Prevalence of hepatitis C infection among general population and high-risk groups in the EU/EEA: A systematic review update

Although significant improvement in efficacy measured by sustained virological response, the high acquisition costs of direct-acting antivirals limit the access for patients and influence the costs of health care resource utilization in hepatitis C. It is important to have the latest estimates of prevalence, especially in the high risk groups, for cost of illness, cost-effectiveness and budget impact studies. Original studies on the estimates of the prevalence among general and high-risk populations in the European Union/European Economic Area (EU/EEA) were retrieved from Medline and Embase for the period from 2015 to 2018. All included studies were evaluated for risk of selection bias and summarized together in narrative form. Results from previous reviews and the updated searches were compared per country among different populations, respectively. Among 3871 studies identified, 46 studies were included, with 20 studies used for the estimate for the general population, 3 for men who have sex with men (MSM), 6 for prisoners and 17 for people who inject drugs (PWID). Compared with the results reported in previous systematic reviews, the updated estimates were lower than previous ones in most available countries. Anti-HCV general population prevalence estimates ranges from 0.54% to 1.50% by country. The highest prevalence of anti-HCV was found among PWID (range of 7.90% - 82.00%) followed by prisoners (7.00% - 41.00%), HIV-positive MSM (1.80% - 7.10%), HIV-negative HIV status-MSM (0.20% - 1.80%), pregnant women (0.10% -1.32%) and blood donors (0.03% - 0.09%).

Our study highlights the heterogeneity in anti-HCV prevalence across different population groups in EU/EEA. The prevalence also varies widely between European countries. There are many countries that are not represented in our results, highlighting the need for the development of robust epidemiological studies.

Introduction
Infection with hepatitis C virus (HCV) leads to an asymptomatic acute stage. However, approximately 75% of acutely infected patients face substantial risk of developing chronic HCV infection [1]. During the two decades after infection, 27% develop liver cirrhosis and 25% develop hepatocellular carcinoma (HCC) [2,3].Worldwide, an estimated 71 million people were living with chronic HCV infection (1.0% of the global population) [4]. In the European Union/European Economic Area (EU/EEA), it was estimated that more than 14 million people were living with chronic HCV infection, suggesting a relatively higher prevalence of 1.5% in this region [4].
Given the slow rates of liver disease progression and peaks in transmission that occurred in the 1990s, many countries are yet to experience the full burden of HCV-related disease [5]. However, decades-long delay between infection and the expression of chronic liver disease or liver cancer made it difficult to link these diseases to earlier HCV infections.
Reliable and timely prevalence data is therefore important to describe the current burden of disease.
Most people infected with HCV remain unaware of their infection. The hidden burden estimated based on limited data from EU/EEA shows that less than 15% of those chronically infected with HCV are aware of their diagnosis [6][7][8]. An anti-HCV antibodies serology test is recommended as the first-line diagnostic test by European Association for the Study of the Liver (EASL) for HCV screening, which is evidence of past or current HCV infection [9]. If the result is positive, then current infection should be confirmed by a sensitive RNA test. Anti-HCV antibodies are detectable by enzyme immunoassay (EIA) in the vast majority of patients with HCV infection. In addition, rapid diagnostic tests (RDTs) are also recommended in settings where there is limited access to laboratory infrastructure and testing or populations where access to RDT would facilitate linkage to care [10]. The primary goal of diagnostic testing is to identify and link infected individuals to appropriate treatment. Several modelling studies suggest that scaling up HCV treatment can lead to substantial reductions in anti-HCV prevalence and reduce transmission [11][12][13][14]. The introduction of direct-acting antivirals (DAAs) has been a major breakthrough in the treatment of hepatitis C. However, the high acquisition costs of sofosbuvir-based regiments limit the access for patients and influence the costs of health care resource utilization in hepatitis C [15]. It is important to have the latest estimates of prevalence, especially in the high risk groups, for cost of illness, cost-effectiveness and budget impact studies.
We chose the most published reviews with high quality, according to an overview of systematic reviews on clinical burden of HCV infection [16]. We updated two previous systematic reviews undertaken respectively among general population [17] and high-risk groups [18] in 2015. In Europe, the high-risk groups for acquisition of HCV include people who inject drugs (PWID), men who have sex with men (MSM) and people in prison. We aim to update and expand the estimates for anti-HCV prevalence.

Objectives
The objective of the study is to update the anti-HCV prevalence (the serologic markers used as proxies for chronic infection in this study) among general population and high-risk population (MSM, prisoner, and PWID).

