Abubakar, Ibrahim

Flanagan, Stuart

Ghosh, Indrajit

Lemoine, Maud

Maponga, Tongai

Matthews, Philippa C

Ocama, Ponsiano

Story, Alistair

English

UCL Discovery

OPINIONHepatitis B Virus: Infection, liver disease,carcinogen or syndemic threat? Remodellingthe clinical and public health responsePhilippa C. MatthewsID1,2,3*, Tongai Maponga4, Indrajit Ghosh5,6, Maud Lemoine7,Ponsiano Ocama8, Ibrahim Abubakar9, Alistair Story6, Stuart Flanagan3,51 The Francis Crick Institute, London, United Kingdom, 2 Division of Infection and Immunity, UniversityCollege London, London, United Kingdom, 3 Department of Infectious Diseases, University College LondonHospitals, London, United Kingdom, 4 Division of Virology, Tygerberg Hospital, University of Stellenbosch,Stellenbosch, South Africa, 5 Mortimer Market Centre, Central North West London NHS Foundation Trust,London, United Kingdom, 6 Find & Treat, Inclusion Health, University College London, London, UnitedKingdom, 7 Department of Metabolism, Digestion and Reproduction, Division of Digestive Diseases, Sectionof Hepatology, Imperial College London, London, United Kingdom, 8 Makerere University College of HealthSciences, Kampala, Uganda, 9 Faculty of Population Health Sciences, University College London, MortimerMarket Centre, London, United Kingdom* philippa.matthews@crick.ac.ukBackgroundHepatitis B virus (HBV) is a blood-borne virus that establishes chronic liver infection, associ-ated with potential complications of cirrhosis and/or hepatocellular carcinoma (HCC). Assuch, it poses a major threat to global public health, accounting for 300 million chronic infec-tions, and more than 500,000 deaths each year [1]. It can also be regarded as a ‘syndemic’ chal-lenge—namely, as one component of multiple, complex interacting health and social needs.The global prevalence of HBV infection is estimated at 4%, but the burden of morbidityand mortality is focused in the WHO Africa and Western Pacific regions, where the popula-tion prevalence is 6–7% [2], and healthcare delivery is poorly resourced. Outside these settings,HBV disproportionately affects marginalised groups who may lack reliable access to healthcareservices (including refugees and migrants, the LQBTQ+ community, people experiencinghomelessness, injecting drug users, incarcerated people, and sex workers).Under the umbrella of international Sustainable Development Goals, specific eliminationtargets have been set for viral hepatitis for the year 2030 [3]. Clinical guidelines provide recom-mendations for HBV prevention, screening, surveillance and treatment (e.g. [4–6]). Preventivemeasures mainly focus on immunisation. Vaccination is combined with maternal screeningand antiviral prophylaxis, with or without Hepatitis B immunoglobulin (HBIg), as a packageof measures to reduce mother-to-child transmission. Diagnosis requires access to screeningfor hepatitis B surface antigen (HBsAg), ideally supported by testing for HBeAg and HBV viralload (VL), while surveillance and risk-stratification demands regular follow-up with laboratoryassays (to monitor VL and liver health) alongside imaging with elastography and/orultrasound.Treatment for those meeting eligibility criteria is typically with a long-term oral nucleos(t)ide analogue agent (e.g. tenofovir, entecavir). However, a minority of those diagnosed withchronic infection qualify for treatment, among whom only a further minority can reliably andaffordably access monitoring and medication. Furthermore, clinical guidelines are not uni-form, do not cover all clinical scenarios (such that a substantial proportion of patients fall intoPLOS GLOBAL PUBLIC HEALTHPLOS Global Public Health | https://doi.org/10.1371/journal.pgph.0001359 December 2, 2022 1 / 5a1111111111a1111111111a1111111111a1111111111a1111111111OPEN ACCESSCitation: Matthews PC, Maponga T, Ghosh I,Lemoine M, Ocama P, Abubakar I, et al. (2022)Hepatitis B Virus: Infection, liver disease,carcinogen or syndemic threat? Remodelling theclinical and public health response. PLOS GlobPublic Health 2(12): e0001359. https://doi.org/10.1371/journal.pgph.0001359Editor: Eleanor Ochodo, Stellenbosch University,SOUTH AFRICAPublished: December 2, 2022Copyright: © 2022 Matthews et al. This is an openaccess article distributed under the terms of theCreative Commons Attribution License, whichpermits unrestricted use, distribution, andreproduction in any medium, provided the originalauthor and source are credited.Funding: PCM is funded by Wellcome, grantreference 110110/Z/15/Z, by the Francis CrickInstitute, and by the University College LondonNIHR Biomedical Research Centre. PO has fundingfrom NIH to study HBV, HIV and liver cancer. Thefunders played no role in the study design, datacollection and analysis, decision to publish, orpreparation of the manuscript.Competing interests: We have read the journal’spolicy and the authors of this manuscript have thefollowing competing interests: PCM receivesfunding for a PhD student from GSK.