Prevalence of HCV infection in Europe in the DAA era: Review

In 2016, the Global Health Sector Strategy, ratified by the 69th World Health Assembly, set the ambitious goal of eliminating hepatitis C virus (HCV) and hepatitis B virus infections by 2030, emphasizing the importance of national screening programmes. Achieving this goal depends on each country's ability to identify and treat 80% of chronic hepatitis C cases, a critical threshold set by the World Health Organization. Traditionally, estimates of HCV prevalence have been based on interferon era studies that focused on high‐risk subgroups rather than the general population. In addition, the incomplete data available from national registries also limited the understanding of HCV prevalence. The 2016 report from the European Centre for Disease Prevention and Control highlighted that HCV rates varied across European counties, ranging from .1% to 5.9%. However, data were only available for 13 countries, making the overall picture less clear. Additionally, the epidemiological data may have underestimated the true burden of HCV due to lack of awareness among those with chronic infection. The main objective of this review is to provide a comprehensive summary of HCV epidemiology in Europe in the current era of direct‐acting antivirals (DAAs). The data included in the analysis range from the end of 2013 to December 2023 and have been categorised according to the United Nations Geoscheme. The resulting synthesis underscores the noteworthy impact of DAA treatment on the epidemiological situation.


| INTRODUC TI ON
In 2016, the 69th World Health Assembly endorsed the Global Health Sector Strategy to eliminate hepatitis C virus (HCV) and hepatitis B virus (HBV) infections by 2030, 1 thus reinforcing the need for national screening programmes.The possibility of pursuing and finally achieving the HCV elimination goal would rely on the capability of each country to identify and treat most patients infected with HCV, as treatment of 80% of eligible people with chronic hepatitis C (CHC) was among the World Health Organization (WHO) global targets. 1,2wever, estimates of HCV prevalence have long been based on interferon (IFN) era studies that targeted specific high-risk subgroups rather than the general population.Official data from national registries are mostly lacking, with the exception of very few Countries. 3Even recently, most data on HCV prevalence come from high-risk populations [i.e.people who inject drugs (PWID), men who have sex with men (MSM), prisoners, migrants, people attending addiction services (AS)], which have been extensively studied in the context of specific public-health policies, even before the WHO goal set and the advent of the direct-acting antivirals (DAA) era.
Consequently, what is truly lacking in this context is the prevalence of HCV infection in the general population, as available data are mostly derived from limited real-life studies, most of which were conducted a long time ago. 3In addition, the Polaris Observatory, the universal registry created by the Center for Disease Analysis, only provides estimates of HCV prevalence and disease burden modelling rather than raw country-specific data. 4 2016, the European Center for Disease Control (ECDC) report indicated that HCV prevalence ranged from .1% (Belgium, Ireland and Netherlands) to 5.9% (Italy), with estimates representative for the general population being available for only 13 Countries. 3[7] Taking all these matters into consideration, it shouldn't be surprising that the WHO advocacy brief publication gave a boost to design epidemiological studies, either spontaneous or funded by the Governments of individual countries.All of them have helped to generate useful information to describe the real current HCV epidemiological scenario in Europe, which has changed significantly over the past decades, mainly thanks to the hundreds of thousands of people treated with DAAs. 4 In this review, we report currently available data on HCV prevalence in the European general population, obtained from studies published between late 2013 and December 2023.Data were analysed according to each sub-region of Europe, as classified by the United Nations geoscheme (Northern Europe, Western Europe, Eastern Europe, Southern Europe) (Figures 1 and 2).][10][11][12][13][14] Recently, a study explored the existence of public health policies to keep pace with the WHO global elimination programme in five Northern Europe Countries (Denmark, Finland, Iceland, Norway, Sweden) and found that three of them (Finland, Iceland and Norway) have national viral hepatitis strategies, while all countries currently provide therapy with DAA by means of public health. 15[21][22][23][24][25][26][27][28][29][30] In studies conducted in Northern Europe, anti-HCV prevalence in the general population ranged between .65% and 2.65% (Table 1; [21][22][23][24][25][26][27][28][29][30] One study from Sweden reported that most seropositive subjects (24 out of 34, 71%) were already aware of their status. 