Monday, July 4, 2011

A systematic review of hepatitis C virus epidemiology in Europe, Canada and Israel

Markus Cornberg1, omie A. Razavi2, Alfredo Alberti3, Enos Bernasconi4, Maria Buti5,6, Curtis Cooper7,
Olav Dalgard8, John F. Dillion9, Robert Flisiak10, Xavier Forns11, Sona Frankova12, Adrian Goldis13,
Ioannis Goulis14, Waldemar Halota15, Bela Hunyady16,17, Martin Lagging18, Angela Largen2, Michael Makara19,
Spilios Manolakopoulos20, Patrick Marcellin21, Rui T. Marinho22, Stanislas Pol23, Thierry Poynard24,
Massimo Puoti25, Olga Sagalova26,Scott Sibbel2, Krzysztof Simon27, Carolyn Wallace2, Kendra Young2,
Cihan Yurdaydin28, Eli Zuckerman29, Francesco Negro30, Stefan Zeuzem31

Article first published online: 8 JUN 2011
DOI: 10.1111/j.1478-3231.2011.02539.x

Background and Aim: Decisions on public health issues are dependent on reliable epidemiological data. A comprehensive review of the literature was used to gather country-specific data on risk factors, prevalence, number of diagnosed individuals and genotype distribution of the hepatitis C virus (HCV) infection in selected European countries, Canada and Israel.
Methodology: Data references were identified through indexed journals and non-indexed sources. In this work, 13 000 articles were reviewed and 860 were selected based on their relevance.
Results: Differences in prevalence were explained by local and regional variances in transmission routes or different public health measures. The lowest HCV prevalence (≤0.5%) estimates were from northern European countries and the highest (≥3%) were from Romania and rural areas in Greece, Italy and Russia. The main risk for HCV transmission in countries with well-established HCV screening programmes and lower HCV prevalence was injection drug use, which was associated with younger age at the time of infection and a higher infection rate among males. In other regions, contaminated glass syringes and nosocomial infections continue to play an important role in new infections. Immigration from endemic countries was another factor impacting the total number of infections and the genotype distribution. Approximately 70% of cases in Israel, 37% in Germany and 33% in Switzerland were not born in the country. In summary, HCV epidemiology shows a high variability across Europe, Canada and Israel.
Conclusion: Despite the eradication of transmission by blood products, HCV infection continues to be one of the leading blood-borne infections in the region.
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Chronic hepatitis C (CHC) is a major health burden in Europe. Recent data suggest that patients with CHC have a higher overall morbidity and mortality (1, 2). A significant portion of liver transplantation in Europe is attributable to cirrhosis and hepatocellular carcinoma because of CHC (3). The socioeconomic impact of hepatitis C virus (HCV) infection is tremendous. The incidence of complications of CHC will not decline over the next 10 years despite improved efficacy of antiviral therapy because most patients with CHC remain undiagnosed (4). Prevention of new infections, HCV screening and early treatment have the potential to reduce the overall morbidity and mortality. However, the cost-effectiveness of HCV screening may depend on the HCV prevalence (5). Decisions on public health issues such as HCV screening and prevention measures are dependent on reliable epidemiological data regarding HCV prevalence and transmission routes. The epidemiological status in Europe is continuously evolving and may vary significantly among the different regions throughout Europe (6). Thus, different countries may need different strategies to reduce the overall burden of HCV infection.
Because epidemiological data are the basis for the development of preventive measures, we aimed to systematically identify, review and characterize HCV epidemiology throughout Europe. We included Canada and Israel in our analysis because their healthcare systems and the epidemiological situation are similar to many European countries.

Methods
A comprehensive review of the literature was used to gather country-specific data on risk factors, prevalence, number of diagnosed individuals and genotype distribution. The countries studied were Canada, Czech Republic, France, Germany, Greece, Hungary, Israel, Italy, Norway, Poland, Portugal, Romania, Russia, Spain, Sweden, Switzerland, Turkey and the UK. References were identified through two sources: indexed journals and non-indexed sources. Indexed articles were found by searching PubMed and regional databases using the following terms: ‘hepatitis C AND country name AND (incidence OR prevalence OR mortality OR viremia OR genotype OR diagnosis OR treatment OR SVR)’. Furthermore, references cited within the articles were used. Approximately 13 000 articles were reviewed and 860 were selected based on relevance. In addition, non-indexed sources were identified through searches of individual country's Ministry of Health's websites and international health agency reports. Finally, authors from each country provided government reports and proceedings of local conferences that were not published in the scientific literature. The search included publications in local languages, although reports in English accounted for over 90% of the data sources.
In every case, the prevalence values referred to the prevalence of anti-HCV antibodies, which included spontaneously cured and treated/cured individuals, whereas the HCV genotype distribution values were based on studies in the viraemic, or HCV RNA-positive population. Hepatitis C epidemiology is determined by practices, risk factors and access to care in a particular community. Community-based studies were reported, but the focus of this study was to identify/estimate prevalence in the general population. The first- and second-generation immunoassay tests provided false-positive results, which overestimated the total infected population (7, 8). Care was taken to use only studies that used the latest generation tests to estimate the country's prevalence when available or reported. In some countries, blood donor data were the main source available for prevalence. Blood donors represented a self-selected population of healthy motivated adults. The infected general population was composed of high-risk groups [e.g. injecting drug users (IDUs), dialysis patients and recipients of blood transfusions] as well as non-high-risk groups that contracted the disease through contact with infected blood (e.g. nosocomial infections, dental procedures, etc.). The donor population was a good proxy for the latter group. When multiple data sources were available, a systematic process using multi-objective decision analysis was used to rank and select the most appropriate sources (9). When insufficient data were available for prevalence, we estimated the country's prevalence using other countries in the region with a known prevalence and similar risk factors. The estimates were often for 2004 because of the lack of more recent data. When available, subtypes were assessed individually and summed to provide a value for the corresponding genotype

Results
The collected data were segmented by country according to transmission risk factors, prevalence, HCV genotype distribution and diagnosed population size. The European Center for Disease Prevention and Control (ECDC) provided incidence rates for the European countries. In this publication, their estimates were used for newly diagnosed populations because most countries in the report did not distinguish between chronic and acute cases of HCV infection.
Surveillance systems also vary widely between and within countries in Europe. A publication by ECDC documented 38 different surveillance systems in 27 countries; six countries had more than one system (10). Surveillance systems vary by structure, reporting practices, data collection methods and case definitions used (11). For these reasons, caution should be exercised when comparing case reporting data across countries.
Not all countries in Europe were analysed. Those chosen were deemed representative of the region. When key data were available but a detailed analysis was not performed, the overall prevalence of anti-HCV was included in the summary map. Overall, we estimate that 11.3–14.7 million adults in Europe, including all of Russia and Turkey, are anti-HCV positive.

Canada
The Public Health Agency of Canada (PHAC) has collected data on the number of hepatitis C reported cases through its Notifiable Disease Reporting System. In addition, the Enhanced Hepatitis Strain Surveillance System (EHSSS), administered by PHAC, records risk factor information for reported cases. EHSSS covers approximately 40% of the Canadian population, with its sentinel surveillance system operating in 11 sites across Canada. The prevalence and incidence of HCV infections have been estimated through an actuarial modelling approach that included estimates of the populations at risk by place of birth and exposure category.

Risk factors
According to the PHAC, IDU was the predominant risk factor among individuals with chronic infections, accounting for 58% of cases (12). Between 2004 and 2008, IDU accounted for 63% of acute HCV infections (13). Since the introduction of blood screening for HCV in 1990, the risk of contracting HCV from blood transfusion or blood products has been virtually eliminated. However, the portion of the prevalent population with HCV acquired from blood transfusion today remains >10% (12).

Prevalence
Over the past decade, the PHAC has synthesized the most relevant data concerning the prevalence, incidence and mortality of HCV and developed models to estimate the disease burden in Canada (12, 14, 15). The PHAC estimated the populations at risk by place of birth and exposure. In addition, it modelled current and projected HCV incidence and prevalence among those born in Canada and immigrants. The model capitalized on the data available through the EHSSS. It adjusted for under-reporting and asymptomatic infection, as well as limited available epidemiological studies, specifically incident cases among IDUs.
The PHAC estimated an overall prevalence of 0.78%, or 242 500 infected individuals, in 2007. Prevalence increased with age through the fifth decade in males, and then declined, with an overall prevalence in males of 0.95%. In females, prevalence increased with age through all of adulthood, with an overall prevalence of 0.61%, resulting in a male-to-female prevalence ratio of 1.6:1. Prevalence in the adult population was 1.01% (12).
There is a paucity of prevalence studies conducted on other specific populations, such as organ tissue donors (16) and EEG clinic patients (17).

Diagnosed/incidence
Through the PHAC's Notifiable Disease Reporting System, the number of HCV cases reported annually was available from 1991 through 2008 (18). The number of reported cases increased to a peak of 19 652 in 1998 and has declined annually since (Table 1). Incidence by age and gender was estimated at 26/100 000 population (12). Incidence was higher in males (34/100 000) than that in females (18/100 000). Incidence was also the highest in 20–40 year olds, peaking in the 25–29-year age cohort, supporting IDU use as the most frequently reported risk factor. Overall, the PHAC estimated that two-thirds of the infected population was diagnosed in Canada (14).

Genotype
Multiple studies quantified genotype distribution in Canada (19–24). A large number of samples were collected from 138 community and academic centres throughout Canada as part of the POWeR study. The POWeR study provided expanded access to therapy among HCV-infected patients diagnosed in communities throughout Canada and referred to hepatitis C treatment clinics. This study provides the best representation of genotype distribution for the country as a whole. Genotype 1 was the most prominent genotype (60%), followed by genotype 3 (22.3%) and genotype 2 (15.4%) respectively (19). Another study reported data from the Laboratory Centre for Disease Control's Sentinel Health Unit Surveillance System representing eight health unit sites located throughout Canada. Although it sampled across the country, the study lacked representation from the larger, more metropolitan areas in Canada (21). Another study focused on patients from Saskatchewan had the same limitation (20). Conversely, other studies, whose patient samples were from Montreal, also were not the most representative of HCV genotype distribution countrywide (22, 23). However, all genotype studies show great consistency in the predominance of genotype 1 (between 60 and 67% of the study populations), with more than one study indicating genotype 1a as the dominant subtype (20, 21).

Summary
The PHAC provides country-wide estimates of incidence, prevalence and disease burden using data captured through the national surveillance system for HCV infections. Nationally collected data show that IDU is the predominant risk factor behind newly acquired cases, with younger age cohorts (20 and 30 year olds) most affected. HCV genotype 1a is the most dominant. The number of reported cases of HCV has declined in Canada since 1998. Although an estimated two-thirds of cases are diagnosed, there remains a poor awareness of risk factors in the general population (14). The PHAC recommends continued promotion of public awareness to address the HCV-positive population in Canada.

Czech Republic
There is no general screening programme in the Czech Republic. Specific subgroups are screened on a regular basis including blood donors, pregnant women, prisoners, haemodialysed patients, drug users starting weaning programmes and healthcare workers, but the data are not published regularly (25).

Risk factors
Studies on risk factors are sparse from the Czech Republic. Injection drug use has been reported as a major risk factor, increasing over the past few years, which likely accounts for a large portion of new HCV infections (26). In a 2002 study of 216 HCV-infected patients in Prague, 16% reported injection drug use. Other risk factors reported from this study include blood transfusion (15%), surgery (14%), dialysis (12%), profession-related (10%), invasive procedure (6%), sexual contact (2%) and tattooing (1%) (27). Unpublished data by authors suggested that IDU accounted for 50% of new infections in urban areas. The same studies also showed that immigration from endemic countries was contributing as a source of new infections (25).

Prevalence
Community studies have not been performed; however, it was suggested that the overall prevalence in the country was around 0.5–1% (28). When the risk factors were compared with its neighbouring countries, the prevalence of HCV infection was estimated at 1.5–2.0%, similar to Poland. Two studies reported prevalence among drug users (29, 30). One suggested that the prevalence among injection drug users was lower than that in other countries in Europe. In a study of 760 IDUs from nine regions in the country, 29.7% were found to be anti-HCV positive (30). Two blood donor studies were published and reported a prevalence between 0.2 and 0.44% (31, 32). The studies among blood donors represented healthy, adult populations that were not representative of the general population.

