Open access Protocol LINK-­B: study protocol of a retrospective and prospective project for identification and linkage to care of people living with hepatitis B in a large health area of Barcelona Ana Barreira Díaz ‍ ‍,1,2,3 Ariadna Rando,4 Anna Feliu-­Prius ‍ ‍,1,2 Adriana Palom,1 Francisco Rodríguez-­Frías,3,4 Elena Vargas-­Accarino,1,2 Judit Vico-­Romero,1 Nieves Palomo,1 Mar Riveiro-­Barciela,1,2,3 Rafael Esteban,1,3 Maria Buti1,2,3 To cite: Barreira Díaz A, ABSTRACT Rando A, Feliu-­Prius A, et al. Introduction An estimated 290 million people are living STRENGTHS AND LIMITATIONS OF THIS STUDY LINK-­B: study protocol of a ⇒ A large number of hepatitis B virus surface antigen-­ with hepatitis B virus (HBV) worldwide; in Spain, the retrospective and prospective positive individuals in a specific area will be included. prevalence of hepatitis B virus surface antigen (HBsAg) project for identification and ⇒ The tools used in the programme to facilitate health- linkage to care of people living is 0.4%. In our setting, many HBsAg-­positive individuals are not linked to care, which implies a barrier to receiving care communication and promote adherence to with hepatitis B in a large health area of Barcelona. BMJ Open treatment and controlling the infection. The main objective follow-­up are based on information technology. 2022;12:e062680. doi:10.1136/ of this project is to evaluate the performance of a ⇒ The potential impact of the COVID-­19 pandemic on bmjopen-2022-062680 programme designed to achieve appropriate linkage to linkage to care is a limitation that may have been specialist care of HBsAg-­positive individuals, newly tested mitigated with the new tools applied. ► Prepublication history and additional supplemental material or previously tested and lost to follow-­up. for this paper are available Methods and analysis This is a retrospective and online. To view these files, prospective study in which all HBsAg-­positive cases INTRODUCTION please visit the journal online recorded in the microbiology database will be identified. Hepatitis B virus (HBV) infection remains a (http://dx.doi.org/10.1136/​ bmjopen-2022-062680). The retrospective phase will include cases detected major global health problem.1 Chronic HBV between 2018 and 2020, and the prospective phase will infection affects around 290 million people ABD and AR are joint first run from January 2021 to June 2022. The project will worldwide and is a leading cause of cirrhosis, authors. be carried out in a tertiary university hospital covering hepatocellular carcinoma,2 liver transplan- the northern health area of Barcelona with a catchment tation requirement and liver-­related deaths, Received 09 March 2022 population of 450 000 inhabitants and 16 affiliated Accepted 14 December 2022 accounting for more than 800 000 deaths primary care centres. The central laboratory detects annually.3 The Spanish population has an approximately 1200 HBsAg-­positive individuals every estimated hepatitis B virus surface antigen year; therefore, we expect to identify around 4000 patients over the duration of the project. The medical records of (HBsAg) prevalence of 0.4%,4 and this figure HBsAg-­positive individuals will be consulted to identify is likely to increase due to considerable immi- and retrieve those who have not been appropriately linked gration from regions where HBV is endemic.5 to care. Candidates will be contacted to offer specialist Although highly effective hepatitis B vaccines disease assessment and follow-­up. A website will be are available and prevention of viral transmis- created to provide HBV-­related information to primary sion has improved,6 HBV infection remains care physicians, and a mobile phone application will be a major cause of acute hepatitis7 and is asso- available to patients to improve the linkage circuits and ciated with a high health and economic © Author(s) (or their ensure follow-­up continuity. burden.8 employer(s)) 2022. Re-­use Ethics and dissemination The Vall d’Hebrón Hospital Hepatitis B is usually an asymptomatic permitted under CC BY-­NC. No commercial re-­use. See rights Ethics Committee (PR(AG)201/2021) and the Spanish infection,9 and this may explain why a and permissions. Published by Agency of Medicines and Medical Devices approved this large percentage of infected individuals are BMJ. study. The findings will be disseminated through peer-­ unaware of their condition. In 2019, only For numbered affiliations see reviewed publications and conference presentations. This 10% of people with HBV infection world- end of article. programme could increase the number of HBsAg-­positive wide had been diagnosed, and 22% of them individuals properly linked to care and achieve better HBV Correspondence to (6.6 million people) were receiving treat- monitoring, which will have a positive impact on WHO’s Dr Maria Buti; ment,3 even though HBV therapy is orally viral hepatitis elimination goals. ​mbuti@​vhebron.