‘grey zones’) and are difficult or impossible to apply in some settings due to resource con-straints [7]. Substantial health inequities represent barriers to the global attainment of elimina-tion targets.By viewing HBV primarily as a cause of liver disease, an infectious agent, a carcinogen, oras a syndemic challenge, clinical and public health approaches can be distinctly shaped andrefined (Fig 1). We discuss the ramifications of designing HBV strategies specific to each ofthese ‘lenses’, and highlight the urgent need to align an integrated response.HBV as a liver diseaseManagement of HBV as a liver disease is underpinned by laboratory tests, radiological investi-gation, and/or histopathological assessment. Guidelines apply an algorithmic approach tothese results to determine end-organ disease, alongside risk factors including age, sex, ethnicorigin, and family history of liver cancer [4–6]. Typically, if objective measurements of liverhealth are normal, HBV is not treated, irrespective of virological markers or risk factors. Thisapproach is exemplified by the management paradigm for children and teenagers in whichFig 1. Summary of clinical and public health approaches to HBV that are driven by viewing it as an infection, liver disease, carcinogen orsyndemic challenge. Figure created using BioRender with a licence to publish.https://doi.org/10.1371/journal.pgph.0001359.g001PLOS GLOBAL PUBLIC HEALTHPLOS Global Public Health | https://doi.org/10.1371/journal.pgph.0001359 December 2, 2022 2 / 5antiviral treatment is not routinely offered as there is typically no laboratory or imaging evi-dence of liver disease, despite potentially high VL and HBeAg-positive status (a phenotype pre-viously described as ‘immune tolerant’).This stratification of therapy aims to target those at highest short-term risk of liver disease,and avoids unnecessary treatment of individuals with the lowest chances of developing long-term complications. However, the approach requires significant clinical infrastructure tomaintain regular surveillance, and is associated with unchecked viral replication (with the riskof viral integration at high VL, and liver disease evolution even at low VL [8]), while sustainedviraemia is a reservoir for ongoing community transmission.HBV as an infectionViewing HBV primarily as an infectious agent builds on established approaches for otherchronic blood-borne viruses, such as HCV and HIV, as well as containment approaches toother viruses that threaten population health. Suppressing or clearing HBV or HCV lowers thelong-term risks of cirrhosis and liver cancer, liver enzymes and fibrosis scores can improveover time [9], and there is a benefit to quality of life [10]. Approaches to BBV prevention areunified by common principles, as reductions in viraemia translate into a lowered transmissionrisk. For HIV this is headlined by the public health message ‘undetectable = untransmittable’(U = U) based on a reduction in new infections in treated populations [11]. During theSARS-CoV-2 pandemic, public health measures implemented due to the risk of severe disease(albeit occurring in a minority), aimed at strict containment, irrespective of the specific clinicalphenotype in infected individuals.HBV vaccination has reduced HBV and HCC incidence, but is not sufficient to achieveelimination targets due to the large established population reservoir of HBV infection, gaps invaccine-mediated immunity, and practical challenges in delivering a universal three-dose vac-cine regimen starting at birth. While prevention for HBV is ideally tackled by populationimmunisation, there is an argument for tackling established infection by treating early andaiming for universal virologic suppression [7].Quantification of VL and viral antigens (HBsAg and HBeAg) and DNA provide a proxy forviral replication, and are universally incorporated into treatment algorithms. However, consid-ering HBV as a high-risk agent of infection would uncouple treatment from specific quantita-tion of any laboratory markers, thus minimising both the potential for long-term liver disease(in individuals), and reducing onward transmission (in populations). For those with estab-lished infection, this perspective supports mandating universal access to first-line treatment,which would simplify and unify clinical algorithms, reduce the clinical infrastructure requiredfor treatment stratification, and redress inequities. The approach has to account for the risksand costs of long-term therapy, even when the individual risk of complications or transmissionare small.HBV as a carcinogenThe lifetime risk of HCC in chronic HBV infection has been estimated as 27% in males and8% in females, and broadly increases with VL, ranging from 108 per 100,000 person-years foran HBV DNA level of<300 copies/mL to>1000 per 100,000 person-years for VL 1 millioncopies/mL [12]. Cancer incidence is higher in the context of cirrhosis, with a 5-year cumulativeHCC risk