Genotype
The most frequent genotype in the Czech Republic was genotype 1 (26, 28, 33). HCV genotype 1b was the most frequent subtype in blood donors (33), whereas 1a was more frequent among IDUs (26). The study, most likely representative of the general population (others were limited to IDUs), reported 79.3% with genotype 1, 1% with genotype 2 and 19.7% with genotype 3 (33). In a study published in 2009 of 222 HCV-positive IDUs, 23.5% were infected with genotype 3 (26) compared with only 3% in a study of IDUs from 2001 (28). Additionally, genotype 1a was represented in only 23% of the IDU sample in 2001 (28), but 40.5% of IDUs in the 2009 study (26).

Summary
Given the lack of general population studies, Poland was used as an analogue to estimate a prevalence of 1.5–2.0%. Currently, the most common risk factor of HCV infection is IDU, especially among young people. There is no general screening programme in the Czech Republic. Specific subgroups are screened on a regular basis including blood donors, pregnant women, prisoners, haemodialysed patients, drug users starting weaning programmes and healthcare workers, but the data are not published, except for a few one-centre experiences (26, 29). HCV represents the second leading indication for liver transplantation in the Czech Republic (20–25%) after alcoholic liver disease.

France
The National Hepatitis C Prevention Program was implemented in France in 1999 and renewed in 2002 to reduce HCV transmission, increase screening and improve access to treatment (34, 35). The National Institute for Surveillance set up a national surveillance network, and two national population-based prevalence surveys were conducted in 1994 (36) and 2004 (34, 37, 38) among metropolitan residents. The 2004 study surveyed 14 416 residents aged 18–80 years. The metropolitan residents accounted for approximately 70% of the 2004 total population. The survey excluded active drug users and samples from rural residences, and it likely over-represented the immigrant population, but it was one of the most robust studies in the region and represented the best dataset available for risk factors, prevalence and percent diagnosed.

Risk factors
There are numerous studies on the HCV risk factors for existing and new infections (36–53). The most recent and robust study in the prevalent population reported the analysis of the 2004 national survey (37). A multivariable regression was used to identify the key risk factors. The most commonly identified risk factors included a history of surgery (88%), piercing (51%), history of endoscopy (43%), blood transfusion before 1992 (35%), over 10 sexual partners (29%), lifetime nasal drug use (28%) and lifetime IV drug use (26%). Although only 26% of the prevalent population reported lifetime IV drug use, it was the largest factor in predicting a positive HCV infection. Through regression analysis, other important factors identified were lifetime nasal drug use, born in a high-endemic country, blood transfusion before 1992, tattoo and beneficiary of medical welfare. Analysis of newly diagnosed individuals (2001–2007) by the French Institute for Public Health Surveillance revealed gender differences between male and female risk factors. Males showed high rates of IDU (40–47%) as a key risk factor, while females showed a lower range (17–21%). Females, on the other hand, showed transfusions as the major risk factor (33–39%). Overall, IDU was the largest risk factor by percentage (32%), although only slightly over transfusions (26.5%) (54). Because active drug users were not part of the cohorts analysed, IDU could account for a larger portion of the infected population.
Sixty-four positive and 227 control cases were studied to capture risk factors in the incident population (40). The most commonly identified risk factors included anaesthesia (33%), general anaesthesia (22%), invasive diagnostic procedure (23%), drug use (17%) and IDU (16%). Similar to the national survey, the authors took care to compare data of the infected population with a control group and use regression analysis to identify the key risk factors. Even though one-third of the incident population had anaesthesia at some point in time, it had a lower matched odds ratio than some of the other factors because of the presence of the same risk factor in comparison with the control group.
Earlier studies supported the above conclusions. A 2006 study reported the importance of nosocomial transmission (41). All anti-HCV-positive individuals resulting from a population-based prevalence survey confirmed that IDU (odds ratio=29.2), history of transfusion (odds ratio=7.0) and absence of paid employment (odds ratio=3.1) remained statistically significant after an exploration of many risk factors in the study (36). In a study of newly diagnosed patients, drug use was reported as the main risk factor for HCV infection (51, 33 and 31% in 1997, 2000 and 2003 respectively) (55). In studies tasked to correlate genotype with risk factors among chronic HCV patients, recent drug use was found to be significantly linked to increases in genotypes 1a and 3a, lending further credence to the large and recent role for IDU transmission (56, 57).

Prevalence
There were a number of studies estimating prevalence in the general population (34–38, 58–60). The most definitive results are provided by the 2004 prevalence survey analysis and showed a rate of 0.84% for 18–80 year olds (0.71% for 20–59 year olds) (34, 37, 38). The prevalence was distributed bimodally (ages 40–49 and 60–69), with the lowest prevalence among 18–29 year olds (37). The results of the 1994 study showed a prevalence of 1.05% using a similar methodology with a smaller sample size (n=6283) and a more limited age range (20–59 years) (36). Comparison of the two studies showed that HCV prevalence declined from 1.05 to 0.71% in individuals 20–59 years of age between 1994 and 2004. The decrease was attributed to a decrease in incidence over time because of the positive impacts of a syringe programme and the application of standard precautions in healthcare settings (34, 35). Similar results were obtained by other investigators. A prevalence of 1.3% was reported in a study based in Lyon with a large sample size (58). Other studies reported a 1999 prevalence of 1.1% for the entire country (59) and a 1996 prevalence of 1% (60). While population-based studies are essential for determining the overall prevalence in the country, it is important to note that active drug users are less likely to participate in health surveys, which may result in rates that are lower than the actual national average.
There were a number of studies in subpopulations as well. A 2004–2005 national survey found prevalence among IDUs to be nearly 60% (61), consistent with the 2004 national survey results of 56% (37), while a prevalence of 73% was reported among a smaller sample of IDUs in 2002 (62), potentially indicating a decline in prevalence among IDUs in France. A number of separate studies reviewed the prevalence of HCV among blood donors (63–68). This subpopulation represents healthy adults without previous infections. Between 1993 and 2000, the prevalence declined from 1.23 to 0.23% among blood donors, similar to the observed decline in the general population (63). Other subpopulations studied include HIV-positive patients, pregnant women and various high-risk groups (43, 45, 68–74).

Diagnosed/incidence
True incidence data in the general population were not available. An incidence of 9/100 person-years among IDUs and an annual incidence from 0 to 17.5% among haemodialysis patients from 1981 to 1991 have been observed (58, 75–77). Other studies that reported incidence were actually studying the newly diagnosed rate. For example, an assessment of the southwest France's campaigns to evaluate the implementation of HCV guidelines estimated a newly diagnosed rate of 43/100 000 persons in 1997, declining to 26/100 000 by 2003 (55).
The 2004 national prevalence study showed that 57.3% of anti-HCV-positive persons were already aware of their seropositivity or were previously diagnosed. Among the anti-HCV-positive study population, 93.2% of past or current IDUs, 66.5% of individuals who had transfusions before 1992 and 25.6% of the other population were previously diagnosed (37).

Genotype distribution
Numerous genotype distribution studies dating back to 1995 showed genotype 1 to be the most predominant (41, 56, 57, 78–85). In the largest and best sample of HCV genotypes, 1769 samples were collected from 26 referral centres; 57% of the sample was genotype 1, 9.3% genotype 2, 20.8% genotype 3, 8.9% genotype 4, 2.7% genotype 5, 0.2% genotype 6 and 0.9% mixed genotypes (57). Similarly, a 1999 study showed genotypes 1 and 3 as the most common genotypes (57 and 22% respectively) (56).

Summary
France has the most active programmes to manage HCV infection through screening, improving access to treatment and reducing transmission. The National Institute for Surveillance runs national surveys to determine the prevalence, risk factors and profile of the infected population. Investigators have used regression to determine the risk factors that contribute to new infections and have shown IDU to be a key risk factor with most new infections in younger populations. The epidemiology of HCV in France is marked by a relatively low prevalence (0.84% in 2004), which has declined from 1.05% in 1994. The most common genotype is 1, with 1b dominating; the second most common genotype is 3.

Germany
In Germany, there is no general anti-HCV screening programme. Newly diagnosed cases of HCV infection have to be reported to the Robert Koch Institute (RKI), but there is no discrimination between newly diagnosed chronic or acute HCV infections. There are national guidelines in place that recommend anti-HCV testing in all patients with elevated ALT and in risk groups (86).

Risk factors
Risk factor data are collected as part of the national surveillance of HCV in Germany. For HCV cases reported in 2009, 34% indicated IDU (87). In confirmation of IDU as the primary risk factor for HCV infection in Germany today, one study recorded risk factors for over 10 000 patients from 352 centres throughout Germany. Similar to national surveillance data, this study found that the vast majority of patients (45.5%) reported IDU as the primary transmission factor for HCV (88). Other significant risk factors reported by Huppe and colleagues and RKI were transmission through blood products (17.4%) and medical procedures (9.0%). As blood products have been screened for HCV in Germany since 1991, and no HCV transmissions have been reported because nucleic acid amplification technique testing became mandatory in 1999, the risk factors reported above represent the distribution in the prevalent population (89). In a cohort of acute HCV patients admitted for antiviral therapy, IDUs were significantly younger than non-IDUs, while the proportion of patients who acquired HCV by medical procedures increased with age (90). Clearly, IDU is driving newly acquired cases for the past decade or more. Another recently identified potential risk factor is men who have sex with men (MSM), particularly HIV-positive MSM, and is the subject of ongoing scientific studies (87).

Prevalence
A few German studies address prevalence in specific subgroups, such as children or surgical patients (91–95). For example, one study reported a prevalence rate of 2.4% among a large cohort of 13 823 screened emergency room patients in 2008 and 2009 (95). Others limit the study population to IDUs, with prevalence findings in excess of 60 to over 80% (94, 96–99). There is also limited prevalence research involving blood donors, most demonstrating a prevalence of <0.5% in this subpopulation (100–103). However, none of these studies lend themselves to extrapolation to the general population in Germany.
There have been two community-based prevalence studies in Germany. From 1993 to 1996, 5312 randomly selected individuals, ages 18–70, were tested. Individuals were selected from small, medium-sized and large cities in five different German states, providing a good representation of the German adult population. An overall prevalence of 0.63% was recorded, 0.90% in females and 0.41% in males. In both males and females, prevalence increased with age, with the exception of the 31–40-year age cohort in females (104). The findings from the 1998 German National Health and Examination Survey, with samples obtained from 6748 adults throughout Germany (ages 18–79), showed an overall prevalence of 0.4%, 0.3% in males and 0.4% in females (105). Both studies found elevated prevalence in females, although the variance between genders was not statistically significant. A study of 1064 orthopaedic surgery patients in east Germany identified no cases of HCV, indicating the potential of different prevalence rates in West Germany and East Germany (106).

Diagnosed/incidence
Newly diagnosed incidence is reported annually by the RKI. The latest data from 2009 indicate an incidence rate of 6.6/100 000 inhabitants in Germany (87). Age and gender distribution show peak incidence in both males and females in the 25–29 age cohort, with male incidence in excess of female incidence at a ratio greater than 2:1 in this same age cohort. Newly diagnosed cases have declined from 2004 to 2009, with an annual rate of decline between 8 and 13% (Table 2) (87). It was estimated that 100 000 individuals, or 38% of the prevalent population, had been diagnosed as of 2004 (107).
Table 2.  Diagnosed cases reported by Robert Koch Institute (87)
Year200420052006200720082009
Number of cases903682747449686762235412
Genotype
There are several studies reporting genotype distribution (108–112); all provide a local or a regional analysis on small subsets of patients. The most representative study reported genotype distribution for a large cohort of patients (9455) located throughout Germany (88). Genotype 1 represented 61.7% of patients, genotype 2 in 6.9%, genotype 3 in 28%, genotype 4 in 3.2% and other genotypes in 0.2% of patients. Over the study period, from 2003 to 2005, there was a decline in the percentage of patients with genotype 1 and an increase in the percentage of patients with genotypes 2 and 3. Additionally, the mean patient age was higher for genotype 1 and lower for genotype 3.

