation of which has actually been required since 2013. The high prevalence level of at least 3.8 % in this group supports the conclusion that neither the RKI recommendation nor the EU Directive is being stringently implemented / applied. What would the effects be of thoroughgoing screening and rapid onset of HCV treatment were to be implemented in this particular group? The Eco-Hep model provides targeted calculations to address this matter.

50

www.dgvs.de

51

http://www.rki.de/DE/Content/Infekt/EpidBull/Merkblaetter/Ratgeber_HepatitisC.html#doc2389942body Text12

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Screening b: Pregnant women Anti-HBs testing is a standard component of the prenatal examination. Even though the presumed numbers of HCV cases is likely to be small, leading experts recommend inclusion of HCV testing as well. The Viral Hepatitis Plan of Action states: Pregnant women should be tested as early as possible, not only for HIV, but also for HBsAg to prevent infection of the unborn child. To date, the test is carried out in the 32nd week of pregnancy. An antiviral treatment that would prevent transmission during parturition would have to be started earlier than this. It would make sense to test for HCV at the same time, particularly if risk factors are present. The risk of infection in newborn children whose mothers are HCV RNA-positive is about 6%.52 The Eco-Hep model calculates the potential effect of integration of the HCV test in the prenatal examination, which would minimise or eliminate entirely the risk of transmission to newborns. Screening c: PWIDs undergoing replacement therapy Some PWID patients in Germany receive replacement therapy. The objective of this screening is to test all persons currently receiving replacement therapy. This would be particularly interesting due to the fact that the highest prevalence is presumed to occur in this group. Testing within the group of PWID can contribute to reduction of inter-personal transmission and have a positive impact on injection behaviour.53 This is also recommended in the Viral Hepatitis Plan of Action: "The framework that exists for hepatitis prevention and testing is not utilised to a sufficient extent for drug consumers integrated in the medical care system via a replacement therapy." The model shows, on the one hand, how high the costs of thoroughgoing testing of this group by replacement therapy physicians would be. It is also assumed that transmissions can be stopped by means of education and counselling efforts within this group. Screening d: Testing of PWIDs by the "Community" International experts (e.g. INHSU) recommend testing of PWIDs by the "Community". Provision of low-threshold tests without medical personnel will raise acceptance and usage levels of test offerings by a considerable margin. Experts assume that testing will reduce the risk of transmission within the group of PWID and will also impact high-risk consumption behaviour in a positive manner.54 The Eco-Hep model investigates the cost levels for low-threshold tests in this highincidence group. 52

Croxson M et al. Vertical transmission of Hepatitis C virus in New Zealand. NZMJ, 9 May 1997, Vol 110, No 1043:165-7 53 Aspinal et al., 2014; Bruneau et al.,2014 54 Aspinal et al., 2014; Bruneau et al.,2014

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Screening e: HIV There is a national register of HIV-positive persons in Germany. HCV tests are recommended in the S3 Guidelines for HIV-Positive Persons and this recommendation should be followed consistently. In Germany, 6% of HCV patients are also infected with HIV.55 In association with HIV, liver damages is caused by hepatitis C more rapidly and must therefore be treated in any event.56 With the new DAAs, the chances for curing hepatitis in HIV-positive persons are comparable to those for HIV-negative persons.57 The Eco-Hep model investigates the cost levels for consistent implementation of the S3 Guideline recommendations, i.e. assuming all HIV patients are consistently tested for HCV. Screening f: Check-up 35 The Eco-Hep model investigates the impact of HCV testing within the framework of the Check-up 35 supported by the health insurers. Inclusion of HCV testing is recommended by leading experts (see Viral Hepatitis Plan of Action). A study published in 2015 demonstrates that as many as 83% of HCV patients can be identified at much lower costs using three risk questions and testing of the ALT level (GPT).58 This model investigates the level of HCV diagnostic costs resulting from all persons who make use of the Check-up 35 undergoing an oral risk history and/or measurement of the ALT level before HCV testing. Screening g: Immigrants The Eco-Hep model investigates, using Russian immigrants as the calculation sample (4.1% original HCV prevalence; Lavanchi 2010), what the effect would be of subjecting all persons in this group of persons to HCV tests. The prevalence level was reduced to 1% / 2.5% to select a conservative approach in this risk group. This group was selected as the exemplary sample due to the very good data available on it which can serve as an adaptive basis for the group of all migrants. Notice: The model assumes that, in theory, all non-diagnosed patients (100%) could be shifted to the group of diagnosed patients within three years as a result of the screening measures mentioned. In reality, this will not be feasible for various reasons. Assuming a maximum benefit of screening, the model reveals the entire range of interventions: From base case without screening to elimination model with maximum screening effectiveness. 55

Robert Koch Institute (RKI): Hepatitis C im Jahr 2014. Epid Bull 2015; 22:289-299 Sarrazin C et al. Update der S3-Leitlinie Prophylaxe, Diagnostik und Therapie der Hepatitis-C-Virus(HCV)Infektion, AWMF-Register-Nr.: 021012 Z Gastroenterol 2010; 48: 289-351 57 Sarrazin C et al. Aktuelle Empfehlung zur Therapie der chronischen Hepatitis C. Z Gastroenterol. 2015 Apr;53(4):320-34 (Addendum zur S3 Leitlinie HCV 58 Ingmar Wolffram, David Petroff, Olaf Bätz, Katrin Jedrysiak, Jan Kramer, Hannelore Tenckhoff, Thomas Berg, Johannes Wiegand; Prevalence of elevated ALT values, HBsAg, and anti-HCV in the primary care setting and evaluation of guideline defined hepatitis risk scenarios; Journal of Hepatology 2015 vol. 62 j 1256–1264) 56

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9.2. Cost factor prevention The costs of effective prevention are very hard to quantify since this requires parallel implementation of a variety of measures. Primary recommendation59: Consistent implementation of regulations intended to prevent injuries cause by sharp / pointed instruments in the hospital and healthcare sector Harm reduction (including replacement therapy, syringe exchange programme and HCV treatments) Awareness activities Anonymous testing opportunities at no charge Safe sex campaigns The publishers of the report consider the data to be still insufficient in this regard, making calculation of the costs of the individual measures and their implementation very difficult. For this reason, this cost factor was not taken into account for the present calculation.

