Advertisement

Health inequalities in the management of chronic Hepatitis B Virus infection in patients from sub-Saharan Africa in high income countries

  • Author Footnotes
    a Postal address: Gastroenterology and Hepatology Department, Level 8 A Block, Royal Perth Hospital, 197 Wellington Street, Perth, Western Australia 6000
    Tim Mitchell
    Correspondence
    Corresponding author: Name: Telephone: +61 8 9224 2179
    Footnotes
    a Postal address: Gastroenterology and Hepatology Department, Level 8 A Block, Royal Perth Hospital, 197 Wellington Street, Perth, Western Australia 6000
    Affiliations
    Institute of Liver Studies, King’s College Hospital, London, United Kingdom

    Gastroenterology and Hepatology Department, Royal Perth Hospital, Perth, Australia
    Search for articles by this author
  • Jeremy S. Nayagam
    Affiliations
    Institute of Liver Studies, King’s College Hospital, London, United Kingdom

    Department of Inflammation Biology, King’s College London, London, UK
    Search for articles by this author
  • Geoffrey Dusheiko
    Affiliations
    Institute of Liver Studies, King’s College Hospital, London, United Kingdom

    University College London Medical School, London, UK
    Search for articles by this author
  • Kosh Agarwal
    Affiliations
    Institute of Liver Studies, King’s College Hospital, London, United Kingdom
    Search for articles by this author
  • Author Footnotes
    a Postal address: Gastroenterology and Hepatology Department, Level 8 A Block, Royal Perth Hospital, 197 Wellington Street, Perth, Western Australia 6000
Open AccessPublished:November 03, 2022DOI:https://doi.org/10.1016/j.jhepr.2022.100623

      Summary

      Chronic hepatitis B virus disproportionately affects migrant communities in high income countries with changing migration patterns demonstrating an increase in migrants from sub-Saharan Africa.
      Chronic hepatitis B virus is endemic in sub-Saharan Africa yet the natural history of chronic infection experienced by patients remains incompletely understood with evidence of variability across genotypes and regions within sub-Saharan Africa.
      Clinical guidelines recommending treatment thresholds are not specific to sub-Saharan African patients and are based on natural history studies from Western Pacific Asian countries.
      Access to standard of care treatment is available for sub-Saharan African people with chronic hepatitis B virus infection in high income countries however the evidence base for these treatments was not established in this cohort and areas of uncertainty regarding HCC surveillance and treatment discontinuation in particular remain.
      Participation in phase three clinical trials for chronic hepatitis B therapies is almost non-existent amongst sub-Saharan African patients, even when residing in high income countries that participate in multicentre trials.
      Engagement with sub-Saharan African patients with chronic hepatitis B in high income countries is challenging due to stigma associated with the diagnosis, absence of routine screening systems and the complexities involved in navigating the healthcare system. Nonetheless, improved engagement is critical if we are to achieve global hepatitis B virus elimination.

      Keywords

      Conflict of interest statement

      We have no conflict of interest to declare.

      Financial support

      None.

      Author contributions

      TM – conceptualisation, literature search, writing - original draft.
      SN – conceptualisation, literature search, writing - original draft.
      GD – supervision, writing - review and editing.
      KA – supervision, writing - review and editing.

      Introduction

      Chronic Hepatitis B Virus (HBV) infection affects approximately 300 million people worldwide.
      GBD 2019 Hepatitis B Collaborators
      Global, regional, and national burden of hepatitis B, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019.
      It is estimated that one patient dies every 30 seconds from their illness.

      World Health Organisation. Global Hepatitis Report 2017. Geneva, 2017.

      In response to this global disease, the World Health Organisation (WHO) is targeting the elimination of viral hepatitis as a public health threat by 2030.

      World Health Organisation. Global Hepatitis Report 2017. Geneva, 2017.

      Progress so far has not been consistent across all regions and must be accelerated if these targets are to be met.
      GBD 2019 Hepatitis B Collaborators
      Global, regional, and national burden of hepatitis B, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019.
      Sub-Saharan Africa (SSA) has the second highest prevalence of chronic HBV in the world, at 6.5%, so that it is estimated that approximately 80 million people are living with chronic HBV.
      GBD 2019 Hepatitis B Collaborators
      Global, regional, and national burden of hepatitis B, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019.
      ,

      World Health Organisation. Global Hepatitis Report 2017. Geneva, 2017.

      The high rates of chronic infection are largely determined by early childhood infection including residual mother to child transmission. Chronic HBV is responsible for 41% of cirrhosis cases in SSA compared with only 13% in Europe.
      • Alberts C.J.
      • Clifford G.M.
      • Georges D.
      • Negro F.
      • Lesi O.A.
      • Hutin Y.J.
      • et al.
      Worldwide prevalence of hepatitis B virus and hepatitis C virus among patients with cirrhosis at country, region, and global levels: a systematic review.
      Progressive disease is common in SSA, where 90 000 people per year die from cirrhosis and hepatocellular carcinoma (HCC).
      • Spearman C.W.
      • Afihene M.
      • Ally R.
      • Apica B.
      • Awuku Y.
      • Cunha L.
      • et al.
      Hepatitis B in sub-Saharan Africa: strategies to achieve the 2030 elimination targets.
      Despite reductions in the cost of antiviral treatment, efforts at HBV elimination in SSA have historically been hampered by a combination of low awareness, low rates of diagnosis, impaired access to nucleic acid testing, inadequate infrastructure and healthcare resources, lower vaccination uptake and access to antiviral treatment.
      • Spearman C.W.
      • Afihene M.
      • Ally R.
      • Apica B.
      • Awuku Y.
      • Cunha L.
      • et al.
      Hepatitis B in sub-Saharan Africa: strategies to achieve the 2030 elimination targets.
      ,
      • Lemoine M.
      • Eholie S.
      • Lacombe K.
      Reducing the neglected burden of viral hepatitis in Africa: strategies for a global approach.
      In high income countries, HBV disproportionally affects migrant populations from endemic areas, who contribute a high proportion of cases of chronic HBV.
      • Ahmad A.A.
      • Falla A.M.
      • Duffell E.
      • Noori T.
      • Bechini A.
      • Reintjes R.
      • et al.
      Estimating the scale of chronic hepatitis B virus infection among migrants in EU/EEA countries.
      For example, migrants contribute 25% of chronic HBV cases in European Economic Area countries whilst only representing 5-10% of the total population.
      • Ahmad A.A.
      • Falla A.M.
      • Duffell E.
      • Noori T.
      • Bechini A.
      • Reintjes R.
      • et al.
      Estimating the scale of chronic hepatitis B virus infection among migrants in EU/EEA countries.
      The disparity is even higher in the United Kingdom (UK) where 6% of the population contribute 72% of chronic HBV cases.
      • Ahmad A.A.
      • Falla A.M.
      • Duffell E.
      • Noori T.
      • Bechini A.
      • Reintjes R.
      • et al.
      Estimating the scale of chronic hepatitis B virus infection among migrants in EU/EEA countries.
      A significant proportion of migrants now originate from endemic countries within SSA rather than Asia or Eastern Europe.

      European Centre for Disease Prevention and Control. Epidemiological assessment of hepatitis B and C among migrants in the EU/EEA. Stockholm: ECDC, 2016.

      ,

      Connor P. At Least a Million Sub-Saharan Africans Moved to Europe Since 2010. Washington, D.C.: Pew Research Centre, 2018.

      Thus a recent report indicated that in London, individuals identifying as Black ethnicity are almost five times more likely to test positive for HBV than Caucasian patients.

      Public Health England. Hepatitis B in London. London: Public Health England, 2019.

      Despite increasing migration from regions without established HBV detection and treatment programs, routine screening of immigrants is still not performed in the UK.

      UK National Screening Committee. Screening for Hepatitis B and Hepatitis C among ethnic minorities born outside the UK. United Kingdom, 2011.

      • Evlampidou I.
      • Hickman M.
      • Irish C.
      • Young N.
      • Oliver I.
      • Gillett S.
      • et al.
      Low hepatitis B testing among migrants: a cross-sectional study in a UK city.
      • Williams R.
      • Holt A.P.
      Screening immigrants for tuberculosis--why not for HBV infection?.
      The large African diaspora exposes deficiencies and provides an opportunity for improved care in chronic HBV. Guidelines on the management of chronic HBV from major hepatology or infectious disease societies are not based on evidence from SSA patients, instead recommending treatment and surveillance principles established from cohort studies in Western Pacific Asian and Caucasian patients.
      • Aberra H.
      • Desalegn H.
      • Berhe N.
      • Mekasha B.
      • Medhin G.
      • Gundersen S.G.
      • et al.
      The WHO guidelines for chronic hepatitis B fail to detect half of the patients in need of treatment in Ethiopia.
      The COVID-19 syndemic has highlighted the impact societal determinants of health have on the outcomes of disease, particularly in Black and minority ethnic groups.
      • Horton R.
      Offline: COVID-19 is not a pandemic.
      Failure to develop a nuanced, evidenced based approach to chronic HBV in SSA populations will prevent the realisation of the WHO’s ambitious viral hepatitis elimination target and may lead to a similar chronic HBV syndemic in high income countries, driven by the social stigmas and healthcare inequity experienced by migrant populations.
      • Aldridge R.W.
      • Nellums L.B.
      • Bartlett S.
      • Barr A.L.
      • Patel P.
      • Burns R.
      • et al.
      Global patterns of mortality in international migrants: a systematic review and meta-analysis.
      ,
      • Ochieng B.M.
      Black African migrants: the barriers with accessing and utilizing health promotion services in the UK.
      In this Public Health article, we will review the evidence base for chronic HBV management in high income countries and discuss the evidence gaps that require immediate attention regarding SSA patients, particularly hepatocellular carcinoma surveillance, involvement in clinical trials and linkage to care.

