Testing for hepatitis C virus and hepatitis B virus/hepatitis D virus: Current scenarios and perspectives in Italy

Abstract

Liver disease accounts for approximately 4% of all deaths worldwide, and viral hepatitis affects more than 300 million people. The World Health Organization aims to reduce new hepatitis infections by 90% and deaths by 65% by 2030 through vaccination and screening programs. In Italy, screening for hepatitis C virus (HCV) benefits from dedicated government funding, whereas testing for hepatitis B virus (HBV) and hepatitis D virus (HDV) is supported by recommendations from scientific societies but does not benefit from dedicated national public health programmes. This expert-opinion review summarises the experience of tertiary-level Italian centres actively engaged in hospital-based testing for HCV, HBV, and HDV and identifies practical pathways to improve testing and linkage to care. This article presents proposals to improve the effectiveness of viral hepatitis management in Italy by: (1) Strengthening coordination between hospital units and integrating information systems between general practitioners and hospitals; (2) Implementing a centralised reporting system and a structured referral network to ensure that patients with positive test results receive appropriate therapies in a timely manner; (3) Providing the resources needed to increase testing in public addiction treatment services (Servizi per le Dipendenze) and prisons; (4) Promoting screening in high-risk populations, including vulnerable and older populations; and (5) Implementing a national awareness campaign on viral hepatitis. These measures could help Italy make concrete progress towards eliminating HCV infection and controlling HBV/HDV infection within the next decade.

Key Words: Viral hepatitis; Hepatitis C virus; Hepatitis B virus; Hepatitis D virus; Screening programmes; Linkage to care; Specific therapies

Core Tip: Italy has achieved hepatitis B control targets but still faces major gaps in hepatitis C virus elimination and hepatitis D virus underdiagnosis. This expert-opinion review highlights structural and organisational barriers to testing, including fragmented screening strategies and a lack of integrated pathways. It discusses evidence-supported approaches, such as targeted opportunistic screening and reflex testing, alongside expert-opinion proposals including centralised reporting and linkage-to-care models.

INTRODUCTION

Liver disease represents a major global health challenge, accounting for approximately two million deaths each year and nearly 4% of all deaths worldwide. The leading causes of liver-related mortality are complications of cirrhosis and hepatocellular carcinoma (HCC), the most common primary liver cancer[1]. According to the 2024 report from the United States Centres for Disease Control and Prevention, “viral hepatitis affects more than 300 million people globally”, the majority of whom remain undiagnosed or untreated[2]. Data from the World Health Organization (WHO) Global Health Observatory estimate that approximately 254 million individuals are living with hepatitis B virus (HBV) infection and 50 million with hepatitis C virus (HCV) infection worldwide, while nearly 6000 new viral hepatitis infections occur each day[3]. In 2022 alone, chronic HBV and HCV infections were responsible for an estimated 1.3 million deaths globally, corresponding to nearly 3500 deaths per day. Hepatitis D virus (HDV), a defective virus that requires HBV for replication, affects 5%-10% of individuals chronically infected with HBV worldwide[4]. HDV/HBV coinfection represents the most aggressive form of chronic viral hepatitis, being associated with accelerated progression towards advanced liver disease, liver-related mortality, and HCC development.

In Italy, the prevalence of HDV infections has markedly declined since the 1980s, primarily owing to the successful implementation of universal HBV vaccination programmes. Nevertheless, several populations remain at increased risk of HBV infection, including individuals originating from endemic areas, people who inject drugs, people living with human immunodeficiency virus (HIV) or HCV infection, individuals with high-risk sexual behaviours[5-7], and older adults who were not included in the national HBV vaccination campaign.

Several studies have attempted to estimate the global and regional prevalence of HDV infection, yielding markedly heterogeneous results[8-11]. Estimates published in 2018 and 2019 put the global number of people with HDV infection at approximately 48-60 million and 62-72 million, respectively, whereas subsequent analyses revised the estimate downwards to approximately 12 million in 2020. Such variability largely reflects substantial methodological limitations, including differences in diagnostic accuracy, lack of comprehensive population-based studies, heterogeneity in screening strategies, and the marked geographical variability of HDV infection[12]. The substantial contribution of both HBV and HCV infections to the global burden of liver disease underscores the critical importance of vaccination (for hepatitis B), screening, early diagnosis, and antiviral treatment strategies aimed at reducing the long-term complications and liver-related mortality.