59

Kautz et al, Saving lives in Europe, 2015 (www.elpa-info.org)

29

C RESULTS The following pages present a selection of the epidemiological and cost economic calculations of the Eco-Hep model based on the assumptions of the different scenarios for the period 2015 – 2040.

Burden of illness according to stage of illness and HCV-caused management costs (without HCV treatment); status quo 2015 4,437

100% 90%

70% 60%

diagnosed

39.462 80%

107.321 98,243,791 €

40% 30% 20% 10%

Non-diagnosed

50%

51,473,685 €

97.855

41,579,220 € 0% Infected individuals

Healthcare costs F0-F3

F0 F1 F2 F3 F4 DCC HCC LTX

F4

End-stage

HCV-positive affected persons 54,010 69,727 38,409 43,030 39,462 3,215 978 244

Healthcare costs 3,370,236 € 7,070,330 € 8,780,369 € 22,358,284 € 51,473,685 € 31,337,679 € 22,262,670 € 44,643,442 €

Currently, about 80% of the HCV-caused healthcare expenditures (without HCV treatment) are spent on late sequelae such as e.g. cirrhosis cirrhosis, decompensated cirrhosis, liver cancer and liver transplants. 20% of persons currently infected are currently in these critical late sequelae stages.

30

Base Case: Health status

In the base case scenario, only a gradual drop is achieved in the number of patients with late sequelae (liver cancer and transplantation) and in F4 (cirrhosis). The number of patients in stages F0 – F3 drops until 2021, then stagnates at a level of around 50,000 patients. Elimination scenario: Health status

In the elimination scenario, numbers of patients in all three health stages drop continuously and rapidly. Beginning in 2026, the number of patients with fibrosis or cirrhosis is below 1000. Advanced stage patient counts (liver cancer and transplantation) also drop quickly to below 1000, at which level they then stagnate due to a lack of curative treatments for HCC. 31

Base Case: HCV management costs (without HCV treatment) according to health status

In the base case, HCV management costs are, on the whole, reduced only very gradually. Costs for management of late sequelae at first increase until 2019, the go down reflecting reduced numbers of diagnosed patients.

Elimination scenario: HCV management costs (without HCV treatment) according to health status

In the elimination scenario, costs rise due to screening, then drop very rapidly, reflecting the HCV treatments that are then carried out. Beginning in 2026, the

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annual expenditures for patients with fibrosis and cirrhosis will be below 100,000 euros. Assumed change in number of patients with viraemic HCV

2015 2020 2025 2030 2035 2040

Base Case: 249,075 112,442 73,903 68,118 64,068 61,352

Elimination scenario: 249,075 102,147 5,596 2,178 1,291 834

Differences in prevalence of viraemic HCV patients were shown in a comparison of the two scenarios. In the base case (status quo 2015) it is assumed that a gradual stagnation or reduction of annual treatment figures will set in beginning in 2022, since by then most of the diagnosed patients will have received HCV treatments. In the elimination scenario, with constant treatment figures of 25,000, the number of viraemically positive persons can be very rapidly reduced.

33

Number of diagnosed patients 180,000 160,000 140,000 120,000 100,000 80,000 60,000 40,000 20,000 2015 2017 2019 2021 2023 2025 2027 2029 2031 2033 2035 2037 2039

Base Case

Elimination Scenario

Here the numbers of diagnosed and non-diagnosed patients were compared for the two scenarios. Whereas in the base case scenario the number of diagnosed patients falls constantly, a pronounced increase is registered initially in the elimination scenario. The difference between the two scenarios is that in the base case scenario no target screening takes place and diagnostics are done more randomly, whereas in the elimination scenario the risk groups are subjected to targeted screening. Therefore, in the elimination scenario all HCV carriers will be diagnosed within a brief period.

34

Assumed change in diagnosis rates and treated patients Base Case:

30,000

250,000

25,000

200,000

20,000

150,000

15,000

100,000

10,000

50,000

5,000

Number of diagnosed patients

2039

2037

2035

2033

2031

2029

2027

2025

2023

2021

2019

-

2017

-

Numer of treated patients

300,000

2015

Nmber of diagnosed/undiagnosed patients

250,000 persons infected with HCV, of whom 60% are diagnosed. 25,000 annual treatments with INF-free DAAs. 5,500 new infections per year. No targeted screening.

Number of undiagnosed patients

Number of treated patients

Elimination scenario:

300.000 250.000 200.000 150.000 100.000 50.000 -

30.000 25.000 20.000 15.000 10.000 5.000 2015

2020

2025

Number of diagnosed patients

2030

2035

2040

Number of treated patients

Number of diagnosed/undiagnosed patients

250,000 persons infected with HCV, of whom 60% are diagnosed. 25,000 annual treatments with INF-free DAAs. No new infections. Non-diagnosed patients are identified by means of targeted screening.

Number of undiagnosed patients

Number of treated patients

35

The difference between the status quo 2015 (base case) and implementation of the recommended measures (elimination scenario) inheres in these facts: a) The number of non-diagnosed patients can be significantly reduce with a very brief period b) The number of treatments can be kept constant until 2023 c) Elimination can be achieved by 2030 with screening, prevention and treatment. Presumed cost development (healthcare costs, indirect costs, treatment costs, screening costs) Base Case: 250,000 persons infected with HCV, of whom 60% are diagnosed. 25,000 annual treatments with INF-free DAAs. 5,500 new infections per year. No targeted screening.

Elimination scenario: 250,000 persons infected with HCV, of whom 60% are diagnosed. 25,000 annual treatments with INF-free DAAs. No new infections. Non-diagnosed patients are identified by means of targeted screening.