      Hepatocellular carcinoma surveillance

      Chronic HBV is an important risk factor for the development of HCC although there is geographic variation in the risk of HCC in chronic HBV, which is seen across the different viral phenotypes.
      European Association for the Study of the Liver
      EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection.
      The 5 year cumulative incidence of HCC for low viral replicators, chronic HBV without cirrhosis and chronic HBV with compensated cirrhosis in East Asian populations is 1%, 3% and 17% respectively, which are higher than the 0.1%, 1% and 10% in Western Europe and the United States.
      • Fattovich G.
      • Bortolotti F.
      • Donato F.
      Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors.
      It is suggested that this is related to risk-factor exposure and age of acquisition more than genetics.
      • Terrault N.A.
      • Lok A.S.F.
      • McMahon B.J.
      • Chang K.M.
      • Hwang J.P.
      • Jonas M.M.
      • et al.
      Update on Prevention, Diagnosis, and Treatment of Chronic Hepatitis B: AASLD 2018 Hepatitis B Guidance.
      Despite only sparse data in SSA patients, guidelines elevate ethnicity as an important factor in HCC development.
      • Fattovich G.
      • Bortolotti F.
      • Donato F.
      Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors.
      A specific risk factor pertinent to SSA is aflatoxin B1 (AFB1), a mycotoxin synthesized by Aspergillus flavus and Aspergillus parasiticus, which is a potent hepatocarcinogen.
      • Spearman C.W.
      • Dusheiko G.
      • Jonas E.
      • Abdo A.
      • Afihene M.
      • Cunha L.
      • et al.
      Hepatocellular carcinoma: measures to improve the outlook in sub-Saharan Africa.
      Chronic aflatoxin B1 (AFB1) exposure confers an increased risk of developing HCC.
      • Spearman C.W.
      • Dusheiko G.
      • Jonas E.
      • Abdo A.
      • Afihene M.
      • Cunha L.
      • et al.
      Hepatocellular carcinoma: measures to improve the outlook in sub-Saharan Africa.
      The signature mutation induced by aflatoxins is the mutation at codon 249 in the tumor suppressor gene TP53 (R249S).
      • Spearman C.W.
      • Dusheiko G.
      • Jonas E.
      • Abdo A.
      • Afihene M.
      • Cunha L.
      • et al.
      Hepatocellular carcinoma: measures to improve the outlook in sub-Saharan Africa.
      Epidemiologic studies have demonstrated a strong correlation between dietary intake of AFB1, TP53 mutations and the incidence of HCC, in HBV-infected individuals in SSA and elsewhere.
      • Chu Y.J.
      • Yang H.I.
      • Wu H.C.
      • Liu J.
      • Wang L.Y.
      • Lu S.N.
      • et al.
      Aflatoxin B1 exposure increases the risk of cirrhosis and hepatocellular carcinoma in chronic hepatitis B virus carriers.
      ,
      • Kimanya M.E.
      • Routledge M.N.
      • Mpolya E.
      • Ezekiel C.N.
      • Shirima C.P.
      • Gong Y.Y.
      Estimating the risk of aflatoxin-induced liver cancer in Tanzania based on biomarker data.
      Maize, and other staple foodstuffs including ground nuts, are susceptible to contamination by improper drying in tropical and sub-tropical climates conferring chronic hazardous exposure.
      • Spearman C.W.
      • Dusheiko G.
      • Jonas E.
      • Abdo A.
      • Afihene M.
      • Cunha L.
      • et al.
      Hepatocellular carcinoma: measures to improve the outlook in sub-Saharan Africa.
      AFB1 levels exceeding WHO safety levels have been documented in several SSA countries.
      • Spearman C.W.
      • Dusheiko G.
      • Jonas E.
      • Abdo A.
      • Afihene M.
      • Cunha L.
      • et al.
      Hepatocellular carcinoma: measures to improve the outlook in sub-Saharan Africa.
      The major international liver societies have published guidelines on surveillance for HCC in patients with chronic HBV (Table 1) that incorporate six monthly ultrasound with or without alpha-feto protein (AFP). Although there is a consensus that all patients with cirrhosis should be entered into a surveillance programme, noting this is necessary to diagnose early HCC that may be treated with curative intent, the wide variations in recommendations for SSA patients reflect in part the lack of data for this population. EASL acknowledges that despite increasing migration to Europe of individuals from endemic regions, the overall impact on HCC incidence has not been investigated.
      European Association for the Study of the Liver
      EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection.
      Locally formulated risk stratification scores need to be developed and validated to incorporate known risk factors and diminsh the burden of surveillance of low risk populations.
      European Association for the Study of the Liver
      EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection.
      ,
      • Sarin S.K.
      • Kumar M.
      • Lau G.K.
      • Abbas Z.
      • Chan H.L.
      • Chen C.J.
      • et al.
      Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update.
      ,
      • Cargill Z.
      • Brown S.E.
      • Dusheiko G.
      • Agarwal K.
      Risk stratification in chronic hepatitis B patients for hepatocellular carcinoma surveillance: management in migrant sub-Saharan African populations.
      Table 1Society recommendations for HCC surveillance in African patients with chronic HBV.
      AASLD
      • Terrault N.A.
      • Lok A.S.F.
      • McMahon B.J.
      • Chang K.M.
      • Hwang J.P.
      • Jonas M.M.
      • et al.
      Update on Prevention, Diagnosis, and Treatment of Chronic Hepatitis B: AASLD 2018 Hepatitis B Guidance.
      African males aged > 40 years
      EASL
      European Association for the Study of the Liver
      EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection.
      No recommendation
      APASL
      • Sarin S.K.
      • Kumar M.
      • Lau G.K.
      • Abbas Z.
      • Chan H.L.
      • Chen C.J.
      • et al.
      Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update.
      All African patients aged > 20 years
      Scoring systems have been developed to stratify the risk of HCC in individuals with chronic HBV, and to expedite and improve HCC surveillance programmes. GAG-HCC, CU-HCC and REACH-B were derived and validated in Western Pacific Asian populations.
      • Yuen M.F.
      • Tanaka Y.
      • Fong D.Y.
      • Fung J.
      • Wong D.K.
      • Yuen J.C.
      • et al.
      Independent risk factors and predictive score for the development of hepatocellular carcinoma in chronic hepatitis B.
      • Wong V.W.
      • Chan S.L.
      • Mo F.
      • Chan T.C.
      • Loong H.H.
      • Wong G.L.
      • et al.
      Clinical scoring system to predict hepatocellular carcinoma in chronic hepatitis B carriers.
      • Yang H.I.
      • Yuen M.F.
      • Chan H.L.
      • Han K.H.
      • Chen P.J.
      • Kim D.Y.
      • et al.
      Risk estimation for hepatocellular carcinoma in chronic hepatitis B (REACH-B): development and validation of a predictive score.
      GAG-HCC and CU-HCC, included patients with cirrhosis and therefore weight the risk of cirrhosis in cacluations.
      • Yuen M.F.
      • Tanaka Y.
      • Fong D.Y.
      • Fung J.
      • Wong D.K.
      • Yuen J.C.
      • et al.
      Independent risk factors and predictive score for the development of hepatocellular carcinoma in chronic hepatitis B.
      ,
      • Wong V.W.
      • Chan S.L.
      • Mo F.
      • Chan T.C.
      • Loong H.H.
      • Wong G.L.
      • et al.
      Clinical scoring system to predict hepatocellular carcinoma in chronic hepatitis B carriers.
      REACH-B only used non-cirrhotic patients in the derivation cohort, and therefore does not include cirrhosis as a variable.
      • Yang H.I.
      • Yuen M.F.
      • Chan H.L.
      • Han K.H.
      • Chen P.J.
      • Kim D.Y.
      • et al.
      Risk estimation for hepatocellular carcinoma in chronic hepatitis B (REACH-B): development and validation of a predictive score.
      All scores include a weighting for HBV DNA; despite some precision in Western Pacific Asian patients on long-term nucleos(t)ide analogues (NA), replacing HBV DNA with transient elastography (TE) in the mREACH-B score improved accuracy.
      • Jung K.S.
      • Kim S.U.
      • Song K.
      • Park J.Y.
      • Kim D.Y.
      • Ahn S.H.
      • et al.
      Validation of hepatitis B virus-related hepatocellular carcinoma prediction models in the era of antiviral therapy.
      ,
      • Wong G.L.
      • Chan H.L.
      • Chan H.Y.
      • Tse P.C.
      • Tse Y.K.
      • Mak C.W.
      • et al.
      Accuracy of risk scores for patients with chronic hepatitis B receiving entecavir treatment.
      Future risk models will likely be biomarker driven, for example GALAD, which incorporates AFP, AFP-L3 and des-gamma-carboxy-prothrombin into a model with age and sex.
      • Johnson P.J.
      • Pirrie S.J.
      • Cox T.F.
      • Berhane S.
      • Teng M.
      • Palmer D.
      • et al.
      The detection of hepatocellular carcinoma using a prospectively developed and validated model based on serological biomarkers.
      There is an important need to validate these scores in different ethnic cohorts, in whom differing modes of transmission, age of acquisition, HBV genotypes, and past or current environmental risk factors could alter risk stratification.
      • Wong V.W.
      • Chan S.L.
      • Mo F.
      • Chan T.C.
      • Loong H.H.
      • Wong G.L.
      • et al.
      Clinical scoring system to predict hepatocellular carcinoma in chronic hepatitis B carriers.
      ,
      • Yang H.I.
      • Yuen M.F.
      • Chan H.L.
      • Han K.H.
      • Chen P.J.
      • Kim D.Y.
      • et al.
      Risk estimation for hepatocellular carcinoma in chronic hepatitis B (REACH-B): development and validation of a predictive score.
      A larger proportion of Western Pacific Asian patients acquired HBV through perinatal transmission, are infected with genotype B or C, and consequently have higher rates of HBeAg positive infection and disease.
      • Wong V.W.
      • Janssen H.L.
      Can we use HCC risk scores to individualize surveillance in chronic hepatitis B infection?.
      Individuals born in SSA are more likely to have acquired HBV via horizontal or parenteral transmission in childhood and there are higher rates of anti-HBe positive infection.
      • Kramvis A.
      The clinical implications of hepatitis B virus genotypes and HBeAg in pediatrics.
      There are regional differences in the prevalence of HBeAg entire positivity within Africa, with this group more prevalent in West and Central Africa where genotype E is predominant.
      • Spearman C.W.
      • Dusheiko G.
      • Jonas E.
      • Abdo A.
      • Afihene M.
      • Cunha L.
      • et al.
      Hepatocellular carcinoma: measures to improve the outlook in sub-Saharan Africa.
      Genotype A1 is most common in Eastern and Southern Africa and chronic infection is associated with a higher relative risk of HCC development than non-A genotypes.
      • Kramvis A.
      • Kew M.C.
      Epidemiology of hepatitis B virus in Africa, its genotypes and clinical associations of genotypes.
      SSA faces a increasing burden of harmful levels of alcohol consumption although the relative contribution of alcohol to HCC development differs by region and cultural or religious beliefs.
      • Spearman C.W.
      • Dusheiko G.
      • Jonas E.
      • Abdo A.
      • Afihene M.
      • Cunha L.
      • et al.
      Hepatocellular carcinoma: measures to improve the outlook in sub-Saharan Africa.
      Metabolic dysfunction-associated fatty liver disease is increasing in prevalence adding an attendant HCC risk.
      • Spearman C.W.
      • Dusheiko G.
      • Jonas E.
      • Abdo A.
      • Afihene M.
      • Cunha L.
      • et al.
      Hepatocellular carcinoma: measures to improve the outlook in sub-Saharan Africa.
      The rising prevalence in SSA is of concern. It will be important to raise public awareness in MAFLD, to offset the effects of the increasing morbidity from the disease in Africans.
      • Spearman C.W.
      • Afihene M.
      • Betiku O.
      • Bobat B.
      • Cunha L.
      • Kassianides C.
      • et al.
      Epidemiology, risk factors, social determinants of health, and current management for non-alcoholic fatty liver disease in sub-Saharan Africa.
      Untreated HIV- and HBV or HCV coinfection increases the risk of progressive disease and of HCC.
      • Spearman C.W.
      • Dusheiko G.
      • Jonas E.
      • Abdo A.
      • Afihene M.
      • Cunha L.
      • et al.
      Hepatocellular carcinoma: measures to improve the outlook in sub-Saharan Africa.
      Critically, a scale up of anti-retroviral treatment of HBV-HIV disease with regimens including tenofovir or tenofovir alafenamide, active against hepatitis B, will reduce the risk of HCC. Similarly, the diagnosis and cure of hepatitis C will be the most effective secondary preventive measure, but both measures will necessitate improving awareness and providing effective linkage to antiviral treatment. Within SSA, a coordinated agronomic approach to rendering crops less susceptible to AFB1 needs to be considered. These measures include prevention of contamination with adequate irrigation and use of fungicides, sun-drying on cloth and not soil, and hand-sorting to remove mouldy crops.
      • Spearman C.W.
      • Dusheiko G.
      • Jonas E.
      • Abdo A.
      • Afihene M.
      • Cunha L.
      • et al.
      Hepatocellular carcinoma: measures to improve the outlook in sub-Saharan Africa.
      AflasafeR, a biopesticide applied to maize to displace aflatoxin-synthesing fungal strains has been developed to reduce toxin-producing aflatoxin contamination of crops.
      • Spearman C.W.
      • Dusheiko G.
      • Jonas E.
      • Abdo A.
      • Afihene M.
      • Cunha L.
      • et al.
      Hepatocellular carcinoma: measures to improve the outlook in sub-Saharan Africa.
      The Partnership for Aflatoxin Control in Africa (PACA) is a group that aims to mitigate aflatoxin exposure. Primary prevention measures to all these ancillary factors that increase the risk of HCC in HBV infected sub-Saharan Africans living in the African diaspora will be key to reducing the ultimate incidence of HCC in these cohorts.
      It is striking that despite the acknowledgement that individualised risk calculators are needed for patients of different ethnicities and from different geographical regions, there have been no generalisable prescriptive guidelines derived or validated in patients from SSA with chronic HBV. This brings into question our ability to formulate an appropriate risk-stratified HCC surveillance system for SSA chronic HBV patients (box1).
      Future research opportunities for HCC in SSA patients with chronic HBV
      Tabled 1
      • Validate surveillance for HCC in SSA patients in high income countries both to improve surveillance in Europe and to transfer rationale to low and midle income contries in SSA
      • Identify demographic trends in incident HCC and provide data
      • Gather data to determine virological risk factors and the role of biomarkers, including quantitative HBsAg, HBeAg, HBcrAg, HBV RNA, HBV genotypes, precore mutations and basal core promoter genotypes as well as occult hepatitis B, and HIV, HCV or HDV coinfection
      • Improve stratification of HCC risk in SSA patients and ascertain genetic or familial factors
      • Publish results of transarterial treatments, ablation, hepatic resection and transplantation together with antiviral treatment in populations of SSA descent
      • Publish results of systemic therapies and biological behaviour of tumours in SSA patients
      • Collaborate with SSA centres to transfer skill sets and resources necessary to improve locoregional, surgical and systemic therapies to offer more options to resource poor regions of SSA
      • Using digital technologies improve multidisciplinary management of HCC in European centres with an eye on encompassing SSA centres at a supranational level to improve outcomes
      • Determine the impact of acquired risk factors (e.g. alcohol use, MAFLD) on HCC development in SSA patients with chronic HBV in high income countries

