Late presentation of chronic HBV and HCV patients seeking first time specialist care in Spain: a 2-year registry review

1 Vol.:(0123456789) Scientific Reports | (2021) 11:24133 | https://doi.org/10.1038/s41598-021-01885-0 www.nature.com/scientificreports Late presentation of chronic HBV and HCV patients seeking first time specialist care in Spain: a 2‑year registry review Camila A. Picchio1, Sabela Lens2,3,4, Manuel Hernandez‑Guerra5, Juan Arenas6, Raúl J. Andrade4,7, Javier Crespo8, Javier García‑Samaniego4,9, Manuel Romero‑Gómez10, Juan Turnes11, José Luis Calleja4,12, Miguel Ángel Simón13,14, Trenton M. White1, Mar Riveiro‑Barciela15, Anna Pocurull2,3,4, Dalia Morales‑Arraez5, Alexandra Gómez6, Maria Buti4,15,16 & Jeffrey V. Lazarus1,16* Chronic viral hepatitis infection affects an estimated 325 million people globally. People who initiate treatment after significant disease progression face increased risk of severe liver complications and death. Data are scarce on the characteristics and risk factors of people who present late to care in Spain and globally. Data were collected from January 2018 to December 2019 to report late presentation (LP) to specialist care at 11 large university hospitals in Spain to assess related risk factors using a multivariable logistic regression model. 2290 (CHB = 505, CHC = 1785) patients were analysed, with 581 (25.2%) presenting late. Hepatitis C patients more frequently reported LP compared to hepatitis B patients (28.1% vs 15.0%; p < 0.001). Older age (p < 0.001), being male (p < 0.001), being Spanish‑born (p < 0.001), and having an unknown origin of referral (p = 0.08) were associated with a higher likelihood of LP. Advanced liver disease was identified in 533 (23%) patients and late‑stage liver disease in 124 (5.4%). LP, including with irreversible liver damage, to viral hepatitis specialist care is frequent in Spain, despite being a country with unrestricted treatment access. Initiatives to reduce LP should specifically target men, older individuals, foreign‑born populations for CHB, and Spanish nationals for CHC. Abbreviations HBV Hepatitis B virus HCV Hepatitis C virus CHB Chronic hepatitis B CHC Chronic hepatitis C WHO World Health Organization OPEN 1Barcelona Institute for Global Health (ISGlobal), Hospital Clínic, University of Barcelona, Barcelona, Spain. 2Liver Unit, Hospital Clinic, Universidad de Barcelona, Barcelona, Spain. 3IDIBAPS, University of Barcelona, Barcelona, Spain. 4CIBER Hepatic and Digestive Diseases (CIBERehd), Instituto Carlos III, Madrid, Spain. 5Department of Gastroenterology, University Hospital of the Canary Islands, San Cristóbal de La Laguna, Spain. 6Biodonostia, Liver Diseases Research Group, Osakidetza Basque Health Service, Donostia University Hospital, San Sebastián, Spain. 7Unidad de Gestión Clínica de Enfermedades Digestivas, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain. 8Gastroenterology and Hepatology Unit, Hospital Universitario Marqués de Valdecilla, IDIVAL, University of Cantabria, Santander, Spain. 9Liver Unit, Department of Gastroenterology, Hospital Universitario La Paz, IdiPAZ, Madrid, Spain. 10UCM Digestive Diseases, Hospital Universitario Virgen del Rocío, Institute of Biomedicine of Seville, Universidad de Sevilla, Seville, Spain. 11Complejo Hospitalario Universitario de Pontevedra, Instituto de Investigación Sanitaria Galicia Sur (IISGS), Pontevedra, Spain. 12Gastroenterology and Hepatology Department, Hospital Universitario Puerta del Hierro de, Universidad Autónoma de Madrid, Madrid, Spain. 13Department of Digestive Diseases, Hospital Clínico de Zaragoza, Zaragoza, Spain. 14Instituto de Investigación Sanitario Aragón (IIS Aragón), Zaragoza, Spain. 15Liver Unit, Hospital Universitario Vall d’Hebron, Barcelona, Spain. 16These authors contributed equally: Maria Buti and Jeffrey V. Lazarus. *email: Jeffrey[email protected] 2 Vol:.