21Only one study included patients who had already achieved a sustained virological response (SVR): Millbourn et al. reported that only 2 out of 11 (18%) patients who were found to be anti-HCV positive but HCV-RNA negative cleared the infection after treatment. 22Kileng et al. found a higher prevalence (.40%) of anti-HCV in people aged 50-59 years, when compared with younger (40-49 years-old; .08%)and older (60-104 years-old) age groups, although data on active HCV infection were only partial. 19No age-based analysis was reported in the remnant studies.In their study, Kileng et al. reported   an independent association between anti-HCV and intravenous drug abuse (IVDA), smoking, and unemployment or disability.IVDA was associated with the highest chance of previous exposure to HCV [current IVDA: odds ratio (OR) 35.4 (95% confidence interval (CI) 17.4-71.9);previous IVDA: OR 15.7 (95% CI 10.2-24.2)]. 19IVDA was also the main risk factor for anti-HCV positivity in two other studies.In fact, a history of IVDA was self-reported by 100% of seropositive individuals (n = 4) identified in an emergency department (ED) in Denmark 22 and in 76% of people (pregnant women and their partners) enrolled in a Swedish study. 21st data from UK came from the ED setting, as in 2014 the one-week campaign entitled 'Going Viral' demonstrated the

Key points
• The ambitious goal of hepatitis C virus (HCV) elimination set by the World Health Organization gave boost to redefine HCV epidemiology all over the world, as most data mainly came from complex mathematical models rather than from real-life studies.
• According to studies referring to 2013-2023, anti-HCV prevalence in the European general population differed according to countries and testing setting, as it ranged between .20% and 8.96%.The highest seroprevalence was observed in Southern Europe.
• Differently from what previously described, most seropositive subjects had no HCV-RNA detectable.

Moreover, a large proportion of those carrying active
HCV infection was already aware of their status.feasibility of opt-out screening programmes for blood-borne viruses (BBV) in EDs. 24According to published data, HCV seroprevalence in this setting ranged between 1.46% and 2.65%, [25][26][27][28][29] lowering to .26%-.46% 26,29 when considering those unaware of their status (Table 1; Figures 1 and 2).[26][27][28][29][30] Results from a study conducted in one single ED in Liverpool led the authors to suggest a potential detrimental role of a concomitant offer of HIV screening on HCV testing acceptance. 30cently, in Lithuania, where official data estimate an anti-HCV prevalence of 2.4%-2.9%, 3 health authorities established a general population screening program targeting the 1945-1994 birth cohort.
In order to improve screening effectiveness, General Practitioners (GPs) received a fee to promote and perform HCV serological testing.However, results of this policy are not yet available. 31ong Northern Countries, Iceland represents an epidemiological unicum, with the vast majority of HCV infection belonging to PWID and a registry of all HCV infections kept since 1991.In this scenario, during a 'treatment as prevention' approach programme, 8.2% of the adult population received an HCV test: 183 new infections were diagnosed.However, all infected people were PWID. 32e search for studies from Finland, Estonia and Latvia retrieved no results, probably because of the aforementioned low prevalence of HCV infection in these countries.

| [France, Belgium, the Netherlands, Luxembourg, Germany, Switzerland, Austria]
Most of Western European Countries have historically been considered at low-prevalence of HCV infection [Belgium .1%;France .8%-4.7%;Netherlands .1%-1.1%; Germany .3%-1.0%], although data were lacking for some of them. 3Nevertheless, they faced significant changes in the epidemiology of HCV infection in recent decades.In the last years, 10 studies have attempted to describe HCV distribution in Western Europe in the current DAA F I G U R E 1 Prevalence of anti-HCV and HCV-RNA (bold) positivity in the general population according to studies published in Europe according to each country with data available.HCV, hepatitis C virus.era; most of them were cross-sectional and mainly came from France, Belgium and Germany and found an anti-HCV prevalence in the general population between .20% and 2.70% (Table 2; Figures 1 and 2).
France is one of the Countries with the clearest picture of HCV epidemiology.4][35] As for the DAA era, a study on blood donors found no active infections using HCV Nucleic Acid Testing in 260 donors attending blood donation centres between 2016 and 2018, suggesting a decrease in HCV prevalence compared to previous years. 36Brouard et al. also reported HCV-RNA (but no anti-HCV) data in the general population during the first trimester of 2016; they screened 6945 subjects in a telephone survey (i.e. the BaroTest) who had previously consented to be tested for HCV (and HBV) by a self-administered fingerpick blood sampling on dried blood spot test.Overall, 11 (.16%) had active HCV infection.
