It is estimated that 185 million people have been infected with hepatitis C virus (HCV) worldwide [1], most of whom are unaware of their infection [2]. The burden is highest in low- and middle-income countries (LMIC), which account for over 80 % of cases of chronic HCV infection [1]. People living with HCV may experience considerable barriers to accessing testing, treatment and care, particularly in low-income countries [3, 4].

Populations at increased risk of HCV include people who inject drugs (PWID) [5], people receiving medical procedures (including transfusion of blood and blood products) in an unsafe setting [6, 7], men who have sex with men (MSM) (in particular, those who are infected with HIV) [8], and children born to mothers who have HCV [9]. Intranasal drug use and cosmetic procedures (such as tattooing, body piercing, and manicures) have also been implicated as risk factors for HCV [10]. The relative importance of these risk factors varies depending on the geographical setting and population studied.

Chronic HCV infection leads to an increased risk of liver cirrhosis and liver cancer, and contributes to approximately 360,000 liver-related deaths annually [11, 12]. Testing for and diagnosis of HCV is expected to reduce the risk of liver-related disease, by facilitating earlier access to HCV treatment and care. On this basis, European and American HCV guidelines have recommended targeted HCV testing for high risk groups, without necessarily the evidence to demonstrate that early diagnosis is of benefit [13–15].

A recent narrative synthesis of eight studies concluded that testing interventions can lead to increases in test uptake, but other outcomes were not examined in detail [16]. The aim of our review was to investigate and quantify through meta-analysis the effectiveness of targeted HCV testing interventions on patient-important outcomes, including test uptake, case detection, uptake of HCV treatment, and the prevention of liver-related morbidity and mortality. The study was conducted as part of a series of systematic reviews to inform World Health Organisation (WHO) Guidelines on the Screening, Care, and Treatment of Hepatitis C, with particular reference to LMIC [17].

This systematic review and meta-analysis provides for the first time a quantitative assessment of the effectiveness of targeted HCV testing interventions in increasing the uptake of HCV testing, treatment, and care. Our review examined more outcomes and identified more primary studies than previous reviews of testing interventions [16, 35], and also included non-English language and economic evaluation studies. Targeted testing interventions—comprising both practitioner-based and media/information-based strategies—were associated with increased test uptake (pooled RR 2.9, 95 % CI 2.0, 4.2), although the association with HCV case detection was less marked (pooled RR 1.7, 95 % CI 1.3, 2.2). This is to be expected even in the most effective of testing interventions, where testing on the basis of risk (rather than on the basis of symptoms) will increase the proportion of negative tests conducted. Targeted testing interventions were also associated with increased HCV treatment uptake (pooled RR 3.3, 95 % CI 1.1, 10.0), but there was insufficient evidence for improvements in SVR or liver-related morbidity. The latter may be due to the short periods of follow-up used by the primary studies included in the review, and their focus on immediate outcomes of test uptake and case detection. While further studies examining the longer-term impact of testing would be desirable, such studies are impractical and other data showing treatment leads to SVR, reduced morbidity, and improved survival are already very strong [36, 37].

The success of targeted HCV testing interventions was dependent on both the risk-group targeted, and the type of strategy adopted. Targeting of individuals known to be PWID was associated with increased test uptake and case detection, whereas targeting individuals with any HCV risk factor was less effective. This may be due to the difference in estimated HCV prevalence between studies targeting individual PWID (range 16.8–70.2 %) and studies targeting individuals with any HCV risk factor (range 0.4–3.0 %).

Studies targeting groups at increased risk of PWID (e.g. homeless persons, or selected birth cohorts) improved test uptake, but there was less evidence for an increase in case detection. This could be because within a group-targeting strategy, those individuals at lower risk are more likely to agree to testing, whereas those at higher risk may not respond to the offer of a test unless they are questioned about their history of risk behaviour.

Practitioner-based studies were effective in increasing test uptake and cases detected, but media/information-based studies were less effective. There was limited detail of the types of interventions employed in the media/information-based studies, but it may be that these interventions were not sufficiently intensive, or only raised awareness of HCV, rather than providing practical information on testing programmes. Information campaigns rely on individuals to self-assess their risk, and former PWID in particular may not self-identify as being part of a risk group, particularly if their exposure was not recent. It has also been suggested that the impact of media campaigns may be short-lived [38], and therefore any positive effects may have been missed in studies that evaluated the campaign some months or years later [21, 22, 33].