      Antiviral treatment

      The main goals of therapy for chronic HBV are to improve survival and quality of life by preventing disease progression and complications of end stage liver disease, such as HCC.
      European Association for the Study of the Liver
      EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection.
      Long term treatment with NA is associated with a histological improvement in liver fibrosis and a reduction in the need for liver transplantation for decompensation.
      European Association for the Study of the Liver
      EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection.
      ,
      • Chang T.T.
      • Liaw Y.F.
      • Wu S.S.
      • Schiff E.
      • Han K.H.
      • Lai C.L.
      • et al.
      Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B.
      Although the risk is reduced by effective NA therapy, HCC can still develop. The residual risks of HCC have been extensively documented in non-SSA populations.
      Large cohorts of Western Pacific Asian patients treated with NA have identified a significant reduction in the development of HCC in both patients with cirrhosis and without cirrhosis.
      • Nguyen M.H.
      • Yang H.I.
      • Le A.
      • Henry L.
      • Nguyen N.
      • Lee M.H.
      • et al.
      Reduced Incidence of Hepatocellular Carcinoma in Cirrhotic and Noncirrhotic Patients With Chronic Hepatitis B Treated With Tenofovir-A Propensity Score-Matched Study.
      Those with pre-existing cirrhosis have a 5.49 times greater risk incidence of HCC development that those without cirrhosis at baseline.
      • Wang X.
      • Liu X.
      • Dang Z.
      • Yu L.
      • Jiang Y.
      • Wang X.
      • et al.
      Nucleos(t)ide Analogues for Reducing Hepatocellular Carcinoma in Chronic Hepatitis B Patients: A Systematic Review and Meta-Analysis.
      The risk reduction from NA is predicted to be 73% in non-cirrhotic patients and 77% in cirrhotics.
      • Nguyen M.H.
      • Yang H.I.
      • Le A.
      • Henry L.
      • Nguyen N.
      • Lee M.H.
      • et al.
      Reduced Incidence of Hepatocellular Carcinoma in Cirrhotic and Noncirrhotic Patients With Chronic Hepatitis B Treated With Tenofovir-A Propensity Score-Matched Study.
      A European study with mainly Caucasian and Asian patients, identified a low but significant rate of HCC in those on long term NA, which was despite achieving a virological response.
      • Arends P.
      • Sonneveld M.J.
      • Zoutendijk R.
      • Carey I.
      • Brown A.
      • Fasano M.
      • et al.
      Entecavir treatment does not eliminate the risk of hepatocellular carcinoma in chronic hepatitis B: limited role for risk scores in Caucasians.
      A study of Caucasians treated with NA (entecavir or lamivudine) identified a higher risk of HCC in treated cirrhotics compared to non-cirrhotics, with incidence at 5 years of 9% compared to 1%.
      • Papatheodoridis G.V.
      • Manolakopoulos S.
      • Touloumi G.
      • Nikolopoulou G.
      • Raptopoulou-Gigi M.
      • Gogos C.
      • et al.
      Hepatocellular carcinoma risk in HBeAg-negative chronic hepatitis B patients with or without cirrhosis treated with entecavir: HepNet.Greece cohort.
      A large study of Caucasian patients on long term NA who were followed from year 5 to year 10 after commencing NA, identified no change in the yearly incidence of HCC across the first and second 5 years in non-cirrhotics (0.5% vs 0.5%), but there was a significant reduction in the second 5 years of treatment in cirrhotics (3.2% vs 1.6%).
      • Papatheodoridis G.V.
      • Idilman R.
      • Dalekos G.N.
      • Buti M.
      • Chi H.
      • van Boemmel F.
      • et al.
      The risk of hepatocellular carcinoma decreases after the first 5 years of entecavir or tenofovir in Caucasians with chronic hepatitis B.
      An area of debate is which NA, tenofovir or entecavir, is associated with the better risk reduction of HCC in HBV. Although a recent systematic review and meta-analysis concluded that tenofovir is associated with a lower risk of HCC than entecavir, conflicting data has emerged from a large study which reported no difference between agents when adjusting for factors including age and cirrhosis, which was echoed in a recent meta-analysis with propensity matched subjects.
      • Choi W.M.
      • Choi J.
      • Lim Y.S.
      Effects of Tenofovir vs Entecavir on Risk of Hepatocellular Carcinoma in Patients With Chronic HBV Infection: A Systematic Review and Meta-analysis.
      ,
      • Hsu Y.C.
      • Wong G.L.
      • Chen C.H.
      • Peng C.Y.
      • Yeh M.L.
      • Cheung K.S.
      • et al.
      Tenofovir Versus Entecavir for Hepatocellular Carcinoma Prevention in an International Consortium of Chronic Hepatitis B.
      The majority of this data is from Western Pacific Asian populations and has not been reported in other ethnicities. As yet, there is no data in SSA patients with chronic HBV to inform guidelines or clinical management.
      Highly potent and cost-effective oral antiviral treatments are widely available for patients with chronic HBV living in high income countries.
      European Association for the Study of the Liver
      EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection.
      A reduction in the risk of HCC has been observed in patients with and without cirrhosis, clearly demonstrating clinical endpoint benefit.
      European Association for the Study of the Liver
      EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection.
      Although maintenance suppressive treatment is required, treatment costs with either generic entecavir or tenofovir are low – less than £150 per year. Guidance for physicians highlighting the optimal timing of treatment to prevent complications such as cirrhosis and HCC has been published by the international liver societies.
      European Association for the Study of the Liver
      EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection.
      ,
      • Terrault N.A.
      • Lok A.S.F.
      • McMahon B.J.
      • Chang K.M.
      • Hwang J.P.
      • Jonas M.M.
      • et al.
      Update on Prevention, Diagnosis, and Treatment of Chronic Hepatitis B: AASLD 2018 Hepatitis B Guidance.
      ,
      • Sarin S.K.
      • Kumar M.
      • Lau G.K.
      • Abbas Z.
      • Chan H.L.
      • Chen C.J.
      • et al.
      Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update.
      The guidelines describe the classic four phases of chronic HBV infection and propose treatments based on natural history studies such as REVEAL-HBV, from data ascertained in Taiwan.
      • Iloeje U.H.
      • Yang H.I.
      • Su J.
      • Jen C.L.
      • You S.L.
      • Chen C.J.
      • et al.
      Predicting cirrhosis risk based on the level of circulating hepatitis B viral load.
      However, current indications for treatment have not been based on molecular biology, natural history and morbidity of chronic HBV in a SSA population. Although the prevalence of chronic HBV associated HCC in west, central, east and south SSA has been detailed, regional prospective natural history studies in large, endemic chronic HBV populations in SSA have not been evaluated. Despite the authors’ encouraging studies to take place in other populations at high risk of HCC, such as African Americans, there are few data on the efficacy of prevention of HCC by long-term maintenance suppressive therapy with NA in SSA patients.
      • Nguyen M.H.
      • Yang H.I.
      • Le A.
      • Henry L.
      • Nguyen N.
      • Lee M.H.
      • et al.
      Reduced Incidence of Hepatocellular Carcinoma in Cirrhotic and Noncirrhotic Patients With Chronic Hepatitis B Treated With Tenofovir-A Propensity Score-Matched Study.
      The majority of the data to frame guidelines has been reported separately in either Western Pacific Asian or Caucasian cohorts, and it is not clear how generalizable the findings are. Nonetheless long-term prospective studies comparing antiviral treatment to no treatment would now be ethically impossible, given the advent of effective and affordable anti-viral treatments.
      There is an absence of studies to confirm a reduction in liver related morbidity after prolonged NA therapy in SSA patients. The underlying lack of validation of current guidelines in these patients potentially justifies the need for specific guidelines to be developed in this population, while examining the utility and relevance of current guidelines.
      • Dusheiko G.
      • Lemoine M.
      An appraisal of the WHO hepatitis B treatment guidelines applicability to Africans.
      Leaving patients with chronic HBV and evidence of hepatic inflammation untreated for a prolonged period is unethical. Therefore selection of SSA patients for treatment will have to be reasonably based on guidelines derived from data in other populations until, (and if) definite evidence teaches us otherwise. The existing international guidelines for therapy of hepatitis B rely on a clinical diagnosis and a combination of abnormal serum aminotransferase concentrations, and HBV DNA levels.
      European Association for the Study of the Liver
      EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection.
      The widespread lack of access to HBV DNA measurement has resulted in secondary but poorly predictive WHO guidelines in areas where HBV DNA testing is unavailable.
      • Aberra H.
      • Desalegn H.
      • Berhe N.
      • Mekasha B.
      • Medhin G.
      • Gundersen S.G.
      • et al.
      The WHO guidelines for chronic hepatitis B fail to detect half of the patients in need of treatment in Ethiopia.
      These guidelines are reliant on non-invasive scores that favour treatment of advanced disease rather than treatment to prevent the onset of cirrhosis and sequelae of cirrhosis.
      • Aberra H.
      • Desalegn H.
      • Berhe N.
      • Mekasha B.
      • Medhin G.
      • Gundersen S.G.
      • et al.
      The WHO guidelines for chronic hepatitis B fail to detect half of the patients in need of treatment in Ethiopia.
      ,

      World Health Organisation. Guidelines for the prevention, care and treatment of persons with chronic hepatitis B infection. Geneva: World Health Organisation, 2015.