Summary
National surveillance for HCV infection occurs in Germany, and provides information on the epidemiological trends of HCV. The RKI as well as other researchers identified the majority of newly diagnosed cases in younger age cohorts that are also attributable to IDU. An increase in genotype 3, with a decline in the percentage of patients infected with genotype 1, also indicate a trend towards the increased significance of IDU in perpetuating the disease in Germany (genotype 1 predominates in patients with post-transfusion hepatitis, while genotype 3 is seen more commonly in patients acquiring HCV through IDU) (88,110). The RKI has called for increased surveillance, supplemental epidemiological studies and targeted prevention measures in the at-risk population of IDUs in Germany.

Greece
In Greece, there are no national screening efforts. HEPNET-GREECE (Hepatitis Network–Greece) for hepatitis C is a national retrospective–prospective study initiated in 2003 that is sponsored by the Government and provides useful information regarding the epidemiology and course of chronic hepatitis. In addition, there are available data on prevalence, risk factors, diagnosed cases and genotype distribution from several studies in blood donors or patient samples.

Risk factors
A relatively small number of studies identified the risk factors associated with HCV transmission in Greece. One study of 434 unselected patients with chronic HCV established the same two risk factors in the study population as are located throughout Europe: transfusion (39%) and IDU (18%). Blood screening for HCV was initiated in the early 1990s. As expected, Savvas et al. (113) found that infection acquired before 1981 was more commonly related to transfusion, while infections after 1981 were associated with IDU. With a somewhat larger study population of 1229 CHC patients, blood transfusion was identified as the source of transmission in 25% of enrolled patients, and 30% of enrolled patients had a history of IDU, demonstrating again the two primary causal routes in the prevalent population (114). Another study included 309 HCV patients with origin and/or residence in Thessaly, Greece. After identifying three municipalities with a higher frequency of anti-HCV positivity than others, they investigated the potential risk factors for the variance. The sole risk factor more frequently identified in these municipalities was a history of the use of non-disposable, multiple-use glass syringes for medical purposes. Therefore, iatrogenic transmission may be responsible for pockets of high prevalence of HCV throughout Greece, particularly in the older population (115). In the first community-based study in the general population, similar risk factors were reported in the southwestern part of the country: blood transfusion, IV drug abuse and history of operation. In this region, non-disposable syringes were used extensively for parenteral anti-microbial treatment in the past, allowing one to conclude a potential association with anti-HCV positivity and past iatrogenic transmission (116). Recently, Raptopoulou and colleagues reported epidemiological data from 2817 patients followed at 20 hepatology centres throughout Greece between the years 1997 and 2006. The study showed that 90% of HCV infections acquired after 1992 belong to the IDU group, and therefore, in the near future, Greek hepatologists will be facing a significant number of young patients with cirrhosis or hepatocellular carcinoma (117).

Prevalence
The estimated prevalence was 1–1.9%. There were a number of prevalent studies published but nearly all were in subgroups (pregnant women, military personnel, company employees and volunteer blood donors) and reported a range of 0.37–1.5% (116, 118–124). Researchers identified communities with prevalence well in excess of 1% because of a history of improper sterilization techniques. One rural community on the island of Zakinthos had an anti-HCV positive rate of 6.8% (118), while a 10.9% prevalence was recorded for individuals attending primary care services on the island of Crete (125). Other studies also demonstrated an elevated prevalence of HCV in high-risk populations (126–128). No cases were identified in two separate studies that included only children (129, 130).

Diagnosed/incidence
Incidence was estimated at 5.0/10 000 in Greece in 1990 (114). A doubling in the incidence rate occurred from 1970 to 1990, propelled by genotype 3, and to a lesser extent, genotype 1b. Modelling annual incidence rates from prevalence and the natural history of HCV in a cohort of CHC patients, researchers arrived at a similar finding of 5.0/10 000 person-years in the late 1980s (131). The incidence of reported HCV cases in Greece has declined since 1999; the Hellenic Centre for Infectious Diseases Control estimates a 50% decline in HCV incidence since 1990 (132).
Although reported HCV cases do not represent the entire incident population because of under-reporting and the asymptomatic nature of the disease, it is likely that a downward trend is apparent. Still, the number of cirrhotic and HCC cases as well as HCV-related mortality will only decline in the next 30 years if complete elimination of new HCV infections is achieved from 1990 onwards (131). Therefore, while the pool of individuals newly acquiring HCV may be declining, the disease burden will remain in the immediate future.

Genotype
Recently, the results were reported from the large HEPNET-GREECE cohort study, with 2817 patients included in the analysis (117). One study relied on patients in Athens (113); another had the added benefit of recruiting CHC participants from multiple clinical sites throughout Greece (114). All studies reported similar changes in HCV genotypes during the last two decades. The studies reveal a remarkable similarity of estimates: genotype 1 is reported as the most prevalent (47, 46.9 and 45.1%), with genotype 3 as the next most prevalent (27, 28.1 and 34%). Genotype 4 was found in 15.2, 13.2 and 13.9% of patients, and genotype 2 in 8.3, 6.9 and 7% of patients (113, 114, 117).
All studies report an association between genotype 1 and blood transfusion while genotype 3 was associated with IDU. In addition, genotype 1 was associated with advanced age vs. genotype 3 and younger age cohorts. Genotype 4 was present more frequently relative to other European countries. It was detected in approximately 15% of the population and was equally distributed among patients with different modes of transmission (113, 114, 117). Genotype 4 seems to be imported to Greece both from immigrants and returning expatriate communities who lived in Africa. Data tracking the temporal pattern of incidence specific to genotype revealed a moderate increase in incidence associated with genotypes 1 and 4 (1.3–1.6 times), with a significant increase in genotype 3-specific incidence (13 times) from 1970 to 1990. These data indicate that IDU was the precipitating factor in recent decades in Greece.

Summary
Epidemiological data of HCV infection in Greece are limited. Studies of blood donors and reports from Liver Units are the main sources of data. The HEPNET-GREECE cohort nationwide study is the most definite source for epidemiological data in Greece. The epidemiological characteristics of HCV infection can be summarized as follows: (i) there are some isolated areas in Greece where the prevalence of the disease is high (6–10%) because of unsafe parenteral injections or invasive medical procedures, (ii) there is a significant change in genotype distribution because of an increase of illegal drug use, (iii) genotype 1 is predominant among chronically infected patients, while genotype 3 incidence has been growing rapidly (increased 13-fold) and (iv) 15% of infections are genotype 4.

Hungary
Limited national data are available from the National Centre for Epidemiology in Hungary, mainly results of a national seroepidemiological study performed in 2000 that estimated the overall number of anti-HCV-positive individuals. The National Communicable Disease Reporting System captures only acute cases detected annually, and reporting is not mandatory. No national screening programme is in place.

Risk factors
Only two studies examined possible risk factors. Previous surgery, having more than three pregnancies, blood transfusion and tattooing were associated with HCV infection (133, 134). High rates of HCV infection in the IDU population also indicate IDU as a risk factor (135), although the rates of IDU in Hungary are reportedly lower than that in other European countries (136).

Prevalence
Based on a national seroepidemiological study in 2000 by the National Centre for Epidemiology in Hungary, there were an estimated 60 600 HCV cases in Hungary, which represented 0.6% of the population (135). In 2001, a study of 477 hospital workers found a prevalence of 2.7%, indicating that occupation could be a potential risk for infection (137). A large blood donor study in south Hungary in 2001 indicated that the prevalence of HCV in 45 719 blood donors was 0.4% (133). Earlier blood donor studies reported slightly higher prevalence rates. One reported a prevalence of 0.73% in 15 864 blood donors (134); another screened 9707 blood donors and found a prevalence of 0.53% (138). Studying 120 children who received one or more blood transfusions before implementation of anti-HCV screening, a rate of 1.7% was observed (133).
Barna et al. (134) found that prevalence increased with age. Mihaly et al. (137) also reported an increased prevalence with age, from 0% in those <21 to 9.5% in those older than 50 years.

Diagnosed/incidence
The number of cases per 100 000 inhabitants decreased slightly from 0.4 in 2001 to 0.2 in 2005 (10, 135). Only acute HCV cases are reported annually via the national communicable disease reporting system (135), and thus represent an underestimate of the total incidence measure for Hungary.

Genotype
The most common genotype in Hungary is genotype 1b, with estimates ranging from 54.5 to 85.5% (137, 139). A study including a small number of workers from a hospital treating patients with tropical and infectious disease most likely does not accurately depict the genotype distribution for the rest of Hungary (137). Reporting in 211 patients with CHC, genotype 1b (85.5%), 1a (6.0%), mixed (5.0%), 1a+1b (3.0%) and 3 (0.5%) were observed (139). In a more recent study including 118 patient samples, the overwhelming majority of patients were genotype 1 (94.1%). Genotype 2 was identified in 0.8% of patients, genotype 3 in 3.4% of patients and genotype 4 in 1.7% of patients (140). In a small study of patients with CHC, all were genotype 1 (141), while 98% of the 47 blood donors examined were genotype 1 (138).

Summary
The overall estimated prevalence of HCV infection is low (0.6%) in Hungary; the relatively low rate of IDU may contribute. Most chronic HCV cases diagnosed today were acquired before 1992 via transfusions and other blood products. Over 90% of chronic infections are genotype 1.

Israel
Healthcare is universal and participation in a medical insurance plan is compulsory. Health insurance is covered by four HMOs with Clalit Health Services (CHS), the largest medical provider, managing close to 60% of the population. There is no HCV patient registry in the country, but data are collected and maintained by different health services. Given the large immigrant population, substantial data exist on seroprevalence and genotype by country of origin. Some of the data reported here are based on previously unpublished data reported by the author using a database of 3 926 182 individuals insured by CHS between 2001 and 2010, of which 789 689 were tested for HCV (20% of all ages and 29% of age >20 years) (142).

Risk factors
Multiple researchers identified immigration from the former USSR as one of the key sources of HCV infections in the country. The authors suggested that mass vaccination using non-disposable needles in the former Soviet Union and the spread of infection within families could be the cause of a higher prevalence among immigrants (143, 144). The risk factors among immigrants and native Israelis were assessed in a case–control study of 434 blood donors (143). IDU was associated with HCV infection in both groups, accounting for 14% of cases in native Israelis and 10.2% of cases in immigrants. Another risk factor was blood transfusion, which, before 1990, accounted for 42% of native Israeli cases and 11.7% of immigrant cases. Other strong risk factors among native Israelis included close contact with infected individuals and surgery. The risk factors identified in the former Soviet Union immigrants included gum surgery, hospitalization without surgery and receiving injection therapies (143). IDU was found to be a significant risk factor among 29 acute hepatitis C patients, accounting for 20.6% of infections, but a higher percentage of patients (65.5%) could have been exposed through medical procedures (145).

Prevalence
Most of the studies looked at specific subgroups in the population, with many focusing on immigrants. While immigrants made up 40% of the tested population, they accounted for over 70% of HCV infections (142). Studies involving only immigrants indicated a wide range of prevalence rates from 1.3 to 26.5% (144, 146, 147).
Community studies assessing HCV prevalence were not published, and only a few blood donor studies were performed (148–150). The best estimate of prevalence came from unpublished data from CHS. Among 789 689 individuals tested, 1.96% were HCV antibody positive in 2001–2010. The infection rate reached more than 4% among immigrants from the former USSR (142). The Magen David Adom National Blood Services reported an overall prevalence of 0.1% among all blood donors, with a higher prevalence among immigrants (0.8%) as compared with natives (0.04%) (151). The prevalence among IDUs was 75%, consistent with that of other countries (152–154).

Genotype distribution
The CHS data showed a genotype distribution of 1 (70%), 2 (8%), 3 (20%) and 4 (3%) among natives (142). Only one published study reported the genotype among infected individuals, but the sample size was small (n=29) (155). Both studies showed that the predominant genotype was 1.

Diagnosed/incidence
Analysis of CHS data showed that newly diagnosed cases declined from a peak of 2500 in 2001 to <1000 per year in 2010 for a total of 16 183 cases in 2001–2010. As CHS covered approximately 60% of the population, it was estimated that approximately 27 000, or 33%, of the infected individuals were already diagnosed. The Ministry of Health reported that the number of acute HCV patients was 0.351 per 100 000 in 2005–2009, a decline from 0.811 per 100 000 from 2000 to 2004 (156). However, this represented only reported cases and there were no estimates for under-reported or unreported cases.

