We have carried out a population-based screening for HCV infection in a presumed low-prevalence area. In clinical practice, the identification of individuals with viraemic HCV infection is most important. For surveillance purposes, however, reliable data for both current infection and recovered disease, either spontaneously or through treatment, is of interest. In this survey of individuals aged 40 years and older, the prevalence of chronic (viraemic) HCV infection was 0.2%. In comparison, the last population survey in Norway in 2001, including people aged 30 years and older, revealed a prevalence of chronic HCV infection of 0.5%, an estimate which also included treatment-recovered cases [3]. In our study, the prevalence of current and treatment- recovered chronic HCV infection was 0.4%, of which a high proportion (61.2%) had already received treatment with achieved SVR. A modelling study in 2013 estimated the viraemic prevalence in Norway to be 0.43% [29]. The slightly higher estimate in this study compared to ours might partly be explained by different study designs, where the modelling study was based on historical data and expert opinions.
The present study revealed that a substantial proportion (39.4%) of individuals with chronic HCV infection were unaware of their infectious status, a finding which is in line with the results of others [5, 9,10,11, 29]. Of the 13 previously undiagnosed individuals, 69% had a history of IDU, thus should theoretically have been detected by a risk-based screening strategy. This suggest that the current recommendation of risk-based screening is suboptimal in identifying all chronically infected persons hidden in the general population. One reason for this is that infected persons may not consider themselves as being at risk for HCV infection, i.e. persons with occasional drug use, especially in the remote past, and individuals who received blood transfusion before 1992 [9, 17]. Others have pointed out that the stigma associated with IDU; and the socio-demographic characteristics of PWIDs, create barriers that impede testing and linkage to care in this population [30].
Strengths and weaknesses
The strength of this study is the large sample size in a general population, which enhances the probability that the study population is representative of the general population. However, there are important limitations. First, The Tromsø 7 study only included individuals aged 40 years and older. This age restriction was inherent to the overreaching study design of Tromsø 7, but clearly introduces a selection bias. IDU is the main mode of transmission of HCV [31], and it is estimated that 29.8% (range 25.0–34.8) of PWIDs in Western Europe are younger than 25 years [32]. In the municipality of Tromsø, it is estimated that the number of PWIDs is approximately 300 (personal communication, Inger Hilde Trandem, MD, Social Medical Center, Tromsø, May 28, 2018). There is no clear data on their age distribution, but it is reasonable to assume that the proportion of young PWID in Tromsø is comparable to the findings in the above mentioned study. Due to the age restriction, the prevalence of HCV infection in our study is most likely underestimated.
Second, even if participation rates were generally high across all age groups, self-selection is still an important issue that may affect the representativeness of the study sample. The attenders in population surveys tend to be more educated and have a healthier life style than non-attenders [33]. The second survey of the Tromsø study (Tromsø 2) showed that various psychiatric disorders and alcohol abuse were significant predictors of nonattendance in health surveys [34], and a Canadian study demonstrated that non-response bias is a problem in alcohol and drug use surveys [35]. It is therefore reasonable to assume that current and former PWIDs are less likely to participate in health surveys, also resulting in underestimation of the true HCV prevalence and reducing the efficiency of screening in the general population.
The interpretation and significance of indeterminate RIBA reactions are unclear. In one study, 4.9% of RIBA indeterminate cases were found to be HCV RNA positive [36]. Still, most individuals with indeterminate RIBA have a negative HCV RNA test, which may represent previous resolved HCV-infection as well as unspecific antibody reactions [25]. Reports have shown that approximately half of those with indeterminate RIBA have a resolved HCV infection [37, 38]. In this study, we have chosen to include persons with RIBA indeterminate result in the HCV-exposed cohort, which could have led to overestimation of anti-HCV positive. However, the number of RIBA-indeterminate records was low, making the contribution of these less important.