The WHO global hepatitis strategy aims “to reduce new hepatitis infections by 90% and deaths by 65% between 2016 and 2030”[13] through vaccination and screening programmes, and countries have been encouraged to develop national elimination plans as part of efforts to align with international public health goals. Large-scale screening strategies are particularly relevant in the current therapeutic era, given the continued expansion and improvement of antiviral treatment options for all forms of chronic viral hepatitis. More than a decade after their introduction, direct-acting antivirals (DAAs) have revolutionized the treatment of HCV infection, achieving sustained virological response rates exceeding 95%-98% across virtually all patient populations[14,15]. Despite their remarkable efficacy and favorable safety profile, however, only approximately 21% of the estimated global HCV-infected population has received DAA therapy to date. This persistent treatment gap likely reflects the declining effectiveness of existing screening and case-finding strategies rather than limitations of antiviral therapy itself. Importantly, successful HCV eradication through DAA treatment provides substantial clinical benefits and also significant socioeconomic advantages by reducing liver-related morbidity, mortality, healthcare utilisation and viral transmission. In parallel, with the ageing of the HCV-infected population, comorbidities and concomitant medication profiles have increased clinical relevance. Because oral DAA regimens exhibit distinct drug-drug interaction profiles, careful selection of the antiviral combination is essential, particularly in elderly and medically complex patients[16]. Similarly, the widespread use of nucleos(t)ide analogues (NUCs) as a lifelong treatment for chronic hepatitis B has profoundly modified the natural history of the disease. Long-term NUC therapy effectively suppresses viral replication, promotes fibrosis regression in patients with cirrhosis, reduces the risk of liver-related events and may allow resolution of liver decompensation[17]. Finally, identifying patients with hepatitis D infection has become increasingly relevant following the introduction of novel therapeutic options. Bulevirtide, currently the first and only drug approved in the European Union for the treatment of hepatitis delta, has demonstrated the ability to reduce both HDV-RNA and aminotransferase levels in a substantial proportion of treated patients[18,19].

Within the Italian healthcare setting, important differences remain between HCV and HBV/HDV screening policies. HCV screening currently benefits from dedicated government funding and structured national public health initiatives, primarily driven by the availability of highly effective curative therapies and by the strategic objective of HCV elimination. Conversely, HBV and HDV testing rely predominantly on recommendations issued by scientific societies and are therefore considered components of appropriate clinical practice rather than part of a formally funded national screening programme. At present, no specific national legislation exists for HBV/HDV screening in Italy, nor dedicated public funding. Moreover, the implementation of alternative HCV screening strategies such as in-hospital testing outside the age cohorts currently covered by national legislation may require deviations from existing public health policies and therefore necessitates careful evaluation of cost-effectiveness and healthcare resource allocation.

AIMS AND METHODS

This expert-opinion review aims to summarize the experience of tertiary-level Italian centres—highly specialized university and referral hospitals equipped with advanced hepatology and infectious disease units—actively involved in hospital-based testing for HCV, HBV, and HDV, with the objective of identifying diagnostic and organisational pathways that may support the development of more effective screening and linkage-to-care protocols for patients with chronic viral liver diseases in the current Italian context. The present expert opinion is based on a non-systematic, narrative review of the literature integrated with the direct clinical experience of the authors. Relevant publications were identified through targeted PubMed searches and institutional sources, including reports from the Italian National Institute of Health [Istituto Superiore di Sanità (ISS)] and data from the Italian Platform for the Study of Viral Hepatitis Therapies (PITER), considering studies published up to 2025 focusing on viral hepatitis epidemiology, screening strategies, and linkage to care models in Italy. Priority was given to recent peer-reviewed articles, national surveillance data, and selected regional experiences. To minimize the risk of selection bias associated with expert-opinion methodology and regionally derived evidence, a pragmatic purposive approach was adopted to include projects representative of different geographic areas and healthcare settings. This strategy was intended to capture the heterogeneity of the Italian healthcare system while providing a balanced and clinically relevant overview of the national context despite the lack of comprehensive population-based epidemiological data.

Hepatitis C

Italian epidemiological landscape: One of the major limitations in the Italian HCV scenario is the absence of robust, nationwide population-based epidemiological studies that accurately define HCV prevalence and disease burden. Historically, epidemiological estimates have largely relied on small cohort studies, regional experiences, or data derived from selected referral centres, inevitably introducing substantial risks of selection bias and limiting the generalisability of the findings. Consequently, most estimates regarding HCV prevalence in Italy have been limited by the lack of comprehensive and homogeneous national data. In particular, epidemiological observations derived from specific regions have frequently been extrapolated to generate national prevalence estimates, despite the marked heterogeneity in disease burden, healthcare organisation, screening implementation, and treatment access across different Italian regions. Historically, Italy has been considered the Western European country with the highest reported prevalence of HCV infection[20-22]. More recent estimates generated using the "Polaris Observatory" modelling approach, based on the natural history of HCV disease progression, suggested an overall prevalence close to 1% up to 2020, although with substantial regional variability ranging from 0.4% to 1.4%[23]. An updated analysis of HCV epidemiology in Italy up to 2021 further revised these estimates downward, reporting an overall prevalence of approximately 0.66%, again with marked interregional heterogeneity (Table 1)[24]. Particularly concerning was the unexpectedly high and geographically heterogeneous prevalence of patients with F4 cirrhosis, especially considering that these patients often present with symptomatic advanced liver disease and have represented a priority population for antiviral treatment since the introduction of DAAs in 2015[24]. However, it should be emphasized that current prevalence estimates are likely influenced by the incomplete capture of cases within electronic healthcare registries and by the persistence of substantial underdiagnosis because of insufficient testing coverage. As a consequence, the actual burden of liver disease, particularly at advanced stages, is likely underestimated, complicating efforts aimed at viral hepatitis elimination.

Table 1 Estimates of the absolute number and percentage of individuals with viremic hepatitis C virus infection in Italy according to macroarea up to January 2021.