(1234567890) Scientific Reports | (2021) 11:24133 | https://doi.org/10.1038/s41598-021-01885-0 www.nature.com/scientificreports/ HCC Hepatocellular carcinoma DAAs Direct-acting antivirals SVR Sustained virologic response LP Late presentation ALD Advanced liver disease LSLD Late-stage liver disease AST Aspartate aminotransferase ALT Alanine transaminase APRI Aminotransferase platelet ratio OR Odd’s ratio HIV Human immunodeficiency virus Viral hepatitis currently affects an estimated 325 million people globally1. In 2016, the World Health Organization (WHO) adopted the “Global Health Sector Strategy on Viral Hepatitis, 2016–2021”, which sets out to eliminate viral hepatitis as a public health threat by 2030 by reaching targets that principally aim to reduce new hepatitis infections by 90% and deaths by 65%2. Recent data in the WHO European region report that an estimated 15 million people live with chronic hepatitis B virus (HBV)3 and an estimated 14 million people with hepatitis C virus (HCV), equivalent to one in 50 people affected4. Diagnosis can be challenging as chronic HBV and HCV infections may remain clinically silent for decades with symptoms only occurring once the disease has significantly progressed. HBV and HCV infected individuals are at an increased risk of developing liver cirrhosis, decompensated liver disease, hepatocellular carcinoma (HCC), and liver-related death5, 6. The risk of disease progression is related to several factors with viral replication being an important factor in fibrosis progression and thus, in the risk of developing HCC. Therefore, antiviral therapy that can suppress viral replication in the case of hepatitis B and direct-acting antivirals (DAAs) against HCV7, can modify the natural course of the disease and reduce or prevent the development of disease progression, particularly if therapy is initiated in early stages of the disease. In the case of chronic hepatitis C (CHC) infection, although antiviral therapy results in sustained virologic response (SVR) in ≥ 95% of cases, for patients that present late to care, there is still a risk of HCC for those that have developed advanced fibrosis or cirrhosis8, 9. In Spain, access to HCV DAA therapy has been unrestricted since mid-2017, yet only half of the patients with HCV-RNA know their status and are receiving therapy10. Viral elimination through completion of DAA treatment therapy can reduce all-cause mortality in HCV patients11. Similarly, timely diagnosis and treatment initiation of patients with HBV is required to prevent patients from progressing to severe adverse clinical outcomes, which is estimated to be as high as 15–40%12. For virtually all transmissible infectious diseases, late presentation (LP) to care has both individual and population health implications. Screening to identify these individuals before significant liver damage occurs has reduced HBV and HCV incidence13 and prevalence and has been shown to maintain or improve quality of life14. Thus, to optimise the benefits of available treatment regimens and work towards the WHO elimination goal, patients need to be diagnosed earlier. In a 2017 consensus paper15, LP was defined as: (1) presentation with advanced liver disease (ALD) in untreated patients with chronic hepatitis B and C showing significant fibrosis (F ≥ 3); or (2) presentation with late-stage liver disease (LSLD) in untreated patients with chronic hepatitis B or C and including at least one symptom of decompensated cirrhosis (i.e., jaundice, hepatic encephalopathy, clinically detectable ascites, variceal bleeding) and/or HCC in patients with no previous antiviral treatment. There are few studies evaluating late presentation in general, and population level studies are largely unexplored. The aim of this study is to report the prevalence of LP of chronic infection with HBV and HCV at first visits with specialists prescribing therapy and managing HBV and HCV in Spain, which has unrestricted treatment access, and describe the risk factors associated with HBV and HCV late presentation to care. Methods This is a retrospective (Jan 2018–Feb 2019) and prospective (Mar–Dec 2019) cohort study (data collection was first retrospective and subsequently prospective) of adult patients (18years or older) with chronic HBVor HCV infection presenting for consultation with a liver specialist in 11 Spanish university hospitals in eight of Spain’s 17 autonomous communities from 1 January 2018 to 31 December 2019. Chronic HCV infection was defined by the presence