Screening strategies in a low-prevalence area: Whom and how to screen
Our study was integrated in an established population-based survey with repeated health surveys since 1974. The attendance rate was 64.3% and the estimated cost per newly detected chronic HCV infection was approximately NOK 90000 (€ 9629). HCV-screening of the general population outside such an established population survey would have been more laborious and at an expected considerably higher costs, thus making it less feasible. As discussed above, it is likely that persons belonging to risk groups for HCV infection attended the study to a lesser degree than the general population, reducing the efficiency of such an approach. On the other hand, the study has unmasked several individuals with chronic HCV infection that did not define themselves as belonging to known risk groups. A recent Spanish pilot study for an eventual population-based screening program included the adult population (20–75 years) in a small health area with a participation rate of 46.2% (2637/5706) [39]. HCV RNA was detected in 13 persons (0.5%), of whom five were unaware of the disease.
In low-prevalence countries, routine screening of the entire population has not been considered to be cost-effective [15,16,17,18], and screening are limited to high-risk populations. However, the high proportion of undiagnosed HCV infection clearly underscores the limitations of the risk-based screening approach and the need to reconsider screening strategies in order to achieve the diagnosis rate of 90% promoted by the WHO.
In the US, it is recommended a one-time screening of persons in the high-prevalence 1945–1965 birth cohort, in addition to targeted risk-based testing [40]. In the present study, the highest prevalence of anti-HCV and viraemic HCV infection was found in the age group 50–59 years, i.e. in people born between 1956 and 1965, which may be explained by a later onset of the epidemic of IDU in Norway, with a gradual increase in the number of PWID from the onset of IDU in 1973 until a peak was reached in 2000 [7]. In a birth-cohort analysis, 73% of the HCV-infected population in Norway was born between 1955 and 1980 [41]. A systematic review including several countries concluded that screening of birth cohorts, drug users, and high-risk populations was cost-effective [18]. However, recent studies indicate that universal screening of the general population may be an effective strategy. In France, where the prevalence of chronic HCV infection is 0.3% [2], a modelling study showed that universal screening of all individuals aged 18–80 years was the most effective screening strategy, and also the most cost-effective, assuming rapid initiation of treatment after diagnosis [19]. Likewise, in Spain with an HCV RNA prevalence 0.35–0.41%, a recent modelling study concluded that screening of the general adult population would identify a larger number of additional individuals with chronic HCV infection than screening high-risk groups or screening the age-cohort with the highest anti-HCV prevalence plus high-risk groups [20].
Others suggest strategies to improve targeted screening of people in high-risk groups in various settings. Primary care practitioners can play an important role in targeted screening, especially in former PWID, whereas screening of current PWID is more appropriate in settings like outpatient clinics, opioid substitution programs, jails, and psychiatric clinics [17, 42,43,44,45,46]. In a screening and medical follow-up programme in Northern Norway, primary care practitioners were encouraged to screen patients with former or present risk factors for HCV infection, which led to an increase in the number of newly diagnosed HCV infections in the subsequent years [47]. Technical bottlenecks in HCV testing can lead to missed opportunities in the HCV cascade of care, e.g., when a high proportion of anti-HCV positive individuals are not followed up with a confirmatory test for HCV RNA [48]. The availability of a new point-of-care (PoC) test with high sensitivity and specificity (close to 100%) for detection of HCV RNA might contribute to simplification of HCV testing and thus enable decentralisation of HCV care and treatment [49]. New technology, such as the use of dried blood spot and saliva sampling could increase access to HCV testing, e.g. in people with difficult venous access [50, 51].
There are potential negative effects associated with screening large numbers of persons in a population with low prevalence of HCV infection. In our study, the proportion of false positive anti-HCV tests was 38.2% (83/217). False-positive results can cause harm by way of anxiety and stigmatization, although such effects are difficult to quantify [52].
Implications
Modelling studies have indicated that screening in the general adult population may be an effective screening strategy [19, 20]. Universal screening may allow diagnosis and treatment of asymptomatic infected persons, avoiding the development of complications and onward transmission, thus saving health costs. To be effective, people with the highest risk of infection must also attend the screening project. Based on this, strategies to improve targeted screening of people in high-risk groups in various settings, including primary care-based interventions, may still be the most effective approach in low-prevalence regions. To overcome the high costs associated with screening in the general population, the use of a birth-cohort screening strategy could be considered, which in our case would be based on the finding of the highest prevalence of anti-HCV and chronic HCV infection in people born between 1956 and 1965. Finally, implementation of simplified testing methods may increase access to HCV testing in both risk groups and birth cohorts.