Macroarea	Absolute number and 95%CI[25]	Prevalence and 95%CI (%)[25]
Italy	398610 (396960-400260)	0.66 (0.66-0.67)
North	150983 (149557-152410)	0.54 (0.53-0.54)
Centre	105351 (104188-106513)	0.88 (0.87-0.89)
South	98928 (87623-100233)	0.72 (0.71-0.73)
Isles	43348 (42513-44183)	0.67 (0.66-0.68)

95%CI: 95% confidence interval.

HCV screening in Italy: In May 2021, Italy officially introduced a national screening programme for active HCV infection aimed at identifying previously “undiagnosed HCV infections, improving the possibility of early diagnosis, starting patients on treatment to avoid complications of advanced liver disease and extrahepatic manifestations, as well as interrupting the circulation of the virus, preventing new infections”. Initially conceived as a pilot intervention for the 2020-2021 period, the programme targeted individuals born between 1969 and 1989, people attending public addiction treatment services [Servizi per le Dipendenze (SerDs)], and incarcerated individuals, supported by an allocation of 71.5 million euros[25]. The implementation of regional screening programmes was substantially delayed by the coronavirus disease 2019 (COVID-19) pandemic. Consequently, following the extension of the government decree in 2023, most regional screening initiatives became operational (Figure 1). Through subsequent extensions, the decree currently remains in force until December 2026[26]. According to data from the PITER platform, coordinated by the National Centre for Global Health of the ISS, active screening strategies initially focused on younger birth cohorts (1969-1989) with the intention of subsequently expanding testing to older individuals (1948-1967). This graduated approach was considered the most cost-effective strategy according to available modelling analyses[22]. One of the first regional experiences was conducted in Lombardy, where individuals born between 1969 and 1989 were offered free point-of-care HCV testing during COVID-19 vaccination campaigns. Interestingly, the prevalence of HCV infection observed in this cohort was lower than initially anticipated. Nevertheless, the investigators emphasized that extending screening to individuals born before 1969 could substantially improve case-finding effectiveness[27]. To date, the regional implementation of HCV screening programmes across Italy has been highly heterogeneous, largely reflecting differences in healthcare organisation, public health logistics, resource allocation, and local governance structures among regions. Consequently, both screening uptake and outcomes have varied considerably nationwide. Overall adherence to screening initiatives remains suboptimal, and only a limited proportion of the allocated financial resources has been utilised thus far. To address these issues, the ISS and the Italian Ministry of Health have promoted greater coordination among regions actively involved in HCV screening, leveraging national infrastructures such as the Integrated Epidemiological System for Acute Viral Hepatitis (SEIEVA)[28], the PITER platform, and specialized virology laboratories capable of molecular characterization of circulating viral strains[29]. Several regional initiatives have explored alternative and opportunistic screening models. In the Veneto Region, targeted interventions have been developed to identify untreated HCV-infected individuals beyond the birth cohorts included in the national screening programme[30]. Moreover, since 2021, an in-hospital HCV screening campaign has been implemented at the University Hospital of Padua to improve awareness and diagnostic capacity among healthcare professionals involved in disease prevention, diagnosis, and management[31]. Notably, 77% of patients with detectable HCV viral load identified during the screening programme fell outside the age range currently covered by the national free-screening recommendations, suggesting that opportunistic hospital-based testing could substantially improve HCV case detection by identifying infected individuals currently excluded from national policies[31]. Similarly, another HCV screening initiative conducted within the framework of the national programme involved individuals accessing healthcare facilities in the Lombardy region between June 2022 and December 2022. All individuals born between 1969 and 1989 admitted to hospital or attending blood collection centres were offered anti-HCV antibody and HCV-RNA testing, excluding individuals with known anti-HCV positivity and/or previous antiviral treatment[32]. Among 120193 individuals screened across 75 centres, the prevalence of active HCV infection was approximately 0.1%, although significantly higher prevalence rates were observed among older individuals and hospitalised patients. Based on these findings, the authors advocated for extending opportunistic screening strategies to birth cohorts born before 1969. Consistent with these observations, a recent Italian cost-consequence analysis concluded that extending screening programmes to the 1948-1968 birth cohort would represent a cost-effective strategy capable of preventing delays in diagnosis and treatment associated with significant long-term clinical and economic consequences[33]. Importantly, although the original government decree envisaged the progressive extension of screening to older age cohorts, this expansion has not yet been implemented. Notably, additional financial allocation may not be necessary, as a substantial proportion of the initial 71.5 million euros in initial funding remains unspent. Despite the implementation of multiple initiatives nationwide, albeit with marked heterogeneity, the ISS recently reported that only about 30% of the target population has been actively invited to screening, while merely 21% of invited individuals ultimately underwent testing, corresponding to an average screening coverage of approximately 6.6% of the entire eligible population. By June 2023, the national screening programme had enabled nearly 1 million people to be tested and more than 10000 active HCV infections to be identified. These numbers remain lower than expected based on epidemiological estimates, suggesting the persistence of a substantial hidden reservoir of HCV infection in Italy[34]. More broadly, the implementation of effective HCV screening strategies across Europe remains hampered by the absence of universally accepted screening models, difficulties in reaching vulnerable and high-risk populations, fragmentation of diagnostic pathways, and suboptimal linkage to care. These limitations are further exacerbated by methodological heterogeneity, poor integration between healthcare systems, and insufficient real-world evidence to support large-scale implementation strategies[35-37].