Summary
While there were a few recent studies describing the epidemiology of HCV, data from CHS provided the best estimates for the country. The prevalence was estimated at 1.96%, with a higher rate among immigrants. Genotype 1 was predominant, with subtype 1b being more common. Risk factors included IDU, blood transfusion before 1990 and other forms of iatrogenic transmission.

Italy
Hepatitis C virus screening and surveillance is minimal at a national level in Italy. There is an active surveillance programme only for newly detected symptomatic acute cases. Instead, the majority of our knowledge comes from regional or local studies, which are difficult to extrapolate to the general population.

Risk factors
Risk factors for HCV infection have traditionally been related to nosocomial and healthcare-related transmission, or from IDU. The high prevalence of HCV in the elderly, particularly in the central and southern regions, can be explained by the extensive use in the 1960s to 1970s of some popular therapies (vitamins, nutrients, etc.) given by parenteral injections with multi-use syringes.
Recent risk factor analyses confirm nosocomial and healthcare-associated transmission as the major routes of transmission in Italy. Researchers studied a southern Italian municipality, Apulia, to estimate prevalence and risk factors. They reported blood transfusions (26%), glass multi-use syringes (88%), surgical interventions, household contacts and IDU as the major risk factors (157). Others used a sample based in Naples, an area with a known elevated incidence of liver cancer. This study estimated HCV and HBV prevalence and performed an extensive risk factor analysis. The risk factors included household contacts (10.7%), sexual intercourse with HCV-positive partners (29.6%), IDU (27.8%), history of blood transfusions received before 1993 (27.6%) and those with prolonged dental therapies (8.9%) (158). A study conducted on the Camporeale, Sicily, population provided further evidence for hospital-based transmission. A population-based, random sample of nearly 800 individuals indicated that the use of glass multi-use syringes, hospitalizations, surgical interventions and blood transfusions, as well as age older than 45 years were independently associated with HCV infection. An initial association with glass multi-use syringes was also suggested, but may have been a surrogate measure for hospital admission generally (159). Based on the sample size and its comparability with other recent studies, the best risk factor estimates for blood transfusions (27.6%) and injection drug users (27.8%) are the estimates generated by Fusco et al. (158).

Prevalence
A large number of recent prevalence estimates exist (157–200). These, however, vary substantially by study location and sample type and represent considerable heterogeneity of estimate. This heterogeneity is likely marked by two distinct waves of disease. There is a marked age-specific prevalence distribution and evidence that nearly 60% of HCV-positive subjects are currently older than 65 years (201); these mark the first wave. The second, smaller wave is apparent in urban areas of northern Italy and may be marked by more serious infection, potentially because of the comorbidities of HIV and alcohol abuse. Certainly, there is also a significant North–South increasing gradient in the prevalence of chronic HCV infection, but pockets of high prevalence in close rural communities have been described in different regions of the country (165).
In a southern Italian town, an estimated overall age-adjusted prevalence of 2.6% was reported. The study reported male prevalence rates (3.1%) slightly higher than females (2.4%) (157). A study carried out in Naples reported a much higher prevalence in 2008 of 7.5% (158). Another study in a northern Italian population estimated a prevalence of 2.6% (161). The best estimate of prevalence likely arises from Ansaldi et al. (165), in 2005, whereby an age-adjusted estimate of 4.4% (2.7% overall observed rate) was derived from a number of samples submitted to a diagnostic laboratory for alternate purposes throughout Italy. A clear north–south gradient was demonstrated, with a reported age-adjusted prevalence of 1.6% in the north, 6.1% in central Italy and 7.3% in the south. Because of an increase in prevalence with age, the prevalence in the adult population was 5.2%. Pockets of comparatively high prevalence have been reported in central and southern Italy (11.1, 16.3 and 22.4%), but appear to outlay the reasonable range for a population-based estimate (163, 169, 176).

Diagnosed/incidence
Estimating incidence has been historically difficult, as the recent studies vary substantially. In Italy, there is an active surveillance programme for the incidence of symptomatic acute hepatitis cases reporting a rate of 0.2/100 000 in 2009 for HCV, but this is certainly a significant underestimation, as HCV infection is rarely symptomatic during the acute phase. The most recent incidence reports from 2008 suggest a decline in overall incidence from 1997 to 2005 (range 2.6/100 000–0.7/100 000 person-years) (10). One study estimated a rate of 4.13/100 000 persons from a blood donor population from 1996 to 2000 (160). Another study reported a rate of 50.3/100 000 from a northern Italian population in a study ranging from 1986 to 1996 (172). Yet another reported a rate of 1.4/10 000 person-years (or 14/100 000) around Rome over a 7-year time period ending in 2002 (174). In blood donors from 1994 to 1999, a rate of 2.41/100 000 person-years was recorded (202). The historical data decline in incidence rate is likely due to improvements in historical risk factors like blood transfusions and other parenteral sources because of improved testing for HCV. The best estimate for incidence may be from Rome; however, it is based on a subsample and should be considered with caution at 1.4/10 000 person-years for 2002 (174). It was estimated that 300 000 individuals, or 12% of the prevalent population, had been diagnosed as of 2004 (107).

Genotype
A number of studies have estimated the genotype distribution of HCV subtypes in Italy (157, 159, 165, 203–208). The largest study comes from southern Italy (208). These data appear to match well with other researchers' work (165, 207). Comparing all studies, genotype 1b appears to be the most frequent type of infection (30.7–60%), with genotype 2 following (21.3–34.8%). The best estimate is likely from Matera et al. (208), in which genotype 1 was estimated at 62%, genotype 2 at 27%, genotype 3 at 7% and genotype 4 at 5%.

Summary
The epidemiology of HCV in Italy has some unique features: a stark difference in age distribution, a clear north–south prevalence gradient and evidence of very high endemic areas of HCV infection that often occur in rural areas of the country. The high prevalence of HCV in the elderly particularly in the central and southern regions can be explained by the extensive use of historically important and popular therapies given with multi-use syringes. The risk factors for HCV infection in Italy have been traditionally related to nosocomial and healthcare-related sources. Recently, IDU has been implicated, but the country's low incidence numbers suggest this as less of a problem than selected northern European countries. Genotype 1 is most predominant; however, genotype 2 is more highly represented than in other countries in Europe. Despite the large numbers of studies reviewed, no truly representative estimate exists; future projections may be significantly improved with general population studies.

Norway
The Oslo Health Study, a large population-based study conducted in 2000–2001 and commissioned in part by the Norwegian Institute of Public Health, is the most definitive source of population-level HCV estimates for Norway. National screening guidelines do not exist.

Risk factors
The results from the Oslo Health Study provided the best estimates with respect to risk factors. Among 72 infected individuals identified in a community sample, the most common risk factor reported was injection drug use at 67%. Blood transfusion was also identified as a possible mode of transmission (6%); however, 24% of the infected individuals did not have a known risk factor (209). In another study, IDU was also reported as the main risk factor (28%) among a group of 51 HCV patients referred for possible liver transplantation (210).

Prevalence
The few studies in Norway reported a prevalence of <1% (209, 211–214). The most representative study was the Oslo Health Study, reporting a prevalence of 0.70%, with the highest prevalence seen in ages 40–45. This study included 11 456 individuals ages 30 and older from a random sample of community members in Oslo during 2000–2001. This study did not include active drug users, who have an exceptionally higher prevalence rate (an 81% prevalence rate in the IDU population was observed in 2009) (209, 215). While population-based studies are essential for determining the overall prevalence in the country, it is important to note that active drug users are less likely to participate in health surveys, which may result in rates that are lower than the actual national average. In Norway, the prevalence of IDU is near the median for countries reporting to the European Monitoring Centre for Drugs and Drug Addiction (136).
Specific groups such as IDUs have been studied by researchers and report values that are substantially higher than the general population, ranging from 56 to 93% depending on the year (216, 217). Other groups such as pregnant women have been studied and prevalence rates similar to that of the general population Oslo Health Study have been reported (213). One blood donor study has been reported that yielded a rate much lower than that of the general population (0.11% compared with 0.70%) (214).

Diagnosed/incidence
Incidence rates as reported to the ECDC are similar to the low prevalence rates reported previously. These have ranged from 0.4 to 0.8 cases per 100 000 people from 1996 to 2005 (10). However, it is believed that the reported rates are underestimating the actual incidence rate. Given that the size of the HCV prevalent population is approximately 30 000 individuals and the viral epidemic reached Norway 40 years ago, there are approximately 10–20 cases per 100 000 persons per year (218).

Genotype
The most representative study for genotype distribution comes from the Oslo Health Study. In this study, the most common genotype identified from a community sample was genotype 1 (61.5%); both subtypes 1a and 1b were represented equally (28%). Genotype 3a was also a commonly identified genotype, in 28% of patients, and genotype 2b in 10.5% of patients (209). Another researcher found genotype 3 to be the most common (50%). However, this study consisted mainly of IDUs, which may explain the difference in the genotype distribution between the two studies (219).

Summary
Hepatitis C virus prevalence is relatively low in Norway, estimated to be <1% in the general population. The rate of new infections has also remained low, with a reported incidence of 0.4–0.8/100 000 from 1996 to 2005. However, few recent population-based studies have been performed, indicating the need for further research to fully understand the current trends of infection in this country. A significant portion of new cases are likely arising from IDU among the younger generations.

Poland
Hepatitis C has been a notifiable disease in Poland since 1997. The surveillance system in Poland covers both acute and newly detected chronic HCV. Outside of these newly diagnosed data reported annually, no national-based statistics are available for HCV. Poland does not have a national screening programme in place.

Risk factors
In an early study from 1991 to 1995, in 107 patients with acute and chronic HCV infection, surgery (28%) and hospitalization in a non-operative ward (17%) were common risk factors (220). More recent studies have identified additional risk factors. From a group of 250 HCV-infected individuals, blood transfusion before 1993 was the most frequently reported risk factor, accounting for 26.8% of infections. This was followed by healthcare-related occupational exposure (13.6%) and IDU (8.8%). Drug use was significantly higher in younger males; 82% of infected drug users in this study were men under the age of 45. In females under the age of 45, the majority of infections (60%) were accounted for by blood transfusion before HCV screening. This high percentage was likely because of the use of transfusion to increase haemoglobin levels during postpartum iron deficiency (221). In another report, the risk associated with medical procedures was assessed. In 194 non-IDU patients, transfusions, healthcare occupation, minor surgery and dental care were found to be significant sources of infections (222). Similarly, in a study of voluntary blood donors and hepatitis C patients, the main infection routes identified were associated with diagnostic and therapeutic procedures performed in medical service units (223). A large study including 17 930 persons identified the following significant independent risk factors for anti-HCV positivity: more than three hospitalizations in a lifetime [odds ratio (OR): 1.8], blood transfusion before 1992 (OR: 2.9) and IDU (OR: 6.2) (224).
These reports highlighted the importance of healthcare in the transmission of HCV, both through procedures and employment in the field. The risk of infection from IDU was suggested to be lower in Poland than that in other countries (221), but this could be because of the fact that studies to date were performed in healthcare settings that under-represent the IDU population.

Prevalence
The Institute of Infectious and Parasitic Diseases at Warsaw Medical University reported that 750 000 individuals were infected with HCV in 2006 corresponding to a prevalence of 1.9% (135). In a fairly large study of 2561 non-randomized volunteers, a prevalence rate of 1.9% was found (225). Another study included 143 non-randomized volunteers with risk factors for chronic HCV, but who had not been diagnosed, and found a prevalence of 2.09% (226). One of the best estimates for the prevalence in Poland comes from a study of 1069 students, where the prevalence varied between 1.4% in medical students and 1.9% in students in non-medical majors (227). A recent study including 9029 healthcare workers and 8901 consecutive patients of large multispecialty hospitals and outpatients not involved in the management of liver diseases reported a prevalence rate of 1.42% among healthcare workers and 1.92% among patients (224). Another study included 278 infants aged 3–12 months and found no cases of HCV, even in children who had been hospitalized at least one time, indicating that infection is rare in the first year of life (228).
In a large blood donor study of 4 233 119 donors between 1994 and 2003, a prevalence of 0.46% was reported, with a decreasing trend in prevalence across time (229). In a smaller study of 44 298 blood donors between 1998 and 2000, a prevalence of 0.5% was recorded, with no differences among gender and age (230). Bielawski et al. (225) also found no differences by age.
While no studies reported a difference by age, there may be a difference in rates by gender. According to three studies, males had a higher prevalence than females. One study found that prevalence was significantly higher in men (2.3%) compared with women (1.7%) (225). While only 31.5% of another study population was male, all three cases were found in males (226). Flisiak et al. (224) reported male sex as a significant independent risk factor for anti-HCV presence (OR: 1.7).