between 10–17% [13]. However, existing tools to predict the development of livercancer are blunt and imprecise. Risks are reduced by antiviral therapy, suppression of VL toundetectable limits, and HBeAg seroconversion [14], and increased by a positive family historyof liver cancer, coinfection with HCV,HDV, and excess alcohol. Excess mortality due to HCCPLOS GLOBAL PUBLIC HEALTHPLOS Global Public Health | https://doi.org/10.1371/journal.pgph.0001359 December 2, 2022 3 / 5is substantial (e.g. SMR 15.9 [15]). Framing HBV as a potent carcinogen could shape strategyapproaches informed by other oncogenic threats, namely education, prevention, screeningand risk reduction. For example, using public health approaches to tobacco smoking as a pre-cedent, interventions aim to minimize any exposure, irrespective of the presence of end-organdisease in individual smokers.HBV as a syndemic challengeHBV needs to be tackled alongside other physical and mental health challenges, and withinsight into many other coexisting vulnerabilities linked to, for example, socioeconomic depri-vation, homelessness, migration, racism, stigma and discrimination, sex work and substancemisuse. Some of these groups face extreme marginalisation and harsh health inequities. Aholistic view of HBV as part of a syndemic challenge highlights the need to focus on preventionand harm minimisation, targeted information, outreach testing with peer support, trauma-informed care, and linkage to services that can also provide care for diverse and complexhealth and social needs. The syndemic concept provides the basis for integrating HBV withexisting clinical infrastructure, avoiding the vertical silo approach which is inefficient and inac-cessible to many vulnerable groups. Decentralising services provides opportunities for HBVmanagement to be combined into existing healthcare programmes (for example offering carethrough existing services for maternal and child health, sexually transmitted infections,migrant health), leading to better access and improved efficiencies as a result of shared use ofresources and extended staff roles.ConclusionThe conventional paradigm of assessing HBV primarily as a liver disease (as enshrined in allclinical guidelines) is based on evidence of hepatic inflammation, fibrosis or cancer. Thisapproach misses crucial opportunities to improve individual outcomes by intervening early toprevent complications. Taking a view of HBV as an infection, carcinogen or part of a syndemicchallenge underpins strategies for wider screening, early intervention and robust public healthinterventions for prevention, and can reduce health inequities (Fig 1), providing foundationsfor progress towards elimination goals.References1. 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Spearman CWN, Sonderup MW, Botha JF, van der Merwe SW, Song E, Kassianides C, et al. SouthAfrican guideline for the management of chronic hepatitis B: 2013. S Afr Med J. 2013; 103: 337–349.PMID: 239674977. McNaughton AL, Lemoine M, van Rensburg C, Matthews PC. Extending treatment eligibility for chronichepatitis B virus infection. Nat Rev Gastroenterol Hepatol. 2021; 18: 146–147. https://doi.org/10.1038/s41575-020-00398-x PMID: 33323992PLOS GLOBAL PUBLIC HEALTHPLOS Global Public Health | https://doi.org/10.1371/journal.pgph.0001359 December 2, 2022 4 / 58. Wang X, Liu X, Wang P, Yu L, Yan F, Yan H, et al. Antiviral Therapy Reduces Mortality in HepatocellularCarcinoma Patients with Low-Level Hepatitis B Viremia. J Hepatocell Carcinoma. 2021; 8: 1253–1267.https://doi.org/10.2147/JHC.S330301 PMID: 347080079. Wang T, Smith DA, Campbell C, Mokaya J, Freeman O, Salih H, et al. 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Fattovich G, Bortolotti F, Donato F. Natural history of chronic hepatitis B: special emphasis on diseaseprogression and prognostic factors. J Hepatol. 2008; 48: 335–352. https://doi.org/10.1016/j.jhep.2007.11.011 PMID: 1809626714. Jiang X-Y, Huang B, Huang D-P, Wei C-S, Zhong W-C, Peng D-T, et al. Long-term follow-up of cumula-tive incidence of hepatocellular carcinoma in hepatitis B virus patients without antiviral therapy. World JGastroenterol. 2021; 27: 1101–1116. https://doi.org/10.3748/wjg.v27.i11.1101 PMID: 3377637615. Montuclard C, Hamza S, Rollot F, Evrard P, Faivre J, Hillon P, et al. Causes of death in people withchronic HBV infection: A population-based cohort study. J Hepatol. 2015; 62: 1265–1271. https://doi.org/10.1016/j.jhep.2015.01.020 PMID: 25625233PLOS GLOBAL PUBLIC HEALTHPLOS Global Public Health | https://doi.org/10.1371/journal.pgph.0001359 December 2, 2022 5 / 5

Hepatitis B Virus: Infection, liver disease, carcinogen or syndemic threat? Remodelling the clinical and public health response

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Hepatitis B Virus: Infection, liver disease, carcinogen or syndemic threat? Remodelling the clinical and public health response

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