Most of them were aged 46-75 (vs.18-45) years, reported IVDA (p < .05)or had been exposed to unsafe beauty practices (i.e.tattoos or piercing without single-use materials). 37Only one study, conducted in a single hospital in Paris, reported seroprevalence data in patients attending the Oral and Maxillofacial Surgery Department.
Over a 12-month period, 8 out of 787 (1.02%) individuals tested anti-HCV positive: most of these (88%) were unaware of their status and only 3 (38%) had active infection. 38 Belgium -as opposed to most European Countries -HCV is not a notifiable disease; the reference prevalence data are from 1993 to 1994, with .87%(.12%-1.10%) of people being seropositive. 39In 2003, a salivary test-based study reported an anti-HCV prevalence of .12%(.09%-.39%), with this lower seroprevalence being partially attributed to the lower sensitivity of the test used. 40re recent studies (2013-2018) reported HCV seroprevalence ranging between .25% and 1.71% in the Belgian general population.
Two of them also showed that most seropositive subjects were already aware of their status (55% and 74%, respectively). 41,42Data on active infection rates were reported by three authors and ranged from .12% to .72%(Table 2; Table S1; Figure 1). 41,42,44The low prevalence of positive HCV-RNA in anti-HCV positive adults could be explained by the inclusion of SVR patients in 2 out of 3 studies, where they accounted for 55% and 37% of seropositive subjects, respectively (Table S1). 41,42In another study, Bielen et   individuals showing detectable HCV-RNA.Five out of 12 (42%) patients with active infection had significant fibrosis (≥F2) according to transient elastography. 41In another study, Lanthier et al. tested 200 volunteers during a 1-day screening campaign in a single hospital in Brussels by using a finger-stick test.All three anti-HCV positive subjects identified were already aware of their status, and two of them had even previously undergone anti-HCV therapy. 43In the primary  41 In addition to age, IVDA, 41,42 country of birth, 41,42 history of HBV infection and imprisonment 41 were associated with an increased risk of anti-HCV positivity.In the only one prospective study conducted in Dutch hotspots in high-prevalence areas, the overall prevalence of anti-HCV was .20%(7 out of 3434) but no cases of active HCV infection were detected. 45This low prevalence was in line with national estimates, that is .16%. 46Recently, the CELINE (Hepatitis C elimination in the Netherlands) programme reported HCV data in individuals who were lost to follow-up (LTFU) in the 14 years prior to data collection.Of 1537 LTFU subjects, 888 were contacted: 172 were tested for HCV RNA and 143 tested positive (83%): of these, 123 started DAA therapy during the study, with SVR achieved in all 91 who had an SVR12 result available at the end of the study.
Interestingly, 28% of viraemic patients had advanced fibrosis or cirrhosis at the time of re-evaluation: 3 had decompensated cirrhosis, 2 were diagnosed with hepatocellular carcinoma (HCC), and a further 3 developed HCC during the study follow-up. 47nally, three studies come from Germany, where reference HCV prevalence ranges from .2% to 1.9% 48 and where a national check-up programme, including anti-HCV testing was offered to people aged ≥35 years.0][51] All studies analysed large cohorts of subjects from different settings (ED, GP and private practices).0][51] In one study, the authors reported that most HCV-RNA positive individuals were unaware of their status (Table S1). 50In the studies by Petroff et al. intravenous drug use was the strongest independent factor associated with seropositivity, together with tattoos 49,50 and end-stage renal disease. 50fortunately, updated data are not available for Luxemburg, Switzerland and Austria.In Eastern Europe, HCV infection remains a significant public health problem.Reference data on anti-HCV seroprevalence vary widely across the region, ranging from .27% to 3.50%.It is estimated that approximately 1.16 million people in Eastern Europe had been infected with HCV. 52,53ong Eastern Countries, Romania has consistently reported the highest prevalence of HCV in Europe, with rates of 5.90% in 1990 and 3.23% in 2010.More recently, 500 000 subjects were estimated to carry HCV infection, thus corresponding to 2.7% of the Romanian population. 54,55Within Romania, Moldova has been identified as the region with the highest HCV burden. 55In this region, studies have highlighted the role of nosocomial transmission, particularly through in-hospital diagnostic and therapeutic procedures, as a significant source of infection. 55,56[59] The lowest anti-HCV prevalence was reported by Butaru et al. who tested 15 383 subjects in Oltenia and found 119 (.77%) of them being anti-HCV positive.Half (49%) of these individuals were unaware of their status. 57Other studies reported higher seroprevalence; in Moldavia, Huiban et al. reported anti-HCV prevalence of 2.64%, 58 while Butaru et al. found 2.50% of positive anti-HCV among subjects with at least one known risk factor for HCV. 59Although in the latter study also clustered people (i.e.HIV-coinfected, MSM, PWID, prisoners) were included, the study involved Family Medicine Officers, and considered also those who had ever undergone haemodialysis, blood (or blood components) transfusions or organ transplants, as well as health-care workers. 57fortunately, little data is available on rates of active infections in Romania, as most studies provided only seroprevalence data (Table 3; Table S1; Figure 1).due to under-reporting of these behaviours in self-administered questionnaires.