​net administered, well tolerated and effective in Barreira Díaz A, et al. BMJ Open 2022;12:e062680. doi:10.1136/bmjopen-2022-062680 1 Open access suppressing viral replication in almost all cases.10 Elimi- medical records will be evaluated by a physician or expert nation of hepatitis B is a goal of the WHO, and early iden- nurse to determine whether they have been linked to tification of infected individuals and linkage to care are specialist care. crucial to achieve this objective.11 Hence, it is essential to A nurse will initially call patients who have not been design new strategies that involve both the patient and linked (maximum of five attempts per patient). If patients the primary care physician (PCP) to ensure proper HBV cannot be contacted by telephone, a letter will be sent management through regular contacts, motivational to their home address. In both the telephone and letter tactics and simplified access to the specialist linkage contact, patients will be informed of the date and time circuit. of their visit with a hepatologist to review their HBsAg-­ Vall d’Hebrón Hospital in Barcelona is a tertiary univer- positive status (figure 1, online supplemental figure S2). sity hospital with a catchment population of 450 000 In patients who meet the European Association for the inhabitants and 16 affiliated primary care centres. Around Study of the Liver hepatitis B treatment criteria,1 oral 1200 HBsAg-­positive individuals are detected every year nucleos(t)ide analogues will be provided according to in its central laboratory, which receives samples from the clinical guidelines. Subsequent visits will be scheduled hospital and primary care, and many of them do not reach at the discretion of the hepatologist, depending on the appropriate specialist evaluation of their liver disease or clinical situation of each patient. In addition, a simpli- the need for HBV treatment. Linkage of these patients fied referral pathway will be available to PCPs, who can to appropriate specialist follow-­ up will have a positive directly contact the study nurse to set up the appointment impact on the course of their infection and WHO’s viral with the hepatologist. In patients already linked to care hepatitis elimination goals. and receiving adequate follow-­up, no further interven- The goal of this project, called LINK-­B, is to achieve tions will be undertaken. linkage to specialist care of documented HBsAg-­positive patients in the Vall d'Hebrón health area. The secondary Information technology aims are to determine the barriers to linkage in patients New information and communication technologies have with HBV and to set up comprehensive, effective, hepa- proven useful in medicine in promoting adherence titis B guidance and referral pathways in collaboration to follow-­up and treatment by personalising care and with primary care professionals. actively involving the patients.12 13 Use of these tools could improve follow-­up of HBsAg-­positive individuals. A web-­based site will be designed to provide medical METHODS AND STUDY DESIGN information and enable direct contact between PCPs, Study design nurses and hepatologists. Educational programmes, This will be a single-­centre, two-­part, retrospective and including scientific material and linkage pathways, will prospective study. In the retrospective part, a list of be designed in collaboration with PCPs and incorporated HBsAg-­positive cases recorded in the laboratory between in the website to guide physicians in decision-­making. January 2018 and December 2020 will be reviewed, The medical information provided will include answers and in the prospective part all positive cases identified to frequently asked questions about hepatitis B, algo- between January 2021 and June 2022 will be recorded rithms for management of patients with HBV infection (online supplemental figure S1). In total, we expect to in various clinical situations, information on HBV preven- collect around 4000 HBsAg-­positive individuals. A dedi- tion and indications for treatment, and news or new cated registry will be set up to record their data. Patients’ relevant information on viral hepatitis. To introduce the Figure 1 Information technology tools developed as part of the project and the main uses. HBV, hepatitis B virus. 2 Barreira Díaz A, et al. BMJ Open 2022;12:e062680. doi:10.1136/bmjopen-2022-062680 Open access Figure 2 Phone application (app) features shared with patients. PROMs, Patient Reported Outcomes Measures. website to PCPs, a meeting will be held with representa- B e antibodies, hepatitis B surface antibodies, hepatitis tive physicians from all primary care centres belonging B core antibodies, HIV antibodies and hepatitis C virus to the Vall d’Hebrón Hospital health area. The reasons antibodies, as well as haematological and biochemical for inadequate linkage will be documented by a patient-­ parameters such as platelet count, prothrombin time, reported survey, taking into account the characteristics of international normalised ratio, bilirubin, creatinine, the patients and the health providers. The website will be alanine aminotransferase, aspartate aminotransferase, hosted on the general website of Vall d’Hebrón Hospital gamma-­ glutamyltransferase, alkaline phosphatase, and will be accessible to all PCPs in the hospital’s health albumin, gamma globulin, FIB-­4 score and APRI. In addi- area. tion, liver imaging results (ultrasound, CT), liver stiffness In addition, a