      Other scores, not including HBV DNA, such as TREAT-B, are being validated in SSA, but guidelines which do not include HBV DNA measurement are seemingly unnecessary in high-income countries.
      The relatively low replicative state in anti-HBe positive SSA patients but dichotomous risk of HCC in the region could potentially imply that thresholds for treatment are different in SSA individuals. Studies to confirm a reduction in liver related morbidity after prolonged NA therapy will be difficult to ascertain prospectively. Until specific evidence and guidelines can be substantiated, treatment should be offered SSA patients who would otherwise meet established treatment criteria.
      European Association for the Study of the Liver
      EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection.
      Consideration could also be given to earlier initiation of treatment for patients outside this criteria with additional risk factors for HCC development (e.g. increased age, MAFLD). Other markers including serum pregenomic RNA and HBcrAg require further study, as does the necessity to widen treatment indications in a SSA population.
      TE is readily available in the UK to rule in minimal fibrosis and defer treatment in patients with a serum HBV DNA concentration consistently <2000 IU/ml and normal serum aminotransferases.
      European Association for the Study of the Liver
      EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection.
      TE can also identify advanced fibrosis or cirrhosis.
      European Association for the Study of the Liver
      EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection.
      A composite guideline utilising serum markers, serum aminotransferases and a single TE measurement necessitates a minimum of investigations and follow up appointments in tertiary centres, which are suited to migrant populations and sustainable in a high income healthcare system.
      • Yoshida K.
      • Post G.
      • Shimakawa Y.
      • Thursz M.
      • Brown A.
      • Ingiliz P.
      • et al.
      Clinical utility of TREAT-B score in African and non-African HBV-infected patients living in Europe.
      There are moves to place non invasive technologies to stage hepatic fibrosis in more accessible community settings.
      Current recommended treatments for chronic HBV include entecavir and tenofovir disoproxil (TDF) with an emerging role for tenofovir alafenamide (TAF).
      European Association for the Study of the Liver
      EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection.
      Guidelines point to excellent response rates in randomised controlled trials; long-term meta-analyses demonstrate a significant reduction in progression to cirrhosis, HCC risk and mortality.
      European Association for the Study of the Liver
      EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection.
      Nonetheless, on average, patients with SSA ethnicity comprised <5% of the patients of the major clinical trial study cohorts with an expected lack of representation of the most common African genotypes A1 and E. Long term registry studies assessing outcomes and safety are similarly comprised almost exclusively of Western Pacific Asian patients.
      • Fattovich G.
      • Bortolotti F.
      • Donato F.
      Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors.
      Although limited data from studies in SSA populations suggest good viral suppression, the follow up duration of these studies is relatively short.
      • Desalegn H.
      • Aberra H.
      • Berhe N.
      • Mekasha B.
      • Stene-Johansen K.
      • Krarup H.
      • et al.
      Treatment of chronic hepatitis B in sub-Saharan Africa: 1-year results of a pilot program in Ethiopia.
      ,
      • Cuenca-Gomez J.A.
      • Lozano-Serrano A.B.
      • Cabezas-Fernandez M.T.
      • Soriano-Perez M.J.
      • Vazquez-Villegas J.
      • Estevez-Escobar M.
      • et al.
      Chronic hepatitis B genotype E in African migrants: response to nucleos(t)ide treatment in real clinical practice.
      Current data suggest that persistently undetectable HBV DNA in serum can be achieved in SSA patients. However, similar to Caucasian and Asian patients, loss of HBsAg is rare as current nucleoside analogue treatments do not eradicate cccDNA. Current studies of functional cure are being undertaken worldwide and it is important that SSA patients are included in these studies to determine the effect on HBsAg in predominantly anti-HBe positive patients. This is especially important as SSA patients could be considered to be at higher risk of the most widely reported potential adverse effects of long-term TDF – renal impairment and bone disease.
      Renal function has been shown to decline faster in African-American people without known chronic kidney disease than in Caucasian populations.
      • Peralta C.A.
      • Katz R.
      • DeBoer I.
      • Ix J.
      • Sarnak M.
      • Kramer H.
      • et al.
      Racial and ethnic differences in kidney function decline among persons without chronic kidney disease.
      In the UK, hypertension and diabetes – two major risk factors for renal disease – have a significantly higher prevalence in patients of SSA origin compared with the rest of the population.
      • Cappuccio F.P.
      • Cook D.G.
      • Atkinson R.W.
      • Strazzullo P.
      Prevalence, detection, and management of cardiovascular risk factors in different ethnic groups in south London.
      Data from HIV/HBV coinfected patients has confirmed a statistically significant decline in renal function in SSA patients on TDF.
      • Villa G.
      • Phillips R.O.
      • Smith C.
      • Stockdale A.J.
      • Beloukas A.
      • Appiah L.T.
      • et al.
      Renal health after long-term exposure to tenofovir disoproxil fumarate (TDF) in HIV/HBV positive adults in Ghana.
      Switching HIV/HBV coinfected patients to TAF is associated with improved eGFR and a reduction in proteinuria.
      • Surial B.
      • Beguelin C.
      • Chave J.P.
      • Stockle M.
      • Boillat-Blanco N.
      • Doco-Lecompte T.
      • et al.
      Brief Report: Switching From TDF to TAF in HIV/HBV-Coinfected Individuals With Renal Dysfunction-A Prospective Cohort Study.
      Conversely, a recent publication from HIV/HBV coinfected patients in the USA, including 40% Black ethnicity, reported significant weight gain early after switching from TDF to TAF.
      • Mallon P.W.
      • Brunet L.
      • Hsu R.K.
      • Fusco J.S.
      • Mounzer K.C.
      • Prajapati G.
      • et al.
      Weight gain before and after switch from TDF to TAF in a U.S. cohort study.
      This could have a detrimental impact on the management of metabolic risk factors such as diabetes, hypertension and coexistent fatty liver disease.
      Chronic HBV has been shown to be associated with an increased risk of hip fracture in African American patients, before treatment has even been commenced.
      • Byrne D.D.
      • Newcomb C.W.
      • Carbonari D.M.
      • Nezamzadeh M.S.
      • Leidl K.B.
      • Herlim M.
      • et al.
      Risk of hip fracture associated with untreated and treated chronic hepatitis B virus infection.
      Vitamin D deficiency is significantly more common in SSA migrants to Europe compared with East Asian migrants and may further contribute to the risk of bone related adverse effects.
      • Eggemoen A.R.
      • Knutsen K.V.
      • Dalen I.
      • Jenum A.K.
      Vitamin D status in recently arrived immigrants from Africa and Asia: a cross-sectional study from Norway of children, adolescents and adults.
      Resistance may be under-reported in SSA patients as there is relatively little data to predict treatment resistance in SSA HBV mono-infected patients receiving either entecavir or tenofovir. Amino acid substitutions in the reverse transcriptase associated with reduced tenofovir sensitivity have been reported; although there is a high genetic barrier to selection of tenofovir resistance, a prior history of lamivudine and adefovir will increase the risk of resistance. There are few studies of adherence to therapy and virologic breakthrough in SSA patients.
      • Mokaya J.
      • Maponga T.G.
      • McNaughton A.L.
      • Van Schalkwyk M.
      • Hugo S.
      • Singer J.B.
      • et al.
      Evidence of tenofovir resistance in chronic hepatitis B virus (HBV) infection: An observational case series of South African adults.
      Despite higher response rates observed in genotype A patients with high ALT and low HBV DNA level, pegylted interferon alpha remains an accepted, but presently uncommonly, utilised treatment in the UK.
      • Buster E.H.
      • Hansen B.E.
      • Lau G.K.
      • Piratvisuth T.
      • Zeuzem S.
      • Steyerberg E.W.
      • et al.
      Factors that predict response of patients with hepatitis B e antigen-positive chronic hepatitis B to peginterferon-alfa.
      Although the side effect profile is significant the limited duration of treatment may appeal to a younger migrant population who are averse to the stigma associated with life-long treatment.

