Long-term effectiveness and cost-effectiveness of antiviral treatment in hepatitis C

Long-term effectiveness and cost-effectiveness of antiviral treatment in hepatitis C



"We conclude that antiviral therapy may prolong life, improve long-term health-related quality-of-life and be reasonably cost-effective in treatment-naïve patients with chronic hepatitis C as well as in former relapsers/nonresponders. Further research is needed in patients with specific co-morbidities or risk profiles.".....All HTA reports concluded that initial combination therapy with peginterferon plus ribavirin may be cost-effective in treatment-naïve patients with CHC. The criterion used to state probable cost-effectiveness was either 'good-value-for-money' (e.g. results were falling within the range of selected well-accepted health technologies reported in the literature, defined by NHS decision makers) or a certain threshold (e.g. 50 000€/QALY in the German study or 30 000£/QALY in the UK studies).



Journal of Viral Hepatitis Aug 6 2009 Early view


G. Sroczynski 1 , E. Esteban 1 , A. Conrads-Frank 2 , R. Schwarzer 1 , N. Mühlberger 1 , D. Wright 2 , S. Zeuzem 3 and U. Siebert 1,2,4

1 Institute for Public Health, Medical Decision Making and Health Technology Assessment, Department of Public Health, Information Systems and Health Technology Assessment, UMIT – University of Health Sciences, Medical Informatics and Technology, Hall i.T., Austria ; 2 Institute for Technology Assessment and Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA ; 3 Department of Internal Medicine, Gastroenterology, Hepatology, Pneumology and Endocrinology, Johann Wolfgang Goethe-University, Frankfurt a. M., Germany ; and 4 Centre for Health Decision Science, Department of Health Policy and Management, Harvard School of Public Health, Boston, MA, USA

Correspondence to Uwe Siebert, MD, MPH, MSc, ScD, Professor of Public Health (UMIT), Adjunct Professor of Health Policy and Management (Harvard University), Chair, Department of Public Health, Information Systems and Health Technology Assessment, UMIT – University for Health Sciences, Medical Informatics and Technology, Eduard Wallnoefer Center I, A-6060 Hall i.T., Austria. E-mail: public-health@umit.at



This project was supported in part by an unrestricted educational grant from Hoffmann La-Roche Ltd, Basel, Switzerland. The authors had complete and independent control over study design, analysis and interpretation of data, report writing, and publication, regardless of results.



ABSTRACT

Summary. We systematically reviewed the evidence for long-term effectiveness and cost-effectiveness of antiviral treatment in patients with chronic hepatitis C. We performed a systematic literature search on the long-term effectiveness and cost-effectiveness of AVT in hepatitis C (1990–March 2007), and included health technology assessment (HTA) reports, systematic reviews, long-term clinical trials, economic studies conducted alongside clinical trials and decision-analytic modelling studies. All costs were converted to 2005€. Antiviral therapy with peginterferon plus ribavirin in treatment-naïve patients with chronic hepatitis C was the most effective (3.6–4.7 life years gained [LYG]) treatment and was reasonably cost-effective (cost-saving to 84 700€/quality adjusted life years [QALY]) when compared to interferon plus ribavirin. Some results also suggest cost-effectiveness (below 8400€/(QALY) of re-treatment in nonresponders/relapsers. Results for patients with persistently normal alanine aminotransferase (ALT) levels or with special co-morbidities (e.g. HIV) or risk profiles were rare. We conclude that antiviral therapy may prolong life, improve long-term health-related quality-of-life and be reasonably cost-effective in treatment-naïve patients with chronic hepatitis C as well as in former relapsers/nonresponders. Further research is needed in patients with specific co-morbidities or risk profiles.


Introduction




Chronic hepatitis C (CHC) is an emerging problem in public health. Hepatitis C virus (HCV) infects an estimated 123 million persons worldwide [1]. HCV infection is the leading cause of chronic liver disease with serious sequelae such as end-stage cirrhosis, liver cancer and liver transplantation [1–3]. Therefore, as the most common blood-borne infection, it imposes a significant personal and social burden on those infected, as well as substantial costs to society.