In the Czech Republic, a seroprevalence survey conducted in 2001 identified .20% of anti-HCV positivity in the general population. 61No updated data have been provided so far.More recently, two prospective studies reported higher anti-HCV prevalence rates (Table 3; Figure 1). 62,63In 2015, Chlibek et al. involved 3 research centres to investigate the prevalence of HCV infection in the general adult population and found 50 (1.67%)out of 3000 anti-HCV positive participants, with 28 (56%) of them carrying active infection. 62The highest prevalence of HCV was found in those aged 30-44 years (3.58% anti-HCV positivity and 2.08% HCV-RNA positivity).In this age group, IVDA was reported by only 2.7% of subjects.After excluding PWID, prevalence of anti-HCV and HCV-RNA declined to .88% and .58%,respectively. 62In the study by Dyrhonová et al. 627 people with at least one risk factor for HCV infection were tested at a single GP office.Among them, those referring past IVDA or tattoos were limited (.43% and 2.7%) as well as those previously incarcerated (.31%): recipients of medical care before 1992 (24%) and those with altered liver enzymes (11%) accounted for most of this study cohort.Overall, 03%) subjects tested anti-HCV positive, and 4 (21%) of them were already aware of their status.Among them, 11 (58%) did not report high-risk behaviours.Finally, only 5 (26%) of seropositive individuals were HCV-RNA positive, and fibrosis was significant in all cases (F2 in 2, F3 in 2 and F4 in 1); HCC was also found in the patient with cirrhosis. 63 Poland, epidemiological studies conducted in different subpopulations prior to DAA approval have reported HCV infection rates ranging from .9% to over 4.0%. 64More recently, a routine surveillance strategy led to tracking new HCV diagnosis and demonstrated an increase in HCV reporting.In 2014 and 2015, a total of 3076 (7.00 per 100 000) and 4285 (11.14 per 100 000) cases were reported, respectively. 65,66The ECDC reported 1244 per 100 000 individuals in 2021. 67This increase in HCV prevalence may reflect improved access to diagnostic testing and increased reporting rather than changes in Polish epidemiology.Rosińska Of these, 12 (1.74%) were anti-HCV positive, with no differences between age groups.However, the highest seroprevalence was found in young women (5.49%). 69 The study included 3826 participants with 2.93% of them testing positive for anti-HCV antibodies; notably, only 12 subjects were aware of their infection status.Unfortunately, the authors did not report HCV-RNA data. 71 data are available for other Countries (Slovakia, Hungary, Bulgaria).Most studies coming from Southern Europe were conducted in Italy and Spain, with very few data coming from Greece (Table 4; Table S1; Figures 1 and 2).No information is available for Portugal, Slovenia and Croatia, where data were mostly collected before DAA spread.
In Italy, the Italian Ministry of Health allocated more than 71 million euros for HCV screening programmes across the Country in 2019. 72Due to the coronavirus disease-19 (COVID-19) pandemic, screening plans were delayed in most regions, and official data are largely not available, yet.However, even before fundings allocation, several spontaneous micro-elimination programmes had been carried out (Table 4; Table S1).The vast majority of these studies were conducted in two regions (i.e.Lombardy, Northern Italy, and Campania, Southern Italy) and confirmed the 'North-South HCV gradient', described in earlier epidemiological studies.According to them, anti-HCV prevalence in the general population ranged from .23% to 8.96% (Table 4; Figure 1).Only one study reported no anti-HCV detection in a point-of-care test-based study conducted in 291 subjects attending a university open-day and aged 20 (18-79)   years. 73cording to published studies, 54%-88% of seropositive individuals were already aware of their status (Table 4; Table S1).