mobile phone application (app) will be measurement, and endoscopy and liver biopsy findings created and offered to all patients who attend the first will be collected. Data will include information recorded visit with a hepatologist at our centre and who meet the at the time of the diagnosis and during monitoring and criteria required for its use (eg, they understand the treatment of all HBsAg-­positive individuals. language of the app, they correctly handle the mobile Patients meeting the linkage criteria will be scheduled device). The app is an adaptation of an app called NORA for a blood test and a visit with the hepatologist at the previously designed by our hospital’s neurology depart- hospital. In the initial visit, a thorough anamnesis will ment and used in patients who had stroke.13 It can be be performed. All analytical parameters will be reviewed downloaded from all mobile servers, but requires creden- and fibrosis will be evaluated by non-­invasive methods tials (given to each patient individually) for use. The (serology and transient elastography). In patients whose app will provide information on HBV infection, remind condition requires treatment, nucleos(t)ide analogues participants about visits and blood tests, and monitor will be prescribed. In addition, patients will be informed HBV therapy in those requiring medication (figure 2). about the app and offered the possibility to use it by The app will also allow communication between patients creating a user account. The next visits and complemen- and the hepatology team on issues related to HBV infec- tary examinations will be scheduled at the discretion of tion through a chat that will be answered within 48 hours. the hepatologist. Patients who are considered not to need Doubts or queries will be resolved by the nurse or by the follow-­up in the hospital after appropriate evaluation by hepatologist if necessary. The app also includes question- the specialist can be followed up by the PCP. Patients can naires regarding quality of life and adherence to medica- also request this option. tion, as well as patient surveys on linkage-­to-­care issues. Patients will be trained in the use of the app so they can Patient and public involvement take full advantage of its support. No patients were involved in the design, recruitment or performance of this study. Methods Demographic and clinical variables will be recorded: sex, Statistical analysis age, ethnicity, risk factors for HBV infection, social situa- An Excel table will support all the data in coded form, tion, comorbidities, geographical area, reference health in which patients’ personal data will not be identifi- centre, duration and stage of HBV infection, degree of able. Normally distributed quantitative variables will fibrosis, presence of hepatocellular carcinoma (HCC), be compared using Student’s t-­ test and expressed as and HBV therapy (eg, duration, drugs, side effects). We mean±SD. Variables with a non-­ normal distribution will also record whether patients were aware of having will be analysed using the Mann-­ Whitney U test and HBV infection, whether they received a diagnosis but were expressed as median and IQR. Categorical variables will not linked to care, and the reasons for lack of linkage and be compared using the χ2 test or Fisher’s exact test when treatment. frequencies are less than 5%, and expressed as frequen- Laboratory parameters will include HBsAg, quantitative cies and percentages. Statistical significance will be set at hepatitis B surface antigen, hepatitis B e antigen, hepa- a p value of <0.05. All statistical analyses will be carried titis B core-­related antigen, HBV DNA levels, hepatitis out using IBM SPSS V.20. Barreira Díaz A, et al. BMJ Open 2022;12:e062680. doi:10.1136/bmjopen-2022-062680 3 Open access Ethics and dissemination infection, while investigating the use of information and This study complies with the criteria of the Vall d’He- communication technologies to improve the care of these brón Hospital Ethics Committee (reference number patients. One of the main contributions will be to estab- PR(AG)201/2021) and the Spanish Agency of Medicines lish an appropriate, simplified referral circuit in collab- and Medical Devices, and will be conducted according oration with PCPs in order to improve communication to the principles of the Declaration of Helsinki, Good between professionals and ensure correct identification Clinical Practice guidelines and local regulatory require- and care of patients with HBV. ments. Informed consent forms will be provided to partic- If the circuit and information tools employed show posi- ipating individuals and all data will be anonymised. tive results in relation to the management and follow-­up of individuals with hepatitis B infection, this programme Study outcomes is also expected to have a positive impact on the course of The primary endpoint of the study will be the number their infection and on WHO’s elimination targets. of HBsAg-­ positive individuals identified retrospectively and prospectively and linked to specialist care through Author affiliations 1 Liver Unit, Hospital Unversitario Vall de Hebrón, Barcelona, Spain our dedicated programme for this