This report is based on research conducted by the Oregon Evidence-based Practice Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No. 290-2007-10057-I). The findings and conclusions in this document are those of the author(s), who are responsible for its contents; the findings and conclusions do not necessarily represent the views of AHRQ. Therefore, no statement in this report should be construed as an official position of AHRQ or of the U.S. Department of Health and Human Services.
The information in this report is intended to help health care researchers and funders of research make well-informed decisions in designing and funding research and thereby improve the quality of health care services. This report is not intended to be a substitute for the application of scientific judgment. Anyone who makes decisions concerning the provision of clinical care should consider this report in the same way as any medical research and in conjunction with all other pertinent information, i.e., in the context of available resources and circumstances.
None of the investigators have any affiliation or financial involvement that conflicts with the material presented in this report.
People who inject drugs (PWID) are a key population affected by hepatitis C virus (HCV). Treatment options are improving and may enhance prevention; however access for PWID may be poor. The availability in the literature of information on seven main topic areas (incidence, chronicity, genotypes, HIV co-infection, diagnosis and treatment uptake, and burden of disease) to guide HCV treatment and prevention scale-up for PWID in the 27 countries of the European Union is systematically reviewed.
Methods and Findings
We searched MEDLINE, EMBASE and Cochrane Library for publications between 1 January 2000 and 31 December 2012, with a search strategy of general keywords regarding viral hepatitis, substance abuse and geographic scope, as well as topic-specific keywords. Additional articles were found through structured email consultations with a large European expert network. Data availability was highly variable and important limitations existed in comparability and representativeness. Nine of 27 countries had data on HCV incidence among PWID, which was often high (2.7-66/100 person-years, median 13, Interquartile range (IQR) 8.7–28). Most common HCV genotypes were G1 and G3; however, G4 may be increasing, while the proportion of traditionally ‘difficult to treat’ genotypes (G1+G4) showed large variation (median 53, IQR 43–62). Twelve countries reported on HCV chronicity (median 72, IQR 64–81) and 22 on HIV prevalence in HCV-infected PWID (median 3.9%, IQR 0.2–28). Undiagnosed infection, assessed in five countries, was high (median 49%, IQR 38–64), while of those diagnosed, the proportion entering treatment was low (median 9.5%, IQR 3.5–15). Burden of disease, where assessed, was high and will rise in the next decade.
Key data on HCV epidemiology, care and disease burden among PWID in Europe are sparse but suggest many undiagnosed infections and poor treatment uptake. Stronger efforts are needed to improve data availability to guide an increase in HCV treatment among PWID.
Citation: Wiessing L, Ferri M, Grady B, Kantzanou M, Sperle I, Cullen KJ, et al. (2014) Hepatitis C Virus Infection Epidemiology among People Who Inject Drugs in Europe: A Systematic Review of Data for Scaling Up Treatment and Prevention. PLoS ONE 9(7): e103345. https://doi.org/10.1371/journal.pone.0103345
Editor: Yury E. Khudyakov, Centers for Disease Control and Prevention, United States of America
Received: February 20, 2014; Accepted: June 29, 2014; Published: July 28, 2014
Copyright: © 2014 Wiessing et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: EMCDDA has funded this study through seven partial contracts with AH, MP, PV, JL, VH, and CM to carry out the tasks as specified for these authors in the author contributions. EMCDDA has coordinated and carried out the tasks in this study as specified for LW in the author contributions. LW had full access to all the data in the study and had final responsibility for the decision to submit for publication. Lucy Platt, Bethan Mcdonald, and Andrea Low are members of the EMCDDA DRID group who were partly funded by the Bill and Melinda Gates Foundation funded HIV Modelling Consortium to undertake a systematic review of HIV and HCV co-infection which fed into the co-infection review included here. The Bill and Melinda Gates Foundation funded HIV Modelling Consortium had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: Maria Emília Resende (MER) is an employee of Merck Sharp & Dohme and is a member of the EMCDDA DRID Group. MER provided support to Mário Martins, Domingos Duran and Graça Vilar, who are members of the EMCDDA DRID Group, in identifying studies on viral hepatitis in Portugal, but has not been involved in any way with the setting up, writing up of, or commenting on the study. There are no patents, products in development or marketed products to declare. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials.
