Infection with hepatitis B and C virus in Europe: a systematic review of prevalence and cost-effectiveness of screening

For both systematic literature searches, data were extracted using a data-extraction form by two authors (SH and IV). For the prevalence search, the form included year, country population of the study, the sampling method, laboratory test used, participation rate, number of participants, and HBsAg and anti-HCV-Ab results. For the cost-effectiveness search, the form included year and country of study, target population for screening, screening scenario, type of model used, outcome measure(s) used, monetary value and year, discounting percentage (costs/effects), results, and conclusions. The quality of the prevalence studies was assessed by reviewing the representativeness of sampling (eg, random vs convenience sampling) and, for the general population, whether estimates were standardized by age and sex.

Prevalence estimates were summarized by country. When multiple general population prevalence estimates were available for one country, we used the estimate that was most representative for the entire country regarding demographic coverage. In case multiple representative general population prevalence estimates for one country were found, the average prevalence was calculated weighted by study size. Where estimates for 3 or more regions in a country were available, regional estimates were presented only when the difference between regions was more than 0.5%. Countries were grouped into low, intermediate, and high HBsAg and anti-HCV-Ab prevalence using cut offs of ≤ 1%, > 1% to ≤ 2%, and > 2%. On the basis of prevalence estimates in the general population for infection with HBV and HCV and 2009 population size [36], we estimated the total number of people in that country who would likely test positive for HBsAg or anti-HCV-Ab. Search terms used for both searches are available in Additional file 1. The methods of our systematic literature reviews and their reporting are consistent with those recommended by the PRISMA statement and specified in advance in a protocol that is available from the corresponding author on request [37].

HBsAg general population prevalence estimates were found for 13 of the 34 countries in our review, ranging from 0.1% to 5.6% by country (Figure 1a, Table 1). The estimated number of people with chronic HBV infection ranged from 3,718,889 in Turkey to 4,466 in Ireland (Table 1). Prevalence estimates of anti-HCV-Ab in the general population were found for 13 of the 34 countries in our review, ranging from 0.4% to 5.2% by country (Figure 1b, Table 2). The estimated number of people who were anti-HCV-Ab positive ranged from 3,122,779 in Italy to 37,025 in Sweden (Table 2). For only a minority of countries (9/34) information was available on both estimates. Countries in the north-western part of Europe had a low prevalence for both infections whilst those in the south and south-east had an intermediate to high prevalence (Additional file 3: Figure S2).

HBsAg prevalence estimates for first-time blood donors were found for 24 countries, ranging from 0.0% to 5.2% (Additional file 3: Figure S3.1a, Additional file 4: Table S3.1.a). Anti-HCV-Ab prevalence estimates for first- time blood donors were available for 23 countries, ranging from 0.02% to 3.3% (Additional file 3: Figure S3.1b, Additional file 4: Table S3.1.b). The prevalence of HBsAg and anti-HCV-Ab in first-time blood donors was on average respectively 3 and 4 times lower than the corresponding prevalence for the general population in countries that had both estimates available (12 countries for HBsAg and 11 for anti-HCV-Ab).

Estimates of antenatal HBsAg prevalence were found for 11 countries, ranging from 0.1% to 4.4% (Additional file 3: Figure S3.2a, Additional file 4: Table S3.2.a). Estimates of antenatal anti-HCV-Ab prevalence were found for 6 countries, ranging from 0% to 1.7% (Additional file 3: Figure S3.2b, Additional file 4: Table S3.2.b). The antenatal HBsAg prevalence was on average 3 times higher than the general population prevalence in 6 of the 7 countries that had both estimates available. The country where it was lower was Spain (based on regional data from Catalonia), likely reflecting the effect of the HBV vaccination programme for adolescents. In Italy and the United Kingdom, the antenatal anti-HCV-Ab prevalence was lower than the general population prevalence. In Germany and Greece, it was higher.

An estimate of HBsAg prevalence in PWID was available for 21 of the 34 countries in this review, ranging from 0% to 21.3% (Additional file 3: Figure S3.3a, Additional file 4: Table S3.3.a). An estimate of anti-HCV-Ab prevalence in PWID was available for 29 of the 34 countries, ranging from 5.3% to 90% (Additional file 3: Figure S3.3b, Additional file 4: Table S3.3.b). The HBsAg prevalence in PWID was on average 9 times higher than that in the general population (in 6 of the 8 countries that had both estimates available). In Romania and Ireland, the general population HBsAg estimate was higher. The estimate of anti-HCV-Ab prevalence in PWID was on average 47 times higher than that in the general population (in 13 countries that had both estimates available).

Estimates of HBsAg prevalence in migrants were found for 5 countries. The HBsAg prevalence in migrants ranged from 1.0% to 15.4% (Additional file 4: Table S3.4.a). Estimates of anti-HCV-Ab prevalence in migrants were found for 5 countries, ranging from 0% to 23.4% (Additional file 4: Table S3.4.b). The estimate of HBsAg and anti-HCV-Ab prevalence in migrants was on average respectively 6 and 2 times higher than that in the general population in all countries that had both estimates available (4 countries for HBsAg and 4 for anti-HCV-Ab), except for Italy, where the estimate of anti-HCV-Ab prevalence in migrants was lower than that in the general population.