of HCV-RNA for > 6months and chronic HBV infection by HBsAg detection for > 6 months16, 17. Patients with acute hepatitis as well as those with acute liver failure were excluded. Those presenting for care with a liver specialist (hepatology department, infectious diseases department, internal medicine department, or “other”) were referred by a primary care office or other specialist. In Spain, only specialists are permitted to treat and manage chronic viral hepatitis patients and, therefore, referrals from other departments are needed before being seen by a specialist. Data from each patient’s visits with specialists were collected in a non-identifiable Excel collection template through review of medical records in each hospital’s medical record system by authorised personnel. Standard demographic variables (gender, nationality, date of birth), epidemiological (mode of transmission, year of diagnosis, vaccination status), laboratory parameters (alanine aminotransferase [ALT], aspartate aminotransferase [AST], platelet count), viral hepatitis B and C serologies and viral load (HBsAg, HBeAg, HBV-DNA, HCV-RNA, HCV genotype and subtype), fibrosis stage, and clinical outcome variables, such as decompensated cirrhosis and hepatocellular carcinoma (HCC), were collected. Variables on the type of centre and information on referral of patients were also collected. Late presentation was defined based on the consensus definition proposed by Mauss etal.15 (Box1). 3 Vol.:(0123456789) Scientific Reports | (2021) 11:24133 | https://doi.org/10.1038/s41598-021-01885-0 www.nature.com/scientificreports/ Variables. The date of birth of patients were collected and later birth year was extracted in order to calculate age at time of presentation to care. Country of origin was re-categorised into “Spanish-born” and “Foreignborn” and consisted of responses as “Spain” or “España” versus all other possible nationalities. HBV-DNA and HCV-RNA were recorded as UI/mL, ALT and AST values were recorded as UI/L, and platelet counts were standardised and recorded as × 103/µL. The upper limit of normality (ULN) for ALT and AST values was set at 40UI/mL. HBeAg and HBsAg were collected dichotomously as “positive” or “negative” for HBV patients. In the case of HCV-related variables, genotype letter and number were collected. Fibrosis stage was reported as F0-F4 and later re-categorised to create the variable “advanced liver disease”, which included all patients with fibrosis ≥ F3 and an aminotransferase platelet ratio (APRI) score > 1.5 based on the initial (first or second) patient visits with the liver specialist. Patients who did not have a reported fibrosis stage had their APRI index score calculated using reported AST and platelet count values using the standard formula [(AST/upper limit of the normal AST range) × 100/platelet count]. The variable LSLD included any patient with a reported liver complication (jaundice, hepatic encephalopathy, ascites, variceal bleeding) defining decompensated cirrhosis and/or HCC in addition to a fibrosis score > F3. If fibrosis stage or HCC or liver complications were not available, the patient entry was excluded from analysis. Mode of transmission was collected categorically and included: sexual, same sex; sexual, hetero; IV drug use; blood transfusion; other; unknown. In the instance of HBV-related variables, being correctly vaccinated against HBV was collected as “yes,” “no,” and “unknown”. Year of diagnosis and was collected as a continuous variable in years. If an HCV patient had a reported year of diagnosis prior to 1989 (year of the discovery of the virus), this was considered a diagnosis of “non-A non-B” hepatitis. Origin of patient referral was also collected categorically (primary care; other specialty in the same centre; gastroenterology or hepatology specialist from another centre; other specialist from another centre; other; unknown). Blank answers were treated as missing values. Any anomalies in databases were verified with the co-author from each corresponding centre to be verified and modified if needed. Data that did not meet inclusion criteria were removed from the database and excluded from analysis; under the age of 18 (n = 