Gastroenterology Report, 8(5), 2020, 362–366 doi: 10.1093/gastro/goaa010 Advance Access Publication Date: 27 March 2020 Original article ORIGINAL ARTICLE Current trends in access to treatment for hepatitis B in immigrants vs non-immigrants Mireia Miquel 1,2,†, Albert Pardo3,†, Montse Forné2,4, Gemma Martı́nez-Alpin5, Adrià Rodrı́guez-Castellano3, Meritxell Casas1, Mercè Rosinach4, Mercè Roget5, Blai Dalmau1, Rocı́o Temin ~ o4, Joan Carlos Quer3, Jordi Sanchez-Delgado1,2,*, Jordi Ortiz5 and Mercedes Vergara1,2 1 Liver Unit, Gastroenterology Department, Parc Taulı́ University Hospital, Institut d’Investigacio i Innovació Parc Taulı́ I3PT, Autonomous University of Barcelona, Sabadell, Spain; 2Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; 3 Gastroenterology Department, University Hospital Joan XXIII, Tarragona, Spain; 4Liver Unit, Gastroenterology Department, University Hospital Mútua Terrassa, Barcelona, Spain; 5Liver Unit, Gastroenterology Department, Consorci Sanitari de Terrassa, Terrassa, Spain *Corresponding author. H.U. Parc Taulı́, Parc Taulı́ s/n, Sabadell 08206, Spain. Tel: þ34-937458356; Email: Jsanchezd@tauli.cat † These authors have contributed equally to this work. Abstract Background: Universal vaccination for hepatitis B virus (HBV) and migratory movements have changed the demographic characteristics of this disease in Spain and in Europe. Therefore, we evaluated the characteristics of the disease and the pos- sible differences according to origin (immigrants vs non-immigrants) and access to treatment. Methods: This is a multicenter cross-sectional study (June 2014 to May 2015) in which outpatients with a positive HBsAg were seen and followed in four Hepatology units. Demographic and clinical data and indication and access to treatment were collected in two different regions of Catalonia (Spain) where there are no barriers to treatment due to a comprehensive coverage under the National Health System. Results: A total of 951 patients were evaluated (48.1% men). Of these, 46.6% were immigrants (58.7% of them were born in Africa) and were significantly younger compared to non-immigrants. The proportions of patients with alcohol consumption, being overweight, and other indicators of metabolic co-morbidities were significantly higher in non-immigrants. Among the 937 patients receiving HBeAg examination, 91.7% were HBeAg-negative. Chronic HBeAg-positive infection was significantly higher in immigrants (3.9% vs 0.6%, P ¼ 0.001) and chronic HBeAg-negative hepatitis was higher non-immigrants (31.7% vs 21.4%, P < 0.001). Not only was the proportion of patients who met treatment criteria significantly higher among non- immigrants (38.4% vs 29.2%, P ¼ 0.003), but also the proportion of those with indication of effectively receiving therapy at the time of data collection (83.2% vs 57.8 %, P < 0.001). Conclusions: The immigrant population with HBV is younger and has a lower prevalence of metabolic co-morbidities and a higher frequency of chronic HBeAg infection. Despite having access to care and an indication for treatment, some do not get adequately treated due to several factors including local adaptation that precludes access to treatment. Key words: hepatitis B; prevalence; immigration; access to treatment Submitted: 7 August 2019; Revised: 27 September 2019; Accepted: 20 October 2019 C The Author(s) 2020. Published by Oxford University Press and Sixth Affiliated Hospital of Sun Yat-sen University V This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. 362 Hepatitis B in immigrants vs non-immigrants | 363 Introduction Two circumstances in recent decades have played an important role in the epidemiology of hepatitis B virus (HBV) infection in Europe. The first is the implementation of universal vaccination programs with a significant decrease in its prevalence [1, 2]. In a recent population study,<0.5% of HBsAg carriers were observed [3]. According to these data, Spain (which several years ago had been considered an area of intermediate prevalence [4]) is now a low prevalence region [5]. The second event is related to the significant flow of immigrants who currently represent 12% of the population [6]. Given that a significant proportion