There was considerable heterogeneity across the two testing outcomes (test uptake and HCV cases detected), which could not be accounted for by the variables examined in the stratified analyses. A review of the forest plots for these outcomes demonstrated that this heterogeneity derived from variable precision and different effect sizes pointing in the same direction, rather than from directly contradictory findings. The variable precision observed here is due to the vastly different sizes of population denominator used by the different studies (from small clinic-based studies to population-level interventions), leading to very narrow confidence around some estimates, and thus minimal cross-over with other studies. The range in positive effect sizes is likely to be due to the variability in targeting strategies used, as well as the heterogeneity of the intervention and comparison groups across the studies. For example, in the two studies that targeted PWID through GP practices, Cullen et al. [25] identified their target group by asking GPs to recruit current methadone users, whereas Cullen et al. [29] identified PWID through medical records that suggested a history of injecting. The testing intervention in Cullen et al. [25] appeared considerably less effective, because baseline HCV testing among methadone users in GP settings was already very high. Similarly, of two studies that targeted a birth cohort living in an area of socioeconomic deprivation, Anderson et al. was more successful in detecting HCV cases than Litwin et al., possibly due to less routine testing and higher HCV prevalence in the Anderson et al. study.

Across the four studies that reported on treatment and care outcomes [25, 28, 29, 31], 64 % of the estimated chronic HCV population attended a specialist appointment, but only 11 % commenced treatment within a median of 2 years of follow-up. While allowing for the short follow-up period, this suggests that uptake of treatment (in the context of interferon based therapies) within testing interventions is likely to be low, and considerably lower than assumptions used in various studies modelling the cost-effectiveness of testing [22, 39, 40]. In comparison, attendance at specialist appointments was relatively high, suggesting that patients who attended appointments were assessed as unsuitable for treatment, due to patient preference, provider preference, or co-morbidities such as mental health or substance use. It is important that testing interventions provide adequate pre-test counselling, to allow patients to understand the implications of a positive test and the treatments available. In addition, treatment services need to be ready to manage ‘screened’ populations, who may be inherently different to patients who have presented spontaneously for testing.

The majority of the targeted interventions reported in this review were conducted in General Practice settings, of which most were conducted in countries (UK, France, and Ireland) where primary healthcare provision is universal. Current or former PWID are likely to have better access to universal health systems, and this may have contributed to the success of testing interventions in these settings. It should also be noted that all of the primary studies included in this review were based in high-income countries, and the applicability of these results to LMIC is therefore uncertain. Although there is a lack of evidence for targeted HCV testing interventions in these settings, a recent review of HIV testing interventions in LMIC concluded that provider-initiated HIV testing could be effective in increasing test uptake, although the impact on treatment uptake and risk behaviour was equivocal [41]. The HIV-testing studies were based in a number of countries across sub-Saharan Africa and Asia, and delivered testing through hospital outpatient clinics, methadone programmes, and sexual health services. It is therefore probable that HCV testing interventions would be similarly feasible in a range of different LMIC settings. In addition, it might be expected that the relative effect of testing interventions would be even greater in LMIC settings than reported here, given that baseline testing and treatment is likely to be very low.

It is anticipated that approaches to HCV case-finding will undergo considerable changes in the future, as a result of advances in HCV testing, treatment, and care. These include the introduction of rapid testing (providing access to on-the-spot testing and diagnosis for hard-to-reach populations), and the advent of new interferon-free therapies, which will have increased tolerability and efficacy compared to previous regimens. As knowledge and awareness of these developments increase, it is likely that there will be increased willingness, from both providers and patients, to test for HCV and to seek assessment for treatment. This review captures the effectiveness of testing interventions during the era of interferon-based therapies, and the effect sizes quoted here are therefore likely to under-estimate the future effectiveness of testing interventions in the interferon-free era.

This meta-analysis provides for the first time a quantitative assessment of targeted HCV testing interventions, demonstrating that these strategies were effective in diagnosing cases and increasing treatment uptake. Strategies involving practitioner-based interventions yielded the most favourable outcomes. While evidence is lacking on longer-term outcomes, data from studies of treated patients provides strong evidence that increased treatment uptake would translate into improved SVRs, and subsequently to reductions in liver-related morbidity. It is therefore recommended that testing should be targeted at and offered to individuals who are part of a population with high HCV prevalence, or who have a history of HCV risk behaviour.