Date source and search strategy
Original research studies on the estimates of the prevalence among general and high-risk population in the EU/EEA were retrieved from Medline and Embase for the period from 2015 to 2018. The search strategy used was consistent with previous reviews [17, 18] and shown in additional file 1. The search terms covered the following domains: diseaserelated (HCV infection), outcome-related (anti-HCV/HCV RNA prevalence), and geographicrelated search terms (EU/EEA). Two separate searches were conducted: to maximize the yield of the search, no population-specific search terms were included among general population, MSM and prisoners. However, PWID-specific terms were included due to two reasons: The previous reviews didn't conduct literature database searching and the result of prevalence among PWID was only from European Monitoring Centre for Drugs and Drug Inclusion/exclusion criteria and data extraction Inclusion/exclusion criteria included population, outcomes of interest, study designs, publication timeframe, and geographical scope. Studies were included if they: 1) reported anti-HCV seroprevalence among general population, pregnant women, first-time blood donors, PWID, MSM, or prisoners; 2) measured the actual presence of viral markers (anti-HCV antibody in this study) in bodily fluid or dried blood spot samples in human subjects; 3) reported original data; 4) were published after 2015 to present among general population, pregnant women, first-time blood donors, MSM, or prisoners and published after 2009 to present among PWID; 5) reported outcomes in one or more EU/EEA member states or any of their regions. Studies were excluded if they 1)targeted non-representative populations, e.g. homeless, migrants, patients with specific diseases etc.; 2) didn't report specified serological markers, or reported study not conducted in humans or only selfreported/unconfirmed prevalence; 3) reported modelled or extrapolated data only, or opinion papers, editorials, guidelines or recommendations, correspondence articles, systematic reviews or meta-analysis; 4) were published out the targeted timeframe; 5) reported data on non EU/EEA countries only. More details on inclusion/exclusion criteria are shown in additional file 1.
The extraction form included year, country, population of the study, the sampling method, laboratory test used, participation rate, number of participants, and anti-HCV results. For studies reporting the prevalence in MSM, data on HIV sero-status was also extracted.

Quality assessment
Each included study was evaluated for risk of selection bias using frameworks developed by Hofstraat and Hahne et [17,18]. For studies among general population and prisoner, three domains were included: whether estimated were standardized by age and sex, the representativeness of sampling (e.g. random vs convenience sampling) and geographical coverage. For PWID and MSM studies, just one domain was included: geographical coverage. Points were awarded in each domain for a lower risk of bias, and a total score calculated by summing the values in each domain. An estimate among general population and prisoner was considered of high quality when it reached a study quality score ≥4. A high-quality estimate of prevalence in PWID and MSM was defined as a study quality score ≥1.

Data analysis
All included studies were summarized together in narrative form and in summary tables that tabulate the important description of the study population, recruiting period, results and study quality. According to the results of the systematic review previously performed, an algorithm was applied to different populations separately: If a single high quality prevalence estimate was available for a country, this was used. If a high quality estimate was not available, low quality estimates were used (these were pooled when possible).
Data per country were pooled according to standard error and sample size. Then 95% confidence intervals were calculated by estimated average and pooled sample size.
Results from previous reviews and the updated searches were compared per country among different populations, respectively.
Overall population were categorized into 2 groups: (1) general population, inclusive of mono-HCV infected patients with no recognized risk factors for reinfection (communities, screening participants, pregnant women, and blood donors); (2) high-risk populations, inclusive of HCV infected MSM, prisoner, and PWID. The majority of EU/EEA countries offer antenatal HCV screening and blood donors screening. These two subgroups among general population are the most complete population prevalence source and used as a proxy population [17]. However, we conduct separate analysis between pregnant women, blood donors and other general population because previous systematic review reported that they are not representative enough. . Some estimates among general population included exclusively multiple subgroups, overlapping with high-risk population. When pooled together, however, these subgroup data was excluded and pooled with relevant high-risk population based on the results of quality assessment.