of these Figure 1. Origin of the immigrant population (Source: IDESCAT.CAT). people come from areas of high prevalence of HBV, it has been considered that this new scenario could explain an attenuated considered native cases (non-immigrant) and those who were decline in the infection rate in the general population [7, 8]. born abroad as immigrants. Presently, nearly half of the patients infected with HBV in Spain are immigrants [3]. There are scarce data on the impact of immigrants with HBV in Spain and Europe [9–13]. There are pre- Variables sumably some differences between the non-immigrant and im- The following clinical-variables data were collected: sex, date, migrant population (such as the demographic characteristics, and country of birth; the level of education (without studies, pri- the evolutionary phase of the disease, and even cultural mary, high school, and university); and the presence of the aspects) that may have significant implications in the diagnosis, usual epidemiological risk factors in relation to the transmis- follow-up, and management of the disease. Therefore, the main sion of hepatitis B (transfusion of blood products, intravenous objective of this study was to analyse the characteristics of im- drug use, tattoos or piercings, infected first-degree relatives, migrant and non-immigrant patients infected with HBV moni- and high-risk sexual relationships). Likewise, the history of al- tored in four specialized Hepatology units. More specifically, we evaluated the differences including access to treatment be- cohol consumption (high-risk consumption was defined as that tween immigrant and non-immigrant populations in two large >30 grams per day) and the presence of other co-morbidities (di- metropolitan areas in Spain where there are no expected bar- abetes mellitus, hypertension, dyslipidemia, and overweight) riers to treatment due to the comprehensive health coverage were recorded. under the National Health System (NHS). The following laboratory data were collected (that closest to the date of inclusion): complete liver biochemistry, serological markers of HBV (HBsAg, HBeAg, antiHBc, antiHBs, and antiHBe) Materials and methods and HBV viral load. In all the centers, the quantification of the Study design HBV DNA was carried out by real-time polymerase chain reac- tion with a measurement interval between 20 and This was an observational multicenter cross-sectional study in 1,700,000,000 IU/mL. The criteria recently defined by the four major reference hospitals in Catalunya, Spain (H. Parc European Association for the Study of the Liver (EASL) were Taulı́, H. Consorci Sanitari de Terrassa, H. Mútua de Terrassa used to characterize patients into four groups with respect to and Hospital Joan XXIII). The first three serve a population of the evolutionary phase of the infection: (i) chronic HBeAg-posi- around 900,000 inhabitants, of whom 9.68% are of immigrant or- igin, and the fourth (H. Joan XXIII) serves a population of about tive infection, (ii) chronic HBeAg-positive hepatitis, (iii) chronic 250,000 inhabitants and a proportion of immigrants of 16.06% HBeAg-negative infection and (iv) chronic HBeAg-negative hep- (Figure 1) [6]. All have protocols for the intake of immigrants atitis. We evaluated whether patients met criteria for therapy that include the systematic determination of HBV serology as according to EASL guidelines [14]. Likewise, data on whether the well as referral circuits between primary and specialized care patients were effectively receiving antiviral treatment or not for hepatitis B. The study was approved by the Clinical Research according to these recommendations were collected. In cases in Ethics Committee of each center and was registered in the clini- which liver biopsy or elastography was performed, the cal trial database (NCT: 02548325). The information was col- METAVIR classification for fibrosis and the liver-stiffness value lected via electronic medical records. The identity of patients in kPa was recorded (a threshold of 7.5 kPa was considered to es- was maintained confidential for all purposes, complying with tablish the suspicion of significant fibrosis) [15]. the Organic Law of 15/1999, on the