Diagnosed/incidence
Hepatitis C has been a notifiable disease in Poland since 1997. All symptomatic cases, both acute and chronic, are reported to the National Institute of Public Health. Based on reported cases, the number of cases per 100 000 inhabitants has ranged from 5.05 to 7.9 between 2000 and 2008, with the most recent number diagnosed of 6.17/100 000 in 2008 (231–239). The variation in the number of cases is likely because of a surveillance artefact associated with a new case definition (231, 232, 239).
Consistently across the years, there have been a larger number of cases in men than that in women (7.1/100 000 vs. 5.3/100 000 in 2008), and urban areas have shown case rates twice that of rural areas (7.7/100 000 vs. 3.8/100 000 in 2008). Peak incidence was observed in the 50–65-year age cohort in both males and females in 2008 (231). The Institute of Infectious and Parasitic Diseases at Warsaw Medical University estimated that 20 000 cases out of 750 000 infections have been diagnosed corresponding to a diagnosis rate of 2.7% (135).

Genotype
The most common genotype in Poland is genotype 1. In 179 patients with chronic liver disease, 57.5% were genotype 1, 31.3% genotype 3 and 4.8% genotype 4, with a significant increase in genotype 3 in those infected after 2000 compared with those infected before 2000, from 19.1 to 38.9%. Genotype 1 was found mainly in those whose HCV was thought to be acquired through blood transfusion (68.8%), with 34.8% of those acquired thorough injection drug use. Genotype 3 was most prevalent in IDUs (240). Another study examined three different groups, and while genotype 1b was the most prevalent, the distribution of the genotype varied by group, which may indicate which genotypes lead to more serious disease. In 50 blood donors who were anti-HCV negative but HCV RNA positive (indicating recent infection), 36% were genotype 1b, 2% genotype 1a, 40% genotype 3a, 14% genotype 4 and 8% mixed. Among 70 anti-HCV-positive blood donors, 75.7% were genotype 1b, 4.3% genotype 1a, 14.3% genotype 3a, 4.3% genotype 4 and 1.4% genotype 6. Among 170 hepatitis patients, 85.3% were genotype 1b, 0.6% genotype 1a, 10.6% genotype 3a, 1.2% genotype 4 and 2.4% mixed (241).

Summary
The best estimate for the prevalence of HCV infection in Poland is approximately 1.9%. The reported number of cases of HCV infection has increased from 5.4/100 000 inhabitants in 2000 to 7.7/100 000 inhabitants in 2006. Whether this is a true increase in the number of cases or a surveillance artefact associated with a new case definition is undetermined. There are a larger number of newly diagnosed cases in men than women, and men are generally diagnosed at a younger age, indicating different modes of infection between the genders. The majority of chronic infections in Poland are genotype 1.

Portugal
There is minimal epidemiological research for HCV in Portugal, with only one published national estimate. National screening guidelines are not in place.

Risk factors
Only one study provides risk factor analysis; it identifies IDU (58.7%) as the most significant risk factor. Blood transfusions (15.2%), surgery (22.2%) and sexual contacts (18.9%) were also suggested as major risk factors. A large proportion of cases has unidentified risk factors (14.1%) in this analysis (242).

Prevalence
One prevalence estimate was generated in the Coimbra District of Colombia in 1994 at 0.46% of the population, and is very unlikely to represent the total population (243). Another study of 131 124 blood donors found an overall prevalence of 0.9% using a second-generation test (244). Lower prevalence was observed in the north (0.68%) than that in the central region (1.0%) or the south (1.59%). The same study also reported HCV prevalence in IDUs between 70 and 92%. Consistent with IDU as a significant transmission factor, notified cases of HCV infection to the Ministry of Health from 1993 to 1997 were the highest in 15–34 year olds, with a male-to-female ratio of 4:1. A national prevalence of 1.5% was estimated by the authors (244).

Diagnosed/incidence
The incidence rate reported by ECDC was 0.9/100 000 in 2005 (10). A general downward trend in incidence rates over time was suggested for Portugal, with a peak in 1998 at 6.9/100 000 person-years declining until 2003 to a rate of 0.7/100 000 person-years.

Genotype
Three reports are available describing the genotype distribution in Portugal (242, 245, 246). Areias et al. provide the most robust and representative sample available; however, no subgenotyping of HCV infection was carried out. Genotype 1 was the most prevalent genotype (52.2%), followed by genotype 3 (34.0%). Genotype 4 was recorded in 7% and genotype 2 was seen at the smaller proportion of 2.4% (242). Smaller studies also suggest that genotype 1 is the most prevalent genotype (71.4 and 59.3% respectively) (245, 246).

Summary
Epidemiological data in Portugal were limited and in some cases dated. Higher prevalence of genotype 3, the age distribution of newly reported cases and a single risk factor study are suggestive of continued transmission by IDU. However, further epidemiological analyses are warranted for Portugal.

Romania
Preliminary data from a nationwide cross-sectional survey conducted from 2006 to 2008 provide the best data for the prevalence and risk factors of HCV in Romania. National screening guidelines are not in place.

Risk factors
The causes of HCV infection have varied over time in Romania. Before1989, the majority of infections was caused by blood transfusions and contaminated medical equipment. Currently, other percutaneous routes (such as IDU) are thought to contribute to a greater portion of infections (247).
In one study of patients in Romania, percutaneous transmission was suggested to be the main route of infection, accounting for 85.9% of cases out of 461 infected patients. Among percutaneous routes of transmission, the following breakdown was reported: bleeding dental procedures (77.3%), general surgery (58.2%), blood transfusion (34.8%), beauty salon visits (18.5%), injections under poor conditions (17.8%), tattoos (5.4%), piercing (4.1%), intravenous drug administration (1.1%) and haemodialysis (0.2%). Non-percutaneous routes were identified in 8.9% of patients, and 5.2% were thought to be community-acquired infections (248). Other studies have also identified percutaneous routes as a major source of infection, attributing transfusions and contaminated medical equipment as likely causes of infection (249–251).

Prevalence
Recent studies on the prevalence of HCV infection in Romania are scarce. Many have focused on blood donor populations (252–254), with a range of 0.3–4.9%. However, studies conducted in this population are not reflective of the general trends in the country. Blood donors in Romania are compensated and screened for a variety of infections and therefore are likely to have a lower prevalence of HCV infection (247).
The overall prevalence in the general population of Romania is 3.5% according to preliminary results of a community study (251). In this study, HCV prevalence was determined for 8039 healthy adults, ages 19–69 years old, from 54 centres spanning all areas of the country. This study also reported a higher prevalence in rural areas compared with urban areas (4.43 and 2.76% respectively), as well as in older age groups, and in those with lower education and income levels (251). The difference in the rural and urban areas may be attributed to educational level and medical practices (247). This study also suggested a significant regional variation, ranging from 0.56 to 7.19% between counties, as well as by age, ranging from 1.5% in the 19–29-year age group to 6.49% in the 60–70-year age group (247).
Two other community studies were performed in the early 1990s. A report published in 1994 found a prevalence of 4.9% in a multidistrict study in the area of Transylvania (255). From a 1990 study of the city of Bucharest, the prevalence rates for multiple groups were ascertained. Out of 100 low-risk adults, 4.5% were found to be positive for anti-HCV antibodies (256).

Genotype
The most common genotype reported in Romania is genotype 1. This result is confirmed in a study by Grigorescu et al., which found 93.46% of 153 patients and 99.13% of 461 patients infected with genotype 1. The most common subtype is 1b (248). Further breakdowns of genotype distribution are not reported by other studies. Currently, the Romanian Health Insurance Agency does not reimburse for genotyping, which may contribute to the lack of genotype distribution studies in the country (250).

Summary
Romania has one of the highest HCV prevalence rates in the European Union (EU), estimated at around 3.5%. The main contributors are blood transfusions before 1995 and the use of incomplete sterilized medical equipment before 1989. After the Communist Era, the main cause of transmission was through percutaneous routes. A 2008 study indicated a large difference in prevalence between counties (0.56–7.19%) and age groups (1.5% in youth to 6.49% in elderly). These data suggest that the HCV prevalence in the young Romanian population born after 1990 is below 1.5%, and there may be a tendency towards decreasing prevalence in future years.

Russia
In Russia, morbidity rates for acute and chronic HCV are reported by the Ministry of Health annually; there has been mandatory registration of newly diagnosed cases for CHC since 1999 and for acute hepatitis C since 1992–1993. Other epidemiological information on HCV is derived from regional or local studies, showing local variances, making extrapolation to the national level difficult. A national screening policy is in place, but does not cover all the cases in the country. Specific subgroups are screened on a regular basis including blood donors, pregnant women, prisoners, haemodialysed patients, drug users starting weaning programmes, healthcare workers and others (257).

Risk factors
Detailed risk factor analysis for HCV transmission was the focus of few studies. It has been suggested that one of the main routes of transmission in the younger population is IDU (258). This corresponds to the results of a study of 46 HCV-positive blood donors, where drug addiction was the only risk factor identified to be significant in males younger than 30 years old, accounting for 35% of the transmission for this age and gender group and 13% overall. Additionally, previous blood transfusion was associated with both genders over 30, accounting for 40% of infections in this age group and 26% of infections overall (259). However, these data are from older workers and small groups of individuals and may not reflect the risk profile for the entire Russian Federation today.
Another study suggested the significance of sexual transmission in sexually abused children, with a difference in anti-HCV detection rates of 8.1% between children with and without reported sexual contact (258). A more recent study examined trends of HCV infection over time. During two 6-year time periods (1995–2000 and 2001–2006), the majority of transmission routes were artificial (IDU, hospital); however, there was also an increase in natural transmission routes (sexual, other contact) during 2001–2006. IDU transmission varied over time in Moscow, potentially accounting for 39.5–56.4% of infections from 1994 to 2001, decreasing slightly in 2002–2004 (20.5–30.1%), and further decreasing in 2006–2007 (16.5–18.6%). Vertical transmission accounted for infections in 0.2–1.3% of children. Many cases had unknown transmission routes: 13.3% during 1994–2000 and 30.6% from 2001 to 2006 (260).

Prevalence
Many Russian studies focus on prevalence rates among blood donors, reporting a wide range of values ranging from 0.93 to 2.5% (259, 261–267). Other studies report on specific subpopulations such as children, pregnant women or rural villages (262, 263, 268, 269).
A study testing 2217 blood samples from former USSR regions found a prevalence of 1.3% in Moscow, 3.0% in Tuva and up to 5.3% among the population of the republics of Central Asia (270). In another study, out of 4216 individuals living in various parts of Russia and Mongolia, a prevalence of 2% was recorded in the European part of Russia (0.7–3.8% depending on the region) and a prevalence of 2.5% was recorded in the non-European part of Russia (2.4–2.7% depending on the region) (271). However, samples for this study were taken from students, voluntary blood donors and healthy adult volunteers and likely represent a lower bound for the actual prevalence in this region. Another study looked at a random sample of 374 adults, aged 25–64, from Siberia, and compared this with blood donors from the same region. The adult general population was found to have a prevalence of 2–2.5 times that of the blood donor population (5.3 and 2.1% respectively). In addition, school-aged children (14–17 years old, n=423) were found to have a prevalence of 2.6% (262). Kuzin et al. (263) have reported trends in the general population in the city of Vladimir, with findings that suggest a gradual increase in HCV infection with age. A study of volunteer blood donors from the Russian Republic of Daghestan found similar trends, with prevalence peaking in the ages over 50 years (259). Data from Moscow also indicated a prevalence rate in adults twice as high as in children (270).
Among community samples, the study by Iashina et al. (270) provided the most extrapolative estimate for prevalence in Russia, ranging from 1.3 to 3.0% in European regions and in excess of 3% in non-European regions. This and other studies indicate that there may be a significant regional variation in Russia. Finally, trends in acute and chronic cases have also been reported to differ. In one analysis, the prevalence of acute cases had decreased over the past decade in Russia, mainly consisting of adults aged 15–39 years (averaging 86.4% of acute cases). Conversely, chronic HCV prevalence had increased, with a majority of the cases in adults aged 20–40 years (260).