Figure 1 Regional plans following the “Milleproroghe” Decree, 2025. Orange: No decree; Green: Published decree. MMG: Medici di Medicina Generale; SerD: Servizi per le Dipendenze.

Suggestions and prospects to improve current HCV screening effectiveness: Increasing awareness among the general population: The authors propose that a centralised national communication and awareness campaign could substantially improve participation in HCV screening programs. However, the funds allocated to the Italian national screening initiative are currently dedicated almost exclusively to the procurement of diagnostic tests and do not include financial support for communication campaigns, organisational activities, educational interventions, or information technology infrastructure. This limitation significantly hampers the implementation of effective public engagement strategies.

One-time testing at first healthcare contact: An alternative strategy would involve universal one-time HCV testing at the first contact with hospital or community healthcare services, including community hospitals, primary care facilities, decentralised laboratory networks, and residential care facilities for older people. Such an approach could ensure that every individual undergoes at least one HCV test during their lifetime, thereby minimising missed diagnostic opportunities and facilitating earlier access to treatment. A practical limitation to this approach is the current requirement for informed consent when testing is performed outside the officially funded national screening programme. This strategy underscores the urgent need for the development of a centralised national registry documenting HCV tests performed and corresponding results. Such an infrastructure would facilitate monitoring of screening effectiveness and promote data sharing among central institutions, local healthcare authorities, microbiology laboratories, and infectious disease/hepatology departments. Integrated networks of this type could support timely reporting and management of positive cases while avoiding unnecessary duplicate testing.

Prioritisation of high-yield clinical settings: Optimising HCV screening effectiveness also requires identifying hospital departments where testing should be prioritised. The authors propose that hepatology and infectious diseases units should systematically adopt routine HCV testing protocols. Beyond these settings, prioritisation could be based on two complementary epidemiological criteria: Departments with higher expected HCV prevalence (e.g., emergency departments and psychiatry units) and departments in which a missed diagnosis could significantly affect the management of concomitant diseases (e.g., oncology/haematology units; Table 2). Focusing resources on high- and intermediate-priority settings could improve cost-effectiveness and maximize the identification of HCV-positive individuals. Although this targeted strategy may fail to identify some infections within the general population, it allows more efficient allocation of healthcare resources towards high-prevalence and high-risk populations. Similarly, HCV testing should be substantially reinforced within SerDs and correctional facilities. Current logistical barriers, limited organizational resources, and insufficient prioritization of these highly vulnerable populations represent major unmet public health needs that urgently require intervention.

Table 2 Prioritisation of hepatitis C virus testing in different hospital departments.

	Based on expected prevalence	Based on clinical risk/need for care
Routine testing departments	Hepatology; infectious diseases	Hepatology; infectious diseases
High-priority departments	Emergency department; internal medicine; gastroenterology/endoscopy; ophthalmology; geriatrics; psychiatry	Gynaecology/obstetrics; oncology/haematology
Medium-priority departments	Cardiology; nephrology; surgery	Rheumatology; neurology
Low-priority departments	Paediatrics; infectious diseases1; gastroenterology/hepatology1; internal medicine/hepatology1

¹Classified as low-priority departments because hepatitis C virus testing is part of their routine activity.

Dedicated healthcare personnel: The designation of dedicated healthcare professionals responsible for HCV screening activities could substantially streamline diagnostic pathways and improve organisational efficiency. These professionals could coordinate testing activities across hospital departments and community healthcare facilities, monitor and record results, promptly flag positive cases, facilitate communication between the microbiology laboratory and referral hepatology/infectious disease units, and provide patient education regarding HCV infection and available treatment options. However, it should again be emphasised that current government funding has been allocated predominantly to diagnostic testing costs rather than to the organisational resources required for comprehensive screening implementation.

Improving reporting systems and data integration: Preventing underreporting and fragmentation of diagnostic information requires the implementation of an effective centralised reporting system and stronger communication among stakeholders involved in care pathways. In particular, the authors consider investment necessary to improve interoperability between hospital information technology systems and other National Health Service structures. Currently, the limited integration between primary care data from general practitioners (GPs) and hospital-generated data significantly impairs the ability to reconstruct complete patient care pathways and coordinate linkage-to-care interventions.