The costs of screening are around 797 million euros in the elimination scenario. The above presentation is based only on screening costs for medical staff (321 million 36

euros), PWIDs undergoing replacement therapy (8.8 million euros) and in Check-Up 35 (466 million euros), since the highest diagnosis rates are achievable in these groups. With these three measures, ~ 85,000 – 110,000 HCV-positive persons could be identified within a short period.

Presumed cost development according to cost categories

a) Treatment costs

1,600 € 1,400 €

Millionen

1,200 € 1,000 € 800 € 600 € 400 € 200 €

2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027 2028 2029 2030 2031 2032 2033 2034 2035 2036 2037 2038 2039 2040

- €

Base Case

2015–2019 2020-2024 2025–2029 2030–2034 2035–2040 2015–2040

Base Case: 6,494,317,484 € 1,799,834,299 € 330,701,210 € 224,970,400 € 181,654,206 € 9,031,477,599 €

Elimination Scenario

Elimination scenario: 6,559,514,609 € 3,726,149,597 € 47,596,717 € 131,352 € 68,102 € 10,333,460,377 €

Difference 65,197,125 € 1,926,315,298 € -283,104,493 € -224,839,048 € -181,586,104 € 1,301,982,778 €

Expenditures for treatment depend on how many patients are diagnosed and how many treatments can be offered per year. In both scenarios, 25,000 treatments a year are assumed, but with a decisive difference: In the base case scenario the costs go down because no diagnosed patients are identified within a few years due to a lack of screening. In the elimination scenario, all patients can be identified. The expected result of this is that higher costs will accrue in the first years in particular (2015 – 2024), which then drop off rapidly beginning in 2025. All HCV patients in Germany could be treated with a total expenditure of 10.3 billion euros, whereas in the base case scenario with expenditures of 9 billion euros around 60,000 patients would remain in the non-diagnosed category. 37

b) HCV management costs

2015–2019 2020–2024 2025–2029 2030–2034 2035–2040 2015–2040

Base Case: Elimination scenario: Difference 822,784,785 € 987,555,076 € 164,770,291 € 534,155,143 € 598,286,868 € 64,131,725 € 363,931,379 € 207,848,638 € - 156,082,741 € 271,535,580 € 104,273,253 € - 167,262,327 € 231,754,468 € 66,428,044 € - 165,326,424 € 2,224,161,355 € 1,964,391,879 € - 259,769,476 €

HCV management costs can only be calculated for diagnosed patients. In the base case scenario, the costs fall gradually, but a shift in costs occurs over time. Even now (2015), 80% of HCV management costs are accounted for by treatment of patients with late sequelae. This percentile will increase in the in the base case scenario, since most of the patients diagnosed will be in an advanced disease stage due to a lack of screening. In the elimination scenario, the costs increase at first in the years 2015 – 2019, but this increase is because all patients will be diagnosed in this period and thus require consultation by medical specialists. Due to the rapid identification of all HCV patients, however, expenditures for high-cost late sequelae and complications will soon be clearly reduced (beginning in 2021). In total, the elimination scenario will reduce management costs by at least 300 million euros.

38

c) Indirect costs (loss of productivity) 350,000,000 € 300,000,000 € 250,000,000 € 200,000,000 € 150,000,000 € 100,000,000 € 50,000,000 €

2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027 2028 2029 2030 2031 2032 2033 2034 2035 2036 2037 2038 2039 2040

- €

Base Case

2015–2019 2020–2024 2025–2029 2030–2034 2035–2040 2015–2040

Elimination Scenario

Base Case: Elimination scenario: Difference 941,472,530 € 972,190,187 € 30,717,657 € 331,616,783 € 205,364,962 € - 126,251,821 € 257,588,436 € 2,108,627 € - 255,479,809 € 215,303,769 € 26,088 € - 215,277,681 € 214,770,160 € 13,789 € - 214,756,371 € 1,960,751,679 € 1,179,703,653 € - 781,048,026 €

Indirect costs comprise costs arising from presenteeism und absenteeism. The lower the number of persons who are infected by the hepatitis C virus, the lower the resulting costs will be. Comparison of the two scenarios – base case versus elimination scenario – makes this particularly clear. Whereas in the base case scenario at least 50,000 to 60,000 patients annually will continue to show productivity losses from 2021, these costs will be reduced rapidly in the elimination scenario.

39

d) Total social costs 60,000,000 € 50,000,000 € 40,000,000 € 30,000,000 € 20,000,000 € 10,000,000 €

2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027 2028 2029 2030 2031 2032 2033 2034 2035 2036 2037 2038 2039 2040

0€

Base Case

2015–2019 2020–2024 2025–2029 2030–2034 2035–2040 2015–2040

Elimination Scenario

Base Case: Elimination scenario: Difference 198,004,692 € 210,973,503 € 12,968,811 € 78,209,844 € 42,845,005 € - 35,364,839 € 52,248,628 € 4,548,646 € - 47,699,982 € 34,589,568 € 1,660,133 € - 32,929,435 € 25,441,428 € 822,964 € - 24,618,464 € 388,494,160 € 260,850,251 € - 127,643,909 €

Social costs are costs generated for example by early pensioning, HCV-caused accidents or wage continuation and sick pay. A reduction of diagnosed patients results in costs that can be categorised. Beginning in 2021 in both scenarios, numbers of diagnosed patients are clearly reduced, but with the difference that in the base case scenario the patients are not diagnosed and in the elimination scenario the patients are cured. Individual payers in particular (e.g. BGW) must bear costs that result from a failure to implement regulations and directives consistently (e.g. avoidance of needlestick injuries).