Different antiviral medications are available for treating patients with CHC. Antiviral therapy with peginterferon alpha plus ribavirin yielded the most clinical benefit in terms of sustained virological response (SVR) rates [4–6] and has been deemed the standard of care for patients with CHC infection and elevated alanine amino transferase (ALT) levels [7–9]. However, antiviral therapy is expensive, imposes the risk for severe adverse events, and not all patients benefit from treatment, which imposes concerns regarding the cost-effectiveness of antiviral therapy.



The objective of this study was to systematically review the evidence on clinical long-term effectiveness and cost-effectiveness of antiviral therapy with nonpegylated or pegylated interferon alone or in combination with ribavirin in patients with CHC.





Discussion




We performed a systematic review on the clinical long-term effectiveness and cost-effectiveness of antiviral therapy for patients with CHC. Based on HTA reports and cost-effectiveness studies, antiviral combination therapy in treatment-naïve patients with CHC can be considered to be clinically effective in terms of life-years gained and/or quality-adjusted life-years gained and reasonably cost-effective. The most recent combination therapy with peginterferon plus ribavirin was more effective and also reasonably cost-effective when compared to other well-accepted medical interventions.



Based on few studies, retreatment in patients who had formerly relapsed or did not respond to interferon based mono or combination therapy seems to be reasonably cost-effective as well. However, no published evidence was available on retreatment of patients who had formerly relapsed or did not respond to peginterferon plus ribavirin, which should be addressed in future research.



Based on one study conducted in Italy, antiviral therapy with peginterferon plus ribavirin may be relatively cost-effective even in patients with CHC and persistently normal ALT levels [25]. However, these results must be treated with caution because of the uncertainty around the natural disease progression in this subgroup.



A substantial percentage of patients with CHC have certain risk and comorbidity profiles, such as HIV-coinfection or intravenous drug usage. However, most clinical trials and cost-effectiveness studies excluded these patient groups. Only two cost-effectiveness studies [26,30] evaluated antiviral treatment with peginterferon plus ribavirin in patients with HIV-coinfection and one study [38] examined the cost-effectiveness in IDU-patients with methadone substitution. The results for patients co-infected with HIV varied widely. The evidence was not sufficient to conclude that antiviral therapy with peginterferon plus ribavirin is cost-effective for this specific target population.



Further research is needed in these special populations. Future studies should examine the efficacy, the cost-effectiveness and the need for antiviral therapy in patients with normal ALT levels, with histological mild hepatitis C, and with certain risk and comorbidity profiles (e.g. co-infection with HIV or HBV, haemophilia, IDUs).



All clinical trials used the SVR as an intermediate endpoint for the clinical efficacy, which is associated with normalization of ALT levels, improved liver histology [4,6] and improved quality-of-life [61]. In nonrandomized studies [62–66], 90–100% of patients with a sustained response remained viral negative for up to 10 years, supporting the hypothesis that SVR improves long-term health benefits. However, further epidemiological studies and outcome trials evaluating long-term clinical outcomes (e.g. incidence of cirrhosis and mortality) should be performed to provide more evidence on the long-term benefit of antiviral therapy.



Moreover, further research is needed regarding the natural progression of the disease given different prognostic factors. There is no consistent estimate of the risk of progression to cirrhosis in the literature. In a systematic review of 57 studies on the natural history of hepatitis C [67,68], the authors classified the identified studies into four categories of study design and used regression analysis to derive pooled progression risks estimates for each category. The estimated 20-year risk of cirrhosis was 24% for post-transfusion cohorts, 22% for liver clinic series, 7% for community-based cohorts and 4% for blood donors. Adjusting for demographic and clinical characteristics explained only a small part of this heterogeneity. It has been argued that biases such as referral bias and selection bias may explain the high cirrhosis risks in liver series and post-transfusion cohorts as well as the low estimates in blood donors [69]. The fraction of patients with elevated ALT levels varied between these different settings [67,68]. The review demonstrated that clinical progression of hepatitis C depends on patient characteristics such as ALT levels, gender, daily alcohol intake, etc. Therefore, antiviral treatment considering individual characteristics may be more efficient.