12); HBsAg negative (n = 4); ALT > 600 UI/L (n = 31); no data on liver fibrosis, HCC, or liver complications to calculate LP (n = 11). Statistical analyses. The prevalence of LP was calculated for the whole sample and stratified according to the following categories: chronic HBV or HCV infection, participant centre, sex, country of origin (Spanishborn vs foreign-born), mode of transmission, and origin of referral. Patients who presented late to care were compared to patients without late presentation. Binary logistic regression tested the odds ratios (OR) between late presentation and three variables of interest (sex, age, and country of origin). The level of significance was set to < 0.05, and data were analysed using Stata, version 16. Ethics approval and consent to participate. This study received ethical clearance in 2019 from the Ethical Committee of the Hospital Clínic, Barcelona, Spain (n. HCB/2019/0111), and was performed in accordance with relevant guidelines and regulations. No personally identifiable information was collected from study participants. Results 2290 patients were included in this study (HBV = 505, HCV = 1785). The mean age of the population was 53.8years (SD: 14.4) and men represented 62.6% (n = 1434) of the population (Table1). The majority (77.9%; 1783) of patients were Spanish-born and the majority of patients with viral hepatitis infection had an “unknown” (59.6%; 1366) mode of transmission, followed by injecting drug use (21.4%; 490). Most patients were referred to the liver specialist for the first time from primary care (44.4%; 1016), followed by an “other” referral (17.3%; 396). 8.8% (n = 203) of patients did not have a reported origin of referral. The mean year of diagnosis for 2199 patients with available data was 2011 (SD: 9.2) with a range of diagnosis year from 1966 to 2019. 54.4% (n = 1245) of the data were collected from a review of 2018 patient history and the remaining from 2019 (n = 1045). There were no changes in LP prevalence between the two years of data collection (25.9% vs 25.5%, respectively). Late presentation was detected in 25.7% (n = 588) of all patients. ALD was reported in 552 (24.1%) patients and LSLD was reported in 5.3% (122) of all patients (Table2). Overall, 15.7% (359) presented with stage F4 fibrosis and 7.4% (170) had stage F3 fibrosis at first consultation determined by Fb > 9.5 at most centres (1166; 50.9%) (Supplementary Table1). An additional 23 (1%) who did not have fibrosis stage reported and had AST and platelet count values available had an APRI score greater than 1.5, indicating ALD. Mean ALT was 67.6 UI/L and Box1. Consensus definition of late presentation with chronic viral hepatitis for medical care. Source Mauss etal.15. APRI aspartate aminotransferase to platelet ratio, F3 stage 3 fibrosis, FIB-4 Fibrosis 4, HBV hepatitis B virus, HCV hepatitis C virus, METAVIR Meta-analysis of Histological Data in Viral Hepatitis. Presentation with advanced liver disease (ALD) in untreated patients with chronic hepatitis B and C A patient with chronic HBV or HCV and significant fibrosis assessed by one of the following: serologic fibrosis score ≥ 3 (assessed by APRI score > 1.5, FIB-4 > 3.25, Fibrotest > 0.59 or alternatively transient elastography (FibroScan) > 9.5kPa or liver biopsy (≥ METAVIR stage F3) in patients with no previous antiviral treatment Presentation with late-stage liver disease (LSLD) in untreated patients with chronic hepatitis B and C A patient with a fibrosis score > F3 and presence of at least one symptom of decompensated cirrhosis (jaundice, hepatic encephalopathy, clinically detectable ascites, variceal bleeding) and/or hepatocellular carcinoma in patients with no previous antiviral treatment 4 Vol:.