Chronic infection with the hepatitis C virus (HCV) affects about 160 million people worldwide , . In developed countries, iatrogenic transmission of this blood-borne virus has been substantially reduced and people who inject drugs (PWID), or those who have done so in the past, are now the main group affected –.
HCV infection is a serious public health problem as chronically infected individuals are at risk for long-term sequelae, including liver cirrhosis and hepatocellular carcinoma . Indeed, in Europe, HCV is a leading cause of cirrhosis and primary liver cancer . Since 2001, effective treatment with pegylated interferon and ribavirin has been available. In recent years, there have been advances in treatment with the development of direct acting antiviral (DAA) therapy . PWID in many countries still have limited access to HCV treatment, despite multiple studies providing evidence that this population can be successfully treated – only 1–6% of HCV-infected current and former PWID in the United States, Canada, and Australia were treated –, –. The low uptake of treatment among PWID is due to both physician and patient-associated factors. Firstly, physicians’ concerns about adherence, other co-morbidities including HIV co-infection, treatment side-effects and the potential for re-infection may lead to treatment being withheld , , , . Secondly, poverty, psychiatric co-morbidities, poor social support and stigma are common among PWID and may result in HCV treatment not being viewed as a priority for them –. Other barriers may relate to educational level, problems with accessing diagnostic tests (e.g. in non-urban regions or when access to primary care is difficult), and entering specialist referral pathways , .
Treatment is likely to have a synergistic impact on HCV prevention efforts. Modelling studies suggest that antiviral treatment could play an important, and cost-effective, role in preventing HCV in PWID by reducing the number at risk of transmitting HCV –.
In Europe, many countries have implemented harm reduction programmes ,  as well as health insurance systems to cover treatment costs of PWID (several including DAA). Therefore, access to HCV treatment should be feasible ,  and recent European clinical guidelines state it must be considered for PWID . Although national treatment guidelines have varied substantially and have often been highly restrictive with regard to PWID , , the experience in some European countries has shown that it is possible to expand HCV diagnosis, prevention and treatment of PWID , , –. Key data elements to inform HCV treatment scale-up for PWID cover epidemiological data on the prevalence, dynamics and characteristics of the epidemic, estimates of future burden of disease and associated healthcare needs , –.
To assess data availability for informing a potential future scale up of HCV treatment (including ‘treatment for prevention’) among PWID in Europe, we performed a systematic review of the literature published between 2000–2012, covering the epidemiology of HCV infection, treatment uptake and estimates of the future burden of disease among PWID in European countries (the EU 27) to complement existing routinely collated data (for example on antibody prevalence and harm reduction service provision as collected by EMCDDA – see Table S2 in Web-appendix S1) , , , . Most of these data might be equally important to informing overall HCV prevention policies. (Further detail on the rationale and importance of these data for HCV treatment and prevention policies is given in Table 1 and Discussion, while Table 2 summarises what this study adds to current knowledge.).
Our overall research question was: ‘What data is available in European Union countries to inform a potential scale-up of HCV treatment (for prevention) among PWID?’ This was operationalised into five specific questions, covering seven topic areas, all limited to HCV infection among PWID in Europe:
- What is the incidence of infection?
- What proportion of infections become chronic?
- What are infection characteristics, in terms of genotypes and HIV co-infection?
- What proportions of infected are undiagnosed and, of those diagnosed, enter antiviral treatment?
- What estimates exist of the future burden of disease?