Strengthening referral pathways and linkage to care: Simplification of HCV diagnostic algorithms and monitoring requirements has been shown to facilitate more rapid access to treatment, generating substantial clinical and economic benefits. A survey involving HCV-positive patients, the general population, healthcare professionals from SerDs, and hospital physicians identified time to treatment (from first healthcare contact to treatment initiation) as one of the key determinants of a successful elimination strategy[38]. Nevertheless, failure to ensure timely referral and effective linkage to care remains one of the major unresolved challenges in chronic viral hepatitis management. Table 3 summarises several Italian intra-hospital screening and linkage-to-care programmes developed for HCV infection. The Telepass project, conducted in 2020, evaluated the effectiveness of a recall strategy based on internal hospital databases to identify untreated patients with chronic HCV infection who had not yet been linked to care[39]. Although the study demonstrated the utility of database-driven recall systems in identifying previously untreated HCV-infected individuals, it also highlighted that a substantial proportion of patients within healthcare facilities had not been appropriately referred for antiviral treatment. Similarly, a prospective interventional study conducted at Azienda ospedaliera Sant’Anna e San Sebastiano Hospital in Caserta (Campania Region) evaluated a hospital-based HCV case-finding and linkage-to-care strategy among adult inpatients testing positive for anti-HCV antibodies[40]. Among 529 anti-HCV-positive individuals, 243 had already received DAA therapy and 10 died during hospitalisation. Of the remaining 276 individuals evaluated, 194 were HCV-RNA-positive and 180 subsequently initiated DAA therapy in accordance with international guidelines. The HCV ICEberg Project further demonstrated the potential of active hospital-based case-finding strategies[38]. Between January 2018 and June 2022, 4415 of 49287 individuals tested for anti-HCV antibodies were positive (8.9%). Of them, 1071 (24.2%) had no HCV-RNA test; 53.7% were female, 63.0% were born before 1947, and 27.4% between 1948-1968. Among those who underwent HCV-RNA testing, 348 were positive (348/4415: 7.9%). Overall, a cohort of 230 individuals with untreated active HCV infection was identified, corresponding to 0.5% of the overall screened population. Importantly, opportunistic screening conducted between September 2021 and October 2022 among patients admitted to the General Medicine Unit identified a remarkably high prevalence of anti-HCV positivity (54/856 patients, 6.3%). These findings support the potential value of extending systematic hospital-based testing to all inpatient wards as part of standard clinical practice (Table 3). On the basis of these experiences, the authors propose that, to optimise linkage-to-care pathways, every positive HCV test should generate an immediate dual notification from the microbiology laboratory both to the requesting unit and to the specialist unit responsible for HCV management. Such a dual-alert system could reduce delays in linkage to care. Establishing a clear protocol for referral and follow-up would bridge the gap between diagnosis and treatment, improving patient outcomes. Regarding linkage to care, within the Italian healthcare system, two main organisational scenarios can be identified: Hospitals with dedicated hepatology or infectious diseases units and hospitals without specialised liver disease services. In the former setting, strong intra-hospital collaboration between departments is required to ensure effective management of positive cases. In the latter, the establishment of formal referral networks with external specialist centres becomes essential to guarantee appropriate linkage to care. The organisational characteristics of the different levels of hepatology services are summarised in Table 4. Irrespective of the organisational model adopted, healthcare providers must ensure that patients fully understand the implications of their diagnosis, the availability of effective treatment and the importance of long-term follow-up. To facilitate seamless transition from diagnosis to treatment, discharge letters should systematically include a scheduled outpatient specialist appointment for HCV management. Providing patients with clear information regarding their care pathway may help bridge the gap between discharge and continued clinical care. Figure 2 illustrates a proposed organisational pathway for hospital-based testing and appropriate referral across different settings. Patients managed in day-hospital settings require a slightly different approach, with particular emphasis on maximising each on-site encounter to reinforce adherence, address concerns, monitor treatment progress, and promote patient engagement. Across all settings, effective communication based on clarity, empathy, and patient-centred care remains fundamental for optimising adherence and improving long-term clinical outcomes.

Figure 2 Opportunistic hospital-based testing and referral model for hepatitis C virus and hepatitis B virus/hepatitis D virus infections. Level I, II, and III: See Table 4. INF: Infectious disease; HEP: Hepatology; DEP: Department.

Table 3 Examples of intra-hospital screening and linkage to care programmes for hepatitis C virus infection.

Study	Study design	Study period	Area	Setting	No. of subjects tested	No. of anti-HCV-positive subjects	No. of previously unknown HCV-positive subjects	Rate of linkage to care
Telepass study[39]	Retrospective/prospective	March 2017 to March 2018	Rome, Italy	Surgical units at a university hospital	12260	224	93	35/93 (37.6%)
Caserta model[40]	Prospective	January to December 2019	Caserta, Italy	Tertiary-level hospital	14396	529	276	276/276 (100%)
ICEberg project[38]	Retrospective phase	January 2018 to June 2022	Castellammare di Stabia, Italy	Local health unit	49287	4415	Not available	3344/4415 (75.7%)
ICEberg project[38]	Prospective phase	September 2021 to October 2022	Castellammare di Stabia, Italy	Local health unit	856	54	Not available	54/54 (100%)

HCV: Hepatitis C virus.

Table 4 Characteristics of hepatology departments in level I, II, and III centres.

Level	I	II	III
Type of facility	Community care/single operating unit	Specialised hospital facility	Highly specialised healthcare facility
Level of complexity	Low	Medium-high	High
Position	Basic hepatology care management	Intermediate between community care (general practitioner or outpatient specialist) and highly specialised centres	Highly specialised care management
Multidisciplinary approach	No	Yes	Yes
Advanced technology	No	Yes	Yes
Liver transplant centre	No	No	Yes
Regional/national reference	No	Possibly	Yes
Research/clinical trials	No	Possibly	Yes