Estimates of HBsAg prevalence for MSM were found for 3 countries, ranging from <1% to 4% [38‐41]. Estimates of anti-HCV-Ab prevalence among MSM were available for 3 countries, ranging from 0.07% to 2.9% [41‐43]. The HBsAg and anti-HCV-Ab prevalence in MSM was on average respectively 22 and 3 times higher than that for the general population in all countries that had both estimates available (2 countries for HBsAg and 1 for anti-HCV-Ab).

One economic analysis of HBsAg screening of the general population (considering in the base case 35 year old males with a 2% prevalence) found this was cost-effective (incremental cost-effectiveness ratio (ICER) €23.966/quality adjusted life year (QALY)) [47]. Six studies reported on HCV screening and subsequent treatment of the general population [48‐53]. Two of these reported costs per LY gained, both concluding HCV screening of the general population was cost-effective [48, 50]. Four studies, all from the USA, assessed general population HCV screening by estimating cost per QALY gained [49, 51‐53]. All studies except one [49] concluded general population HCV screening of adults was cost-effective.

Five economic analyses reported on antenatal HBsAg screening [54‐58], presenting estimated costs per LY gained [54‐56], costs per case detected and per infant carrier prevented [57] and costs per case detected [58]. The 3 studies presenting costs per LY gained studied the scenario of universal screening of all pregnant women, with vaccination of infants born to HBsAg positive mothers. Studies were published between 1993 and 1997, and none considered antiviral treatment. ICERs ranged from €2,032 to €26,181 per LY gained. All studies concluded that universal antenatal HBV screening is cost-effective considering the respective thresholds used. One economic analysis of antenatal HCV screening was found, which considered universal antenatal HCV screening and treatment of HCV infection with or without elective cesarean delivery [59]. Neither of these scenarios was considered cost-effective.

No economic analysis of HBsAg screening of PWID was found. Ten studies reported on cost-effectiveness of HCV screening and treatment of PWID [43, 46, 48, 60‐66]. Seven of these reported estimated costs per QALY. These studies varied widely, including different screening settings, treatments considered, and discount rates. Nevertheless, all 7 studies concluded that HCV screening of PWID was likely to be cost-effective considering the respective thresholds used, with ICERs ranging from ─ €3.328 to €41,874 per QALY.

Four economic analyses of screening migrants for HBsAg were found [67‐70]. One of these compared 4 community outreach screening programs by assessing cost per person screened and cost per HBsAg positive individuals identified, concluding that screening in outpatient settings was the most cost-effective but reached the lowest number of participants [69]. The 3 other studies assessing cost per QALY all concluded migrant screening was cost-effective, with ICERs ranging from €8.694 [68] to €46.260 [70]. One economic analysis of HCV screening of migrants was found [66]. In this study, the target group for screening included migrants from countries with a HCV prevalence >10%, as well as from other population subgroups. Separate estimates of cost-effectiveness of screening migrants were, however, not presented.

We found no economic analysis of HBsAg screening of MSM. One economic analysis of HCV screening of MSM at sexually transmitted disease (STD) clinics concluded that HCV screening of MSM in this setting was not cost-effective [43].

We did not find any economic analyses of HBsAg screening of STD-clinic attendees, but 2 of HCV screening of STD-clinic attendees [46, 64]. Universal screening and treatment of UK STD-clinic attendees was assessed as not cost-effective (ICER €125,933/QALY) [46, 64]. Among STD-clinic attendees in the US, HCV screening of non-PWID was only cost-effective when restricted to men with >100 lifetime sex partners [64].

No economic analyses of HBsAg screening of prisoners were found. Regarding HCV screening of prisoners, we found two studies both from England and Wales [71, 72]. The first study found that asking prisoners about their HCV and injecting status prior to laboratory testing can considerably reduce the cost per case detected [71]. The second paper found that HCV screening and treatment of prisoners was not cost-effective (cost per QALY €78,498) [72].

One study assessed HBsAg screening of high-risk groups currently recommended for screening in Italy as cost-effective [73]. However, no costs for the screening programme were taken into account and compliance was set at an unrealistic 100%. Five economic analyses of HCV screening of other population subgroups were found [48, 50, 63, 65, 66, 74]. Both studies that considered screening programmes targeting several population subgroups concluded that the specific programmes considered were potentially cost-effective [50, 66]. Josset et al. reported estimated costs per positive test result for 6 screening scenarios, which varied regarding population subgroups targeted [63]. Analyses of HCV screening of people transfused before 1991 in France and of people with a history of surgery in Italy both concluded this was not cost-effective [48, 65].