More evidence from observational long-term studies on the natural history of hepatitis C and the medical effectiveness of different therapeutic strategies is needed. Prospective studies assessing actual cost for treatment and side effects in the routine health care setting are also necessary.



In conclusion, the combined evidence from decision-analytic studies on long-term health outcomes and costs suggests that peginterferon plus ribavirin may prolong life, improve long-term health-related quality-of-life and be cost-effective in treatment-naïve patients with CHC as well as in former relapsers or nonresponders to interferon alone or combined with ribavirin. Results from a single cost-effectiveness study suggest even reasonably cost-effective antiviral therapy in patients with persistently normal ALT levels. However, more modelling studies are needed to validate these results. No conclusions can be made regarding patients with special comorbidities or risk profiles. Further research is needed in these patient groups.


Results


Included studies


A total of 297 unique references were retrieved. Forty-nine studies [12–60] met the inclusion criteria, including seven HTA reports [15,28,39,41,45,50,59] and one technology appraisal [33] assessing the cost-effectiveness of antiviral therapy with interferon/peginterferon alone or in combination with ribavirin in patients with CHC.



No original clinical trial assessing the clinical long-term effectiveness (e.g. mortality) of antiviral therapy in patients with CHC was identified. The identified HTA reports reported short-term clinical effectiveness in terms of percentage of patients with SVR, but did not report on clinical long-term effectiveness. In the absence of clinical studies, meta-analyses and HTA reports evaluating the clinical long-term effectiveness of antiviral therapy in patients with CHC, we based our results on cost-effectiveness studies using decision-analytic modelling to evaluate the clinical long-term effectiveness of different antiviral therapy options in terms of undiscounted life years and/or quality-adjusted life years gained compared to no antiviral treatment.



The results of three HTA reports [39,45,59] were additionally reported in four publications [24,33,40,44]. In these cases, only the data from the original HTA reports were considered. Two cost-effectiveness studies were not included in Appendices. One study [19] used a population impact model including different comorbidity subgroups and only partial treatment to predict epidemiologic and economic outcomes over the next 30 years rather than traditional lifetime ICERs comparing different treatment options. The other study [32] did not report ICER in terms of costs per life years or QALYs gained. Instead, the authors reported lifetime costs per SVR. Hence, a total of 43 cost-effectiveness studies and HTA reports were considered.



Among 42 publications that included a model-based cost-effectiveness analysis (one HTA report only performed a review on economic evaluations), seven studies [13,20,21,29,42,43,49] evaluated the cost-effectiveness of interferon monotherapy in treatment-naïve patients with CHC. Twelve studies [16,17,23,34,37,41,47,51,56,58–60] evaluated the cost-effectiveness of interferon plus ribavirin in treatment-naïve patients with CHC, and three studies [27,36,55] in interferon-nonresponders or -relapsers. Twenty-one studies [12,14,15,18,22,25,26,30,31,35,38,39,44–46,48,50,52–54,57,59] evaluated the cost-effectiveness of peginterferon plus ribavirin. Among those, 16 studies [12,14,15,18,31,35,39,45,46,48,50,52–54,57,59] evaluated treatment-naïve patients and five studies evaluated other populations such as interferon-nonresponders/relapsers [22], patients with HIV–HCV coinfection [26,30], intravenous drug users (IDUs) [38] and patients with persistently normal ALT levels [25].