Seven separate systematic reviews of the literature were performed, covering HCV incidence, chronicity rates, genotype distribution, HIV co-infection, undiagnosed chronic hepatitis C (CHC) cases, HCV treatment uptake, and burden of disease. Study references were identified through searches of MEDLINE, EMBASE and the Cochrane Library databases for articles published in any language between 1 January 2000 and 31 December 2012. A standard search strategy was agreed (Web-appendix S1) with general keywords regarding viral hepatitis, substance abuse and geographic scope (Table 3), as well as seven search strings with topic area-specific keywords. Additional articles were found through structured email consultations with a large European expert network (on substance use and infectious diseases, including viral hepatitis (see Acknowledgments)) covering each of the 27 countries (Table 4). The protocol was consistent with the PRISMA criteria . Search results per topic area were screened for relevance independently by two researchers on the basis of title and abstract and results compared, retaining articles in case of doubt. Duplicates between the three databases were removed. The remaining articles were retrieved and evaluated independently by two researchers on the basis of the full article text using agreed selection criteria across all seven topic areas. Studies were included for the 27 EU member states. Non-English articles were evaluated with the help of native speakers, country experts and online translation services (Google Translate and BabelFish) and if necessary and possible by contacting the authors. Additional inclusion criteria were reporting data collected since 1990 (except for Burden of disease, due to the long-term perspective of modelling projections). Quality criteria for inclusion (Web-appendix S1) were to have a clearly defined study population of PWID only (having ever injected drugs) or data provided for PWID separately, consistency and clarity of the data reported and an unselected sample of PWID with regard to gender or HBV/HIV co-infection (except for Burden of disease, where due to the small number of studies found, two studies based on HIV co-infected samples were included). Sample sizes below n = 10 were excluded except if they provided the only data for a country on a topic area. For articles excluded in this phase the reasons for this were noted. Data were extracted from the remaining articles into tables for each of the topic areas (Tables S3–S10 in Web-appendix S2) and the reference lists were checked for further studies. Multiple publications for one study were consolidated and treated as one entry, in order to maximise information available per study. Data were presented untransformed (Incidence, Burden of disease) or, where possible, pooled weighted prevalences (median, average, range in %) were calculated per country (Chronicity, Genotypes, Co-infection, Diagnosis, Treatment entry) and study type/setting (Incidence, Chronicity, Diagnosis, Treatment entry). Data availability per country was crudely assessed by the number of (out of seven) topic areas where data were available (Table 4). For Genotypes the sum of the proportions of ‘difficult to treat’ genotypes (1 and 4) , ,  is presented (Table 4). For Co-infection the correlation was assessed with HIV prevalence. Overall, a meta-analysis was considered outside the scope of this review, although for one topic (Chronicity) a limited analysis was performed (Web-appendix S3).
Table 4. HCV infection among people who inject drugs in the European Union - availability by country of key data to scale up antiviral treatment (figures that include data since 2006 (inclusive) are shown in bold and figures not included in the final analyses are in square brackets ).
Overall the systematic search retrieved 2,955 references to publications. After removal of duplicates and clearly irrelevant references, we screened 1,552 references on the basis of title and abstract. 528 articles were retrieved and obtained in full text, of which 144 were included in the quantitative synthesis. The step-wise description of selection and inclusion of studies is depicted in a flowchart in Figure 1. Followed below are detailed study questions, main findings and results for each of the seven topic areas reviewed.
What is the incidence of HCV infection among PWID in Europe and how has this been measured? How does incidence vary between countries?
Data are sparse across Europe and are not easily comparable. The data suggests that incidence is highly variable in the populations studied (Figure 2).
Studies were included that had directly measured incidence of hepatitis C infection in PWID, by using one of the following approaches: 1) a cohort or follow-up study 2) detection of HCV RNA in the absence of anti-HCV in a cross-sectional study 3) assessing anti-HCV avidity in a cross-sectional study. Studies that had indirectly estimated incidence from HCV prevalence data, for example using force of infection calculations, were excluded. 27 studies, from nine countries, reported the incidence of primary HCV infection (Czech Republic, Denmark, Ireland, Finland, France, Netherlands, Sweden, Spain, UK; Table 4). Four countries had undertaken more than one (Czech Republic, Ireland, Sweden, UK); most studies had been undertaken in UK (n = 16, 59%). Three studies measured re-infection (Germany, Netherlands, UK; Table 4) (Table S3 in Web-appendix S2). –.