Diagnosed/incidence
Reports of incidence indicate rapidly increasing numbers of new infections. According to the Ministry of Health, incidence increased from 3.2/100 000 persons in 1996, to 9.1/100 000 persons in 1997 and 11.6/100 000 persons in 1998 (272). Other sources indicate even greater increases after 1998, with an incidence of 19.3/100 000 persons in 1999 (258). More recent data from the Ministry of Health indicate that the incidence has almost doubled 10 years later, reporting a rate of 40.79/100 000 persons in 2009, with 57 966 cases of CHC that year (273). Another report suggested the incidence of CHC to range from 0.07 to 75.3/100 000 persons and the incidence of asymptomatic carriers to be between 17.2 and 198/100 000 persons (274).

Genotype
Several studies have reported on the genotype distribution of HCV in Russia (275–278). The most robust sample included a total of 562 chronically infected patients. Genotype distribution was as follows: 1 (55.7%), 2 (8.2%), 3 (35.1%) and mixed/other (1.1%). Of these patients, 54.8% were subtype 1b, followed by 3a, which was found in 35.1% of patients (277). Similar results were reported, with genotype 1b most frequently found among 388 infected individuals (50.3%), followed by genotype 3a (44.8%) (275). Other studies with smaller sample sizes also suggest that 1b is the most frequent subtype found in Russia (263, 279).

Summary
Hepatitis C virus infection has been increasing steadily over the past 10 years in Russia, with an incidence of 40.79/100 000 individuals in 2009, according to the Ministry of Health. Prevalence estimates from community studies vary significantly by area, suggesting regional variation within the country. The country risk factor profile may vary over time, with some studies suggesting an increase in the proportion of cases transmitted through natural routes such as sexual transmission or other types of personal contact. Additionally, while IDU has continued to be a major source of transmission, it has accounted for a smaller percentage of cases in Moscow in recent years.

Spain
National surveillance of newly diagnosed cases of HCV is conducted on a voluntary basis in Spain. National screening guidelines are not in place. Aside from a genotype study spanning multiple regions (280), the large body of epidemiological research in Spain has been conducted at the local or the regional level.

Risk factors
The identification of risk factors in Spain arises from five studies (281–285). One study reported hospital admission among 65% of acute cases of HCV infection. Ten per cent of the cases in the study were linked to IDU (281). Another study provided an estimate for prevalence of transmission also among acute HCV cases. Hospitalizations were the most prevalent risk factor (72%), followed by IDU (10%) (282). The fact that these studies were performed in referral centres and the low access of IDUs to the Health Care System may have underestimated the role of drug abuse as a cause of acute HCV infection. Prospective data in the context of a tertiary care centre confirm nosocomial transmission in a hepatology ward, although this estimate is based on small numbers of transmission (286). Patient-to-patient transmission was demonstrated in this study by phylogenetic analysis of isolated HCV. There have been two large epidemiological studies in Spain, representing chronic cases of HCV infection. One study reported in retrospective questionnaires that hospital admission (74.5%), dental-related procedures (85.1%), use of syringes (61.7%) and previous surgery (59.5%) were the most frequent risk factors (284). On occasions, several of these factors coexisted together, suggesting that the use of unsafe syringes or medical procedures was an important factor. The other study showed that tattoos (OR: 6.2), blood transfusions (OR: 5.0), intravenous drug use (OR: 4.9) and antecedents of hospitalization (OR: 2.3) were variables associated independently with infection (285). In a population of northern Spain, parenteral drug addiction predominated among those of the fourth decade, while transfusion and surgery predominated in people over 60 years of age (287). Martinez et al. (283) only analysed genotype 4 patients.

Prevalence
Hepatitis C virus prevalence estimation comes from the literature dating to 1992. However, no population-based estimate is available since 2002. The most recent, and likely best, prevalence estimate comes from a study performed in 2002, where a prevalence of 2.64% in adults 25 years of age or older was reported, with no differences in prevalence between genders. Prevalence was reported to be the highest in individuals over 50 years of age, probably related to syringes and unsafe medical procedures and hospital-based transmission (284). Two further studies reported a prevalence of 2.5 and 1.6%, respectively, in 2001 (285, 287). All three estimates suggest an increased prevalence with age. A community-based survey in Zamora (west central Spain) estimated a lower prevalence of 0.74% in 2002 (288). In a European-wide review of overall prevalence, authors assumed that 2.5% of the total population was infected (6).
More recent studies of pregnant women likely represent a self-selected population (289–291), and are likely lower than the total population prevalence. A 1997 estimate including workers of the National Electricity company suggested a 2.4% prevalence estimate (292), whereas a community-based study from Gijon in 1997 presented an estimate of 1.7% (293). Older estimates were not considered for use in our analysis (294–307).
The prevalence among IDUs has been reported to be over 80% in all but one of the studies reviewed (308–313).

Diagnosed/incidence
The best available incidence was reported at 2.3/100 000 persons in 2003 but was based on voluntary reports rather than mandatory reporting (282). Reports to ECDC coincide with this report (10). Incidence trends over time estimated by the ECDC suggest a decline in overall incidence from 1997 to 2005 (range 2.8/100 000–0.6/100 000 persons), likely because of improvement in historical risk factors like blood transfusions and other peritoneal sources. The ECDC estimate showed a modest increase for 2006 at 1/100 000 persons (10). It was estimated that 140 000 individuals had been diagnosed as of 2004 (107).

Genotype
Several studies reported HCV genotype 1 as the most common (280, 314–317). The three most recent and sufficiently powered studies report remarkably similar results. Genotype 1 was found in 64.1–68.3% of the total cases while genotype 3 accounted for 18.5–20.9% (280, 314, 315). The best estimate is derived from Echevarria et al. (280) with the following genotype distribution: 1 (65.4%), 2 (3.1%), 3 (19.6%), 4 (11.6%) and 5 (0.3%). This study contained 3015 samples from 17 regions throughout Spain, all tested in a single laboratory.

Summary
The prevalence of HCV in Spain is among the highest in Europe. Historically, transmission has occurred through hospital-based sources or the reuse of needles. No definitive, recent study estimate for the overall incidence or prevalence is available. High rates of genotype 3 suggest a continued role of IDU, which is also confirmed by high rates of HCV positivity among IDUs. Increasing rates of genotype 4 have been linked to IDU and immigration (280, 315).

Sweden
Mandatory reporting of both acute and chronic cases of HCV since 1990 provides robust data for incidence, prevalence and risk factors in Sweden. Both the clinician and the laboratory are required to report any HCV infection to the Swedish Institute for Infectious Disease Control (SMI) (318). Since 2007, there has been a national screening effort to identify HCV infections due to blood transfusions (before 1992) by offering and recommending free HCV-tests for everyone who have had a blood transfusion. In addition, drug addicts are screened for HCV infection when they seek therapy for their addiction.

Risk factors
Injection drug use in Sweden is the predominant risk factor. The gold standard reference, reporting data from the national database of communicable diseases with all diagnosed and notified HCV-infected individuals in Sweden, reported that the most probable route of transmission was former or ongoing IDU, accounting for 65% of infections. Following IDU, transfusion of blood or blood products (6%) and sexual contact (2%), were the most common risk factors. Still, in a large proportion of cases, the transmission route was unknown or not stated (318), although a more recent study demonstrated that a high percentage of those with unknown route of infection had been hospitalized because of drug related conditions (319). An earlier study had reported a strong observational association with IDU, followed by blood transfusions, tattoos, previous hospitalizations and a history of sexually transmitted disease (320).

Prevalence
The prevalence of HCV infection has been reported in five studies since 1994 (318, 321–324). Unlike other countries in the EU, post-1990 mandatory reporting of HCV has allowed the nationwide detection of HCV prevalence for Sweden. In 2008, the nationwide prevalence was estimated 0.5%, based on all reported cases to SMI (318). This prevalence rate is supported by a more recent study that linked the notifications to other registries and took into account the number of deaths and emigration (319). By the end of 2006, there were 43 000 reported individuals but only 35 000 of them were alive, resulting in a prevalence of 0.4% with a diagnosed HCV-infection. Assuming 20% undiagnosed infections, the overall prevalence was 0.5%. In the original study, females comprised only 30% of the total HCV infections, while males made up the remaining 70%. Anti-HCV-positive cases in children are rare; hence, the prevalence in the adult population is slightly higher than the overall prevalence (0.59%). Another study used a large, although regional, approach from southern Sweden and reported a prevalence of 0.37%, similar to SMI data (322).

Diagnosed/incidence
True incidence data were not available in the literature. However, the mandatory reporting policy does provide the number of cases reported to SMI. A height of reported HCV cases was seen in 1992 followed by another peak in 1997 (52.1/100 000 persons), with a general decrease through 2005 (29/100 000 persons) (10). In absolute terms, the incidence of reported cases for Sweden is an order of magnitude larger than the estimates seen throughout other parts of Europe, particularly southern Europe due to the presence of a longstanding national mandatory reporting policy. The median age of diagnosis confirms the role of IDU, as 84% of new infections were notified before the age of 50 (318). The 2006 and 2007 incidence rates from ECDC reports suggest an overall incidence rate of 21.8 and 23/100 000 persons respectively (11, 325). Approximately, 80% of the HCV infected population was already diagnosed by 2006.

Genotype
A number of studies have estimated genotypes for populations in Sweden (320, 326–329). The most recent and best report estimated the genotype distribution at 1 (45.2%), 2 (19.3%), 3 (33.8%) and 4 (1.7%) (326). Similarly, another study estimated genotype 1 as the most prevalent genotype in Sweden, accounting for 41% of all HCV-positive individuals (328). In another small study, a similar genotype distribution was observed (320). Another study based on hepatocellular cancer groups showed a higher frequency of genotype 1 (327). All studies indicated a significant portion of the population affected by the 1a subtype (24–57%).

Summary
Sweden has a comparatively low prevalence in Europe. Historical parenteral infection is clearly evident in the increasing prevalence patterns in older cohorts. An exceptional reporting system also contributes to a high case identification rate. The mandatory reporting system Sweden uses allows for arguably the best data collection in all of Europe.

Switzerland
Reporting of positive tests for HCV has been mandatory in Switzerland since 1988, providing national estimates for incidence and routes of transmission. Additionally, the Swiss Hepatitis C Cohort Study (SCCS), a large population-based cohort study consisting of confirmed anti-HCV-positive individuals from all regions of the country, provides robust epidemiological data at the population level (330).

Risk factors
The SCCS has provided the most comprehensive and robust data on the risk factors of HCV transmission for the Swiss population (330, 331). The study has been enrolling patients, aged 18 or older, from the year 2000. Through June 2010, there were 3623 patients enrolled. The study protocol allowed for the selection of more than one risk factor, and for some patients, multiple risk factors were reported. More than half of the patient population identified IDU, which was the most commonly reported risk factor. Reported risk factors were as follows: IDU (57%), invasive medical procedures (35%), blood transfusion (23%), sex with HCV-infected partner (13%), accidental needle-stick (10%), occupational exposure (7.6%) and household contact (5%). The Swiss Federal Office of Public Health (FOPH) data also indicate IDU as the most frequently reported risk factor, among 58% of patients (330, 332).

Prevalence
There are a number of Swiss studies that have addressed HCV prevalence in specific high-risk subgroups such as IDUs (333–337). Others found high rates of anti-HCV-positive individuals in patients visiting an emergency room, dialysis patients, organ donors and lymphoma patients (338–341). Conversely, a very low prevalence (0.095%) was reported in dental workers, although the authors indicated that population biases were likely (342). Studies on blood donors demonstrated a prevalence of <1% (341, 343). One robust study measured prevalence in pregnant women (344). 9057 women with consecutive births from obstetric wards in public hospitals from 23 of 26 cantons in Switzerland were enrolled from 1990 to 1991. In these women, aged 15–58, the anti-HCV prevalence was 0.71%.
However, there are no community-based prevalence studies in Switzerland. Therefore, the FOPH relies on the studies completed with pregnant women and blood donors to estimate the prevalence in the general population between 0.5 and 1%. However, as we have seen in other countries in this report, studies in pregnant women and blood donors underestimate the true prevalence in the general population. The estimate provided by Sagmeister and colleagues is probably more representative of the true prevalence in the country. This study used FOPH reported cases and prevalence estimates and future disease burden assumptions to model a prevalence range of 1.25–1.75% (345).
Reporting of positive tests for HCV has been mandatory in Switzerland since 1988. Positive tests are reported to the FOPH, which cross-checks for duplicate reporting. In summary, males represented more infections than females at a ratio of 3:2. Also, age-specific prevalence rates increase to age 20, remain high until age 44 and then decline (330, 345).