Protection of Personal Data. The principal investigator, in order to avoid the repeated inclu- sion of a same case in two of the participating centers, reviewed Statistical analysis the database. If a duplication was detected, the record with the Continuous variables are expressed as mean with standard de- latest date was excluded. viation or median with interquartile range (IQR) and the qualita- tive variables as percentages with a confidence interval of 95%. Study population The continuous variables were compared with the Student’s t- All patients with a positive HBsAg were evaluated in the Liver test in the variables of normal distribution. Non-parametric val- Clinic of each participating hospital between 1 June 2014 and 31 ues were evaluated with the McNemar test. The categorical var- May 2015. We excluded those <18 years of age; those co- iables are compared with chi-square test and the ordinal infected with HIV, hepatitis C, or delta hepatitis; and those in categorical variables with rank-sum test. To perform the statis- which the infection was acute. All those patients who were tical analysis, we used the SPSS program, version 21. A P < 0.05 born in Spain (regardless of their family ethnic origin) were was considered significant. 364 | M. Miquel et al. Table 1. Demographic and clinical characteristics of both populations Characteristic Global (n ¼ 951) Non-immigrant (n ¼ 508) Immigrant (n ¼ 443) P-value Age, years 46 6 14 54 6 12 36 6 10 <0.001 Male gender 457 (48.1) 249 (49.0) 208 (47.0) >0.05 Education level n ¼ 397 n ¼ 235 n ¼ 162 0.036 Without studies 48 (12.1) 27 (11.5) 21 (13.0) Primary 195 (49.1) 131 (55.7) 64 (39.5) High school 113 (28.5) 55 (23.4) 58 (35.8) University studies 41 (10.3) 22 (9.4) 19 (11.7) Transmission routes n ¼ 151 n ¼ 84 n ¼ 67 First-degree family/vertical 42 (27.8) 8 (9.5) 34 (50.7) <0.001 Post-transfusion 36 (23.8) 29 (34.5) 7 (10.4) 0.005 Piercings/tattoos 47 (31.1) 31 (36.9) 16 (23.8) >0.05 Intravenous drug user 3 (2.0) 2 (2.4) 1 (1.5) >0.05 Sexual risk behavior 23 (15.2) 14 (16.6) 9 (13.5) >0.05 Alcohol-consumption history 85 (15.8) 67 (21.0) 18 (8.3) <0.001 Overweight (BMI > 25 kg/m2) 498 (52.4) 314 (61.8) 184 (41.5) <0.001 Co-morbidities n ¼ 553 n ¼ 323 n ¼ 230 Arterial hypertension 73 (13.2) 60 (18.6) 13 (5.7) <0.001 Dyslipidemia 78 (14.1) 66 (20.4) 12 (5.2) <0.001 Diabetes mellitus 37 (6.7) 30 (9.3) 7 (3.0) 0.003 Values are presented as mean 6 standard deviation or n (%). BMI, body mass index. Results A total of 998 patients with a positive HBsAg were included. Of these, 47 were excluded: 30 due to co-infection with another vi- rus (13 HCV, 13 HDV, and 4 HIV), 12 due to acute HBV infection, and 5 due to age <18 years. Finally, 951 cases were analysed; 305 (32.1%) in H. Parc Taulı́, 124 (13.0%) in Mútua de Terrassa, 124 (13.0%) in Consorci Sanitari de Terrassa, and 398 (41.9%) in H. Joan XXIII. Non-immigrant patients had a median follow-up of 5.17 years (IQR: 10.55) and immigrant patients of 3.25 years (IQR: 3.25) (P < 0.001). Demographic characteristics There were 508 (53.4%) non-immigrant and 443 (46.6%) immi- Figure 2. Disease liver stage in non-immigrants and immigrants. grant patients. Immigrants came from: Africa 260 (58.7%), other parts of Europe 88 (19.9%) (mainly from East-Europe: Romania 48 patients, Bulgaria 10 patients), Asia 69 (15.6%), and Latin Characteristics of the infection America 26 (5.9%). There were no diffrences among centers HBeAg was examined in 937 patients (98.5%). Of the 859 (Figure 1). Immigrants were significantly younger than non- patients (91.7%) with a negative HBeAg, 607 (64.8%) were clas- immigrants (36 6 10 vs 54 6 12 years, P < 0.001) without differen- sified as ‘chronic HBeAg-negative infection’ (formerly called ces in distribution by gender. Immigrants had significantly inactive carriers) and 252 (26.9%) as ‘chronic HBeAg-negative higher education level than non-immigrants (P ¼ 0.036) hepatitis’. Of the 78 patients (8.3%) with a positive HBeAg, 58 (Table 1). (6.2%) were classified as ‘chronic HBeAg-positive hepatitis’ and only 20 (2.1%) as ‘HBeAg-positive chronic infection’ (for- Epidemiological risk factors merly called immunotolerant). The proportion of cases in the phase