Incidence of primary HCV infection had been measured in 17 follow-up studies, and in ten cross-sectional studies (nine used HCV RNA in the absence of anti-HCV and one anti-HCV avidity to estimate HCV incidence).
For primary HCV infection, three studies recruited PWID from community settings, 19 through health services (including needle and syringe programmes) and three from both settings. Two were in custodial settings. The re-infection studies were in clinical settings.
The number of PWID at risk of primary infection in studies undertaken outside of custodial settings ranged from 27 (Spain, ‘new PWID’: injecting less than 2 years)  to 2,532 (UK, ‘ever PWID’: having ever injected drugs) ; (median:168 people; mean 424). The measured incidence of primary HCV infection varied from 2.7–3.2/100PY in one UK study (ever PWID)  to 66/100PY in a study from Ireland (ever PWID) . The median incidence was 13/100PY (Interquartile range (IQR) 8.7–28, mean 19/100PY). In the eleven studies only including current/recent PWID the incidence was higher than in the remaining studies (median 26/100PY IQR 9.4–35 vs. median 12/100PY IQR 9.0–16), and ranged from 5.2/100PY years to 42/100PY (both UK) , . The two studies in custodial settings were small, with only eight (25/100PY, Denmark, ever PWID)  and 69 (12/100PY, UK, ever PWID) ,  participants. The three small studies of HCV re-infection reported incidences of 6.9/100PY following a negative HCV RNA test result (N = 347, UK, ever PWID) , 3.4/100PY (N = 11, Netherlands, ever PWID)  and 0–4.1/100PY following treatment induced viral clearance (N = 18, Germany, ever PWID) .
What is the prevalence of chronic HCV infection among anti-HCV positive PWID in Europe? How does chronicity vary by setting, demographics, duration of injecting, and co-infection status?
Twenty-seven studies met the inclusion criteria , , – from fourteen countries (Table 4). These investigated the prevalence of HCV-RNA in 28 populations which included 10,263 anti-HCV positive PWID. Three additional studies were included that investigated the development of chronic infection in 98 PWID acutely infected with HCV –. (Table S4 in Web-appendix S2).
Nine cohort studies , , , , , , –, and 21 cross-sectional studies tested HCV-RNA using PCR as a marker for chronic infection , , –, , , , –, , , , .
PWID were recruited in drug treatment centres, general practices, gastroenterology and hepatology units, infectious diseases and genitourinary medicine clinics, and in the community.
The level of chronic infection in anti-HCV positive PWID ranged between 53% and 97% with a median of 72% (IQR 64–81%). The proportion of acute HCV infections among PWID progressing to chronic infection varied between 0% and 56%.
Based on seven studies with mean age , , , , , ,  and four studies with mean duration of injecting drug use of the anti-HCV positive PWID , , ,  a significant positive linear relation was observed between chronicity rate and both mean age of the population (Regression coefficient = 0.14; 95% CI: 0.00–0.28; P = 0.046) and mean duration of injecting drug use (Regression coefficient = 0.18; 95% CI: 0.02–0.34; P = 0.026). Based on the results of three studies , ,  a significant relationship between HIV-co-infection (OR 1.67, 95% CI 1.07–2.60; P = 0.0025) and chronicity rate was observed. Based on the results of five studies a statistically significant association was found between male gender (OR 1.64, 95% CI 1.06–2.55; P = 0.016) , , , ,  and chronicity rate. Only two studies had examined variation in the prevalence of HCV chronicity by HBV serostatus, and found no association (OR 0.99, 95% CI 0.63–1.57; P = 0.978) , . Furthermore, the pooled average chronicity prevalence in the studies conducted in gastroenterology or hepatology units (84%, 95% CI: 74–91) was significantly higher than in the studies conducted in other settings (71%, 95% CI: 67–75) (Q-value = 5.292; df = 1; P< 0.021). Finally, no geographic trends could be detected.
What is the genotype distribution in PWID in Europe, and is it changing over time? What is the proportion of traditionally ‘difficult to treat’ genotypes (1 and 4)?