Diagnosed/incidence
The newly diagnosed cases of HCV reported by the FOPH provide an estimate of incidence for Switzerland. With the exception of 2009, there has been a decline in the number of new cases annually since 2002. As of 24 October 2010, 1224 new cases of positive HCV serology have been reported to the FOPH (1300 in 2009; 1291 in 2008). As of June 2010, 3623 anti-HCV-positive individuals have been enrolled in the SCCS, which would suggest a diagnosis rate of 4%. However, others reported a diagnosis rate of 14% in 2002 (344). The estimated incidence of acute HCV (per year and 100 000 inhabitants) based on the declared cases was 1.2 in 2009 and 0.6 in 2008 (estimated incidence for 2010: 0.8) (332, 346).

Genotype
The Swiss HCV Cohort Study offers the most definitive source for genotype distribution in Switzerland (330). Genotyping was available for 2207 patients through 2005, with genotype 1 (51%) and genotype 3 (30%) the most prevalent. Genotype 2 was represented in 9% of patients and genotype 4 in 10% of patients

Summary
As of June 2010, 3623 anti-HCV-positive individuals have been enrolled in the SCCS and 3356 (92.6%) were viraemic. The HCV-infected population in Switzerland is characterized by a significant immigration rate, foreign-born persons accounting for about one-third of the total number of patients enrolled in the Cohort (1149, i.e. 31.7%) (346). For comparison, foreign residents in Switzerland were 21.7% of the general population in 2009 (347).
Despite this, the number of new infections reported each year to the FOPH has been declining steadily since 2002 by about one-third, from approximately 2500 declarations to the current 1600. This may, however, suggest lack of efficient case identification in populations of patients not usually considered at high risk of infection.

Turkey
Turkey is lacking a national screening or reporting system for HCV. The epidemiological picture of HCV in Turkey is derived from local or regional studies, which indicate potential geographic differences, making extrapolation to the national level difficult.

Risk factors
A small number of studies identified the risk factors for HCV infections (348–351). A prior history of blood transfusion was identified as a key risk factor in multiple studies (348–350). However, it is unlikely to be a source of new infections, as Turkey began testing for HCV in blood donors in 1996. In an academic hospital in Istanbul, 38.8% of the HCV-infected cohort described a history of transfusion before 1996 (350). Nosocomial risk factors (e.g. history of hospitalization, surgery, dental procedures) are reported for the majority of HCV cases (348–351), while IDU accounted for a very small number of HCV cases (4% or less) (348–350).

Prevalence
Based on the available data, the current best estimate for the prevalence is approximately 1.0%. In a recent randomly selected, large population-based study (n=5471), the prevalence was 0.95% in an adult population 18 years of age or older (352). In a community-based study of 2852 randomly selected individuals, a prevalence rate of 1.0% was recorded (348). Other recent, randomly selected population-based studies report varying estimates of the prevalence across Turkey, from 0.6% (353) in 2888 individuals in the southeast to 2.1% (354) in a study of 1095 individuals in a region near the Black Sea, which may suggest regional differences. Both studies found no significant difference in the prevalence for those living in rural vs. urban areas (353, 354). Other studies reflect the range of prevalence estimates that have been reported in blood donors (0.19–0.68%) (355–361), in patients during routine outpatient visits (2.2–2.4%) (351, 362) and in a less recent population-based study (1.5%) (363).
Prevalence studies of blood donors have lower prevalence rates than the community-based studies. In 44 982 blood donors, a prevalence of 0.35% was reported (356), similar to that found (0.38%) in 6 240 140 blood donors from 1989 to 2004 (357), and in 29 049 blood donors (0.37%) (359). A slightly higher prevalence was reported in 11 234 Turkish soldiers who donated blood in Cyprus (0.46%) (360), while a slightly lower prevalence was reported in 37 886 blood donors from 1993 to 2002 (0.19%) (361).
The prevalence in patients tested during routine outpatient visits was higher than that in the community-based studies. A prevalence of 2.2% was reported in a study of 1320 patients during routine check-ups (362). A prevalence of 2.4% was observed in 1157 patients seeking treatment at an outpatient clinic for various reasons, including testing for HCV (351).
Studies in subgroups also found varying prevalence rates. A study of 302 women of childbearing age found a prevalence of 8.9% (364). The authors hypothesize that the relatively high rate may be attributed to iatrogenic transmission via non-hospitalized childbirth or invasive dental procedures. Another study of 4700 pregnant women indicated a prevalence of 0.1% (365). A study of 1332 engaged couples found a prevalence of 0.1% (366). Another study found a prevalence of 2.5% in 227 elderly individuals living in nursing homes (367).
There are differences reported by gender. Three studies reported no differences in rates by gender, although in general, males had slightly higher rates. The reported rates in males were 0.8, 2.5 and 6%, and the rates in females were 1.1, 2.0 and 5% respectively (348, 353, 362). Erden et al. (351) reported higher prevalence in males (3.7 vs. 1.9%), while Yildirim et al. (354) reported a higher prevalence in females (2.5%) compared with males (1.7%), which may indicate regional differences in the gender rates between Istanbul and Tokat.

Genotype
Genotype 1b is the most prevalent genotype in Turkey, with estimates ranging between 75.3 and 90% (349, 360, 368–370). The most recent estimates of genotype distribution come from a study in 345 patients with chronic HCV infection, and indicated that nearly all of the genotypes of HCV in Turkey are genotype 1 (97.1%), with genotype 1b as the major subtype (87.2%), followed by subtype 1a (9.9%), genotype 3 (1.4%), genotype 2 (0.9%) and genotype 4 (0.6%) (368). A study in 2004 in 365 persons found similar results, showing genotype 1 as the major genotype (95%), with genotype 1b as the major subtype (84%), followed by subtype 1a (11%), genotype 2 (3%), genotype 3 (1%) and genotype 4 (1%) (369). In 53 Turkish soldiers living in Cyprus, genotype 1b (97.1%) and 1a (2.3%) were the most prevalent (360). An analysis of Turkish patients who have lived in Europe for between 5 and 39 years and those who live in Turkey found a difference in subtype prevalence (349). In those who had lived in Europe for an extended period of time, genotype 1a was most prevalent (60%), followed by genotype 1b (20%) and 3a (20%). In those who lived in Turkey, genotype 1b was most prevalent (90%), followed by genotype 1a (10%) (349).

Summary
Overall, Turkey has a low prevalence of HCV infection, estimated to be around 1.0%. This is primarily because of the low rate of IDU and the early introduction of screening of blood donors. There may be regional differences in prevalence within Turkey, with higher rates reported in regions near the Black Sea compared with southeastern Turkey, although this varies between studies. The majority of chronic infections are genotype 1b, with estimates ranging between 75 and 90%.

UK
In 1990, the Health Protection Agency Centre for Infections in England and Wales (HPA) implemented a voluntary reporting system for laboratory-confirmed cases of HCV (371). Health Protection Scotland (HPS) also collects and reports the number of newly diagnosed cases of HCV infection annually (372). Additionally, both the HPA and the HPS have collected data on routes of transmission and genotype distribution throughout the UK. Both health agencies have also conducted thorough analyses of the epidemiological literature for their prospective countries and modelled the natural history of HCV infection to arrive at prevalence estimates for England, Wales and Scotland.

Risk factors
Approximately 20% of laboratory-reported cases in England and Wales from 1996 to 2007 (n=11 520) included information on risk factors (371). In excess of 90% of cases listed IDU as the risk factor for acquisition for infection, mostly males between ages 25 and 44. The reported risk factors included IDU (92.5%), transfusion (1.6%), blood products (0.9%), sexual exposure (1.4%), renal failure (0.6%) and vertical or household transmission (0.3%).
Similarly, HPS collects epidemiological data on individuals diagnosed with HCV in Scotland (373). Risk factor information was available for 12 522 persons (67% of all diagnosed) through 2004. Again, IDU was the most predominant risk factor, encompassing 90% of individuals reporting. Other reported risk factors were blood transfusion/blood products (5%), and occupational, tattoos, body piercing or sexual contact (5%).

Prevalence
The HPA in England and Wales created a model taking into account prevalence data from multiple population segments to estimate prevalence for HCV in the general population (371, 374). Population segments considered include IDUs, pregnant women, blood donors and anonymous serum specimens from Genitourinary Medicine clinics. Since 1986, the HPA has collected residual serum specimens for investigating the prevalence of many diseases, including HCV. The HPA's Bayesian model concluded that in 2003, there were 191 000 anti-HCV-positive individuals, aged 15–59, in England and Wales. This corresponds to a prevalence of 0.6% for this age cohort.
Similarly, HPS has undertaken a meta-analysis of published reports of HCV prevalence in various populations in Scotland (373). HPS estimates a prevalence of 1% for all of Scotland's population. As of 2006, 38 000 living people in Scotland were estimated to be infected with HCV (375).
A large number of studies demonstrate an elevated prevalence rate in the IDU population (376–386). Prevalence rates for pregnant women, blood donors, specimens gathered from clinics, as well as healthcare workers are represented in several studies conducted throughout the UK (382, 387–398).

Diagnosed/incidence
The ECDC reports the incidence of reported HCV cases for the UK (10, 11, 325). Although there is some variation in rates from year to year, incidence remains below 20/100 000 in this decade.
Laboratory-confirmed diagnoses of HCV infection are received from all regions in England by the HPA (371). From 1995 through 2007, a total of 59 938 cases, or 36% of the prevalent population, were diagnosed. There has been an increase in diagnosed cases annually almost every year during this time span, with 7540 reported cases in 2007. HPS also reports on an annual basis the number of newly diagnosed cases of HCV infection. In 2009, there were 2013 reported cases (372). As of 2006, 14 500 individuals, or 38% of the infected population, were already diagnosed in Scotland (375).

Genotype
The HPA implemented a Sentinel Surveillance Study of Hepatitis testing in 2002 to enhance routine surveillance of HCV (371). Twenty-three sentinel laboratories across England participated, providing laboratory test results and demographical data for all individuals tested. As part of a more focused review, genotype distribution and trends data from 10 sentinel laboratories were analysed. Using data from 2002 through 2007, 18 440 samples provided genotyping. Collectively, genotypes 1 and 3 represented 85% of all HCV disease in England. Specifically, the genotype distribution was as follows: 1 (45%), 2 (10%), 3 (40%) and 4 (5%). Although with smaller cohorts and more distant timeframes, other authors found remarkably similar results in genotype distribution in English populations (399, 400). Reported data from HPS and confirmatory testing laboratories in Scotland indicated a similar distribution in the Scottish population, specifically genotypes 1 (47%), 2 (5%) and 3 (47%) (373).
Findings from the Sentinel Surveillance of Hepatitis Study indicated that genotype 3 increased from 42 to 47%, and genotype 1 decreased from 45 to 42%, over the study time period (2002–2007) (371). Findings from all studies, indicating a high proportion of genotype 3 cases, are consistent with the risk factor distribution in the UK, which is heavily weighted to IDU.

