Background
Hepatitis C virus (HCV) is the leading cause of liver-related morbidity and mortality worldwide. Globally, as many as 71 million individuals are infected with chronic HCV [
1,
2], Many HCV infected individuals remain asymptomatic for decades, although progression of the disease accelerates with age [
3,
4].
Following the availability of direct-acting antiviral drugs (DAAs) for the successful treatment of HCV infection [
5,
6], focus has been placed on the identification of infected individuals. The identification of this population is necessary to achieve targets for 2030, established by the World Health Organization [
7].
Italy is considered the country with the highest HCV prevalence rate in Western Europe [
8‐
10] and we have previously published national estimates on the number of infected individuals using a similar modelling approach [
11].
It has previously been estimated that under an assumption of 40% of infected individuals linked‐to‐care, viraemic burden would decline by 60% and eligible patients to treat will be depleted around 2025 leaving a significant proportion of infected individuals undiagnosed and without care [
12]. To achieve HCV elimination goals, increased case finding in targeted, high prevalence groups is required.
In Italy, although a national hepatitis plan exists [
13], decentralized models of HCV are still being implemented without any uniform screening strategies exist across regional networks. There is a dedicated fund for free HCV screening approved by law in Italy which needs to be implemented at the Regional level and to this end an estimate of the number of individuals with HCV for each region is necessary. To address this unmet need, we used a probabilistic approach to estimate the infection rate and a Markov model for liver disease progression. This mathematical modelling approach can be considered a useful tool to aid in the development of national and regional health authority HCV elimination plans.
Discussion
Findings from the present study revealed that an increasing trend in the undiagnosed population with HCV (F0–F3) from South (23.2%) to North (42.1%), independent of similar regional prevalence values. PWID and tattoo risk emerged as the main populations of undiagnosed individuals, with similar distribution observed across regions.
The estimated number (and distribution across Italy) of patients with F4 cirrhosis is particularly concerning. This was unexpected, considering their potential symptomatic disease and the high importance of viral eradication in these patients, who were prioritized for treatment since 2015, when DAAs became available. In fact, around 20% of patients with cirrhosis are also observed in the AIFA treatment DAA monitoring registry for the year 2019 [
16]. These data could suggest the lack of an adequate linkage to care in diagnosed individuals or the first diagnosis of these patients in very severe stages of liver disease, which again emphasises the increased need for screening and immediate linkage to care of individuals with HCV in Italy.
Although a higher estimated HCV prevalence of undiagnosed individuals emerged from some specific regions in Central Italy (e.g. Umbria and Marche) and in the Basilicata region in the South, similar lower prevalence estimates of undiagnosed individuals were generally observed across the four macroareas. This suggests a decrease in the level of prevalence in HCV infection compared to the past in Italy where higher prevalence values and a gradient from North to South (3.9% in Veneto to 16.2% in Campania) of individuals with HCV in Italy mainly related to the nosocomial transmission of infection [
8,
27]. However, considering the distribution of the number of undiagnosed individuals (N = 300,171), an increasing trend as absolute number from the South (23.2%) to North (42.1%) emerged. Why our data suggest a different gradient as absolute estimates of undiagnosed individuals, which is higher in the Northern region compared with other macroareas, may be explained by some epidemiologic and sociodemographic features. First, considering the cohort effect of HCV infection in Italy, infections that occurred in the first wave of infection have a higher probability of being cured by now. Therefore, the high number of patients with fibrosis stage F4/cirrhosis receiving treatment in Italy at the beginning have contributed potentially to the substantial decrease in the number of infected individuals who have had severe liver damage (mainly prevalent in the South). The second wave was mainly associated with key populations (i.e. PWID and tattoos), and the more recent infection that has also been reported in Northern Europe [
28,
29].
Second, the number of F0–F3 infections could be higher in the North compared with other macroareas due to the internal migration of the Italian population who are actively working (aged 30–60 years) from the South and Islands to the Northern areas, where there is a higher rate of employment and work activity in the country [
30]. Of note, these data do not emerge when only the overall prevalence estimated for each macroarea is considered. This can be explained by the fact that the prevalence values consider the whole population with the same age and population, which is also higher in number (the denominator) in Northern compared with Southern Italy. This yields a similar estimated prevalence, despite high absolute infection burden of asymptomatic individuals in the North compared with other macroareas.
While these findings underline the high HCV burden of asymptomatic individuals in the North, substantial heterogeneity exists across regions, necessitating individual elimination plans to be implemented at the regional level.
The recommended screening approved by law starting with birth in the years 1969–1989 is in accordance with the results of this study, although derived using different modelling approaches [
31,
32].