Literature search retrievals
The search for data on anti-HCV prevalence in the general population, MSM and people in prison and PWID identified 2790 and 1081 citations, respectively. After title/abstract screening, 73 articles for the general population and 2 subgroups and 26 articles for PWID were included. Following full text screening of these 99 papers, 53 publications were considered not relevant. Finally, 46 publications were included in the review of prevalence data, with 20 publications used for the estimate for the general population, 3 for MSM, 6 for prisoners and 17 for PWID ( Figure 1). The results of quality assessment are shown in additional file 1.
Anti-HCV prevalence among general population in EU/EEA General population Anti-HCV general population prevalence estimates were found for 7 of the 34 countries in our review, ranging from 0.54% to 1.50% by country (Table 1). More than one estimate was available for 4 countries of 7 countries covered, with the most estimates for Spain (n=3). Eight high quality prevalence estimates from 5 countries (Czech Republic, Ireland, Italy, Portugal and Spain) were available. Multiple high quality estimates were available for a pooled estimate in Italy (n=2). Relatively high anti-HCV prevalence was found in Czech Republic (1.67%), Poland (1.50%) and Italy (1.37%).The estimate for Poland, however, is based one single study with low quality (score =2). The other article reporting the prevalence estimate on general female population in Poland was not pooled. Three estimates were available for Spain, of which only one was of high quality and reported an anti-HCV prevalence of 1.11%. One articles reported 1.14% in Callosa D'En Sarrià and Valencian Region. The other one reported 0.60% in general female population. Subgroup analysis was available for Italy and Poland. In Italy, the prevalence of HCV increased with age, from 0.2% in subjects born after the year 1984, to 4.2% in those born before the year 1935 (P < 0.01). The birth-cohort prevalence peaked (7.0%) in elderly (age > 70 years).
Age > 70 years, low education level, and cohabitation with an anti-HCV positive subject predicted the HCV positivity. In Poland, a higher prevalence was found in the population of post-reproductive age (age >45 years).

Pregnant women
An estimate of antenatal anti-HCV prevalence was found for 6 of the 34 countries in our review, ranging from 0.10% to 1.32% by country (Table 2). More than one estimate was available for the UK of 6 countries covered (n=2). Five high quality prevalence estimates from 5 countries (Poland, Slovenia, Spain, Sweden and the UK) were available. Only estimate of Italy was of low quality. Relatively high anti-HCV prevalence was found in Poland (1.32%) and Spain (0.55%). Relatively low prevalence was reported in the UK (0.10%). The other article reporting the prevalence estimate on Women who attended antenatal clinics in London (0.5%) was not pooled given to the potential geographic bias.
Subgroup analysis was available for the UK and Slovenia. In women born in the UK, prevalence increased with age. However, no statistically significant differences in anti-HCV prevalence between age groups (<20, 20-29 and ≥30 years) were observed in pregnant women in Slovenia.

Blood donors
An estimate of anti-HCV prevalence in first-time blood donors was available for only 2 of the 34 countries in our review, with Greece reporting 0.03% and Italy reporting 0.09% (Table 2). One low quality prevalence estimates for Greece and one high quality estimates for Italy were available. There is no subgroup analysis among blood donors available for both countries.
Anti-HCV prevalence among high-risk population in EU/EEA MSM An estimate of anti-HCV prevalence in MSM was found for 3 of the 34 countries in our review (Table 3). Furthermore, the MSM was divided into two categories: HIV-positive MSM and HIV-negative HIV status-MSM. The prevalence in HIV-positive MSM covered 3 countries, ranging from 1.80% (the UK) to 7.10% (Netherland). The other country, France, reported 5.10%. The prevalence in HIV-negative HIV status-MSM covered 2 countries, ranging from 0.20% (the UK) to 1.80% (France). Two high quality prevalence estimates from 2 countries (the UK and France) were available. Only estimate of Netherland was of low quality. Subgroup analysis was available for the UK and France. Higher prevalence was found in HIV-positive MSM, compared with that in HIV-negative HIV status-MSM.

Prisoner
An estimate of antenatal anti-HCV prevalence was found for 4 of the 34 countries in our review, ranging from 7.00% to 41.00% by country (Table 3). More than one estimate was available for the UK (n=2) and Portugal (n=2) of 4 countries covered. All estimates in prisoners were of low quality. All studies were single center in regional level, except the one in Portugal, which was multi center. Three studies reported ratio of sex with more males than females included. The other three studies didn't report ratio of sex. None of these 6 studies reported data on age. The studies in Portugal and Spain used exhaustive sampling in the included prison. Sampling method for the other studies was not reported.
Extremely high prevalence was found in Norway (41.00%). However, this estimate was from an single low quality study with a small sample size (n=62). There is no subgroup analysis among prisoners available for the four countries.