      Role for nucleos(t)ide withdrawal

      Curtailing NA treatment is currently being appraised in anti-HBe positive patients.
      European Association for the Study of the Liver
      EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection.
      The potential benefits of NA withdrawal include HBsAg seroclearance, as well as the avoidance of potential long-term medication use and related side effects.
      European Association for the Study of the Liver
      EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection.
      The predominant clinical concern is the risk of precipitating acute liver failure.
      • Agarwal K.
      • Lok J.
      • Carey I.
      • Shivkar Y.
      • Biermer M.
      • Berg T.
      • et al.
      A case of HBV-induced liver failure in the REEF-2 phase II trial: Implications for finite treatment strategies in HBV 'cure.
      It is also not known whether increased HBV replication following NA withdrawal could result in an increased risk of HCC.
      • van Bommel F.
      • Berg T.
      Risks and Benefits of Discontinuation of Nucleos(t)ide Analogue Treatment: A Treatment Concept for Patients With HBeAg-Negative Chronic Hepatitis B.
      The initial study included primarily genotype D patients from Greece.
      • Hadziyannis S.J.
      • Sevastianos V.
      • Rapti I.
      • Vassilopoulos D.
      • Hadziyannis E.
      Sustained responses and loss of HBsAg in HBeAg-negative patients with chronic hepatitis B who stop long-term treatment with adefovir.
      Subsequent studies have included both Western Pacific Asian and Caucasian patients. Rates of HBsAg clearance have varied widely, but recent randomised controlled trials including the FINITE and STOP-NUC trial suggest that between 10-19% of individuals may lose HBsAg after nucleoside analogue withdrawal.
      • van Bommel F.
      • Berg T.
      Risks and Benefits of Discontinuation of Nucleos(t)ide Analogue Treatment: A Treatment Concept for Patients With HBeAg-Negative Chronic Hepatitis B.
      ,
      • Berg T.
      • Simon K.G.
      • Mauss S.
      • Schott E.
      • Heyne R.
      • Klass D.M.
      • et al.
      Long-term response after stopping tenofovir disoproxil fumarate in non-cirrhotic HBeAg-negative patients - FINITE study.
      Unfortunately 50-60% relapse 12-36 months after cessation.
      • Papatheodoridis G.
      • Vlachogiannakos I.
      • Cholongitas E.
      • Wursthorn K.
      • Thomadakis C.
      • Touloumi G.
      • et al.
      Discontinuation of oral antivirals in chronic hepatitis B: A systematic review.
      Provocation of a “flare”, the risk of a clinical or virological relapse, severe hepatitis, and a poorly understood primed immune response following cessation of treatment ensures that predicting safe discontinuation remains a challenge.
      • Hall S.A.L.
      • Vogrin S.
      • Wawryk O.
      • Burns G.S.
      • Visvanathan K.
      • Sundararajan V.
      • et al.
      Discontinuation of nucleot(s)ide analogue therapy in HBeAg-negative chronic hepatitis B: a meta-analysis.
      The likelihood of HBsAg clearance is restricted to those with a HBsAg concentration of <1000 IU/mL, or lower, at the time of withdrawal.
      • Liu J.
      • Li T.
      • Zhang L.
      • Xu A.
      The Role of Hepatitis B Surface Antigen in Nucleos(t)ide Analogues Cessation Among Asian Patients With Chronic Hepatitis B: A Systematic Review.
      Genotype may be an important determinant of HBsAg loss.
      • Sonneveld M.J.
      • Chiu S.M.
      • Park J.Y.
      • Brakenhoff S.M.
      • Kaewdech A.
      • Seto W.K.
      • et al.
      Probability of HBsAg loss after nucleo(s)tide analogue withdrawal depends on HBV genotype and viral antigen levels.
      There are however no representative studies of SSA cohorts with genotype A1
      • Jeng W.J.
      • Sheen I.S.
      • Chen Y.C.
      • Hsu C.W.
      • Chien R.N.
      • Chu C.M.
      • et al.
      Off-therapy durability of response to entecavir therapy in hepatitis B e antigen-negative chronic hepatitis B patients.
      A systematic review from 2016 did not include a single African patient
      • Papatheodoridis G.
      • Vlachogiannakos I.
      • Cholongitas E.
      • Wursthorn K.
      • Thomadakis C.
      • Touloumi G.
      • et al.
      Discontinuation of oral antivirals in chronic hepatitis B: A systematic review.
      Features that have been associated with surface antigen loss (anti-HBe positive, lower viral load) are commonly seen in patients from SSA.
      • Yeo Y.H.
      • Ho H.J.
      • Yang H.I.
      • Tseng T.C.
      • Hosaka T.
      • Trinh H.N.
      • et al.
      Factors Associated With Rates of HBsAg Seroclearance in Adults With Chronic HBV Infection: A Systematic Review and Meta-analysis.
      Although the spontaneous rate of HBsAg loss appears similar to Western Pacific Asian populations (1% annually), the rate of surface antigen loss following NA withdrawal has not been studied in this population.
      • Yeo Y.H.
      • Ho H.J.
      • Yang H.I.
      • Tseng T.C.
      • Hosaka T.
      • Trinh H.N.
      • et al.
      Factors Associated With Rates of HBsAg Seroclearance in Adults With Chronic HBV Infection: A Systematic Review and Meta-analysis.
      ,
      • Shimakawa Y.
      • Lemoine M.
      • Njai H.F.
      • Bottomley C.
      • Ndow G.
      • Goldin R.D.
      • et al.
      Natural history of chronic HBV infection in West Africa: a longitudinal population-based study from The Gambia.
      This lack of data may prevent clinicians from offering a valid, potentially beneficial treatment to SSA patients.

      Representation in clinical trials

      Patients from SSA are poorly represented in multicentre therapeutic clinical trials for chronic HBV (Table 2). Despite the continent accounting for 25% of the global disease burden, less than 3% of clinical trials are performed in Africa.
      • Hwenda L.
      • Sidibe M.
      • Makanga M.
      The African Medicines Agency: the key to unlocking clinical research in Africa.
      Suggested barriers to clinical trials implementation include financial capacity, regulatory and ethics review delays and complex logisitical requirements.
      • Toto N.
      • Douglas E.
      • Gmeiner M.
      • Barrett L.K.
      • Lindblad R.
      • Makhaza L.
      • et al.
      Conducting clinical trials in sub-Saharan Africa: challenges and lessons learned from the Malawi Cryptosporidium study.
      Nonetheless, with appropriate planning and determination numerous high quality clinical trials in other infectious diseases, including HIV, have been completed in SSA.
      • Toto N.
      • Douglas E.
      • Gmeiner M.
      • Barrett L.K.
      • Lindblad R.
      • Makhaza L.
      • et al.
      Conducting clinical trials in sub-Saharan Africa: challenges and lessons learned from the Malawi Cryptosporidium study.
      ,
      • Hanass-Hancock J.
      • Carpenter B.
      • Reddy T.
      • Nzuza A.
      • Gaffoor Z.
      • Goga A.
      • et al.
      Participants' characteristics and motivations to screen for HIV vaccine and monoclonal antibody trials in KwaZulu-Natal, South Africa.
      There is no reason why this should not be achievable in chronic HBV.
      Table 2summary of Black ethnicity and genotype involvement in major chronic HBV trials.
      StudyYearStudy populationNumberBlack ethnicityGenotypeExclusion criteria
      Lamivudine vs Placebo, RCT, P3, NEJM
      • Lai C.L.
      • Chien R.N.
      • Leung N.W.
      • Chang T.T.
      • Guan R.
      • Tai D.I.
      • et al.
      A one-year trial of lamivudine for chronic hepatitis B. Asia Hepatitis Lamivudine Study Group.
      1998China (HK, Taiwan, mainland China)3580 (0%)Not specified
      Adefovir vs Placebo, RCT, P3, NEJM
      • Hadziyannis S.J.
      • Tassopoulos N.C.
      • Heathcote E.J.
      • Chang T.T.
      • Kitis G.
      • Rizzetto M.
      • et al.
      Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B.
      2003Canada, Greece, Israel, France, Italy, Australia, Taiwan, Singapore1856 (3.2%)Not specified
      Entecavir vs Lamivudine (E-Ag positive), RCT, P3, NEJM
      • Chang T.T.
      • Gish R.G.
      • de Man R.
      • Gadano A.
      • Sollano J.
      • Chao Y.C.
      • et al.
      A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B.
      2006Europe (41 centres), North America (40), Asia (26), Australia (12), South America (18)71516 (2.2%)A – 27%, B – 20%, C – 27%, D – 12%, E – not mentioned, F – 4.5%
      Tenofovir disoproxil vs Adefovir, RCT, P3, NEJM
      • Marcellin P.
      • Heathcote E.J.
      • Buti M.
      • Gane E.
      • de Man R.A.
      • Krastev Z.
      • et al.
      Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B.
      2008Europe (59%), North America (24%), Australia/NZ (17%)64130 (4.7%)A – 16%, B – 12%, C – 17%, D – 50%, E-H – 4%
      Tenofovir alafenamide vs tenofovir disoproxil (E-Ag negative), RCT, P3, Lancet Gastro Hep
      • Buti M.
      • Gane E.
      • Seto W.K.
      • Chan H.L.
      • Chuang W.L.
      • Stepanova T.
      • et al.
      Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of patients with HBeAg-negative chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial.
      2016Canada (11 sites), USA (14), UK (2), France (2), Italy (4), Poland (4), Romania (5), Russia (10), Spain (1), Turkey (5), Australia (5), NZ (1), India (10), Japan (11), HK (4), South Korea (10), Taiwan (5)4258 (1.9%)A – 5%, B – 24%, C – 38%, D – 31%, E – 2%
      Tenofovir alafenamide vs tenofovir disoproxil (E-Ag positive), RCT, P3, Lancet Gastroenterol Hepatol
      • Chan H.L.
      • Fung S.
      • Seto W.K.
      • Chuang W.L.
      • Chen C.Y.
      • Kim H.J.
      • et al.
      Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of HBeAg-positive chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial.
      2016East Asia (18% of patients), Europe (18%), North America (16%), Australia (2%), NZ (2%), India (13%)87310 (1.1%)

      Nb. categorized as “other”
      A – 7%, B – 17%, C – 52%, D – 23%, E – <1%, F – <1%
      TDF + pegIFN + REP 2139-Mg or REP 2165-Mg vs TDF + pegIFN, RCT, P2, Gastroenterology
      • Bazinet M.
      • Pantea V.
      • Placinta G.
      • Moscalu I.
      • Cebotarescu V.
      • Cojuhari L.
      • et al.
      Safety and Efficacy of 48 Weeks REP 2139 or REP 2165, Tenofovir Disoproxil, and Pegylated Interferon Alfa-2a in Patients With Chronic HBV Infection Naive to Nucleos(t)ide Therapy.
      2020Republic of Moldova400 (0%)A – 3 (7.5%), D – 37 (92.5%)ANC < 1500 cells/mm3
      Clinical trial involvement from SSA patients in high income countries is also low. In high income countries with large populations of SSA patients, the low involvement rate may be due to systemic issues with blood parameters for exclusion criteria and grading adverse events. A study in healthy Eastern and Southern African patients who would be representative of those joining an AIDS clinical trial importantly demonstrated that this population had lower haemoglobin and neutrophil counts and higher bilirubin compared with United States reference intervals.
      • Karita E.
      • Ketter N.
      • Price M.A.
      • Kayitenkore K.
      • Kaleebu P.
      • Nanvubya A.
      • et al.
      CLSI-derived hematology and biochemistry reference intervals for healthy adults in eastern and southern Africa.
      Specifically, 14.9% had an elevated bilirubin and 9.6% low neutrophil count that would have counted as at least a grade 1 adverse event based on US National Institute of Allergy and Infectious Diseases Division of AIDS criteria.
      • Karita E.
      • Ketter N.
      • Price M.A.
      • Kayitenkore K.
      • Kaleebu P.
      • Nanvubya A.
      • et al.
      CLSI-derived hematology and biochemistry reference intervals for healthy adults in eastern and southern Africa.
      The upper limit of normal serum alanine aminotransferase varies based on the local population.
      • Neuschwander-Tetri B.A.
      • Unalp A.
      • Creer M.H.
      • Nonalcoholic Steatohepatitis Clinical Research N.
      Influence of local reference populations on upper limits of normal for serum alanine aminotransferase levels.
      Patients who have an ALT within the normal range at their hospital laboratory may be deemed to be outside the reference range and ineligible to enter trials if the central reference laboratory limit is based on a different ethnic population.
      • Neuschwander-Tetri B.A.
      • Unalp A.
      • Creer M.H.
      • Nonalcoholic Steatohepatitis Clinical Research N.
      Influence of local reference populations on upper limits of normal for serum alanine aminotransferase levels.
      Benign ethnic neutropaenia (absolute neutrophil count <1.5 x 109 cells/L) may also exclude patients from clinical trials, especially phase one trials.
      • Haddy T.B.
      • Rana S.R.
      • Castro O.
      Benign ethnic neutropenia: what is a normal absolute neutrophil count?.
      ,
      • Lakhotia R.
      • Aggarwal A.
      • Link M.E.
      • Rodgers G.P.
      • Hsieh M.M.
      Natural history of benign ethnic neutropenia in individuals of African ancestry.
      This condition has a prevalence of 6-8% but natural history studies have not shown any increased risk of infectious complications.
      • Lakhotia R.
      • Aggarwal A.
      • Link M.E.
      • Rodgers G.P.
      • Hsieh M.M.
      Natural history of benign ethnic neutropenia in individuals of African ancestry.
      In a review of prostate cancer trials, 41.4% of trials excluded patients with benign ethnic neutropaenia.
      • Vastola M.E.
      • Yang D.D.
      • Muralidhar V.
      • Mahal B.A.
      • Lathan C.S.
      • McGregor B.A.
      • et al.
      Laboratory Eligibility Criteria as Potential Barriers to Participation by Black Men in Prostate Cancer Clinical Trials.
      Lowering the threshold for the absolute neutrophil count to 1.0 x 109 cells/L would have improved trial eligibility without exposing patient to increased risk.
      • Vastola M.E.
      • Yang D.D.
      • Muralidhar V.
      • Mahal B.A.
      • Lathan C.S.
      • McGregor B.A.
      • et al.
      Laboratory Eligibility Criteria as Potential Barriers to Participation by Black Men in Prostate Cancer Clinical Trials.
      Greater collaboration between high income countries and low and middle income countries on the search for HBV cure has been suggested. A recent publication focusing on high income countries with ongoing immigration found that HBV elimination will not be possible without the development of curative therapies.
      • Tian F.
      • Feld J.J.
      • Feng Z.
      • Sander B.
      • Wong W.W.L.
      Feasibility of hepatitis B elimination in high-income countries with ongoing immigration.
      Systematic exclusion of patients of SSA origin from therapeutic clinical trials, regardless of whether patients are in high or low and middle income countries, limits diversity in clinical trials and ultimately disadvantages all. Pharmaceutical industry run clinical trials must be more inclusive to SSA patients, resulting in representative cohorts that more accurately reflect the worldwide burden of chronic HBV.