Interestingly, an active HCV infection was found in 7%-74% of anti-HCV positive subjects with HCV-RNA testing available.[76][77][78][79][80][81][82][83] Overall, only 3 studies excluded individuals who already knew of their HCV status (i.e.][86] TA B L E 4 HCV prevalence in the general population in studies from Southern Europe.where SVR patients were excluded.These data seem to come up against the reference 20%-30% threshold derived from historical HCV natural history studies, suggesting a low risk of spontaneous viral clearance. Finally, the prevalence of active infection did not exceed 3.2% in the general population (Tables 1-4; Figures 1 and 2), and some authors were also able to report the proportion of new diagnosis (17%-100%) (Tables 1-4; Table S1).With all the limitations associated with the heterogeneity of published data, we did not observe significant variations in either anti-HCV or HCV-RNA positivity when considering reference years of the studies published during the last decade (2013-2023).
Available studies clearly show a complex and dynamic epidemiological scenario.Most data have been obtained using cross-sectional and retrospective designs, which are well-recognized biases, especially in the context of population studies.Few studies provide information on screening programme adherence, which ranged between 12% and 92% (Table S1); in addition, most studies were conducted in limited settings (mainly health care facilities) and did not include large cohorts of really healthy individuals.For all these reasons, it is difficult to derive any hypothesis on the real HCV burden in the general population, which could potentially have relevant healthand socio-economic implications.In addition, apart from a couple of studies, 41,47,68,85 no clinical information (i.e.liver disease severity) has been reported for positive patients identified through screening programmes.
In conclusion, although real-life data take us away from the ambitious WHO target of HCV elimination by 2030, there is no doubt that the progressive diffusion of screening campaigns may translate into increasing rates of diagnosis and linkage to care, with undeniable benefits in the cascade of care.

2 | NORTHERN EUROPE 2 . 1 |
[Norway, Sweden, Finland, Denmark, Iceland, Ireland, UK, Estonia, Lithuania, Latvia] al. focused on adults attending the ED of a large non-academic hospital: they found an anti-HCV prevalence of 1.31%, with 39% of seropositive F I G U R E 2 Prevalence of anti-HCV and HCV-RNA (bold) positivity in the general population according to studies published in Europe according to United Europe Geoscheme.HCV, hepatitis C virus.TA B L E 1 HCV prevalence in the general population in studies from Northern Europe.Norway Kileng et al.
et al. reported data from a national cross-sectional study conducted in primary care units between 2012 and 2016, in Poland.They found 102 actively infected individuals, after testing 21 875 cases (i.e..47%prevalence). Moe than 20% of them were at risk of having significant fibrosis, as measured by non-invasive serological tests (AST to platelet ratio and fibrosis-4 test).68 In 2016-2017, Piekarska et al. tested 690 individuals with a history (≥1) of hospitalization belonging to 3 different sub-groups: (1) diabetics; (2) with arterial hypertension; (3) healthy young (<35 years) women.
Partially consistent with this finding are the results from the study by Rosińska, who reported that previous caesarean deliveries (≥2 vs. 0) were independently associated with CHC [OR 4.03 (95% CI 2.02-8.03)].Blood transfusion before 1992 and having an HCV-positive partner were independent risk factors for carrying active infection.IVDA and tattoos were found as additional risk factors in males. 68A recent study by Piekarska et al. found a prevalence of 2.39% of anti-HCV seropositivity in patients admitted to Lodz hospital in cardiology and dermatology units.Half of them were viremic. 70Finally, Hartleb et al. conducted a prospective study in the Polish general population, with a special focus on people aged 65 years and older.
Abbreviations: COVID-19, coronavirus disease-19; DH, day hospital; DS, day surgery; GP, General Practitioner; HCV, hepatitis C virus; LHU, local health unit; NA, not available; POC, point of care; RNPS, rapid nasopharyngeal swab.a Prevalence has been calculated in patients with available HCV-RNA testing.b POC testing.