PWID
An estimate of antenatal anti-HCV prevalence was found for 13 of the 34 countries in our review, ranging from 7.90% to 82.00% by country (Table 4). More than one estimate was available for 4 of 13 countries covered, with the most estimates for the UK (n=3). Nine high quality prevalence estimates from 6 countries (Croatia, Hungary, Germany, France, Spain and the UK) were available. Multiple high quality estimates were available for a pooled estimate in the UK (n=3) and France (n=2). Relatively high anti-HCV prevalence was found in Sweden (82.00%) and Spain (72.00%). Relatively low prevalence was reported in the UK (36.50%) and Croatia (34.04%). However, the estimate in Spain was of low quality (score=0). One article in the UK covered the vulnerable population in London, including both PWID and prisoner. Based on the results of quality assessment (score=1), this result was also pooled into the estimate. Another article in the UK reported only subgroup prevalence based on the years when the subjects were born. However, the exact estimate of subjects who were born in the early 1990's was not available. Only estimates from the subjects born after 2000 were pooled. The article in the Croatia reported separated prevalence among PWID in the cities of Zagreb, Split and Rijeka. Data from the three cities in this article were pooled. The same situation came up in the Germany, separated prevalence estimates in native German and former Soviet Union migrants in the same article were pooled together. Subgroup analysis was available for 7 countries. In Hungary, Greece and Spain, the subgroups were based on different injection duration.
Anti-HCV prevalence increased 4-fold among new injectors (injecting < 2 years) from the data in Hungary. Anti-HCV prevalence in Greece has shown a reduction over time, but increases with age and therefore the length of time of drug use. In Spain, a large proportion of PWID were new injectors.

Comparison analysis
Pooled estimates by population and by country based on the results of quality assessment was shown in Table 5. Compared with the results reported in previous systematic reviews, our results updated the prevalence in Czech Republic, Poland, Portugal among general population, Sweden and Spain among pregnant women, Netherland, the UK and France among MSM, France, Spain, Germany, Sweden and Bosnia and Herzegovina among PWID.
Among general population, the updated estimates were lower than previous ones in most available countries. Significant decrease in anti-HCV prevalence was shown in Italy (1.37% vs 5.90%).
Except for Netherland (0.56% vs 0.10%) and Ireland (0.98% and 0.10%), prevalence increased. The same results were reported among high-risk populations, prevalence in most countries decreased, except for the estimates among PWID in Hungary (48.24% vs 24.10%).

Discussion
This is the first review to integrate and contrast prevalence estimates across general population and three key high-risk groups in the EU/EEA. Although gaps in evidence exist, Compared with previous estimates, the current estimates on prevalence among both general and high-risk populations decreased in the most available countries. The estimates of increased prevalence in Netherland and Ireland among general population and in Hungary among PWID, however, were all from single study. According to our results on quality assessment, the estimates in Ireland and Hungary were of high quality and the estimate in Ireland was from a big sample size (n=3795). Although the estimate in Netherland was also from a big sample size (n=6036), the total quality was assessed as low quality.
Estimates of prevalence obtained from blood donor and pregnant women were found to differ from general population an estimate, which is agreed with previous result that they are not a reliable proxy population to estimate prevalence in the general population. Anti-HCV prevalence in blood donor and pregnant women were found to be considerably lower, compared with general population estimates. Within countries, the prevalence of anti-HCV among MSM, prisoners and PWID were much higher than the corresponding prevalence in the general population. Of the high risk groups considered, PWID had by far the highest prevalence. .
The strength of this review is that it covers all general population and high-risk subgroups. The previous reviews, due to pragmatic reasons, extracted prevalence estimates for PWID from the data repository from ECDDA. It is possible that this data set is not exhaustive. In our review update, however, PWID-specific search terms were used to identify potential studies. We believe that the description provided gives a sufficiently thorough review of recently published anti-HCV prevalence estimates. With latest prevalence estimates, our study aim to contribute to the analyses in cost of illness, costeffectiveness and budget impact to optimize the health care resource utilization in hepatitis C management.
However, our study confirmed that there was an evidence gap on anti-HCV prevalence among lots of EU/EEA countries. This limitation of our study also provides idea for further research. In some countries, no national studies had been reported, thus local and reginal data were assumed to be reflective of the whole country. However, by assessing the methodological quality of the studies, this limitation can further mitigated.

Conclusion
This review emphasizes the heterogeneity in anti-HCV prevalence across different population groups in Europe. The prevalence also shows considerable diversity between EU/EEA countries. There are many countries that are not described in our results, emphasizing the existing need to develop robust epidemiological studies. Ethics approval and consent to participate Not applicable.

Consent for publication
Not applicable.

Competing interests
The authors declare that they have no competing interests.     Additional file.docx