Regarding clinical long-term effectiveness data, ten studies [13,20,21,34,42,43,45,47,51,58] reported undiscounted LYs or QALYs gained in treatment-naïve CHC-patients treated with interferon monotherapy, 12 studies [15,34,37,45–47,50,51,54,56–58] reported undiscounted LYs and/or QALYs gained for patients treated with interferon plus ribavirin, and six studies [15,45,46,50,54,57] reported undiscounted LYs and/or QALYs gained for peginterferon plus ribavirin, each compared to no antiviral treatment. Two studies [27,55] reported QALYs gained for patients who formerly relapsed to prior interferon treatment and were retreated with interferon plus ribavirin. One study [30] reported life years gained for CHC-patients with HIV treated with interferon plus ribavirin or with peginterferon plus ribavirin. One study [38] reported LYG compared to no antiviral treatment for IDUs treated with peginterferon plus ribavirin.



Clinical long-term effectiveness of antiviral treatment



Effectiveness varied depending on length of treatment, HCV-genotype and liver histology of CHC-patients and other population characteristics. Compared to no antiviral treatment, interferon monotherapy saved 0.17–2.43 undiscounted life years or 0.53–4.94 QALYs (Table 1), interferon plus ribavirin saved 1.60–5.41 undiscounted life years or 1.10–6.21 QALYs, and peginterferon plus ribavirin saved 3.60–4.70 undiscounted life years or 2.84–4.99 QALYs in treatment-naïve CHC-patients (Table 1). Compared to interferon plus ribavirin, peginterferon plus ribavirin saved 0.6–1.8 undiscounted life years or 0.5–1.9 QALYs (results not shown in tables).



In patients that relapsed after prior interferon treatment, interferon plus ribavirin saved 3.30 life years or 3.10–4.20 QALYs (Table 2) compared to no antiviral treatment [27,55].



In CHC-patients with HIV, interferon plus ribavirin saved 0.00–1.02 undiscounted life years depending on CD4-cell count and liver histology, and peginterferon plus ribavirin saved 0.01–1.07 undiscounted life years, both compared to no antiviral therapy (Table 2) [30]. Peginterferon plus ribavirin saved 0.00–0.37 undiscounted life years compared to interferon plus ribavirin. Based on one New Zealand study [38] conducted in IDUs with CHC, peginterferon plus ribavirin compared to no antiviral therapy saved depending on age and gender 0.81–1.36 life years in nonmaori and 0.46–0.99 life years in maori people. QALYs were not reported.



Cost-effectiveness of antiviral treatment


Health technology assessment reports


Seven HTA reports met the inclusion criteria. Of these, four HTA reports summarized cost-effectiveness studies [15,28,39,45] and six HTA reports [15,39,41,45,50,59] conducted a cost-effectiveness analysis. All HTA reports restricted their assessment to treatment-naïve patients with CHC and evaluated the cost-effectiveness of treatment with peginterferon plus ribavirin, except one HTA report [41] evaluating interferon plus ribavirin.



Economic reviews in HTA reports



The German HTA report included seven economic studies evaluating interferon in combination with ribavirin compared to interferon alone [45]. The ICURs ranged from cost saving to 27 700€/QALY. No study evaluating the health economic outcomes of peginterferon plus ribavirin were identified by the time of the German HTA report was conducted. The 2004 UK HTA report included two published and two unpublished economic studies evaluating peginterferon plus ribavirin compared to interferon plus ribavirin [39]. The ICURs ranged from 700 to 11 800€/QALY. The 2004 Austrian HTA report included six economic studies evaluating peginterferon plus ribavirin compared to interferon plus ribavirin [28]. The ICURs ranged from 3800 to 11 000€/QALY. The Canadian HTA report included nine economic studies evaluating peginterferon plus ribavirin compared to interferon plus ribavirin with ICURs ranging from 700 to 36 300€/QALY [15].