Hepatitis B and D

Italian epidemiological landscape: Following the mandatory national HBV vaccination programme introduced in 1991, Italy became the first European country to be officially recognised in January 2020 as having achieved national hepatitis B control[41]. Initially, the vaccination strategy targeted all newborns and children aged 12 years during a 12-year transition period and subsequently focused exclusively on universal neonatal vaccination[42]. Importantly, the epidemiological impact of HBV prevention in Italy had already begun in 1983 with the introduction of vaccination for children born to hepatitis B surface antigen (HBsAg)-positive mothers, effectively anticipating the decline of HBV transmission by almost a decade. As a consequence, virtually all Italian-born individuals younger than 46 years are currently protected against HBV infection, whereas chronic HBV infection continues to represent a clinically relevant burden among older populations and foreign-born individuals. Overall, the prevalence of HBsAg carriage in the general Italian population has decreased significantly, from approximately 3% during the 1980s to less than 0.6% in recent estimates[43,44]. Within the Italian PITER-B/Delta cohort, the overall prevalence of antibodies to HDV (anti-HDV) was 10.2%. It has been estimated that approximately 5000-10000 HBsAg-positive individuals in Italy currently live with chronic hepatitis D (CHD). Data from the PITER cohort study, conducted between 2019 and 2021 across 46 centres and including 4853 patients, 21.8% of whom were migrants, demonstrated a rapidly evolving epidemiological landscape for HBV infection in Italy, largely driven by the progressive reduction in HBV prevalence among native Italians. Conversely, HBV and HDV infections remain a significant health issue among migrant populations[45], including both recently arrived and long-term settled migrants or individuals born in Italy to migrant families[45-48], as well as among socially marginalized individuals, people who inject drugs, and subjects coinfected with HCV[5,49]. These observations strongly support the need for targeted public health interventions and dedicated screening campaigns in these vulnerable settings. A prospective screening study conducted between 2019 and 2024 among marginalized populations attending non-profit organisations in Tuscany further highlighted the persistence of hidden HBV infections and the critical importance of linkage-to-care strategies[50]. The study demonstrated that HBV infection was particularly prevalent among economic migrants and refugees temporarily residing in shelters. The relatively young mean age of HBsAg-positive individuals (33.6 years) likely reflects both the more recent implementation of universal vaccination campaigns in the countries of origin and suboptimal vaccination coverage in endemic geographic regions.

HBV and HDV testing in Italy: Unlike HCV, Italy currently lacks government-funded national screening programmes for HBV and HDV infection. Nevertheless, despite the marked decline in HBV and HDV prevalence among native Italians following the introduction of mandatory HBV vaccination, several populations remain at substantial risk of infection. Consequently, reinforcing HBV vaccination strategies among HBsAg-negative individuals in high-risk groups remains a public health priority. Multiple studies highlight high rates of HBsAg positivity among migrant populations, emphasising the need for implementation of targeted HBV screening initiatives in these groups. However, migrants frequently encounter major barriers limiting access to healthcare services, including communication difficulties, language barriers, legal and bureaucratic obstacles, cultural beliefs regarding traditional medicine, ethnic disparities, socioeconomic hardship and limited social support systems. Upon arrival in reception settings, infectious diseases are often not perceived as an immediate healthcare priority. In addition, awareness regarding viral hepatitis infection, transmission, evolution and treatment is frequently insufficient, resulting in substantial underdiagnosis and undertreatment. For these reasons, screening and linkage-to-care programmes targeting migrant populations should be implemented in close collaboration with humanitarian organisations, ensuring free access even for undocumented individuals and involving dedicated cultural and bureaucratic mediators capable of facilitating communication and healthcare navigation[51]. People who use drugs represent another population at high risk for HBV and HDV infections because of the coexistence of multiple predisposing factors[8,52]. Many are people who inject drugs[53], engage in high-risk sexual behaviours, are coinfected with HIV[8], or have experienced incarceration, where living conditions increase the risk of infection[54,55]. Older individuals who were not vaccinated against HBV should be considered a vulnerable group. Moreover, a recent Italian study[56] highlighted the widespread circulation of HDV among HBsAg-positive individuals living with HIV, thus underscoring the inclusion of these individuals among groups at high risk for HDV infection. Furthermore, a significant proportion of HBsAg-positive individuals with HIV infection remained untested for anti-HDV, contributing to substantial HDV underdiagnosis. This issue is even more pronounced among HBsAg-positive individuals without HIV infection in Southern Italy, with 35% of them missing anti-HDV testing, indicating inadequate HDV screening[57]. Furthermore, recent Italian epidemiological data suggest that sexual transmission (rather than intravenous drug use) has become the predominant route of acute HDV acquisition, highlighting a further shift in the epidemiology of HDV transmission[58]. These findings reinforce the urgent need to improve awareness of HDV infection among clinicians and to systematically perform anti-HDV testing in all HBsAg-positive individuals, as recommended by international guidelines[12]. Such efforts are particularly relevant in light of the recent approval of Bulevirtide, the first approved HDV-specific treatment in the European Union. However, given the substantial real-world pharmacoeconomic burden of this costly therapy, it remains uncertain whether regional healthcare budgets can accommodate the expenses associated with newly identified HDV patients. In the absence of national legislation on HBV or HDV screening policies, active testing for HBV and HDV in high-risk populations is currently based on clinical appropriateness and recommendations from scientific societies rather than on a funded national programme. Indeed, systematic HDV screening of all HBsAg-positive patients has not been fully implemented in recent years, with almost 30% of HBsAg-positive patients still not tested for anti-HDV antibodies. In particular, the correlation between the lack of screening and the presence of normal or only mildly elevated aminotransferase levels suggests that the diagnosis of HDV infection could be delayed in a substantial proportion of patients until liver disease has already progressed, with a subsequent negative impact on patients' clinical outcomes and therapeutic options. Ultimately, diagnostic approaches are still suboptimal, with significant gaps preventing the achievement of complete and early diagnosis, limiting the possibility of reducing HDV-related morbidity and mortality[59].