      Healthcare engagement and primary prevention

      Elimination targets will not be met in high income countries without an increase in awareness, diagnosis and therefore treatment, of migrant groups.
      • Kim J.U.
      • Ingiliz P.
      • Shimakawa Y.
      • Lemoine M.
      Improving care of migrants is key for viral hepatitis elimination in Europe.
      In low endemicity countries, migrants comprise the majority of chronic HBV patients, although case finding and linkage to care remains an issue.
      • Martin N.K.
      • Vickerman P.
      • Khakoo S.
      • Ghosh A.
      • Ramsay M.
      • Hickman M.
      • et al.
      Chronic hepatitis B virus case-finding in UK populations born abroad in intermediate or high endemicity countries: an economic evaluation.
      Despite demonstrated cost effectiveness and acceptability in the community, routine screening of migrants from moderate to high endemic countries, such as those comprising SSA, is not performed in the UK.
      • Martin N.K.
      • Vickerman P.
      • Khakoo S.
      • Ghosh A.
      • Ramsay M.
      • Hickman M.
      • et al.
      Chronic hepatitis B virus case-finding in UK populations born abroad in intermediate or high endemicity countries: an economic evaluation.
      Concerningly, few GP practices follow current guidelines on who to offer screening.
      • Evlampidou I.
      • Hickman M.
      • Irish C.
      • Young N.
      • Oliver I.
      • Gillett S.
      • et al.
      Low hepatitis B testing among migrants: a cross-sectional study in a UK city.
      Opportunistic programs have shown success in single UK centres at identifying patients with chronic HBV and linking them to care.
      • Hargreaves S.
      • Nellums L.B.
      • Johnson C.
      • Goldberg J.
      • Pantelidis P.
      • Rahman A.
      • et al.
      Delivering multi-disease screening to migrants for latent TB and blood-borne viruses in an emergency department setting: A feasibility study.
      This also provides an opportunity to encourage vaccination among family members of identified patients and prevention of new infections among sexually active adolescents and adults. Screening of migrants arriving from countries with either poor diagnostic capabilities or HBV prevalence >1% appears cost-effective and should be undertaken as part of migration assessment.
      • Martin N.K.
      • Vickerman P.
      • Khakoo S.
      • Ghosh A.
      • Ramsay M.
      • Hickman M.
      • et al.
      Chronic hepatitis B virus case-finding in UK populations born abroad in intermediate or high endemicity countries: an economic evaluation.
      Recent modelling from Canada has reiterated that an aggressive screening and treatment strategy could decrease the incidence of HBV-related HCC by 26.1%, even if elimination in a country with high migration was not possible.
      • Tian F.
      • Feld J.J.
      • Feng Z.
      • Sander B.
      • Wong W.W.L.
      Feasibility of hepatitis B elimination in high-income countries with ongoing immigration.
      Point of care testing utilising HBcrAg has been correlated with viral load, allowing identification of patients who meet treatment thresholds.
      • Shimakawa Y.
      • Ndow G.
      • Kaneko A.
      • Aoyagi K.
      • Lemoine M.
      • Tanaka Y.
      • et al.
      Rapid Point-of-Care Test for Hepatitis B Core-Related Antigen to Diagnose High Viral Load in Resource-Limited Settings.
      When coupled with an contemporary ALT elevation this would facilitate treatment initiation in mobile outreach settings.
      Once identified, treatment uptake in SSA individuals diagnosed with chronic HBV can be complicated by overarching cultural and religious values that vary between patients.
      • Freeland C.
      • Bodor S.
      • Perera U.
      • Cohen C.
      Barriers to Hepatitis B Screening and Prevention for African Immigrant Populations in the United States: A Qualitative Study.
      A review from the United States identified several themes amongst SSA migrants as barriers to chronic HBV treatment. These included a lack of knowledge or acceptance of chronic HBV as a disease, with some languages not having a word for hepatitis.
      • Freeland C.
      • Bodor S.
      • Perera U.
      • Cohen C.
      Barriers to Hepatitis B Screening and Prevention for African Immigrant Populations in the United States: A Qualitative Study.
      Myths regarding the transmission of HBV and stigma surrounding the diagnosis may affect healthcare engagement, especially within small migrant communities.
      • Freeland C.
      • Bodor S.
      • Perera U.
      • Cohen C.
      Barriers to Hepatitis B Screening and Prevention for African Immigrant Populations in the United States: A Qualitative Study.
      • Adjei C.A.
      • Stutterheim S.E.
      • Naab F.
      • Ruiter R.A.C.
      "To die is better than to tell": reasons for and against disclosure of chronic hepatitis B status in Ghana.
      • Mude W.
      • Fisher C.
      • Richmond J.
      • Wallace J.
      • Le Gautier R.
      A qualitative investigation of barriers, support-seeking and coping among South Sudanese people with chronic hepatitis B in Australia.
      A paradigm shift to preventative medicine can also be conceptually difficult to understand for patients who may have previously only attended the doctor with a specific symptoms or problems to be resolved.
      • Freeland C.
      • Bodor S.
      • Perera U.
      • Cohen C.
      Barriers to Hepatitis B Screening and Prevention for African Immigrant Populations in the United States: A Qualitative Study.
      As chronic HBV is often asymptomatic it has been hypothesised that this may contribute to low rates of screening in high income countries, emphasising the need for health care engagement.
      • Freeland C.
      • Bodor S.
      • Perera U.
      • Cohen C.
      Barriers to Hepatitis B Screening and Prevention for African Immigrant Populations in the United States: A Qualitative Study.
      Additionally, chronic HBV presents a unique challenge in comparison to HIV or HCV as the determination for treatment is constantly under review.
      • Kim J.U.
      • Ingiliz P.
      • Shimakawa Y.
      • Lemoine M.
      Improving care of migrants is key for viral hepatitis elimination in Europe.
      Rather than test and treat approaches in other infectious diseases, patients with chronic HBV require ongoing reassessment and engagement to determine if treatment is needed.
      • Kim J.U.
      • Ingiliz P.
      • Shimakawa Y.
      • Lemoine M.
      Improving care of migrants is key for viral hepatitis elimination in Europe.
      This forces care into tertiary centres that might be less accessible to patients and over time, may result in falling follow up and attendance rates.
      • Kim J.U.
      • Ingiliz P.
      • Shimakawa Y.
      • Lemoine M.
      Improving care of migrants is key for viral hepatitis elimination in Europe.
      It is certain that the interruption to outpatient services from the COVID-19 pandemic will result in additional patients lost to follow up with those unfamiliar with the system likely to be at highest risk.
      UK data has shown that it takes around 25 years for outpatient usage in a recently arrived migrant population to reach levels of a non-migrant population.
      • Saunders C.L.
      • Steventon A.
      • Janta B.
      • Stafford M.
      • Sinnott C.
      • Allen L.
      • et al.
      Healthcare utilization among migrants to the UK: cross-sectional analysis of two national surveys.
      Improved approaches are therefore needed to ensure patients remain under review within tertiary clinic settings. This includes greater education, as well as better integration of care. This could include shared care between GP practices in high prevalence areas with hepatology services or an outreach clinic model.
      • Kim J.U.
      • Ingiliz P.
      • Shimakawa Y.
      • Lemoine M.
      Improving care of migrants is key for viral hepatitis elimination in Europe.
      Furthermore, education resources and language translation services are comparatively poor for SSA patients. Task shifting follow up to community teams could improve engagement with patients, reserving tertiary appointments to treatment decision times.
      • Kim J.U.
      • Ingiliz P.
      • Shimakawa Y.
      • Lemoine M.
      Improving care of migrants is key for viral hepatitis elimination in Europe.
      Certainly, with improved infrastructure surrounding telehealth implemented due to the pandemic physical appointments at tertiary centres are no longer required in all cases, making access to specialist review more available.

      Conclusion

      Worldwide elimination of chronic HBV will not occur by 2030 unless an evidence based approach to the management of patients from SSA is adopted by high income countries and leading hepatology societies. With a growing migrant population from SSA living in high income countries we have an opportunity to engage this marginalised group with chronic HBV. Evidence based HCC guidelines must be developed, starting with validation of the current risk scores in this population. Hepatitis B publications must accurately define ethnicity. Collaboration should occur amongst centres to provide ‘real-world’ data to guide our current practice.
      Local health services should create new opportunities for access to chronic HBV diagnosis and treatment for affected patients. Integration with HIV services may increase detection and allow sharing of resources and equipment. In lieu of a screening program, outreach mobile community testing can be instituted, ideally utilising point of care diagnostics in areas of high prevalence. Integration of health technology can link antenatal screening results with appropriate providers for third trimester prophylaxis and labour management without stigmatisation. Post-COVID acceptance of telehealth can ensure specialist care is available to a wider population with increased flexibility.
      Finally, truly global representation of chronic HBV must become the paradigm for clinical trials. Inclusion criteria should be reviewed to ensure SSA patients are not arbitrarily excluded based on physiological laboratory values. Migrant communities should be engaged and educated about chronic HBV and the value in participating in trials. Clinical trials should target centres with a diverse ethnic population, or at least ensure adequate representation of genotypes and ethnicities in the study design. Participation by SSA patients in trials in high income regions will improve awareness of the public health importance and advocacy for chronic HBV. With active engagement of this population in the search for a cure we will de-stigmatise chronic HBV and draw closer to achieving global elimination.

      References

        • GBD 2019 Hepatitis B Collaborators
        Global, regional, and national burden of hepatitis B, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019.
        Lancet Gastroenterol Hepatol. 2022;
      1. World Health Organisation. Global Hepatitis Report 2017. Geneva, 2017.