of ‘chronic HBeAg-positive infection’ was significantly The history of infected first-degree relatives was significantly higher among immigrant patients (3.9% vs 0.6%, P ¼ 0.001), higher among immigrants (15.9% vs 2.7%, P < 0.001), while a his- while the frequency of cases in the ‘chronic HBeAg-negative tory of transfusion was more frequent among non-immigrants hepatitis’ was higher among non-immigrants (31.7% vs 21.4, (9.3% vs 3.2%, P ¼ 0.005). No significant differences were found P < 0.001) (Figure 2). regarding a history of tattoos, piercing, current or previous drug In 709 patients (75.7%), transient elastography was per- use, and high-risk sexual contacts. The reported alcohol con- formed. Although the mean value (kPa) of liver stiffness was sumption was significantly higher among non-immigrants higher in immigrant patients (7.0 6 4.7 vs 6.3 6 3.6, P ¼ 0.02), the (21.0% vs 8.3%, P < 0.001), as well as being overweight and other proportion in which the value was considered suspicious for indicators of metabolic co-morbidity (hypertension, dyslipide- significant fibrosis (>7.5 kPa) was higher among non- mia, and diabetes mellitus) (Table 1). immigrants but without significance (23.9% vs 18.9%, P ¼ 0.1). Hepatitis B in immigrants vs non-immigrants | 365 Table 2. Characteristics of the disease and treatment Characteristic Global (n ¼ 937) Non-immigrant (n ¼ 498) Immigrant (n ¼ 439) P-value HBeAg-positive 78 (8.3) 34 (6.8) 44 (10.0) >0.05 Transient elastography n ¼ 709 n ¼ 376 n ¼ 333 LSM, kPa 6.5 6 4.1 7.0 6 4.7 6.3 6 3.6 0.020 LSM > 7.5 kPa 153 (21.6) 90 (23.9) 63 (18.9) >0.05 Fibrosis degree by liver biopsy n ¼ 188 n ¼ 119 n ¼ 69 >0.05 F0 77 (41.0) 49 (41.1) 28 (40.6) F1 28 (14.9) 18 (15.1) 10 (14.5) F2 26 (13.8) 15 (12.6) 11 (15.9) F3 48 (25.5) 33 (27.7) 15 (21.7) F4 8 (4.3) 4 (3.4) 4 (5.8) Treatment indication 319 (34.0) 191 (38.4) 128 (29.2) 0.003 Under treatment 233 (73.0) 159 (83.2) 74 (57.8) <0.001 Values are presented as mean 6 standard deviation or n (%). LSM, liver-stiffness measurement. Liver biopsy was performed in 188 patients (19.8%) and this proportion was significantly lower among immigrants vs non- immigrants (16% vs 24%, P ¼ 0.002). There were no statistically significant differences between both groups regarding the dis- tribution between the different degrees of fibrosis observed in the biopsy according to the METAVIR classification (Table 2). Treatment indication According to EASL guidelines, 319 patients (34.0%) fulfilled at least one of the criteria for treatment. The proportion was sig- nificantly higher in non-immigrants (38.4% vs 29.2%, P ¼ 0.004). Likewise, the proportion of patients with a treatment indication who, in fact, were receiving any type of therapy at the time of Figure 3. Differences in treatment indicated and treatment effectively received inclusion in the study was higher among non-immigrants com- between non-immigrants and immigrants. The two columns on the left show pared to immigrants (83.2% vs 57.8%, P < 0.001) (Figure 3). the percentage of patients with treatment criteria. The two on the right show the percentage of patients who receive treatment of those who have an indication. Discussion non-immigrants. A possible explanation for this is likely due to The current study demonstrates that immigrants with chronic age and cofactors such as alcohol or being overweight. In addi- HBV who are candidates for antiviral therapy have low access to tion, one of the aspects that we consider most relevant was that treatments compared to non-immigrants. In addition, the results the proportion of immigrants that were not treated despite from this analysis confirm that immigrants infected with HBV rep- meeting criteria of the EASL recommendations [14]. Thus, 42% resent a sizable proportion of patients in urban areas. These of the immigrant patients with an indication of treatment were results are comparable to those observed in a recent study (con- not receiving it at the time of inclusion, whereas this only oc- ducted from a population perspective) which estimates that 55% curred in 17% of the non-immigrants. There are several reasons of patients infected with HBV in a region of Spain are of immigrant that could explain