Suggestions and perspectives to improve HBV/HDV testing: The prevalence of HDV infection is likely underestimated. A recent study evaluating annual HDV serological testing among chronic HBsAg carriers followed at a university centre in Brussels documented a high prevalence of HDV positivity, including 11% coinfected and 1.3% superinfected individuals[60]. Recent Italian studies assessing patients actively followed for CHD revealed that CHD affects both young foreign-born individuals and older native Italians, with nearly two-thirds of patients already presenting with cirrhosis or HCC at the time of first screening. Furthermore, both Italian-born and foreign-born patients frequently exhibited relevant comorbidities[44]. Therefore, screening for HDV infection in all HBsAg-positive individuals is strongly recommended, particularly in high-risk groups and in those with unexplained changes in the liver disease profile, to increase detection and facilitate linkage to care[12].

Increasing education and facilitating testing: A recent internet-based survey conducted among members of three gastroenterology/hepatology societies highlighted the need for increased training programmes dedicated to HDV care[61]. Once again, increased awareness and educational campaigns are needed to promote broader and more systematic testing. An additional priority should be the implementation of standardised diagnostic approaches to increase HDV testing uptake and diagnostic yield.

Early detection of HDV infection: All HBsAg-positive individuals should undergo anti-HDV antibody testing at least once during their clinical history. The recommended screening assay measures total anti-HDV antibodies [immunoglobulin G and immunoglobulin M (IgM)][12]. In patients testing positive for anti-HDV, serum HDV-RNA quantification is recommended. A positive anti-HDV result associated with detectable serum HDV-RNA defines chronic HDV infection. The use of qualitative HDV-RNA tests alone is not recommended. For quantitative HDV-RNA testing, commercially available, well-validated, and highly sensitive assays are recommended. In subjects testing positive for anti-HDV, negative serum HDV-RNA results should be interpreted cautiously, particularly in those originating from African or Asian countries where uncommon HDV genotypes circulate. When clinically indicated, repeat quantification using alternative assays with proven sensitivity is recommended[12]. In conjunction with HDV-RNA quantification, a complete virological characterisation of the HBV serological profile is recommended, including quantitative HBsAg, hepatitis B e antigen (HBeAg)/antibody to HBeAg status, and quantitative HBV-DNA. HDV replication may partially or completely suppress HBV replication, either continuously or intermittently, reflecting the dynamic replicative interplay between the two viruses[12]. Further characterisation of chronic HDV infection can include viral genotype determination, although this analysis is not currently recommended in routine clinical practice. Likewise, serum hepatitis D antigen determination is not currently recommended for the management of patients with HDV infection[12].

Prioritising high-risk categories: As previously highlighted, HBV screening programmes should focus on specific high-risk categories, including individuals at increased risk because of behavioural or medical-history, such as people who inject drugs, individuals with multiple sexual partners, individuals with a history of blood transfusions before the introduction of rigorous screening protocols, migrants from countries with high HBV/HDV prevalence, and Italian individuals older than 45 years who were not included in the mandatory HBV vaccination programme. Specific healthcare settings, such as infectious disease wards and SerDs, serve populations at increased risk of acquiring these infections because of their underlying vulnerabilities. By targeting these high-risk groups, healthcare providers could optimise resource allocation and maximise the detection of HBV- and HDV-positive cases. This approach not only improves the efficiency of healthcare resource utilisation but also increases the likelihood of early diagnosis and timely intervention. In particular, all people who use drugs should undergo screening for HBV, HCV and HIV at admission to SerDs, every 6 months thereafter, and following any identified risk behaviour[46]. First-line HBV testing in these populations should include HBsAg, antibody to HBsAg (anti-HBs), and antibody to hepatitis B core antigen (anti-HBc)[17,62,63].

Reflex testing: Current guidelines recommend reflex testing for HDV coinfection in all HBsAg-positive individuals rather than limiting screening to risk-factor-based strategies[12]. Reflex testing represents the most effective method for estimating the prevalence of anti-HDV and HDV-RNA positivity and for identifying undiagnosed individuals at the national level. This strategy consists of automatically testing all HBsAg-positive individuals for anti-HDV antibodies, followed by HDV-RNA testing in those who are anti-HDV-positive. Given the relatively low number of newly diagnosed HBV cases, this strategy is likely to be sustainable for most healthcare systems. Prioritising high-risk populations, such as patients admitted to hepatology and infectious disease units and vulnerable populations including individuals attending SerDs or prisons, could further optimise resource utilisation and maximise the detection rate of viral hepatitis infections. However, we acknowledge that full implementation of HDV reflex testing in Italy may still be hindered by administrative barriers, including the need for automated laboratory algorithms and unresolved reimbursement arrangements for tests performed without a formal prescription.