It is also worth mentioning that our analysis in the present study was performed up to January 2020, a few months before the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus pandemic [
33]. To cope with the increase in number of COVID-19 patients to emergency departments, the re-organization of healthcare facilities across all Italian regions was necessary resulting in the postponing of medical services and procedures considered as ‘non-essential’ or ‘deferrable’. The potential impact of this deferral has been assessed in a separate analysis by Kondili et al. [
34]. In this modelling approach, it was estimated that deferring DAA treatment for an additional 6 months would, at 5 years, increase the number of HCV patients dying of a liver-related condition in Italy to more than 500 patients, deaths avoidable by a not deferred test and treatment approach. A further analysis also revealed that a 1-year delay in hepatitis diagnosis and treatment could result in an additional 44,800 liver cancers and 72,300 deaths from HCV globally by 2030 [
35]. Regions such as Lombardy may be particularly susceptible to any deferral of DAA treatment [
36], and strategies aimed to increase diagnosis and treatment are warranted.
Limitations
This study has some potential limitations that need to be highlighted. The impact of less frequent routes of transmission (e.g. surgical interventions, colonoscopy, dental intervention/surgery, cosmetics) was not considered, potentially underestimating the number of both diagnosed and undiagnosed individuals.
We acknowledge that variation in prevalence rates was estimated considering baseline rates derived from studies that were not always designed as prevalence studies in the general population and for populations with different risk factors such as sexual transmission, which for this reason could have been underestimated. To partially overcome these limitations, the prevalence retrieved from these articles was not used as a uniform probability throughout all years and ages, but a shape (probability density function modelling) was derived from different sources to more realistically model the prevalence over different years. However, considering the high rate of treatment in Italy in the past 5 years and considering DAA treatment as a preventative measure, the rate of reinfection and new infection would be expected to be low, therefore reducing the extent of any potential underestimation.
We considered non-liver related mortality (i.e. natural mortality due to other comorbid diseases) based on ISTAT (Italian mortality registry) data that are usually used in modelling analysis of HCV natural history. This could have overestimated the alive population with HCV infection estimated. The non-liver related mortality population could be higher than those infected compared to the general population due to extrahepatic manifestations of HCV infection, placing them at higher risk of death earlier in life [
37]. However, this probability has not been modelled due to the lack of numerical data.
A high number of unregistered immigrants (potentially asymptomatic and undiagnosed for HCV) travelling to Italy in recent years [
38,
39], and particularly in the Northern regions [
40] where the highest number of individuals with HCV was observed in our model. This aspect needs to be carefully considered during the interpretation of our estimates. However, based on expert opinion and data derived from other studies, a higher HCV prevalence is not observed in this immigrant population (considering their countries of birth) compared to the Italian population (resident in Italy that are included in general population estimates) [
41]. In separate analyses, we are working to address not only the higher prevalence rate, but also the impact that this brings to society. In this study, the main routes of infections have been considered separately in the evaluation of the number of untreated individuals in Italy and we have not focussed on specific settings (e.g. immigrant or prison population) mainly due to the lack of reliable National data. Further studies should explore the impact of the immigrant population on HCV prevalence separately.
With regard to the prison population, most prisoners have a history of high-risk sexual behavior, injection drug use and tattooing and it appears that the risk of acquisition of HCV infection is linked to these behaviours which are considered in this modelling. For the aim of this study, in the evaluation of the number of untreated individuals in Italy, the main routes of infection were considered separately by risk factor and not specific settings such as homeless, migrants etc., mainly due to the lack of reliable National data. The prison per se was not considered a route of infection, but PWID is recognised as a main route of infection in prison [
42‐
44] rather than the prisoning state itself, and this could result in potential underestimation bias and this could result in potential underestimation bias.
Transition probabilities may vary for different populations that depend on host response and underlying comorbidities [
37]. We have aimed to minimize this variation by considering this uncertainty in the sensitivity analysis.
In this model, we assumed that all F0–F3 infected individuals estimated in the model that were not yet treated as undiagnosed. In the real-life scenario, not all F0–F3 are undiagnosed and therefore a portion of these individuals could be diagnosed and not yet linked to care. Regardless, these data do not influence the infection burden, because although these individuals could be diagnosed, they are estimated as not treated.
Conclusion
By January 2020, the number of individuals with HCV in Italy was estimated at 409,184 (prevalence of 0.68%; 95% CI: 0.54–0.82%), of which 300,171 (0.50%; 95% CI: 0.4–0.6%) were estimated as undiagnosed due to their asymptomatic disease (F0–F3). The target for new diagnosis should focus and screening of PWID, tattoo, and sexual transmission, in younger people (predominantly aged 40–60 years) should be implemented.
An increasing trend in the percentage of the undiagnosed population with HCV (F0–F3) from South (23.2%) to North (42.1%) has emerged, independent of similar regional prevalence values. PWID and those who received tattoos in the past represent the main populations of undiagnosed individuals, with similar distributions across regions. This targeted modelling approach, which addresses the specific profile of undiagnosed individuals, is helpful in planning effective elimination strategies by region in Italy and could be a useful methodology for other countries in implementing their elimination plans.
Acknowledgements
The authors wish to thank Francesca Petrarca, PhD (IWS Consulting, Rome, Italy), for performing statistical modelling and Colin Gerard Egan, PhD (CE Medical Writing SRLS, Pisa, Italy), for his support in medical writing, both funded by AbbVie.
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