40

e) Social costs categorised according to payer Base Case:

DRV

2015-2019 2020-2024 2025-2029 2030-2034 2035-2040 2015-2040

Regional administrative bodies

55,969,713 € 56,092,359 € 41,333,432 € 26,936,371 € 19,285,160 € 199,617,035 €

Health insurers

9,065,086 € 9,084,950 € 6,694,533 € 4,362,726 € 3,123,504 € 32,330,798 €

55,994,778 € 3,620,489 € 972,464 € 805,269 € 802,769 € 62,195,769 €

Regional administrative bodies

Health insurers

Employers

23,165,356 € 1,497,817 € 402,314 € 333,145 € 332,110 € 25,730,741 €

Occupational insurance association

45,335,494 € 7,205,235 € 2,559,338 € 1,924,975 € 1,690,103 € 58,715,145 €

Various payers (rehabilitation costs)

8,474,265 € 708,994 € 286,548 € 227,082 € 207,783 € 9,904,671 €

Elimination scenario:

DRV

2015-2019 2020-2024 2025-2029 2030-2034 2035-2040 2015-2040

26,430,606 € 9,675,205 € 3,598,362 € 1,410,965 € 699,476 € 41,814,614 €

4,280,810 € 1,567,035 € 582,806 € 228,526 € 113,291 € 6,772,468 €

80,570,828 € 20,137,739 € 201,690 € 119 € 59 € 100,910,435 €

Employers

33,332,608 € 8,331,096 € 83,440 € 49 € 25 € 41,747,218 €

Occupational insurance association

54,232,121 € 0 0 0 0 54,232,121 €

Various payers (rehabilitation costs)

12,126,530 € 3,133,930 € 82,348 € 20,474 € 10,113 € 15,373,395 €

41

Overall cost development 2015 – 2040 (not including social costs and costs of extrahepatic manifestations)

Millionen

2,500.00 2,000.00 1,500.00 1,000.00 500.00

2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027 2028 2029 2030 2031 2032 2033 2034 2035 2036 2037 2038 2039 2040

0.00

Base Case

Base Case:

Elimination Scenario

Elimination scenario: Difference

2015-2019

8,258,574,799 €

9,316,658,012 €

1,058,083,213 €

2020-2024

2,665,606,224 €

4,529,801,427 €

1,864,195,203 €

2025-2029

952,221,025 €

257,553,982 €

- 694,667,043 €

2030-2034

711,809,749 €

104,430,693 €

- 607,379,056 €

2035-2040

628,178,835 €

66,509,935 €

- 561,668,900 €

2015-2040

13,216,390,632 €

14,274,954,049 €

1,058,563,417 €

In the overall picture of costs of HCV management, HCV treatment and indirect costs (loss of productivity), a very conservative calculation reveals additional expenditure of ~ 260 million euros. Adding in the cost development for extrahepatic manifestations and the social costs would presumably result in the same total expenditures - but with elimination of HCV by 2030.

42

Summary of results The above results show that implementation of targeted diagnostics and prevention can significantly impact macroeconomic cost development in the period 2015 – 2040. Which costs change when different assumptions are made: base case vs. elimination scenario? a) Medical costs (without HCV treatment): Both scenarios assume an initial volume of ~ 190 million euros in 2015. Most of these costs (~ 80%) represent expenditures for HCV patients in advanced disease stages (~ 18%). In the base case scenario the costs continuously and gradually drop up to 2040, congruent with the reduced numbers of diagnosed patients. Fewer diagnosed patients generate fewer costs. In the elimination scenario, average annual costs of ~ 195 million euros are projected for the years 2015 to 2020. These figures reflect patients identified by targeted diagnostics, who then require medical care until treatment onset. Beginning in 2021, the costs then fall continuously, and more rapidly than in the base case scenario. The largest cost reduction is seen in patients in the cirrhosis stage / late stage. b) HCV treatment costs: Total costs for HCV treatment in the years 2015 to 2040 are around 9 billion euros for the base case compared to total costs in the elimination scenario of 10.3 billion euros. The fact that the elimination case costs are higher by 1.3 billion euros is due to maintenance of the annual treatment rate of 25,000 patients over a longer period. In the base case scenario, only a small number of annual treatments are possible beginning as early as 2021 – with the result that even after 2040 at least 50,000 to 60,000 patients will still require HCV treatment, whereas in the elimination scenario the last HCV treatment would take place in approximately the year 2030. c) Indirect costs: In the Eco-Hep model, indirect costs are defined as those arising from presenteeism and absenteeism. Cost development is nearly the same in the two scenarios: from approx. 300 million euros in 2015 the costs are reduced to approx. 80 million euros by 2020. This is based on the assumption that from 2015 to 2020 in both scenarios the same annual treatment rate of 25,000 HCV treatments will be achieved. However, beginning in 2021, the annual cost reduction in the base case scenario is minimal, whereas the costs in the elimination scenario are reduced significantly and rapidly. Whereas in the base case the annual costs in 2028 would still be at 49 million euros, they would fall in the elimination scenario to below 10,000 euros for that year. Over the entire calculation period 2015 – 2040, approx. 780 million euros in indirect costs can be avoided by the elimination scenario. These savings would benefit employers in particular. 43

d) Screening costs: The costs of screening are around 797 million euros in the elimination scenario. The above presentation is based only on screening costs for medical staff (321 million euros), PWIDs undergoing replacement therapy (8.8 million euros) and in Check-Up 35 (466 million euros), since the highest diagnosis rates are achievable in these groups. The costs comprise expenditures for measurement of GPT, anti-HCV, HCV PCR and payments for medical services acc. to VDGH (EBM) for consultation and blood sampling. e) Costs of extrahepatic manifestations: As was mentioned above, the data situation for Germany makes valid cost calculations for extrahepatic manifestations very difficult to achieve. A work group of US scientists calculated for 2015 that the annual expenses in the US come to at least 1.44 billion US dollars, whereby costly diseases such as B-cell non-Hodgkin's lymphoma or cardiovascular diseases were not included in the calculation. The numbers of persons infected by hepatitis C in the US are greater by a factor of 1060. f) Social costs: The calculations of social costs in the Eco-Hep model include the expenditures of German pension insurers, pension funds, regional administrative bodies, health insurers, employers, occupational insurance associations and other payers of rehabilitation measures. Additional costs were not integrated in the model due to the lack of data, e.g. shortfalls in taxes and payments into unemployment and nursing insurance schemes and expenditures for nursing and housing allowances. Payments for reduced earning capacity pensions, wage continuation, HCV-caused accidents and rehabilitation measures amounted to at least 50 million euros in the year 2015. With further significant cost reductions in the following years in the elimination scenario, the social costs can reduced beginning in 2027 to less than 1 million euros, with further reduction by 2040 to only 90,000 euros. However, this cost reduction depends on the number of treatments and early recognition and screening measures carried out per year as well as consistent implementation of existing regulations and directives (e.g. protection of medical staff from needlestick injuries). In the base case scenario, on the other hand, the level of expenditures in 2027 is still at 10.5 million euros. The burdens will then be reduced, for the most part continuously, by 700,000 euros annually, but are still at 3.3 million euros in the year 2040. The authors wish to emphasise once again at this point that the social costs in particular were calculated very conservatively. The actual costs are presumably much higher. 60