Virological monitoring: Virological monitoring of patients with HDV is based on the quantification of HDV-RNA. Repeated anti-HDV testing is unnecessary in patients already known to be HDV-RNA positive. Similarly, anti-HDV IgM testing is not currently recommended. Whenever possible, viraemia should be monitored using the same assay and preferably at the same referral centre in order to minimise inter-assay variability[62]. The latest European Association for the Study of the Liver clinical practice guidelines recommend that untreated patients with CHD should undergo regular work-up for liver disease at least every 6-12 months [level of evidence (LoE) 3, strong recommendation, strong consensus] and that virological evaluation should ideally include quantitative HBsAg, HBV-DNA and HDV-RNA assays (LoE 5, strong recommendation, consensus)[12]. In patients with CHD receiving antiviral therapy against HDV, HDV-RNA should be quantified every 6 months during treatment and whenever clinically indicated[12].

Examples of currently applicable diagnostic and referral pathways: The pathway proposed in Figure 2 may also be applied to HBV/HDV testing and appropriate patient referral. In addition, Nava and Kondili[49] proposed a diagnostic and referral pathway specifically tailored for people who use drugs, as summarised below.

Early detection within SerDs: All people who use drugs should undergo screening for HBV, HCV and HIV on admission to addiction treatment services, every 6 months thereafter, and after any identified risk behaviour[46]. The primary aim of screening is the early detection of HBV/HDV disease. Red flags include[47]: (1) Elevated aminotransferase levels: Test for HBV, HCV, and HDV; (2) No history of previous HBV vaccination: Test for HBV and vaccinate if appropriate; and (3) Injection drug use: Prioritise screening for infectious diseases.

HBV screening should be offered to all people who use drugs through conventional blood sampling, while rapid testing strategies should be considered for hard-to-reach populations. First-line HBV tests include HBsAg, anti-HBs and anti-HBc[63,64]. These markers are essential for defining HBV infection status. HBV vaccination should be strongly recommended for all individuals without evidence of previous HBV exposure.

Linkage to care: All HBsAg-positive individuals, regardless of the presence or absence of HDV coinfection, should be referred to specialised centres for comprehensive clinical and virological characterisation aimed at defining disease phase and treatment indication.

Italy

To define the Italian epidemiological context more accurately, differences between the population living with HCV infection, which is predominantly Italian-born, and the population living with HBV infection, which includes a substantial proportion of migrants, should be considered when developing targeted, infection-specific interventions. Although HCV screening in Italy is formally regulated at the national level (Law 28/2020; birth-cohort and key-population strategy), implementation has been delegated to regional authorities. This has generated marked interregional variation in screening coverage, settings, data systems, participation, and linkage-to-care pathways. Fragmented governance, narrow eligibility criteria, low participation in population-based approaches, and limited interoperability between regional data systems may therefore contribute to uneven access and efficiency.

Europe

Across Europe, decentralisation of healthcare delivery is not unique to Italy, although the degree of national coordination and system integration varies considerably. In northern and western European countries, including the United Kingdom, the Netherlands, and France, local delivery is generally combined with more integrated national surveillance and clearly defined targets. Robust data systems are also important for monitoring elimination efforts. Spain provides another model in which decentralised and opportunistic screening can be integrated within a coordinated national strategy.

Evidence

Accordingly, the generalisability of the Italian experience must be considered in the context of its particularly fragmented governance structure: The barriers identified here may reflect insufficient system-level integration rather than intrinsic limitations of decentralised screening itself. The evidence reviewed in this article supports several specific actions. Published Italian data and cost-consequence analyses support expanding HCV case-finding beyond the currently funded birth cohorts, particularly to older birth cohorts where the burden of undiagnosed infection is greater[31-33]. International guidelines support anti-HDV testing in all HBsAg-positive individuals and targeted HBV/HCV/HDV testing in populations at increased risk[12,17,62-64]. Existing hospital-based programmes also provide evidence that active case-finding and structured linkage to care can identify previously undiagnosed or untreated HCV infection[38-40]. Other proposals in this review should be regarded as expert opinions based on the organisational gaps identified in the Italian setting and require prospective evaluation. These include implementing a centralised national reporting system; integrating information systems between GPs and hospitals; assigning dedicated personnel to coordinate screening; strengthening formal referral networks; increasing operational resources for testing in SerDs and prisons; and implementing a nationwide viral hepatitis awareness campaign. Overall, the effectiveness of decentralised viral hepatitis screening appears to depend not only on the delivery model but also on the degree of integration between national strategy and local implementation.

Future strategies

Strengthening national coordination through standardised protocols, shared monitoring frameworks, and common performance indicators may improve the effectiveness and equity of regional programmes. By combining evidence-based testing strategies with prospectively evaluated organisational interventions, Italy could make further progress towards eliminating HCV infection and controlling HBV/HDV infection. Priorities include consolidating the current HCV screening programme, developing coherent HBV/HDV testing policies, promoting HBV vaccination among HBsAg-negative people in at-risk populations, and facilitating timely access to treatment for all forms of chronic viral hepatitis.

CONCLUSION

Gaps and biases in epidemiological data continue to complicate the development and implementation of effective strategies for the elimination and control of hepatitis B, C, and D. Broader national and regional collaboration, improved surveillance systems, and more effective screening strategies are required to address these challenges.

ACKNOWLEDGEMENTS

The authors thank Dr. Mattia Hagger for his careful review of the English-language text. Editorial assistance was provided by Monica Luciani and Renata Perego.