Summary
Overall, the UK is considered an area with a relatively low prevalence of HCV infection (0.6–1.0%) depending on the region. New HCV infection in the UK is driven by IDU, the dominant risk factor stated in all the reviewed studies. The high prevalence of drug use in the UK will continue to drive up the prevalence of HCV for the foreseeable future unless or until effective prevention strategies are developed and implemented. It is important to recognize that IDU as a risk factor for acquisition of HCV does not equate to problem drug use. The highest risk of HCV infection is early in experimentation with drugs, where sharing ‘works’ is more common and there is limited exposure to harm reduction messages. There is no reliable evidence about the proportion of individuals who have used injection drugs at least once, who go on to become registered with a drug addiction treatment service. Many, if not the majority, of these individuals never develop a medically recognized drug problem. However, all the estimates of HCV prevalence are based on the size of the drug-using population and are derived from the numbers attending drug problems services. Thus, while the prevalence of HCV infection is high in drug problem treatment centres, probably the majority of those infected with HCV are not in such locations. Given the natural history of drug use in the UK, there is a large cohort of undiagnosed patients unaware of HCV or their infection with it, whose duration of disease places them at a high risk of developing cirrhosis or hepatocellular cancer. Another important factor in the HCV epidemic in the UK is the impact of immigration from countries with political and historical links to the UK, in particular former Eastern European countries and Pakistan, both areas of high endemicity. Given that drug use and areas of residence of immigrants are not uniformly distributed across, then we can assume that HCV infection is not uniformly distributed, with areas of high prevalence focused in cities, particularly in more deprived areas. Adding the problems of deprivation to the disease burden of HCV makes access and treating those affected by HCV even more difficult.

Discussion
Epidemiological data on HCV prevalence and risks factors for transmission are important to implement measures for prevention and HCV screening. Comparison of epidemiological data over time may allow some conclusions about the change of risk behaviours and the success of existing prevention or screening programmes.
We provide a comprehensive review of HCV epidemiology throughout Europe, Canada and Israel. The available data indicate a wide variation in HCV prevalence (Fig. 1) and differences in HCV transmission between countries. Prevalence data differences and dynamics within and between countries may sometimes be explained by local and regional variances in transmission routes or different public health measures. The lowest HCV prevalence (≤0.5%) estimates are from northern European countries, and the highest (≥3%) are from Romania and rural areas in Greece and Italy, as well as portions of Russia

Also, different surveillance systems among different countries may contribute to the varied findings. A publication by ECDC documented 38 different surveillance systems in 27 countries; six countries had more than one system (10). Surveillance systems vary by structure, reporting practices, data collection methods and the case definitions used (11), leading to variance in completeness and representativeness, which must be considered.
The true prevalence is likely to be higher since general population studies exclude high-risk subgroups like active IDUs, homeless, incarcerated and veterans. The HCV infection rate is substantially higher in these subgroups as illustrated by a recent study that showed that HCV prevalence among prisoners in Spain was 22.7% (401). Studies have shown that the overall prevalence is higher than national estimates when these subgroups are considered (402, 403).
We have to acknowledge that HCV prevalence describes, in most cases, anti-HCV positivity, which is not the same as the prevalence of chronic HCV infection. Fifteen to 50% of patients with acute HCV infection show clearance of HCV spontaneously (404–407). Thus, the exact prevalence of patients with chronic HCV is 15–50% lower. An exact number of HCV-infected patients is not possible. However, we estimate that 11.3–14.7 million adults in Europe, including all of Russia and Turkey, are anti-HCV positive.
Injection drug use has become the main risk for HCV transmission in countries with well-established HCV screening programmes of blood products and lower HCV prevalence. For example, in northern European countries such as Norway and Sweden, or in UK or Canada, IDU is the main risk factor for HCV transmission, accounting for more than half of HCV-infected patients (i.e. Norway 67%, Sweden 65%, Canada 58% and UK 90%).
Injection drug use as the main risk for HCV transmission is associated with some other findings such as younger age at the time of infection (i.e. HCV incidence peak in Canada 25–29 years (12)). Many studies in areas with IDU being the main risk factor for HCV transmission reported a higher male-to-female ratio in HCV-infected patients (i.e. 70% in Sweden). This may be explained by different risk behaviours between the genders. IDU is more frequent among males than females (54). However, a different male/female ratio can also be explained by other reasons. For example, MSM are at risk for sexual HCV transmission (408, 409). Spontaneous HCV clearance may occur more frequently in females because of an improved immune response (407). Interestingly, some reports from countries with low IDU prevalence show higher HCV prevalence in females. This may be explained by transmission via blood products (221).
Also, the distribution of HCV genotypes may be related to different routes of transmission, such as IDU. HCV genotypes 1a and 3 are associated with IDU-related infections, whereas HCV genotype 1b is related to transmission via blood products (6). Consistent with this suggestion, HCV genotypes 1a and 3 are more frequent in countries where IDU is the main reason for HCV infection (Table 3).

In some countries with increasing HCV prevalence over the last few years, the increase may be explained by a dramatic increase in IDU. For example, IDU was less frequent in former communist countries such as Russia, Poland and the Czech Republic, but for the past several years, the prevalence of IDU has exploded. This may help to explain the increasing HCV prevalence rates in Eastern European countries.
In a 2006 study from the Czech Republic, only 30% of IDUs were anti-HCV positive (30), increasing to 50% in a study published 1 year later (29). In line with these data, HCV genotype 1a and 3 prevalence increased from 23 and 3%, respectively, reported in a 2001 study (28), to 40.5 and 23.5%, respectively, reported in 2009 (26).
Although a study suggested that IDU as a risk factor is less important in Poland than in other countries (221), epidemiological data suggest that IDU may account for a significant number of HCV cases in Poland. HCV prevalence is higher in urban areas than that in rural areas. Male/female ratio is high (225), and finally HCV genotype 3 prevalence increased (240). Because HCV incidence has increased from 2000 until 2006, mainly in young males, this suggests an increase in HCV transmission via IDU.
Also in Hungary, we noted an increase in HCV genotype 1a infection, which may be explained by an increase in IDU (139, 140). However, IDU was reported to be infrequent in Hungary (136). In Russia, there has been an increase in HCV incidence over the last 10 years, especially in adults aged 20–40 (260), and some studies report a high prevalence of HCV genotype 3 infection (275, 276). Also in Russia, IDU as a risk factor has decreased in more recent reports, and unknown transmission routes increased to 30.6% (260). The patients may fear consequences when admitting drug use and thus the reported results may be biased. Male/female ratio and change of HCV genotype distribution clearly suggest an increase in IDU over the last few years.
As HCV incidence is still increasing in Eastern European countries, mainly because of an increase in IDU, there seems to be a decline in newly acquired HCV infections in western countries. The decline in HCV prevalence of individuals 20–59 years of age observed in France between 1994 and 2004 may thus be because of effective needle share programmes. For example, IDU as a risk factor for newly diagnosed HCV patients declined from 51% in 1997 to 31% in 2003 (55). Studies indicated that HCV prevalence may have declined among IDUs from 73% in a 2002 sample (410) to <60% in samples from 2004/2005 (37, 61). Also, France has established a comprehensive screening programme, which may be responsible for a decline in HCV prevalence. In a prevalence study, about 57% of anti-HCV-positive individuals already knew about their diagnosis. Importantly, >90% of current or previous IDUs had previously been diagnosed (37). Awareness of HCV infection is one of the most important prevention measures. Also in Canada, it is estimated that two-thirds of the HCV-infected population is already diagnosed (12). The HCV prevalence in Canada has been declining since 1998 (Table 1).
In Germany, the RKI, despite no general screening programme, has observed a yearly decline of approximately 10% per year (87). Methadone substitute programmes and increasing numbers of effectively treated patients may account for this change.
This is important information for all countries with increasing HCV prevalence mainly because of IDU. This may especially be important for the Eastern European countries. The number of active IDUs in the EU alone is estimated to be between three-quarters of a million and 1 million (136). However, detailed data from Eastern Europe are lacking.
Without effective prevention measures, HCV transmission occurs rapidly within the IDU population. Reports have shown that in individuals with not >1 year of IDU, 65% were anti-HCV positive (411). HCV prevalence among IDU patients can be as high as 90% (337). Thus, considering the increasing numbers in IDU, there is an unmet need for effective prevention measures with the IDU population, especially in Eastern Europe.
Countries such as Greece, Turkey and Romania with intermediate-to-high HCV prevalence may face different problems, especially in rural areas of the country. IDU is not yet the main cause for HCV transmission in rural areas with limited medical care. Contaminated syringes account for the majority of new HCV infections (115), resulting in high HCV prevalence rates (i.e. up to 10.9% reported for Crete (125), 7% for rural areas in Romania (247)). The main HCV genotype in those patients is 1b. It is interesting that HCV genotype 1a is more frequent among Turks living abroad (60%), where IDU may be the main risk factor compared with a higher prevalence of HCV genotype 1b (90%) in patients living in Turkey (349). The male/female ratio in HCV-infected patients in Turkey is almost 1:1 (348, 353, 362). IDU is suggested to account for only 4% of HCV-infected patients in Turkey (348–350).
Similarly, some parts of southern Italy show a high HCV prevalence mainly because of intravenous therapies with contaminated glass multi-use syringes (157, 159). And in Spain, hospital admission was among the most frequently identified transmission routes in multiple studies (281, 282). Increasing prevalence with age and no gender difference also indicate a historical basis for the transmission of HCV in these regions. However, a high rate of genotype 3 in Spain (280, 314) and a second prevalence wave identified in urban areas in Italy (201) implicate IDU as the primary risk factor of the future.
In those areas in which nosocomial infections are frequent, it is essential to implement high-quality sanitation protocols concerning equipment sterilization, washing and other hygiene measures to prevent further HCV transmission. However, even in countries with lower HCV prevalence, occupational HCV transmission occurs. For example, a German study analysed the route of transmission in 259 patients with acute HCV infection; 28% had been infected by medical procedures or needle stick injury (90).
Another important issue we have to face is immigration. Because of globalization and historical or political relations to countries with high endemicity, immigration will lead to an increase in the transmission of infectious disease. Immigration is a major issue in Israel, as 70% of current HCV-infected individuals were born in the former Soviet Union (151). In Switzerland, about one-third of the infected population was not born in Switzerland (346). Similarly, a large study from Germany reported that 37% of HCV patients had their origin not in Germany; most of the patients were German repatriates returning from the former USSR (88). In the UK, immigration in particular from countries with historical links and high HCV endemicity (India, Pakistan) has a major impact on HCV prevalence. Immigration will also lead to a change in HCV genotype distribution. An example is a high prevalence of HCV genotype 4 in Greece because of immigration from Africa (113). HCV screening for immigrants from areas with high HCV prevalence may be an option to improve diagnosis rates. It will be important that immigrants have access to the public healthcare system.
There are substantial gaps in the quality of data available across Europe (Table 4). Data on new infections are not available in each country, or the data gathered do not distinguish between acute and chronic infections. There are also little data available on the size of the diagnosed population. There is considerable variability among the type and quality of prevalence studies among the countries assessed. Countries like France, Germany and Romania have completed large population studies, although some were limited to urban populations, while others, like Canada and the UK, relied on modelling high-risk populations to estimate the total infected population size. However, there were also many countries that relied on studies in subpopulations to estimate the total prevalence in the country. Our research should help to identify major gaps in HCV epidemiology data by country and prioritize future research. Because many countries in Europe (e.g. Italy, Portugal, Spain, etc.) lack country-wide prevalence estimates–in part because of differences in healthcare delivery and a nationwide health statistics reporting system for HCV–we agree with ECDC recommendations for a harmonized EU-wide surveillance system. It will be important to implement high-quality surveillance programmes that distinguish between acute HCV infection and CHC. Furthermore, it would be beneficial to acquire data on HCV disease burden in those surveillance programmes. Adequate data will allow comparisons across the region, which will enable more accurate disease prevalence figures for planning purposes in the coming years

In summary, HCV epidemiology shows a high variability across Europe, Canada and Israel. Despite eradication of transmission by blood products, there is still an increase in HCV incidence in some countries. Continuous increase in IDU across Europe, especially in Eastern Europe, and immigration will lead to changes in HCV epidemiology. In countries with surveillance programmes and already established healthcare programmes, we observe a decline in HCV prevalence. Obviously, countries that collect data on HCV epidemiology used this information for implementation of prevention measures. Other countries with still increasing HCV incidence may learn from countries with already established programmes. HCV surveillance is the first step, followed by a country-specific HCV screening programme.

 Link To References;
http://onlinelibrary.wiley.com/doi/10.1111/j.1478-3231.2011.02539.x/references


 


Liver International

Special Issue: The global health burden of hepatitis C virus infection
Volume 31, Issue Supplement s2, pages 30–60, July 2011
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