44

Younossi et al, 2015

Hepatitis C generates costs that are not recorded within the hepatitis C context. For example, in most cases the statistics register only the primary diagnosis (e.g. cirrhosis or HCC), but not the underlying causal diagnosis HCV.

45

D DISCUSSION The overall societal relevance of the viral disease hepatitis C at the status quo level of the year 2015 is reflected in a considerable financial impact on both the healthcare and social security systems of the Federal Republic of Germany. Although in past years (particularly 2013 to 2015) highly important advances in medical treatments have been made in this field, these developments, as well as the investments made accordingly, would be for naught if further necessary steps are not taken. The aim of the present report was to present the current, and above all the future, financial burden exerted by hepatitis C on the German healthcare and social security system. It also include investigations and evaluations of ways in which various measures (screening and prevention) impact this burden. Based on the Eco-Hep model, the report arrives at the conclusion that elimination of HCV is feasible. The model provides answers to how, when and above all at what cost this will be possible. Finally, the conclusion is reached that rapid implementation of the recommendations of experts and patient organisations can significantly reduce the period during which expenditures to fight hepatitis C will be required. If we remain at the 2015 status quo of hepatitis C treatment, all diagnosed patients will have completed their treatments within 4-5 years. All the while, the disease will progress unrecognised in the non-diagnosed patients and overall prevalence will remain unchanged due to new infections. Following this scenario, the German healthcare and social security systems would have to bear the same cost burden in the years 2020 – 2021 as in 2015. In the end, the question that is raised is: What is the significance for our society of the fact that hepatitis C can be eliminated? Discussion of this question can take several directions. One aspect is of course the cost. The current discussion of the question "What is the permissible cost of a cure?" has intensified considerably since market introduction of the new DAAs and frequently takes on a despairing tone. This discussion is not focused solely on hepatitis C. Medical progress, longer patient survival times and improved patient prognoses are also bound up with higher costs in the field of oncology. Thus the question of elimination of hepatitis C touches upon aspects of the healthcare system as a whole. What can this society afford? "How much do we want to pay?" The Eco-Hep model shows that programmes targeting the elimination of hepatitis C do not significantly increase the burden on the German healthcare and social security system. What does change is cost distribution: more money is invested in prevention and screening, less in treatment of late sequelae. The Eco-Hep model shows that it makes sense to increase expenditures in the years up to 2024 so that no additional costs will be generated in the medium term and to avoid costs by eliminating hepatitis C in the longer term. 46

However, the discussion of elimination of hepatitis C must not be restricted to the economic aspects alone. There is no gainsaying the fact that this is also a matter of the fates of large numbers of individual persons. It is a matter of a great deal of preventable suffering and an opportunity to improve individual perspectives on life. It is a matter of the community of solidarity in healthcare, an obligation that touches all of us. There is an obligation to treat hepatitis C as soon as it is diagnosed, to treat the late sequelae and to bear the attendant cost burden. Society as a whole has long since undertaken to realise the base case scenario. There is neither an alternative to this, nor would we want one. Would it not be smarter to reallocate funds so as to eliminate hepatitis C with close to the same expenditure - at the same time addressing our obligations more actively and directly than in the past? Elimination of hepatitis C in Germany would also mean that a "scourge of mankind" could be defeated in Germany. A cure for cancer and HIV has alluded us to date, but this is within our reach for hepatitis C. Elimination is feasible. Elimination can be realised in a cost-effective manner. The Eco-Hep model provides a matrix that facilitates mapping out of various approaches and scenarios that aim at elimination of hepatitis C, that helps us compare them and refine the relevant prognoses. The Eco-Hep model offers a basis for decision-making and can thus contribute decisively to discussions of health economics and health policy.

47

E

RECOMMENDED PROCEDURE

The following measures are recommended with the aim of long-term reduction of the macroeconomic burden of HCV in Germany: Maintenance of the current annual treatment rates of at least 25,000 per year Improvement of diagnostics for late sequelae Targeted screening in the above-mentioned risk groups Effective prevention measures Early recognition of extrahepatic manifestations Destigmatisation strategies The measures listed here are supported by the recommendations of the WHO, ELPA, EASL and the Viral Hepatitis Plan of Action. The publications of the Robert Koch Institute61 also refer repeatedly to the importance of the basic elements prevention, screening and rapid allocation to treatment: . . . "The recommendations on prevention of hepatitis C in specific settings (as in healthcare) and in vulnerable groups (such as drug addicts and inmates) were presented in detail in the next-to-last Hepatitis C Annual Report 2013 and have not changed since.“ . . "Therefore screening programs, particularly for vulnerable groups with high prevalence, are important if we are to find these infected individuals, inform them of their status and offer them a treatment to stop the virus spreading. Studies have determined that HCV screening programs (and early therapy) are cost-effective in populations with a high HCV prevalence (such as injecting drug 62;63 users and migrants)." The publishers also recommend that all direct and indirect payers coordinate the measures they take - both measures both within their respective areas of competence and such synergy effects as can be cost-effectively implemented. A combined effort to realise the above recommendations can bring to fruition the elimination of hepatitis C in Germany before 2040 at nearly the same level of expenditure, bringing about a very palpable disburdening of all payers within a reasonable timeframe. For the persons affected, the elimination of hepatitis will mean above all gains in life expectancy and quality of life.