HCV genotypes 1 and 3, (subtypes 1a and 3a), are the most commonly identified among PWID in Europe. Genotype 4 may be increasing. The proportion of the more ‘difficult to treat’ genotypes (1+4) showed large variation (17–91%, median 53%, IQR 43–62%).
43 studies met the inclusion criteria. Data were available from 20 European countries , , , , –, , , , , –, , –. (Table 4, Figure 4 and Table S5 in Web-appendix S2).
Eighteen cohort and twenty-five cross-sectional studies. HCV infection was mainly confirmed by enzyme immunoassays, immunoblot assays and RT-PCR. HCV genotypes/subtypes were determined by reverse hybridization assay and restriction fragment length polymorphisms (RFLPs) assay, sequencing and other PCR-based methods.
A total of 6,488 HCV-infected PWID were genotyped or subtyped (range of subjects: 11–865). PWID were: a) enrolled in drug treatment, screening or national survey programs, b) regularly monitored in drug treatment centres, or c) hospitalised in or referred to specified units.
HCV subtype 1a dominates in Portugal , Spain ,  and The Netherlands , , while it is also common in the Czech Republic  and the UK , , . HCV subtype 1b prevails in Bulgaria , Czech Republic , Estonia  and Romania .
HCV genotype 2 is relatively uncommon with the exception of Greece , , Lithuania , Sweden  and the UK , , . Genotype 3 predominates in Greece , , , , , Poland  and Slovenia  and is common in Austria , Belgium , France ,  and Italy , . Subtype 3a dominates in Belgium , Cyprus  and France , . In Ireland, HCV genotypes 1 and 3 are equally distributed (48%) .
Levels of genotype 4 are particularly high in Southern European countries (Greece , , , Italy , , Portugal  and Spain , ) compared to Western ones (France , , Belgium ,  and The Netherlands , . The lowest rates of genotype 4 were reported in Lithuania , Sweden , Czech Republic , , and UK , ). Genetic diversity of genotype 4 suggests that this genotype is emerging among PWID and among the general population (e.g. 4a in Portugal  and Germany , , 4d in Portugal  and The Netherlands  and 4f in Italy ). Overall, the proportion of ‘difficult to treat’ genotypes (1+4) varies strongly, from 17% in Lithuania to 76–91% in the Czech Republic (Table 4) with a median of 53% (range 17–91%, IQR 43–62%).
Increasing levels of mixed infections are observed, by either different HCV genotypes (Italy 1b/3a , Germany 2a/3b  and Sweden 1a/2b, 1b/2a, 1a/4, 1b/2b ) or different subtypes of the same genotype (Spain 2a/2c and 4c/4d , Belgium 4c/4d , The Netherlands 2a/2b , and Sweden 2a/2b ). This is most likely due to the implementation of newer line probe assays with higher capability in detecting HCV subtypes.
What is the prevalence of HIV among PWID with HCV infection (HIV-HCV co-infection prevalence) in Europe?
Available data for 22 countries in Europe suggest considerable variation in the HIV-HCV co-infection prevalence (0–70%, median 3.9, IQR 0.2–28) among PWID (Table 4, Figure 5), with this being correlated (correlation coefficient = 0.98) with the HIV prevalence among PWID, but generally a median of 15% (IQR 0.0–49%) relatively greater.
Sixty-two studies , , , , , , , , , , , , , , , , , , , , – met the inclusion criteria giving 80 HIV-HCV co-infection estimates. (Table S6 in Web-appendix S2).
Studies either involved diagnostic testing or cross-sectional samples of PWID from a variety of settings involving different sampling methods such as respondent driven sampling, exhaustive sampling and snowball sampling. HCV infection status was not confirmed by RNA status in many studies and so antibody prevalence was used across all studies.
PWID were recruited from drug treatment centres, opiate substitution treatment centres, needle and syringe programmes, hospitals, and prisons.