these inequalities. One is that the decision to origin [3]. This highlights the fact that the population prevalence treat takes into account the evolution of the disease. Since of HBV infection in Spain, which is already below intermediate val- ues, would be even lower if this demographic change had not oc- immigrants have short follow-up after they are first seen, this curred [7]. To our knowledge, there are no published studies precludes many of them from getting adequate therapy. In a addressing these discrepancies in Spain or Europe. The study also previous study carried out in one of the participating centers, it demonstrates that immigrant patients are younger due to a higher was confirmed that the loss of follow-up, which in many cases vertical transmission and most are immunotolerant. This fact is occurred before the end of the evaluation period and the indica- not surprising given that a large number of the immigrant popula- tion for treatment, was significantly higher among immigrant tion come from regions of high prevalence, where this route of patients [16]. Another reason is related to the problems with lo- transmission is more frequent. On the other hand, non- cal adaptation, as well as family and work stability, which are immigrants were older, had a horizontal transmission (i.e. transfu- often lower among the immigrant population and could be de- sion history), and had other cofactors such as the consumption of termining factors. This lower access to treatment in the immi- alcohol and/or the presence of metabolic co-morbidity. grant population is not exclusive in this pathology [17–19]. In Although the study did not show large differences in relation fact, there are data which demonstrate that the immigrant pop- to the phase of the infection (except for the higher prevalence of ulation, in general, has less access to the health system and immunotolerants in immigrant patients) or in the stage of therefore to specific treatments [20–23]. fibrosis evaluated by elastography and liver biopsy, it did iden- One of the strengths of this study is that it is a multicenter tify a higher percentage with an indication for therapy in study, with percentages of immigration that may be 366 | M. Miquel et al. representative of the territory and other areas of Europe. Thus, 6. Idescat. Població estrangera per comarques i Aran. Catalunya. it provides data on access to treatment in accordance with the https://www.idescat.cat/poblacioestrangera/? b¼4 (22 July latest EASL recommendations. However, a limitation is that it is 2017, date last accessed). a cross-sectional study. Consequently, it was not possible to col- 7. Salleras L, Domı́nguez A, Bruguera M et al. Declining preva- lect the data from all the patients lost from follow-up, which lence of hepatitis B virus infection in Catalonia (Spain) 12 would allow determining whether this is one of the causes of years after the introduction of universal vaccination. Vaccine the lower percentage of patients treated. Another limitation is 2007;25:8726–31. the lack of a prospective follow-up that would allow us to delve 8. Calderón Sandubete E, Yang Lai R, Calero Bernal ML et al. into the causes of the lower rate of treatment. Chronic viral hepatitis B and C in immigrant population. Rev In conclusion, patients of immigrant origin are younger, Esp Salud Publica 2014;88:811–8. with a lower prevalence of metabolic co-morbidity and a higher 9. Coppola N, Alessio L, Pisaturo M et al. Hepatitis B virus infec- frequency of HBeAg-positive infection. Although, in general, tion in immigrant populations. World J Hepatol 2015;7:2955–61. immigrants present in an evolutionary phase of the disease 10. Zampino R, Boemio A, Sagnelli C et al. Hepatitis B virus bur- very similar to that of non-immigrants, a lower percentage of den in developing countries. World J Gastroenterol 2015;21: treated cases was observed in a country with a universal health- 11941–53. care system. Although it would be necessary to have more data, 11. Voiculescu M, Iliescu L, Ionescu C et al. A cross-sectional epi- these results suggest the need of additional efforts in order to demiological study of HBV, HCV, HDV and HEV prevalence in improve adherence to follow-up in consultations in this particu- the SubCarpathian and South-Eastern regions of Romania. lar group of patients. J Gastrointestin Liver Dis 2010;19:43–8. 