(1234567890) Scientific Reports | (2021) 11:24133 | https://doi.org/10.1038/s41598-021-01885-0 www.nature.com/scientificreports/ AST was 57.6 UI/L. Seventy-five (3.3%) patients reported at least one liver complication defining decompensated cirrhosis. The most common reported liver complication was clinical ascites (17.9%; 35), followed by jaundice (12.3%; 24). An additional 113 “other” non-decompensated cirrhosis defining liver complications were reported. Chronic HBV and HCV. Patients with chronic HCV infection were more likely to present late to care compared to those with chronic HBV (28.6% vs 15.4%; p < 0.001). ALD was reported more frequently in HCV patients compared to HBV patients (26.9% vs 14.3%; p < 0.001) and LSLD was described in 5.5% (n = 28) and 5.2% (n = 94) of HBV and HCV patients, respectively (p = 0.806). HCV patients had a higher mean ALT at baseline compared to HBV patients: 57 UI/L [95% CI 44.8–70.9] and 70 UI/L [95% CI 67.3–73.7]; p = 0.0069) and AST at baseline (59.9 UI/L [95% CI 57.2–62.6] and 49 UI/L [95% CI 40.2–59.5]; p = 0.0065). HBV patients presenting late to care had a significantly higher proportion of ALT and AST values above the upper limit of normality (≥ 40) in comparison to those not presenting late (ALT: 60.8% v. 26.9%; p < 0.001, AST: 60.8% v. 21.3%; p < 0.001). This same trend was similar among HCV patients (ALT: 78.2% v. 59.9%; p < 0.001, AST: 78.4% v. 50.1%; p < 0.001). Hepatocellular carcinoma (HCC). 55 (2.4%) patients presented with HCC at first consultation (Table3). The majority of HCC patients were Spanish born and male. Those with HCC were significantly older than those without HCC (p < 0.001) and 81.8% of those with HCC at first consultation (n = 55) were chronic HCV patients (n = 45) (p < 0.001). Those with HCV infection and HCC on average were older than those with HBV infection and HCC (64.8years vs. 56years). Country of origin. Of those that presented late to care, the majority (85.7%; 504) were Spanish-born individuals and foreign-born individuals made up 13.2% (n = 78) of those presenting late to care (p < 0.001). HCV patients were primarily Spanish-born individuals (87.3%; 1559) (Map1) whereas about half of all HBV patients were foreign-born individuals (54.5%; 275) (Map2). 34.6% (n = 27) of HBV patients who presented late to care were foreign-born (p = 0.001) compared to 10.0% (n = 51) of HCV patients (p = 0.079). After Spain (1783), patients were primarily from China (66), Romania (39), Georgia (37), Pakistan (39), and Senegal (29). Patients from these mentioned countries all presented late to care (Maps 1 and 2). Chinese and Senegalese patients primarily had chronic HBV, representing 97% (64) and 96.5% (28) of their infections, respectively. In comparison, patients from Georgia primarily had chronic HCV (83.8%; 31). Romanian patients Table 1. Baseline characteristics of all patients included in the 11 Spanish centres, 2018/19. HBV hepatitis B virus, HCV hepatitis C virus. OVERALL (N = 2290) N = 2290 HBV (N = 505) N (%) HCV (N = 1785) N (%) Age, mean (SD) 53.8 (14.4) 46.2 (15.6) 55.9 (13.3) Sex Male 1434 (62.6) 294 (58.2) 1140 (63.9) Female 854 (37.3) 211 (41.8) 643 (36.0) Country of origin N = 2274 Spanish-born 1783 (77.9) 224 (44.4) 1559 (87.3) Foreign-born 491 (21.4) 275 (54.4) 2176 (12.1) Missing values 16 (0.7) 6 (1.2) 10 (0.6) Mode of transmission Sexual, same sex 23 (1.0) 9 (1.8) 14 (0.8) Sexual, hetero 38 (1.7) 11 (2.2) 27 (1.5) Injecting drug use 490 (21.4) 5 (0.9) 485 (27.2) Blood transfusion 185 (8.1) 15 (2.9) 170 (9.5) Other 149 (6.5) 78 (15.4) 71 (4.0) Unknown 1366 (59.6) 385 (76.2) 981 (54.9) Missing values 39 (1.7) 2 (0.4) 37 (2.1) Year of diagnosis (mean, SD) 2011 (9.4) 2013 (8.9) 2010 (9.2) Origin of referral Primary care 1016 (44.4) 276 (54.6) 740 (41.5) Other specialty in the same centre 319 (13.9) 114 (22.6) 205 (11.5) Gastrohep specialist from another centre 228 (9.9) 30 (5.9) 198 (11.1) Other specialist from another centre 79 (3.4) 13 (2.6) 66 (3.7) Other 396 (17.3) 11 (2.2) 385 (21.6) Unknown 203 (8.8) 47 (9.3) 156 (8.7) Missing values 49 (2.1) 14 (2.8) 35 (1.9) 5 Vol.:(0123456789) Scientific Reports | (2021) 11:24133 | https://doi.org/10.1038/s41598-021-01885-0 www.nature.com/scientificreports/ represented both chronic HBV (53.8%; 21) and HCV (46.2%; 18) infections. Similarly, patients from Pakistan also represented both chronic HBV (41.4%; 12) and HCV (58.6%; 17) infections. Age. Overall, those who presented late to care were older (59years vs 51years; p < 0.001) than those who did not present late. This trend did not change for patients with ALD (59years vs 52years; p < 0.001) or LSLD (59years vs 53years; p < 0.001). HCV