        • Alberts C.J.
        • Clifford G.M.
        • Georges D.
        • Negro F.
        • Lesi O.A.
        • Hutin Y.J.
        • et al.
        Worldwide prevalence of hepatitis B virus and hepatitis C virus among patients with cirrhosis at country, region, and global levels: a systematic review.
        Lancet Gastroenterol Hepatol. 2022;
        • Spearman C.W.
        • Afihene M.
        • Ally R.
        • Apica B.
        • Awuku Y.
        • Cunha L.
        • et al.
        Hepatitis B in sub-Saharan Africa: strategies to achieve the 2030 elimination targets.
        Lancet Gastroenterol Hepatol. 2017; 2: 900-909
        • Lemoine M.
        • Eholie S.
        • Lacombe K.
        Reducing the neglected burden of viral hepatitis in Africa: strategies for a global approach.
        Journal of Hepatology. 2015; 62: 469-476
        • Ahmad A.A.
        • Falla A.M.
        • Duffell E.
        • Noori T.
        • Bechini A.
        • Reintjes R.
        • et al.
        Estimating the scale of chronic hepatitis B virus infection among migrants in EU/EEA countries.
        BMC Infect Dis. 2018; 18: 34
      2. European Centre for Disease Prevention and Control. Epidemiological assessment of hepatitis B and C among migrants in the EU/EEA. Stockholm: ECDC, 2016.

      3. Connor P. At Least a Million Sub-Saharan Africans Moved to Europe Since 2010. Washington, D.C.: Pew Research Centre, 2018.

      4. Public Health England. Hepatitis B in London. London: Public Health England, 2019.

      5. UK National Screening Committee. Screening for Hepatitis B and Hepatitis C among ethnic minorities born outside the UK. United Kingdom, 2011.

        • Evlampidou I.
        • Hickman M.
        • Irish C.
        • Young N.
        • Oliver I.
        • Gillett S.
        • et al.
        Low hepatitis B testing among migrants: a cross-sectional study in a UK city.
        Br J Gen Pract. 2016; 66: e382-e391
        • Williams R.
        • Holt A.P.
        Screening immigrants for tuberculosis--why not for HBV infection?.
        Lancet. 2013; 381: 2164-2165
        • Aberra H.
        • Desalegn H.
        • Berhe N.
        • Mekasha B.
        • Medhin G.
        • Gundersen S.G.
        • et al.
        The WHO guidelines for chronic hepatitis B fail to detect half of the patients in need of treatment in Ethiopia.
        Journal of Hepatology. 2019; 70: 1065-1071
        • Horton R.
        Offline: COVID-19 is not a pandemic.
        Lancet. 2020; 396: 874
        • Aldridge R.W.
        • Nellums L.B.
        • Bartlett S.
        • Barr A.L.
        • Patel P.
        • Burns R.
        • et al.
        Global patterns of mortality in international migrants: a systematic review and meta-analysis.
        Lancet. 2018; 392: 2553-2566
        • Ochieng B.M.
        Black African migrants: the barriers with accessing and utilizing health promotion services in the UK.
        Eur J Public Health. 2013; 23: 265-269
        • European Association for the Study of the Liver
        EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection.
        Journal of Hepatology. 2017; 67: 370-398
        • Fattovich G.
        • Bortolotti F.
        • Donato F.
        Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors.
        Journal of Hepatology. 2008; 48: 335-352
        • Terrault N.A.
        • Lok A.S.F.
        • McMahon B.J.
        • Chang K.M.
        • Hwang J.P.
        • Jonas M.M.
        • et al.
        Update on Prevention, Diagnosis, and Treatment of Chronic Hepatitis B: AASLD 2018 Hepatitis B Guidance.
        Clin Liver Dis (Hoboken). 2018; 12: 33-34
        • Spearman C.W.
        • Dusheiko G.
        • Jonas E.
        • Abdo A.
        • Afihene M.
        • Cunha L.
        • et al.
        Hepatocellular carcinoma: measures to improve the outlook in sub-Saharan Africa.
        Lancet Gastroenterol Hepatol. 2022;
        • Chu Y.J.
        • Yang H.I.
        • Wu H.C.
        • Liu J.
        • Wang L.Y.
        • Lu S.N.
        • et al.
        Aflatoxin B1 exposure increases the risk of cirrhosis and hepatocellular carcinoma in chronic hepatitis B virus carriers.
        Int J Cancer. 2017; 141: 711-720
        • Kimanya M.E.
        • Routledge M.N.
        • Mpolya E.
        • Ezekiel C.N.
        • Shirima C.P.
        • Gong Y.Y.
        Estimating the risk of aflatoxin-induced liver cancer in Tanzania based on biomarker data.
        PLoS One. 2021; 16e0247281
        • Sarin S.K.
        • Kumar M.
        • Lau G.K.
        • Abbas Z.
        • Chan H.L.
        • Chen C.J.
        • et al.
        Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update.
        Hepatol Int. 2016; 10: 1-98
        • Cargill Z.
        • Brown S.E.
        • Dusheiko G.
        • Agarwal K.
        Risk stratification in chronic hepatitis B patients for hepatocellular carcinoma surveillance: management in migrant sub-Saharan African populations.
        Gut. 2020;
        • Yuen M.F.
        • Tanaka Y.
        • Fong D.Y.
        • Fung J.
        • Wong D.K.
        • Yuen J.C.
        • et al.
        Independent risk factors and predictive score for the development of hepatocellular carcinoma in chronic hepatitis B.
        Journal of Hepatology. 2009; 50: 80-88
        • Wong V.W.
        • Chan S.L.
        • Mo F.
        • Chan T.C.
        • Loong H.H.
        • Wong G.L.
        • et al.
        Clinical scoring system to predict hepatocellular carcinoma in chronic hepatitis B carriers.
        J Clin Oncol. 2010; 28: 1660-1665
        • Yang H.I.
        • Yuen M.F.
        • Chan H.L.
        • Han K.H.
        • Chen P.J.
        • Kim D.Y.
        • et al.
        Risk estimation for hepatocellular carcinoma in chronic hepatitis B (REACH-B): development and validation of a predictive score.
        Lancet Oncol. 2011; 12: 568-574
        • Jung K.S.
        • Kim S.U.
        • Song K.
        • Park J.Y.
        • Kim D.Y.
        • Ahn S.H.
        • et al.
        Validation of hepatitis B virus-related hepatocellular carcinoma prediction models in the era of antiviral therapy.
        Hepatology. 2015; 62: 1757-1766
        • Wong G.L.
        • Chan H.L.
        • Chan H.Y.
        • Tse P.C.
        • Tse Y.K.
        • Mak C.W.
        • et al.
        Accuracy of risk scores for patients with chronic hepatitis B receiving entecavir treatment.
        Gastroenterology. 2013; 144: 933-944
        • Johnson P.J.
        • Pirrie S.J.
        • Cox T.F.
        • Berhane S.
        • Teng M.
        • Palmer D.
        • et al.
        The detection of hepatocellular carcinoma using a prospectively developed and validated model based on serological biomarkers.
        Cancer Epidemiol Biomarkers Prev. 2014; 23: 144-153
        • Wong V.W.
        • Janssen H.L.
        Can we use HCC risk scores to individualize surveillance in chronic hepatitis B infection?.
        Journal of Hepatology. 2015; 63: 722-732
        • Kramvis A.
        The clinical implications of hepatitis B virus genotypes and HBeAg in pediatrics.
        Rev Med Virol. 2016; 26: 285-303
        • Kramvis A.
        • Kew M.C.
        Epidemiology of hepatitis B virus in Africa, its genotypes and clinical associations of genotypes.
        Hepatol Res. 2007; 37: S9-S19
        • Spearman C.W.
        • Afihene M.
        • Betiku O.
        • Bobat B.
        • Cunha L.
        • Kassianides C.
        • et al.
        Epidemiology, risk factors, social determinants of health, and current management for non-alcoholic fatty liver disease in sub-Saharan Africa.
        Lancet Gastroenterol Hepatol. 2021; 6: 1036-1046
        • Chang T.T.
        • Liaw Y.F.
        • Wu S.S.
        • Schiff E.
        • Han K.H.
        • Lai C.L.
        • et al.
        Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B.
        Hepatology. 2010; 52: 886-893
        • Nguyen M.H.
        • Yang H.I.
        • Le A.
        • Henry L.
        • Nguyen N.
        • Lee M.H.
        • et al.
        Reduced Incidence of Hepatocellular Carcinoma in Cirrhotic and Noncirrhotic Patients With Chronic Hepatitis B Treated With Tenofovir-A Propensity Score-Matched Study.
        J Infect Dis. 2019; 219: 10-18
        • Wang X.
        • Liu X.
        • Dang Z.
        • Yu L.
        • Jiang Y.
        • Wang X.
        • et al.
        Nucleos(t)ide Analogues for Reducing Hepatocellular Carcinoma in Chronic Hepatitis B Patients: A Systematic Review and Meta-Analysis.
        Gut Liver. 2020; 14: 232-247
        • Arends P.
        • Sonneveld M.J.
        • Zoutendijk R.
        • Carey I.
        • Brown A.
        • Fasano M.
        • et al.
        Entecavir treatment does not eliminate the risk of hepatocellular carcinoma in chronic hepatitis B: limited role for risk scores in Caucasians.
        Gut. 2015; 64: 1289-1295
        • Papatheodoridis G.V.
        • Manolakopoulos S.
        • Touloumi G.
        • Nikolopoulou G.
        • Raptopoulou-Gigi M.
        • Gogos C.
        • et al.
        Hepatocellular carcinoma risk in HBeAg-negative chronic hepatitis B patients with or without cirrhosis treated with entecavir: HepNet.Greece cohort.
        J Viral Hepat. 2015; 22: 120-127
        • Papatheodoridis G.V.
        • Idilman R.
        • Dalekos G.N.
        • Buti M.
        • Chi H.
        • van Boemmel F.
        • et al.
        The risk of hepatocellular carcinoma decreases after the first 5 years of entecavir or tenofovir in Caucasians with chronic hepatitis B.
        Hepatology. 2017; 66: 1444-1453
        • Choi W.M.
        • Choi J.
        • Lim Y.S.
        Effects of Tenofovir vs Entecavir on Risk of Hepatocellular Carcinoma in Patients With Chronic HBV Infection: A Systematic Review and Meta-analysis.
        Clin Gastroenterol Hepatol. 2020;
        • Hsu Y.C.
        • Wong G.L.
        • Chen C.H.
        • Peng C.Y.
        • Yeh M.L.
        • Cheung K.S.
        • et al.
        Tenofovir Versus Entecavir for Hepatocellular Carcinoma Prevention in an International Consortium of Chronic Hepatitis B.
        Am J Gastroenterol. 2020; 115: 271-280
        • Iloeje U.H.
        • Yang H.I.
        • Su J.
        • Jen C.L.
        • You S.L.
        • Chen C.J.
        • et al.
        Predicting cirrhosis risk based on the level of circulating hepatitis B viral load.
        Gastroenterology. 2006; 130: 678-686
        • Dusheiko G.
        • Lemoine M.
        An appraisal of the WHO hepatitis B treatment guidelines applicability to Africans.
        Journal of Hepatology. 2019; 70: 1046-1048
      6. World Health Organisation. Guidelines for the prevention, care and treatment of persons with chronic hepatitis B infection. Geneva: World Health Organisation, 2015.