Economic decision analyses in HTA reports



The 2000 UK HTA report reported ICURs of 11 707–27 697 €/QALY for 24–48 weeks of treatment with interferon plus ribavirin compared to interferon alone in treatment-naïve CHC-patients [41]. The 2006 UK HTA report focused on 52 weeks of treatment with interferon plus ribavirin compared to no antiviral treatment in treatment naïve patients with mild hepatitis C and yielded an ICUR of 14 956€/QALY for the base-case analysis [59].



The 2004 UK HTA evaluated 48 weeks of peginterferon plus ribavirin compared to interferon plus ribavirin and reported an ICUR of 19 949€/QALY (Table 3) [39]. The 2006 UK HTA particularly focused on mild CHC-patients and estimated an ICUR of 44 560 €/QALY for mild CHC-patients with genotype-1 and 12 267€/QALY for patients with other genotypes [59]. The German HTA report estimated an ICUR of 10 264 €/QALY for 48 weeks of peginterferon plus ribavirin compared to interferon alone (as the next nondominated strategy) in CHC patients [45]. The 2004 UK HTA report reported an ICUR of 9947€/QALY for 48 weeks of peginterferon plus ribavirin compared to no antiviral treatment (Table 3) [39]. The Austrian HTA report yielded a similar ICUR of 9234€/QALY for 12–48 weeks of peginterferon plus ribavirin compared to no antiviral treatment [50]. The recently published Canadian HTA report estimated an ICUR of 12 906€/QALY [15].



All HTA reports concluded that initial combination therapy with peginterferon plus ribavirin may be cost-effective in treatment-naïve patients with CHC. The criterion used to state probable cost-effectiveness was either 'good-value-for-money' (e.g. results were falling within the range of selected well-accepted health technologies reported in the literature, defined by NHS decision makers) or a certain threshold (e.g. 50 000€/QALY in the German study or 30 000£/QALY in the UK studies).



Cost-effectiveness studies



Interferon monotherapy



One cost-effectiveness study [21] on interferon monotherapy was conducted in Europe (UK); the other eight studies [13,20,29,42,43,49] were conducted in non-European countries (USA, Australia and Japan). ICERs of interferon monotherapy varied over a wide range depending on discount rate, treatment duration and dosage, and population characteristics. The UK study reported ICURs of 800–1100€/QALY when comparing interferon monotherapy with no antiviral treatment (data shown in Appendix only) [21]. The ICURs from the non-European studies ranged from cost saving to 5700€/QALY. All studies considered antiviral therapy with interferon alone to be reasonably cost-effective compared to no antiviral treatment in treatment-naïve patients with CHC.



Interferon plus ribavirin



Nine cost-effectiveness [16,17,23,34,37,41,47,51,59] studies on interferon plus ribavirin were conducted in European countries; four in the UK, two in Spain, one in Germany, one in Switzerland and one in Sweden. The other three studies [56,58,60] were conducted in the USA. ICERs varied over a wide range depending on discount rate, treatment duration and dosage, and population characteristics and ranged from cost saving to 27 700€/QALY (data shown in Appendix only). All studies considered antiviral therapy with interferon plus ribavirin compared to interferon monotherapy in treatment-naïve patients to be reasonably cost-effective.



Three studies conducted in Spain [36], the USA [55] and Japan [27] reported cost-effectiveness ratios for retreatment with interferon plus ribavirin in patients who had been previously treated with interferon and did not respond or relapsed. The Spanish study reported an ICUR of 8400€/QALY compared to no retreatment. The Japanese study reported an ICUR of 32€/QALY in CHC-patients including cirrhosis and the US study reported an ICUR of 154€/QALY in patients with mild or moderate hepatitis C, both compared to interferon alone. All studies concluded that retreatment with interferon plus ribavirin is cost-effective compared to no antiviral treatment.