patients were significantly older compared to HBV patients (56years vs 46years; p < 0.001). Sex. Men were more likely to present late to care compared to women (30.3% vs17.8%; p < 0.001). This trend did not change for patients with ALD where 28.7% (n = 412) of men and 16.3% (139) of women had ALD (p < 0.001). The proportion of patients who presented with LSLD was double in men (6.4%; 92) compared to women (3.5%; 30) (p = 0.011). Origin of referral. Patients who were referred from primary care made up 39.3% (n = 231) of patients who presented late to care (Table4). Table 2. Description of HBV and HCV LP patients (N = 2290), categorised by ALD/LSLD in 11 Spanish hospitals. ALD advanced liver disease, APRI aspartate aminotransferase to platelet ratio, F3 stage 3 fibrosis, F4 stage 4 fibrosis, HBV hepatitis B virus, HCV hepatitis C virus, LP late presentation, LSLD late-stage liver disease. a Late presentation to care includes those with ALD and LSLD, of which, some patients may classify in both categories (i.e. a patient may have fibrosis F4 and a liver complication). b Number of patients for each type of liver complication sum to more than the “YES” total because some patients reported more than one liver complication. Overall HBV (N = 505) HCV (N = 1785) n (%) n (%) n (%) Late presentation to carea Yes 588 (25.7) 78 (15.4) 510 (28.6) Advanced liver disease 552 (24.1) 72 (14.3) 480 (26.9) Missing values 10 (0.4) 2 (0.4) 8 (0.5) Fibrosis stage F3 170 (7.4) 17 (3.4) 153 (8.6) F4 359 (15.7) 48 (9.5) 311 (17.4) APRI > 1.5 23 (1.0) 7 (1.4) 16 (0.9) Late-stage liver disease 122 (5.3) 28 (5.5) 94 (5.2) Hepatocellular carcinoma 55 (2.4) 10 (2.0) 45 (2.5) Missing values 78 (3.4) 0 (0) 78 (4.3) Decompensated cirrhosis defining liver complicationsb Yes 75 (3.3) 19 (3.8) 56 (3.1) Jaundice 21 (0.9) 9 (1.8) 12 (0.7) Hepatic encephalopathy 8 (0.3) 0 (0) 8 (0.4) Ascites 37 (1.6) 11 (2.1) 26 (1.4) Variceal bleeding 18 (0.8) 3 (0) 15 (0.8) Missing values 214 (9.3) 133 (26.3) 186 (10.4) Table 3. Description of patients with and without HCC who presented late to care. Spain, 2018/2019. Missing values not reported. HCC hepatocellular carcinoma. Patients with HCC (n = 55) Patients without HCC (n = 2173) Age, mean (SD) 63.2 (12.6) 53.4 (14.2) Sex Male 42 (2.9) 1352 (94.3) Female 13 (1.5) 803 (94.0) Country of origin Spanish-born 50 (2.8) 1683 (93.7) Foreign-born 5 (1.0) 474 (96.1) 6 Vol:.(1234567890) Scientific Reports | (2021) 11:24133 | https://doi.org/10.1038/s41598-021-01885-0 www.nature.com/scientificreports/ Map 1. Percent of HCV LP patients by country of origin (A) and number of HCV LP patients (N = 510) from each corresponding country (B). HCV hepatitis C virus, LP late presentation. Map was created using Tableau version 2021.1.0 (www. table au. com). 7 Vol.:(0123456789) Scientific Reports | (2021) 11:24133 | https://doi.org/10.1038/s41598-021-01885-0 www.nature.com/scientificreports/ Map 2. Percent of HBV LP patients by country of origin (A) and number of HBV LP patients (N = 78) from each corresponding country (B). HBV hepatitis B virus, LP late presentation. Map was created using Tableau version 2021.1.0 (www. table au. com). 8 Vol:.(1234567890) Scientific Reports | (2021) 11:24133 | https://doi.org/10.1038/s41598-021-01885-0 www.nature.com/scientificreports/ Participating centres. Eleven tertiary hospitals, representing six out of the 17 (35%) autonomous communities in Spain, provided data. Late presentation to care ranged from 4.6% to 34% across the centres and autonomous communities (Table5). HCV patients presented late to care more frequently than HBV patients across all centres. Bivariate logistic regression analyses with late presentation as the outcome (Table6) were conducted for sex, age, origin of referral, and country of origin (Spanish-born vs. foreign-born). Being female was associated with a 50% decreased odds of LP and being Spanish born was associated with double the odds of presenting late. Each additional year of age corresponded to 0.3% greater odds of LP. Compared to primary care as the origin of referral, each of the other origins of referral showed greater odds of late presentation and in particular, having an unknown origin of