61

RKI, Epidemiologisches Bulletin 30, 2015, HCV in 2014 Sroczynski G, Esteban E, Conrads-Frank A, Schwarzer R, Muhlberger N, Wright D, et al.: Long-term effectiveness and cost-effectiveness of screening for hepatitis C virus infection. Eur J Public Health. 2009;19(3):245 – 53 63 Hahne SJ, Veldhuijzen IK, Wiessing L, Lim TA, Salminen M, Laar M: Infection with hepatitis B and C virus in Europe: a systematic review of prevalence and cost-effectiveness of screening. BMC Infect Dis 2013;13(1):181) 62

48

ANNEX A Basic data Basic data as follows are available for calculation of the results:

1

Thein, H. H., Yi, Q., Dore, G. J. and Krahn, M. D. Estimation of stage-specific fibrosis progression rates in chronic hepatitis C virus infection: a meta-analysis and meta-regression. Hepatology, 2008. 482 418-431 2 Lidgren, M., Hollander, A., Weiland, O. and Jonsson, B. Productivity improvements in hepatitis C treatment: impact on efficacy, cost, cost-effectiveness and quality of life. Scand J Gastroenterol, 2007. 427 867-877



1

2014 HCV-RNA prevalence from the CDA model; JVH 2015



1

2014 incident anti-HCV and HCV-RNA cases, estimate from the CDA model; JVH 2015



49

1 2

2014 outputs from the CDA model; JVH 2015 Deutsche Stiftung Organtransplantation



1

Szende, A. & Williams, A., 2004. Measuring Self-Reported Population Health: An International Perspective based on EQ-5D. Rq-5D, p.115.



1

Statistisches Bundesamt, General Actuarial Table 2010/12, adapted to model



1

IMS Health GmbH – Basierend auf diesen Grunddaten wurde eine jährliche Therapieanzahl auf 25.000 hochgerechnet.



50

1

www.aasld.org, (approved by Prof. Zeuzem, Frankfurt a.M.)



1

Fried et al. 2002, Rumi et al. 2010, Manns et al. 2001, Yenice et al. 2006, McHutschison et al. 2009, Hadziyannis et al. 2004, Zeuzem et al. 2004, Grischenko et al. 2009



1

Hezode et al. 2009, Jacobson et al. 2011, Kwo eet al. 2010, McHutchison et al. 2009, Poordad et al. 2011



1

Vietri, J., Prajapati, G., & El Khoury, A. C. (2013). The burden of hepatitis C in Europe from the patients’ perspective: a survey in 5 countries. BMC



1

Siebert, U., Ravens-Sieberer, U., Greiner, W., Sroczynski, G., Wong, J., Kuntz, K., Kallinowski, B., Graf von der Schulenburg, J., Bullinger, M. and Rossol, S. (2002).



51

1

Bruggmann, P. et al., 2014. Historical epidemiology of hepatitis C virus (HCV) in selected countries. Journal of viral hepatitis, 21 Suppl 1, pp.5–33.



1

Müllhaupt, B., Bruggmann, P., Bihl, F., Blach, S., Lavanchy, D., Razavi, H., … Negro, F. (2015) Modeling the Health and Economic Burden of Hepatitis C Virus in Switzerland. PloS One, 10(6), e0125214. 2 Stahmeyer JT et al. 2013 3 Wasem J et al. 2006



1

IMS Health



1

Younossi, Z., Brown, A., Buti, M., Fagiuoli, S., Mauss, S., Rosenberg, W., … others. 2015. Impact of eradicating hepatitis C virus on the work productivity of chronic hepatitis C (CH-C) patients: an economic model from five European countries. Journal of Viral Hepatitis.

• 52

1

The Zenzus Germany

53

B Screening data

1

Statistisches Bundesamt - Ger. Federal Office of Statistics 2013 Heiko Himmelreich et al, Management von Nadelstichverletzungen, Deutsches Ärzteblatt | Jg. 110 | Heft 5 | 1. Februar 2013 3 VDGH, 2015 EBM 4 Statistisches Bundesamt - Ger. Federal Office of Statistics 2014 5 Expert opinion 2



1

Statistisches Bundesamt - Ger. Federal Office of Statistics 2014 Robert Koch Institute Epidemiological Bulletin No. 30 27. July 2015 3 VDGH, 2015 EBM 4 Federal Office of Statistics 2014 5 Expert opinion 2



1

Reitox-report RKI, Druck Studie 2015 3 VDGH, 2015 EBM 4 Expert Opinion 5 Bericht zum Substitutionsregister 2015, BfArM, Bundesopiumstelle / 84.1 / 09.01.2015 6 Expert opinion 2



1

Reitox-report RKI, Druck Studie 2015 3 Quicktest Orasure / VDGH, 2015 EBM / Federal Office of Statistics 2015 4 Expert Opinion 2

• 54

1

Deutsche AIDS-Hilfe 2014, Schmidt et al. BMC Public Health 2014, 14:3, BMC Public Health 3 VDGH, 2015 EBM 4 Statistisches Bundesamt - Ger. Federal Office of Statistics 2014 2



1

Gesundheitsberichterstattung (health reporting), AOLG-Ind. 7.17 - Participation in the statutory health check-up 2 Robert Koch Institute Epidemiological Bulletin No. 30 27. July 2015 3 VDGH, 2015 EBM 4 Statistisches Bundesamt - Ger. Federal Office of Statistics 2014 5 after risk anamneses



1

Statistisches Bundesamt - Ger. Federal Office of Statistics Lavanchy D. et al. (2010) 3 VDGH, 2015 EBM 4 Statistisches Bundesamt - Ger. Federal Office of Statistics 2014 2

55

Basic data on social costs / indirect costs / reduced earnings

a) Reduced earning capacity pension Costs for the year 2013:

9,387,264.00 €

Calculation: Only new registrations of HCV-caused reduced earning capacity pensions 2008 – 2013:

1,088 persons64

Monthly average pension payment: Earlier registrations are not taken into account

719.00 € 65

b) Health insurers: Sick pay Costs for the year 2014:

18,726,000 € / 2014

Calculation: Number of sick leave days resulting from HCV infection with sick note episodes > 42 consecutive days:

4.49 %66

Average number of sick leave days, burden of health insurers over all patients (> 42 consecutive days):

4.8 days67

Average sick pay in GKV System:

96.11 €/day 68

Labour force participation rate: + diagnosis in age group 16 – 65 (Razavi)

41.6% (Younossi)

c) Regional administrative bodies: Invalidity payments to officials Costs for the year 2013:

1,520,400.00 €

Calculation: Only new registrations of HCV-caused work incapacity resulting from HCV in the years 2008 – 2013:

70 persons69

Monthly pension payment (2013):

1,810.00 €

64

Gesundheitsberichterstattung des Bundes - Ger. Federal Health Reporting System, www.gbe-bund.de Deutsche Rentenversicherung - German Pension Insurance: Pension payments in figures 2015, page 34ff 66 Data source IMS Health 67 Data source IMS Health 68 Krauth et al; die Perspektive der Gesetzlichen Krankenversicherung in der gesundheitsökonomischen Evaluation (perspectives of statutory health insurance - health economic evaluation; 2005 (check) 69 Data sources: Zahlen, Daten, Fakten 2015, Beamtenbund und Tarifunion (figures, data, facts, Association of Officials and Tariff Union), January 2015, Stat .Bundesamt (Ger. Federal Office of Statistics), Series 14-6 Invalidity Payment Recipients, own calculations 65

56

d) Employer Wage continuation in case of illness

7,747,255 € / 2014

HCV-caused sick days in the period > 42 days: (sick notes issued by physician (IMS))

average 1.8

Average wage costs for employers: (Federal Office of Statistics 2014)

106.03 € / calendar day

Number of diagnosed patient of working age:

97,578 (Razavi)

Labour force participation rate:

41.6 % (Younoussii)

e) Indirect costs Loss of productivity due to presenteeism:

155,522,324 € / year (2014)

Number of diagnosed HCV patients 18 – 65 years of age: 97578 (Razavi) Labour force participation rate: 41.6 % (Younoussi) Average employee payment in Germany: (Costs for Employers, Statistisches Bundesamt - Federal Office of Statistics) Vietri: (WPAI calculation: HCV-caused productivity losses, adjusted for actual absence)

38,700 €

Loss of productivity due to absenteeism:

35,345,983 € / year (2014)

9.9 %

Number of diagnosed HCV patients 18 – 65 years of age: 97,578 (Razavi) Labour force participation rate: 41.6 % (Younoussi) Average employee payment in Germany: (Costs for Employers, Statistisches Bundesamt Federal Office of Statistics)

38,700 €

Vietri: 2.3 % (WPAI calculation: HCV-caused productivity losses)

f) Occupational insurance association: Compensatory payments due to HCV infections Costs for the year 2014:

70

13,011,299.00 €70

Report of the Employers' Liability Insurance Association for Healthcare and Welfare Services of 08.10.2015

57

g) Various payers (DRV, gkV, pKV, etc.) Prevention and rehabilitation costs:

588,366€ / year

Calculation:

58

Average number of patients, rehabilitation, viral hepatitis:

327

327 adjusted for HCV share 61.6% (average 6 years, GBE 2014)

201.05 patients per year

Rehabilitation costs, inpatient rehabilitation costs: (Reha Report 2015, Deutsche Rentenversicherung - German Pension Insurance )

121.20 € / day

Average duration of rehabilitation: (GBE)

24.1 days

GLOSSARY Hepatitis C Antiviral

Against viruses.

Administration

To treat with, give (e.g. medicines)).

Check-up 35

Persons with statutory insurance may have a general health check done every two years after they reach the age of 35. The purpose of the check is early recognition of diseases – in particular cardiovascular diseases, renal diseases and diabetes mellitus.

Decompensated cirrhosis

Cirrhosis: Scarred shrinkage of an organ; a decompensated cirrhosis is diagnosed when the organ malfunctions.

Direct-Acting-Agent (DAA)

The first generation of DAAs has had marketing authorisation for treatment of hepatitis C since 2011; the second generation of DAAs have been in use since 2014; the treatment takes an average of 8.5 weeks and the cure rate is about 90%. → Protease inhibitors

Elimination

Neutralisation, removal.

Epidemiology

Medical fields covering the genesis, spread and fight against epidemic infectious diseases; in a more general sense, the term also refers to diseases in general, their causes, forms and social consequences in the populace.

Extrahepatic manifestations

Damage to organ systems outside of the liver caused by chronic hepatitis C e.g. affecting the heart, kidneys and brain.

Fibrosis

Transformation of liver cells into functionless support and connective tissue resulting from a chronic liver inflammation; pre-stage of cirrhosis of the liver; stages from F0 (no fibrosis to F4 (cirrhosis) are differentiated. → METAVIR Score

Genotype

Genetic type; there are currently 6 known genotypes of hepatitis C; used to determine the therapeutic approach for a hepatitis C treatment.

Hepatitis

Inflammation of the liver, above all the forms of acute viral hepatitis (hepatitis A to E) caused by hepatitis viruses. 59

Hepatitis C RNA

Hepatitis C ribonucleic acid; the viral genome.

Hepatitis C virus (HCV)

Viral disease transmitted by blood contact (see Fact Sheet "Hepatitis C in Germany").

Hepatic encephalopathy

Central nervous system dysfunction, which can be caused by advanced liver disease, e.g. cirrhosis of the liver.

Casuistic description

Description of an individual case of illness.

Co-infection

Simultaneous infection of a cell or organisms by two different pathogens or two different strains of the same pathogen.

Contraindication

Circumstance or condition that makes (continued) use of a therapeutic measure impossible that would otherwise be considered correct or necessary.