Peginterferon plus ribavirin



Eleven cost-effectiveness studies [12,14,18,39,45,46,48, 50, 52, 57,59] of combination therapy with peginterferon plus ribavirin in treatment-naïve patients were conducted in European countries; two in the UK, two in Belgium, two in Germany, one in Spain, one in Italy, one in Sweden, one in Poland and one in Austria. The other five studies were conducted in the USA [35,53,54], Canada [15] and China [31]. ICERs varied over a wide range depending on discount rate, treatment duration and dosage and population characteristics. ICURs ranged from cost saving to 84 700€/QALY when compared to interferon plus ribavirin (Table 3). All studies considered antiviral therapy with peginterferon plus ribavirin compared to interferon plus ribavirin in treatment-naïve patients as reasonably cost-effective. In one study, therapy with peginterferon plus ribavirin dominated combination therapy with interferon plus ribavirin, and in some other studies peginterferon plus ribavirin dominated even interferon monotherapy. Thus, ICERS were compared to the next nondominated strategy (i.e. either interferon monotherapy or no antiviral treatment). In all of these studies, peginterferon plus ribavirin was the most effective treatment strategy and was considered to be cost-effective for the specific patient population.



Figure 1 shows the distribution of the ICERs of peginterferon plus ribavirin vs the next nondominated strategy in treatment-naïve CHC patients. Some studies reported results separately for genotype 2/3 and other genotypes, and other studies reported results for a mixed population. Most studies reported cost-effectiveness ratios between 5000 and 10 000€/QALY or LYG (39% of results in a mixed population) or between 10 000 and 20 000€/QALY or LYG (35% of results in a mixed population). Only 6% of studies reported cost-saving results. Cost-effectiveness results over 40 000€/QALY or LYG were reported in 17% of studies for populations with HCV genotype 2/3 and in 11% of studies for populations with other HCV genotypes, but in no study evaluating a mixed population.



Several studies focused on specific settings or patient groups (Table 4). One study conducted in Mexico reported retreatment with peginterferon plus ribavirin in patients who had been previously treated with interferon plus ribavirin and did not respond or relapsed to be cost saving, when compared to no treatment [22].



Another study conducted in New Zealand reported ICERs compared to no antiviral treatment ranging from 20 265 to 26 331€/LYG for peginterferon plus ribavirin in CHC patients aged 26–31 years with methadone substitution who were IDUs [38]. No quality-of-life adjustment was performed.



Two studies conducted in the USA reported ICURs for patients with HIV-coinfection treated with peginterferon plus ribavirin [26,30]. ICURs compared to treatment with interferon plus ribavirin varied over a wide range depending on histology, CD4 cell counts and genotypes. Kuehne et al. [30] reported ICURs from 40 000 (in moderate CHC patients with HCV genotype 1 and 350/μL CD4 counts) to 4 145 253€/QALY (in mild CHC patients with HCV genotype non1 and 200/μL CD4 counts). Whereas Hornberger et al. [26] reported ICURs for CHC patients including cirrhosis from cost-saving (HCV genotype 2/3) to 5722 €/QALY (HCV genotype 1). The evidence was not sufficient to conclude that antiviral therapy with peginterferon plus ribavirin is cost-effective.



One study conducted in Italy reported ICURs of 3350 (HCV genotype 2/3) to 18 800€/QALY (HCV genotype 1) for peginterferon plus ribavirin in patients with CHC and persistently normal ALT levels [25].



Material and methods




Since it is the latest state-of-the-art treatment, interferon-based antiviral therapy was the focus in this review. A systematic literature search was conducted using the databases Medline, the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials (CENTRAL) and the NHS databases Abstracts of Reviews of Effects (DARE), health technology assessment (HTA) and Economic Evaluation Database (NHS EED) to identify studies assessing the clinical long-term effectiveness and cost-effectiveness of antiviral therapy with interferon or peginterferon alone or in combination with ribavirin in patients with hepatitis C. The time horizon of the literature search was limited from 1990 to March 2007. All references were imported into a literature database using a literature management software program (EndNote 9.0, Thomson ResearchSoft TM, Thomson Corporation, Stanford, CT, USA).