referral had the greatest odds of LP. Discussion Late presentation to hepatitis specialist care (liver units or gastroenterologist specialists) continues to be a challenge in Spain, with nearly one-fourth of the patients in this study of 11 large university hospitals presenting with advanced liver disease or late-stage liver disease at first consultation with a liver specialist. Patients with chronic hepatitis C infection presented late to care more frequently than those with hepatitis B and were predominantly Spanish-born individuals. Late presentation to care results in more advanced disease progression at baseline, making treatment (for both HBV and HCV) and subsequent cure (in the case of HCV) more challenging. In Spain, cirrhosis and other chronic liver diseases due to HCV and HBV accounted for 1598 deaths (0.38% of total) and 618 (0.15%) deaths in 2017, respectively. Liver cancer accounted for 2860 (0.69%) deaths due to HCV and 409 (0.1%) deaths due to HBV in the same year17. Health systems must ensure that those who are in need of treatment are screened, diagnosed, and linked to specialist care before their liver disease progresses to cause substantial liver damage18. Table 4. Referral origin of LP patients, compared to those who did not present late (Spain, 2018/2019). LP late presentation. Origin of referral Late presentation, n (%) No late presentation, n (%) Primary care 231 (22.7) 785 (77.3) Other specialty in the same centre 90 (28.2) 229 (71.8) GI specialist from another centre 67 (29.4) 161 (70.6) Other specialist from another centre 24 (30.4) 55 (69.6) Other 101 (25.5) 295 (75.5) Unknown 64 (31.5) 139 (68.5) Missing values 11 (22.4) 38 (77.6) Total 588 (100) 1702 (100) Table 5. Proportion of HBV and HCV LP patients categorised by 11 participating Spanish centres, 2018/2019. N/A not available—did not provide HBV data. HBV hepatitis B virus, HCV hepatitis C virus, LP late presentation. *(%) reported in relation to the total of all patients in the hospital. Hospital (city) HBV patients n (%)* % HBV patients with LP n (%) HCV patients n (%)* % HCV patients with LP n (%) Total patients (n) Overall LP n (%) Hospital 1 (Tenerife) 36 (12.2) 6 (16.7) 260 (87.9) 68 (26.1) 296 74 (12.6) Hospital 2 (Santander) 25 (18.4) 4 (16.0) 111 (81.6) 40 (36.0) 136 44 (7.6) Hospital 3 (Madrid) N/A N/A 143 (100) 45 (31.5) 143 45 (7.6) Hospital 4 (San Sebastián) 27 (10.6) 8 (29.6) 226 (89.3) 69 (30.5) 253 77 (13.1) Hospital 5 (Barcelona) 125 (31.0) 16 (12.8) 278 (69.0) 39 (14.0) 403 55 (9.3) Hospital 6 (Madrid) 21 (17.8) 4 (19.0) 97 (82.2) 29 (29.9) 118 33 (5.6) Hospital 7 (Pontevedra) N/A N/A 136 (100) 26 (19.1) 136 26 (4.4) Hospital 8 (Sevilla) 48 (35.8) 13 (27.1) 86 (64.2) 33 (38.4) 137 46 (7.8) Hospital 9 (Barcelona) 163 (38.6) 10 (6.2) 258 (61.4) 90 (34.8) 420 100 (17.0) Hospital 10 (Málaga) 47 (30.7) 16 (34.0) 106 (69.3) 45 (42.4) 153 61 (10.4) Hospital 11 (Zaragoza) 14 (14.3) 1 (7.1) 84 (54.7) 26 (30.9) 98 27 (4.6) 9 Vol.:(0123456789) Scientific Reports | (2021) 11:24133 | https://doi.org/10.1038/s41598-021-01885-0 www.nature.com/scientificreports/ In the instance of human immunodeficiency virus (HIV), a definition of late presentation at the time of diagnosis has aided in surveillance and the identification of risk factors for presenting late with HIV19 in addition to monitoring trends over time20. Delayed linkage to care or loss to follow-up after referral to specialised care poses a significant barrier to timely treatment initiation21 and poses additional risk for ALD and LSLD. A delayed referral for specialised treatment from primary care, where viral hepatitis diagnoses are often made, extends the amount of time individuals live undertreated or untreated with either or both diseases, highlighting deficiencies within the health system. Not only should screening for viral hepatitis be strengthened at the primary care level, but the referral pathway needs to be improved. In our study, we identified patients being referred from other specialists in the same hospital or even other gastroenterology and hepatology services from other hospitals. The former suggests that referral processes in the hospitals need to be strengthened, which is a healthcare