Many European countries had multiple estimates of HIV and HCV prevalence but few recorded HIV-HCV co-infection prevalence (HIV prevalence among HCV antibody positives). Estimates of HIV-HCV co-infection prevalence were available for 22 countries in Europe with thirteen countries having multiple estimates (Belgium, Czech Republic, Denmark, France, Germany, Greece, Hungary, Italy, Latvia, Poland, Slovenia, Spain and UK). The HIV-HCV co-infection prevalence ranged between 0% and 70% in the different countries (median 3.9, IQR 0.2–28). Co-infection prevalences were low (< = 4%) in 11 countries (Austria, Bulgaria, Cyprus, Czech Republic, Denmark, Greece, Hungary, Luxembourg, Romania, Slovenia and UK), moderate (4 to 15%) in three countries (Belgium, Germany and Lithuania) and high (>15%) in eight countries (Estonia, France, Latvia, Italy, Netherlands, Poland, Portugal and Spain). As expected the HIV-HCV co-infection prevalence is higher in settings with higher HIV prevalence, with a strong linear correlation existing between each survey’s HIV prevalence estimate and the corresponding HIV-HCV co-infection prevalence estimate (correlation coefficient = 0.98), with the HIV-HCV co-infection prevalence being a median of 15%(IQR 0.0–49%) relatively greater than the HIV prevalence. No clear relationship existed between HCV prevalence and the HIV-HCV co-infection prevalence.
What percentage of HCV-infected PWID are undiagnosed in Europe?
Ten cross-sectional studies and one retrospective cohort study. All studies were observational and performed in non-clinical settings.
Ten studies among PWID in specialised treatment centres and other drug services, one study among PWID attending general practices.
The proportion of infections in PWID that were previously undiagnosed ranged from 24% to 76% with a median of 49% (IQR 38–64%, n = 13,561).
What is the proportion entering antiviral treatment among diagnosed cases of chronic HCV infection in PWID?
In six observational studies with non-clinical recruitment settings, the proportion of PWID diagnosed with chronic HCV infection that started antiviral treatment was generally low, at 1–19% (median 9.5, IQR 3.5–15) (Table 4, Figure 7).
Twenty-six studies from 11 countries fulfilled the inclusion criteria , , , , , , , , , , , , , , – (Table 4 and Table S8 in Web-appendix S2).
Eight were retrospective cohort studies; 11 were prospective cohort studies; one a randomised controlled trial; one a semi-experimental intervention study and five were cross-sectional studies. Overall, 16 were observational, whereas 10 were intervention studies (one study included both observational and intervention data).
PWID were either patients attending hospitals or specialist services for hepatitis treatment (‘clinical’ – eight studies), or recruited through PWID specific services, general practice and/or community settings (‘non-clinical’ – 18 studies).
The proportion of PWID with diagnosed chronic infection entering antiviral treatment was 1–19% (median 9.5, IQR 3.5–15) in six non-clinical observational studies (four countries, total sample size 3,017) , , , , , . An increasing proportion is seen by setting and study type with progressively selected study populations, with a median of 23% (IQR 17–31) in nine intervention non-clinical studies, 28% (IQR 24–42) in seven observational clinical studies , , , , , ,  and 47% in one intervention clinical study . Four studies with non-clinical recruitment settings provided a proportion of antibody positive PWID self-reporting having ever been treated, with a median of 4.7% (3.4–37, IQR 4.3–13, n = 868) , , , . Three observational studies with non-clinical recruitment settings provided the proportion of diagnosed PWID referred to a specialist for treatment evaluation (median 57%, range 9.0–59) , , as did four intervention studies in non-clinical settings (median 59%, range 21–93, IQR 40–78) , , , .
Burden of disease
What estimates exist of the future burden of disease among PWID with HCV in Europe?
The crude mortality rate (CMR) for all-cause mortality ranged from 2.1–12 cases /100PY. Modelling studies project an increase in the burden of liver disease. HCV treatment could reduce this burden and is cost-effective (Table 4).
All cohort studies had a prospective design and one also included retrospective data. Study settings varied from single centre to nationwide.