First, reference titles and abstracts were screened for relevant articles. In a second step, studies were selected based on a priori inclusion and exclusion criteria after reading the full text document. We included HTA reports, systematic reviews, long-term clinical trials, full health economic studies and decision-analytic modelling studies assessing the cost-effectiveness of antiviral therapy with interferon or peginterferon alone or in combination with ribavirin in patients with HCV infection. Since the benefit of antiviral treatment occurs over a long-time horizon, we only included studies that reported clinical long-term effectiveness and cost-effectiveness in terms of mortality reduction or life-years gained and in terms of cost per life year gained (LYG) or cost per quality-adjusted life-year gained (QALY). We excluded studies in languages other than English or German, editorials, letters, nonsystematic reviews, studies reporting only short-term effectiveness data (e.g. SVR rates), studies assessing other therapies in hepatitis C or assessing antiviral therapy in diseases other than hepatitis C. We also excluded studies that did not report sufficient data to derive incremental cost-effectiveness ratios (ICERs).



We systematically extracted the results from the publications and summarized the information in Appendices reporting clinical outcomes (i.e. study, country, treatment regimen/duration, population characteristics, absolute and incremental life years, absolute and incremental quality adjusted life years) and economic outcomes (i.e. study, country, index year, currency, discount rate, treatment regimen/duration, comparator strategy, population characteristics, ICERs, incremental cost-utility ratios (ICURs). If possible, results were stratified by treatment duration, histology, and/or HCV genotype and different target populations. Results were reported separately for interferon monotherapy, combination of interferon plus ribavirin, and combination of peginterferon plus ribavirin. Economic results for interferon monotherapy and combination of interferon plus ribavirin are available in Appendices.



When necessary and possible, we recalculated ICER or ICUR from the data reported in the publication. We reported results in country-specific currencies. To facilitate comparison across countries and to enable other countries to transfer our results into their currencies, all results were converted to 2005 German Euros (€) using Gross Domestic Product Purchasing Power Parities [10] and the German Consumer Price Index [11] for inflation. Germany was used as the reference country for the cost conversion, because it is the country with the highest population size in Europe.



Acknowledgements and disclosures




This project was supported in part by an unrestricted educational grant from Hoffmann La-Roche Ltd, Basel, Switzerland. The authors had complete and independent control over study design, analysis and interpretation of data, report writing, and publication, regardless of results.



We thank the members of the PanEuropean Hepatitis C Expert Panel for providing local information and reviewing the results of our study: Maria Buti, MD, Hospital General Universitario Vall de Hebron, Barcelona, Spain; Florin Caruntu, MD, Matei Bals Infectious Disease Institute, Bucharest and Carol Davila Medicine and Pharmacy University, Bucharest, Romania; Cihan Yurdaydin, MD, University of Ankara Medical School, Gastroenterology Section, Ankara, Turkey; Scott D. Holmberg, MD, MPH, Epidemiology and Surveillance Branch, Division of Viral Hepatitis Prevention, NCHHSTP, Centers for Disease Control and Prevention, Atlanta, GA, USA; Andrzej Horban, MD, Hospital of Infectious Diseases, Warsaw Poland; Prof. William Rosenberg, Institute of Hepatology, University College London, UK.



Conflicts of interest



Nikolai Muhlberger has received travel support from Hoffmann La-Roche Ltd. to present preliminary results of the study to different audiences. Uwe Siebert has received health technology assessment research grants from the German Federal Ministry of Health and the Austrian Academy of Sciences and unrestricted research grants from Schering Plough and Roche.



Funding interests



This project was supported in part by an unrestricted educational grant from Hoffmann La-Roche Ltd, Basel, Switzerland. The authors had complete and independent control over study design, analysis and interpretation of data, report writing, and publication, regardless of results.