Liver cancer / hepatocellular carcinoma

(HCC); malignant tumour disease and late complication of chronic liver inflammation; in patients with chronic hepatitis C, liver cancer usually develops when a cirrhosis is already present.

METAVIR Score

Designates the stage of liver inflammation and fibrosis; from stage F0 (no fibrosis) to stage F4 (cirrhosis).

Pathogenesis

The totality of factors involved in onset and development of a disease.

PEG Interferon + ribavirin

Polyethylene glycol (PEG) interferon: Substance that inhibits viral synthesis; medical drug used in treatment of hepatitis C, frequently causes flu-like symptoms. Hepatitis C treatment with interferon is always combined with other active substances (ribavirin and/or other active substances such as

→ Protease inhibitors

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Prevention

Any measure that can prevent, delay or render less likely damage to health. Primary prevention: Health education and screening of the populace. Secondary prevention: Early recognition of diseases in highrisk groups. Tertiary prevention: Prevention of exacerbation or recurrence of existing diseases.

Prevention

Any measure that can prevent, delay or render less likely damage to health.

Prevention

Any measure that can prevent, delay or render less likely damage to health.

Progression

Increasing exacerbation (worsening) of a disease.

Protease inhibitors

Active substances that inhibit an enzyme of the hepatitis C virus, thus directly hindering its proliferation.

Replication

Virology: Proliferation of a virus with the help of the host metabolism.

Resection

Surgical removal of diseased or defective parts of an organ or part of the body.

Replacement therapy

Dependency therapy is used in cases of dependence on certain drugs; drugs like opiates, for example, are at first replaced by medical drugs (substitutes); the objective is to improve health and quality of life over the medium term, to stabilise the patient and, over the longer term, to achieve a life without drugs.

Sustained viral response (SVR)

Cure of hepatitis C is defined as the absence of → hepatitis C RNA from the blood 24 weeks after the completion of treatment.

Treatment regimen

Therapy schedule; plan formulated by physicians to treat diseases.

Transaminases

Enzymes that transfer an amino group from one substance to another.

Transmission

Transfer of a pathogen from host to host.

Viraemia

Presence of viruses in the blood.

Viral load

Number of viruses in a millilitre of blood.

Sources: Duden Editorial Board: German versions from the Wörterbuch medizinischer Fachbegriffe, 9th revised and supplemented edition, Berlin 2012; Glossary of Leberhilfe e.V. Information portal DocCheck.com

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Economic terminology Absenteeism

Productivity lost due to absences and working time lost due to sick leave and doctor visits or appointments related to comprehensive treatment and management of a hepatitis C infection. ↔ Presenteeism; → Costs, indirect

Treatment costs

→ Costs, treatment

Total medical expenditure

In the present study, the total medical expenditure comprises the following aspects: - Treatment costs without hepatitis C treatment - Costs of hepatitis C treatment - Treatment costs of late sequelae - Costs of treatment of extrahepatic manifestations

Healthcare costs

→ Costs, health

Health economy

Analysis of healthcare services / the healthcare system or its subdivisions using economic methods; the objective is to improve the efficiency / review the effectiveness of the healthcare services / healthcare system; also considered under the heading of health economy is revision of funds distribution and distribution of healthcare services.

Indirect costs

→ Costs, indirect

Costs, treatment

Costs of treatment a hepatitis C infection including possible late sequelae of the disease.

Costs, health

= Healthcare expenditures; end use of healthcare products and services as well as the capital investments in healthcare infrastructure, including expenditures from both public and private sources (also private households) for medical goods and services, public health and prevention programmes and administrative services.

Costs, indirect

Costs reflecting loss of productivity, work incapacitation, occupational disability (in cases of long-term disease or disability) or premature death; the present report calculates these costs only for the working population and with the help of the literature and data provided by IMS Health. → Absenteeism; ↔ Presenteeism; →

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Costs, medication

Costs of medical drugs used to treat hepatitis C, possible side effects and late sequelae of the disease.

Costs, care and rehabilitation

Expenditures for care comprise, for example: - Costs of semi-residential and short-term care - Nursing allowance

Rehabilitation costs

cover measures the aim of which is to alleviate existing physical or mental disabilities, such as for example physiotherapeutic treatments.

Costs, screening

Expenditures for early recognition screening measures for hepatitis C infections.

Costs, social

Payers of social costs include: - Pension insurers - Regional administrative bodies - Health insurers - Employers - Occupational insurance associations In the present study, the social costs comprise the following factors: -

Reduced earning capacity pension Invalidity payments to officials Sick pay Wage continuation in case of illness Compensatory payments by the occupational insurance associations resulting from hepatitis C infections - Rehabilitation services

Medical drug costs

→ Costs, medication

Medicalmanagement

→ Costs, medical management

Costs of care and rehabilitation

→ Costs, care and rehabilitation

Costs of Presenteeism

Impairment of daily functioning on the job and the resulting loss of productivity. → Absenteeism; Costs, indirect

Screening costs

→ Costs, screening

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Quality-adjusted life years

The concept of quality-adjusted life years (QALYs) combine quality of life and (remaining) life expectancy to form a measurable criterion. The QALY approach focuses on the subjective health of the patients. The relevant health dimensions (from the perspective of the individual patient) quality of life and life expectancy are apprised in the QALY approach.

Social costs

→ Costs, social

Therapy management costs → Costs, therapy management

Sources: Springer Wirtschaftslexikon: http://wirtschaftslexikon.gabler.de/ Lexikon der Bundeszentrale für politische Bildung: http://www.bpb.de/nachschlagen/lexika/lexikon-der-wirtschaft/ DocCheck Flexikon: http://flexikon.doccheck.com/de/Spezial:Mainpage http://www.wirtschaftslexikon24.net/

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Leberhilfe Projekt gUG (Liver Help Project Ltd.)
 Executive Partners
 Babette Herder
 Achim Kautz
 Address Krieler Str. 100
 50935 Cologne
 Contact Email: [email protected]

www.leberhilfe-projekt.de

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