failure. The latter possibly highlights that some patients may have difficult-to-treat hepatic conditions, rather than them presenting late to viral hepatitis care. This nuance should be considered by healthcare providers at the point of care engagement, when, despite presenting with ALD or LSLD, patients may not have initially presented late to care. Strong care pathways (e.g. referral processes) area particular challenge during the ongoing COVID-19 pandemic as primary care centres in Spain are overburdened with COVID-19 cases, and may have less capacity and resources to address other morbidities, including viral hepatitis. In our study, the mean year of patients’ diagnosis was 2011; 7–8years prior to reaching specialist care with a gastroenterologist or hepatologist despite possibly having been in hospital care for comorbidities. Patients who present with hepatocellular carcinoma at first consultation with a specialist initiate treatment once the impact of prolonged and untreated viral hepatitis infection has already resulted in irreversible liver damage. Deaths due to cirrhosis constituted 2.4% of total deaths globally in 201722. In a single-centre study conducted in Denmark, 5.3% (28/527) of patients presenting late (n = 169) had LSLD at first consultation23. Our study reported a similar prevalence of LSLD (5.8%), of which 55 patients presented with HCC at first consultation between the years 2018 and 2019. Similarly, in a study using newly-diagnosed hepatitis B related HCC patients (n = 1276) in Korea, Sinn etal. reported that in 2013, 23.1% of patients with newly diagnosed HCC cases had no prior clinic visits before their HCC diagnosis24. In contrast, in 2003, this prevalence was 50.9%, highlighting the impact of effective targeted screening in Korea. However, any proportion of LP, and specifically of HCC at first consultation, highlights that timely diagnosis and referral needs to be optimized and targeted as a public health challenge. In the study by Sinn etal.24, authors reported that a lower income was associated with a higher risk of LP. Our study did not collect income level variables; however, it would be interesting to further explore potential barriers to accessing specialised care in Spain, which could include socioeconomic barriers. Healthcare is free and universal for all legal residents of Spain in all autonomous communities of the country so cost of care would not be anticipated to be a main factor contributing to LP to care. However, HBV patients were predominantly foreign-born individuals, particularly from sub-Saharan African and Asian countries. Migrants who have irregular legal status in the country would not be entitled to access the public healthcare system, which could be a risk factor contributing to the 15.0% of LP HBV cases in our study. Furthermore, 35% of all HBV patients who presented late to care were not Spanish natives, highlighting the importance of early detection of HBV among migrant populations residing in Spain. In addition, HBV vaccination coverage of foreign-born individuals was not well reported across all centres, with nearly 50% reporting incorrect vaccination among patients and an additional 40.8% in missing values (data not reported in results). Incomplete or incorrect vaccination of HBV among patients arriving to Spain from endemic countries should suggest an urgency for timely HBV screening. Proper vaccination coverage reporting will consolidate current monitoring and surveillance methods and may detect gaps in testing and referral services. Table 6. Odds ratios and their 95% confidence intervals univariate logistic regressions for late presentation. GI gastrointestinal. Variable Odds ratio (OR) 95% Confidence interval p-value Age 1.03 [1.03–1.04] < 0.001 Sex Male (reference group) – – < 0.001 Female 0.49 [0.40–0.61] Country of origin Foreign-born (reference group) – – – Spanish born 2.08 [1.60–2.71] < 0.001 Origin of referral Primary care (reference group) – – – Other specialty in the same centre 1.33 [1.00–1.77] 0.046 GI specialist from another centre 1.41 [1.02–1.94] 0.034 Other specialist from another centre 1.48 [0.89–2.44] 0.124 Other 1.16 [0.88–1.52] 0.271 Unknown 1.56 [1.12–2.17] 0.008