The search for evidence on cost-effectiveness of screening was consistent with the prevalence review: For all three population subgroups with evidence of increased HBV and HCV prevalence compared to the general population (PWID, MSM and migrants) economic analyses of screening were found. This resulted in evidence that HCV screening of PWID and HBsAg screening of pregnant women and migrants are cost-effective interventions to reduce the burden of disease due to viral hepatitis. HCV screening of pregnant women and comprehensive screening of all STD-clinic attendees is probably not cost-effective, although there may be exceptions for some specific local or subpopulation conditions. General population screening for HCV was found cost-effective in the US ‘baby-boom generation’ (born 1945–1965). For other programs, including HBV screening of PWID, HCV screening migrants, HBV and HCV screening of prisoners and MSM, the evidence found in this systematic review was insufficient to draw conclusions.

The strongest evidence regarding cost-effectiveness was available for HCV screening of PWID. The wide range in ICER estimates may be partly explained by differing definitions of PWID, whereby some studies may include former PWID. It is unclear to what extent PWID in Europe are offered HCV screening and are successfully referred once found to be positive. HCV screening programmes for PWID exist in only 16 of the 29 European Union/European Economic Area countries reviewed in 2009 [26] whereby testing coverage and referral to treatment often remain poor [78]. On the other hand, several countries without screening programmes report adequate HCV testing of PWID [79]. This apparent discrepancy may be explained by a lack of definition of what a screening programme entails and/or the possibility that the 2009 review has missed screening programmes of PWID. Nevertheless, optimizing implementation of testing guidelines for PWID and monitoring of this group are among the highest priorities [80, 81].

Regarding HBsAg screening of pregnant women it is likely that it would be even more economically favourable if antiviral treatment of the mother was considered. European countries that currently have selective or no antenatal HBsAg screening programmes, including Bulgaria, Lithuania, Luxembourg, Romania, and Norway, should consider implementing universal antenatal screening [26]. This holds even if these countries have universal infant HBV-vaccination programme with an at-birth dose of vaccine, since prevention of perinatal HBV transmission requires the first dose of vaccine to be given within 24 hours and a very high uptake of vaccination. In addition, providing hepatitis B immunoglobulin is of additional effectiveness [82, 83].

The four publications examining HBsAg screening of migrants born in endemic countries (HBsAg prevalence ≥ 2%) suggest this is cost-effective. Main determinants of ICER were the proportion of eligible people starting treatment, disease progression rates with and without treatment, and costs of treatment [67, 68]. Further research should focus on these areas of uncertainty, as well as on how to optimize participation in screening and referral pathways [69, 84]. Given that HCV could be tested using the same blood sample and that migrants generally have higher HCV prevalence than the indigenous population in European countries, an economic assessment of combined HBV/HCV screening for migrants is a priority [85, 86].

The only study found that considered general population screening for HBsAg [47], suggested this would be cost-effective in populations with a prevalence above 0.3%. This includes nearly all European countries. However, the study considered only men, included no costs for the screening programme (except for a blood test and consultation) and made unrealistic assumptions regarding compliance with treatment. The evidence for general population HBsAg screening can therefore be considered weak. Regarding general population screening for anti-HCV recent studies mainly from the USA suggest this is cost-effective, particularly when targeted at high-prevalence birth cohorts, the so-called baby-boomers (1945–1965). In response to this, CDC has recommended these cohorts to be offered screening [87]. In Europe, a French study from 2003 suggested HCV screening for the general population could be cost-effective [48]. More evidence on general population HCV screening needed is needed for European countries, especially for those with a relatively high prevalence.

The main limitation of our review is regarding the comparability of the estimates found. First this is limited since different laboratory tests were used, particularly for HCV where antibody assay validity has improved in recent years. Second, prevalence estimates were not always standardized by age and sex. Lastly, the definition and sampling of the high risk population groups are likely to influence prevalence estimates found both for these groups as for the general population. A limitation of the cost-effectiveness studies is that most analyses used Markov modeling, necessary since the disease outcomes of chronic HBV and HCV infection take several decades to develop. When not accounting for co-morbidities such as excess of alcohol intake, these models can overestimate the effects of screening and treatment by having too optimistic assumptions about life expectancy. On the other hand, effects of screening are underestimated since these models do not allow quantifying the effect of reduced transmission by lowering viral load due to antiviral treatment and potential behavior change. Since these effects can be considerable [13‐15], dynamic models assessing the effects of screening and treatment need to be developed. This is likely to be of particular relevance for population subgroups where not only the prevalence, but also the incidence, is increased compared to the general population, such as MSM (HBV) and PWID (HCV). A recent study from Martin et al. did include indirect effects of treating HCV infections in PWID. It was not included in our review since it assessed cost-effectiveness of treatment rather than of screening and treatment [88].

Lastly, methods, assumptions, and quality varied between studies, making it difficult to compare results and limiting the possibilities of carrying out meta-analyses. Guidelines such as those developed for economic analyses of vaccination programmes may be helpful to improve the quality of studies [89, 90].