12. Antonucci G, Mazzotta F, Puoti M et al.; on behalf of the Coorte Authors’ contribution Epatiti B SIMIT (COESI-B) Group. Factors associated with ac- cess to antiviral treatment in a multicentre cross-sectional M.M. and A.P. participated in the design, inclusion of patients, study of patients with chronic hepatitis B in Italy. J Viral Hepat statistical analysis, and drafting of the manuscript. M.F., G.M.A., 2012;19:881–9. A.R.C., M.C., M Rosinach, M Roget, J.C.Q., and M.V. participated 13. Antonucci G, Mazzotta F, Angeletti C et al.; Coorte Epatiti B in the design, inclusion of patients, and critical revision of the SIMIT/COESI-B (HIV) Group. Access to treatment for HBV in- manuscript. B.D., R.T., J.S.D., and J.O. participated in critical revi- fection and its consistency with 2008 European guidelines in sion of the manuscript. All authors have read and approved the a multicentre cross-sectional study of HIV/HBV co-infected final manuscript. patients in Italy. BMC Res Notes 2013;6:153. 14. European Association for the Study of the Liver. EASL 2017 Funding clinical practice guidelines on the management of hepatitis B virus infection. J Hepatol 2017;67:370–98. No funding has been received for this study. 15. Cardoso AC, Carvalho-Filho RJ, Stern C et al. Direct compari- son of diagnostic performance of transient elastography in Acknowledgements patients with chronic hepatitis B and chronic hepatitis C. Liver Int 2012;32:612–21. None 16. Pardo A, Vargas M, Martı́nez-Cerezo F et al. Caracterı́stiques clinicoepidemiològiques, segons l‘origen geogràfic, dels Conflicts of interest pacients infectats pel virus de l‘hepatitis B (VHB) al Camp de Tarragona. Tarragona 2010. https://www.academia.cat/files/ None declared. 425-158-DOCUMENT/ProgramaMONTBRIO.pdf (7 December 2018, date last accessed). References 17. Sharma S, Carballo M, Feld JJ et al. Immigration and viral hep- 1. Arı́stegui Fernández J, Dı́ez-Domingo J, Bermúdez Marés et al. atitis. J Hepatol 2015;63:515–22. Vaccination against hepatitis B. Impact of vaccination pro- 18. Hyde TB, Dentz H, Wang SA et al. The impact of new vaccine grammes after 20 years of use in Spain. Is it time for a introduction on immunization and health systems: a review change? Enferm Infecc Microbiol Clin 2015;33:113–8. of the published literature. Vaccine 2012;30:6347–58. 2. Domı́nguez A, Urbiztondo L, Bayas JM et al.; the Working 19. Pannetier J, Gigonzac V, Lydié N et al. Timing of chronic hepa- Group for the Study of the Immune Status in Healthcare titis B diagnosis after migration and its determinants among Workers of Catalonia. Serological survey of hepatitis B immu- sub-Saharan African migrants living in France. PLoS One 2017; nity in healthcare workers in Catalonia (Spain). Hum Vaccin 12:e0189196. Immunother 2017;13:435–9. 20. Brzoska P. Disparities in health care outcomes between 3. Rodrı́guez-Tajes S, Dacal Y, Collazos C et al. Estudi de prevalença immigrants and the majority population in Germany: a trend d’infecció pels virus hepatitis B i C a Catalunya. In: XXVI Congrés analysis, 2006–2014. PLoS One 2018;13:e0191732. de la Societat Catalana de Digestiu, 2017, 13, http://www.scdigesto 21. Salas-Coronas J, Rogado-González MC, Lozano-Serrano AB logia.org/congressos/xxvicongres/index.php?page¼programa. et al. Tuberculosis and immigration. Enferm Infecc Microbiol 4. Solà R, Cruz De Castro E, Hombrados M et al. Prevalence of Clin 2016;34:261–9. hepatitis B and hepatitis C viruses in different counties of 22. Cuenca-Gómez JA, Salas-Coronas J, Soriano-Pérez MJ et al. Catalonia, Spain: cross-sectional study. Med Clin (Barc) 2002; Viral hepatitis and immigration: a challenge for the health- 119:90–5. care system. Rev Clin Esp 2016;216:248–52. 5. Oviedo M, Mun ~ oz MP, Carmona G et al. The impact of immi- 23. Malmusi D, Ortiz-Barreda G. Health inequalities in immigrant gration and vaccination in reducing the incidence of hepatitis populations in Spain: a scoping review. Rev Esp Salud Publica B in Catalonia (Spain). BMC Public Health 2012;12:614. 2014;88:687–701.