purpose. Linkage 2 Medicine Department, Universitat Autonoma de Barcelona, Barcelona, Spain to care is defined as attendance to the first visit with a 3 Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y hepatologist. The secondary outcomes will include the Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain number of patients meeting the treatment criteria and 4 Microbiology Department, Hospital Universitario Vall de Hebrón, Barcelona, Spain the number who initiate treatment. We also wish to evaluate the impact of information technology on the Acknowledgements English writing support was provided by Celine Cavallo. success of linkage to care and on PCPs’ knowledge of the Contributors ABD, MB and MR-­B conceived the project. ABD, MB and MR-­B referral circuit. Hence, additional outcome measures will drafted the project protocol. AB drafted the first version of the manuscript with assistance from MB and MR-­B. ABD, AR, AF-­P, AP, FR-­F, EV-­A, JV-­R, NP, MR-­B, RE include the number of patients using the app, the degree and MB have reviewed the full draft of the article and subsequent revisions and of adherence to follow-­up and treatment, the use of the have approved the final version for submission. website by PCPs, the number of patients referred to the Funding This project is supported by Gilead Sciences through the competitive hepatologist by PCPs and the number of patients who research 'HBV Treat' (protocol number IN-­ES-­320-­6107). initiate treatment through the established circuits. The Competing interests MB has served as a speaker and advisory board member for degree of adherence to follow-­up and treatment will be Gilead, Roche and Arbutus. MR-­B has served as a speaker for AbbVie and Gilead. RE evaluated through records of medical visits attended by has served as a speaker and advisory board member for Gilead, Roche and Arbutus. the patient, as well data from the app section that allows Patient and public involvement Patients and/or the public were not involved in monitoring of medication intake. Finally, to detect critical the design, or conduct, or reporting, or dissemination plans of this research. points that limit linkage to care and potential solutions to Patient consent for publication Not required. improve access to treatment, we will record the specific Provenance and peer review Not commissioned; externally peer reviewed. reasons why each patient has not been linked, together Supplemental material This content has been supplied by the author(s). It has with their demographic and clinical characteristics. not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-­reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and Applicability responsibility arising from any reliance placed on the content. Where the content Even though our publicly funded healthcare system includes any translated material, BMJ does not warrant the accuracy and reliability provides an adequate interconnection between primary of the translations (including but not limited to local regulations, clinical guidelines, and specialised care that facilitates patient linkage, it is terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. expected that a substantial percentage of HBsAg-­positive individuals will not have been appropriately linked to Open access This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which specialist consultation. This programme could be the permits others to distribute, remix, adapt, build upon this work non-­commercially, first step to develop a community service for hepatitis B and license their derivative works on different terms, provided the original work is similar to the highly successful programmes developed properly cited, appropriate credit is given, any changes made indicated, and the use for patients with hepatitis C virus.14 15 is non-­commercial. See: http://creativecommons.org/licenses/by-nc/4.0/. The COVID-­ 19 pandemic has had a considerable ORCID iDs impact on access to healthcare, and this situation lends Ana Barreira Díaz http://orcid.org/0000-0002-4368-8939 importance to projects aimed at actively linking patients Anna Feliu-­Prius http://orcid.org/0000-0002-6835-1718 to follow-­up. In circumstances where face-­to-­face meetings are complex or even risky, information platforms that can help PCPs resolve doubts and make decisions regarding REFERENCES HBV infection are of particular value. Furthermore, the 1 , European Association for the Study of the Liver. Electronic address: ​ use of mobile phone apps that contribute to patients’ easloffice@​easloffice.​eu, European Association for the Study of the Liver. EASL 2017 clinical practice guidelines on the management of autonomy and comfort can be very useful in reinforcing hepatitis B virus infection. J Hepatol 2017;67:370–98. adherence to medication and follow-­up. 2 McGlynn KA, Petrick JL, El-­Serag HB. Epidemiology of hepatocellular carcinoma. Hepatology 2021;73 Suppl 1:4–13. In summary, this project aims to ensure adequate 3 World Health Organisation. Global progress report on HIV, viral linkage to follow-­up and treatment of patients with HBV hepatitis and sexually transmitted infections. 53. 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