        • Yoshida K.
        • Post G.
        • Shimakawa Y.
        • Thursz M.
        • Brown A.
        • Ingiliz P.
        • et al.
        Clinical utility of TREAT-B score in African and non-African HBV-infected patients living in Europe.
        Journal of Hepatology. 2019; 70: 1295-1297
        • Desalegn H.
        • Aberra H.
        • Berhe N.
        • Mekasha B.
        • Stene-Johansen K.
        • Krarup H.
        • et al.
        Treatment of chronic hepatitis B in sub-Saharan Africa: 1-year results of a pilot program in Ethiopia.
        BMC Med. 2018; 16: 234
        • Cuenca-Gomez J.A.
        • Lozano-Serrano A.B.
        • Cabezas-Fernandez M.T.
        • Soriano-Perez M.J.
        • Vazquez-Villegas J.
        • Estevez-Escobar M.
        • et al.
        Chronic hepatitis B genotype E in African migrants: response to nucleos(t)ide treatment in real clinical practice.
        BMC Infect Dis. 2018; 18: 568
        • Peralta C.A.
        • Katz R.
        • DeBoer I.
        • Ix J.
        • Sarnak M.
        • Kramer H.
        • et al.
        Racial and ethnic differences in kidney function decline among persons without chronic kidney disease.
        J Am Soc Nephrol. 2011; 22: 1327-1334
        • Cappuccio F.P.
        • Cook D.G.
        • Atkinson R.W.
        • Strazzullo P.
        Prevalence, detection, and management of cardiovascular risk factors in different ethnic groups in south London.
        Heart. 1997; 78: 555-563
        • Villa G.
        • Phillips R.O.
        • Smith C.
        • Stockdale A.J.
        • Beloukas A.
        • Appiah L.T.
        • et al.
        Renal health after long-term exposure to tenofovir disoproxil fumarate (TDF) in HIV/HBV positive adults in Ghana.
        J Infect. 2018; 76: 515-521
        • Surial B.
        • Beguelin C.
        • Chave J.P.
        • Stockle M.
        • Boillat-Blanco N.
        • Doco-Lecompte T.
        • et al.
        Brief Report: Switching From TDF to TAF in HIV/HBV-Coinfected Individuals With Renal Dysfunction-A Prospective Cohort Study.
        J Acquir Immune Defic Syndr. 2020; 85: 227-232
        • Mallon P.W.
        • Brunet L.
        • Hsu R.K.
        • Fusco J.S.
        • Mounzer K.C.
        • Prajapati G.
        • et al.
        Weight gain before and after switch from TDF to TAF in a U.S. cohort study.
        J Int AIDS Soc. 2021; 24e25702
        • Byrne D.D.
        • Newcomb C.W.
        • Carbonari D.M.
        • Nezamzadeh M.S.
        • Leidl K.B.
        • Herlim M.
        • et al.
        Risk of hip fracture associated with untreated and treated chronic hepatitis B virus infection.
        Journal of Hepatology. 2014; 61: 210-218
        • Eggemoen A.R.
        • Knutsen K.V.
        • Dalen I.
        • Jenum A.K.
        Vitamin D status in recently arrived immigrants from Africa and Asia: a cross-sectional study from Norway of children, adolescents and adults.
        BMJ Open. 2013; 3e003293
        • Mokaya J.
        • Maponga T.G.
        • McNaughton A.L.
        • Van Schalkwyk M.
        • Hugo S.
        • Singer J.B.
        • et al.
        Evidence of tenofovir resistance in chronic hepatitis B virus (HBV) infection: An observational case series of South African adults.
        J Clin Virol. 2020; 129104548
        • Buster E.H.
        • Hansen B.E.
        • Lau G.K.
        • Piratvisuth T.
        • Zeuzem S.
        • Steyerberg E.W.
        • et al.
        Factors that predict response of patients with hepatitis B e antigen-positive chronic hepatitis B to peginterferon-alfa.
        Gastroenterology. 2009; 137: 2002-2009
        • Agarwal K.
        • Lok J.
        • Carey I.
        • Shivkar Y.
        • Biermer M.
        • Berg T.
        • et al.
        A case of HBV-induced liver failure in the REEF-2 phase II trial: Implications for finite treatment strategies in HBV 'cure.
        Journal of Hepatology. 2022;
        • van Bommel F.
        • Berg T.
        Risks and Benefits of Discontinuation of Nucleos(t)ide Analogue Treatment: A Treatment Concept for Patients With HBeAg-Negative Chronic Hepatitis B.
        Hepatol Commun. 2021; 5: 1632-1648
        • Hadziyannis S.J.
        • Sevastianos V.
        • Rapti I.
        • Vassilopoulos D.
        • Hadziyannis E.
        Sustained responses and loss of HBsAg in HBeAg-negative patients with chronic hepatitis B who stop long-term treatment with adefovir.
        Gastroenterology. 2012; 143: 629-636 e1
        • Berg T.
        • Simon K.G.
        • Mauss S.
        • Schott E.
        • Heyne R.
        • Klass D.M.
        • et al.
        Long-term response after stopping tenofovir disoproxil fumarate in non-cirrhotic HBeAg-negative patients - FINITE study.
        Journal of Hepatology. 2017; 67: 918-924
        • Papatheodoridis G.
        • Vlachogiannakos I.
        • Cholongitas E.
        • Wursthorn K.
        • Thomadakis C.
        • Touloumi G.
        • et al.
        Discontinuation of oral antivirals in chronic hepatitis B: A systematic review.
        Hepatology. 2016; 63: 1481-1492
        • Hall S.A.L.
        • Vogrin S.
        • Wawryk O.
        • Burns G.S.
        • Visvanathan K.
        • Sundararajan V.
        • et al.
        Discontinuation of nucleot(s)ide analogue therapy in HBeAg-negative chronic hepatitis B: a meta-analysis.
        Gut. 2021;
        • Liu J.
        • Li T.
        • Zhang L.
        • Xu A.
        The Role of Hepatitis B Surface Antigen in Nucleos(t)ide Analogues Cessation Among Asian Patients With Chronic Hepatitis B: A Systematic Review.
        Hepatology. 2019; 70: 1045-1055
        • Sonneveld M.J.
        • Chiu S.M.
        • Park J.Y.
        • Brakenhoff S.M.
        • Kaewdech A.
        • Seto W.K.
        • et al.
        Probability of HBsAg loss after nucleo(s)tide analogue withdrawal depends on HBV genotype and viral antigen levels.
        Journal of Hepatology. 2022; 76: 1042-1050
        • Jeng W.J.
        • Sheen I.S.
        • Chen Y.C.
        • Hsu C.W.
        • Chien R.N.
        • Chu C.M.
        • et al.
        Off-therapy durability of response to entecavir therapy in hepatitis B e antigen-negative chronic hepatitis B patients.
        Hepatology. 2013; 58: 1888-1896
        • Yeo Y.H.
        • Ho H.J.
        • Yang H.I.
        • Tseng T.C.
        • Hosaka T.
        • Trinh H.N.
        • et al.
        Factors Associated With Rates of HBsAg Seroclearance in Adults With Chronic HBV Infection: A Systematic Review and Meta-analysis.
        Gastroenterology. 2019; 156: 635-646 e9
        • Shimakawa Y.
        • Lemoine M.
        • Njai H.F.
        • Bottomley C.
        • Ndow G.
        • Goldin R.D.
        • et al.
        Natural history of chronic HBV infection in West Africa: a longitudinal population-based study from The Gambia.
        Gut. 2016; 65: 2007-2016
        • Hwenda L.
        • Sidibe M.
        • Makanga M.
        The African Medicines Agency: the key to unlocking clinical research in Africa.
        Lancet Glob Health. 2022; 10: e1088-e1089
        • Toto N.
        • Douglas E.
        • Gmeiner M.
        • Barrett L.K.
        • Lindblad R.
        • Makhaza L.
        • et al.
        Conducting clinical trials in sub-Saharan Africa: challenges and lessons learned from the Malawi Cryptosporidium study.
        Trials. 2020; 21: 680
        • Hanass-Hancock J.
        • Carpenter B.
        • Reddy T.
        • Nzuza A.
        • Gaffoor Z.
        • Goga A.
        • et al.
        Participants' characteristics and motivations to screen for HIV vaccine and monoclonal antibody trials in KwaZulu-Natal, South Africa.
        Trials. 2021; 22: 897
        • Karita E.
        • Ketter N.
        • Price M.A.
        • Kayitenkore K.
        • Kaleebu P.
        • Nanvubya A.
        • et al.
        CLSI-derived hematology and biochemistry reference intervals for healthy adults in eastern and southern Africa.
        PLoS One. 2009; 4e4401
        • Neuschwander-Tetri B.A.
        • Unalp A.
        • Creer M.H.
        • Nonalcoholic Steatohepatitis Clinical Research N.
        Influence of local reference populations on upper limits of normal for serum alanine aminotransferase levels.
        Arch Intern Med. 2008; 168: 663-666
        • Haddy T.B.
        • Rana S.R.
        • Castro O.
        Benign ethnic neutropenia: what is a normal absolute neutrophil count?.
        J Lab Clin Med. 1999; 133: 15-22
        • Lakhotia R.
        • Aggarwal A.
        • Link M.E.
        • Rodgers G.P.
        • Hsieh M.M.
        Natural history of benign ethnic neutropenia in individuals of African ancestry.
        Blood Cells Mol Dis. 2019; 77: 12-16
        • Vastola M.E.
        • Yang D.D.
        • Muralidhar V.
        • Mahal B.A.
        • Lathan C.S.
        • McGregor B.A.
        • et al.
        Laboratory Eligibility Criteria as Potential Barriers to Participation by Black Men in Prostate Cancer Clinical Trials.
        JAMA Oncol. 2018; 4: 413-414
        • Tian F.
        • Feld J.J.
        • Feng Z.
        • Sander B.
        • Wong W.W.L.
        Feasibility of hepatitis B elimination in high-income countries with ongoing immigration.
        Journal of Hepatology. 2022;
        • Kim J.U.
        • Ingiliz P.
        • Shimakawa Y.
        • Lemoine M.
        Improving care of migrants is key for viral hepatitis elimination in Europe.
        Bull World Health Organ. 2021; 99: 280-286
        • Martin N.K.
        • Vickerman P.
        • Khakoo S.
        • Ghosh A.
        • Ramsay M.
        • Hickman M.
        • et al.
        Chronic hepatitis B virus case-finding in UK populations born abroad in intermediate or high endemicity countries: an economic evaluation.
        BMJ Open. 2019; 9e030183
        • Hargreaves S.
        • Nellums L.B.
        • Johnson C.
        • Goldberg J.
        • Pantelidis P.
        • Rahman A.
        • et al.
        Delivering multi-disease screening to migrants for latent TB and blood-borne viruses in an emergency department setting: A feasibility study.
        Travel Med Infect Dis. 2020; 36101611
        • Shimakawa Y.
        • Ndow G.
        • Kaneko A.
        • Aoyagi K.
        • Lemoine M.
        • Tanaka Y.
        • et al.
        Rapid Point-of-Care Test for Hepatitis B Core-Related Antigen to Diagnose High Viral Load in Resource-Limited Settings.
        Clin Gastroenterol Hepatol. 2022;
        • Freeland C.
        • Bodor S.
        • Perera U.
        • Cohen C.
        Barriers to Hepatitis B Screening and Prevention for African Immigrant Populations in the United States: A Qualitative Study.
        Viruses. 2020; 12
        • Adjei C.A.
        • Stutterheim S.E.
        • Naab F.
        • Ruiter R.A.C.
        "To die is better than to tell": reasons for and against disclosure of chronic hepatitis B status in Ghana.
        BMC Public Health. 2020; 20: 663
        • Mude W.
        • Fisher C.
        • Richmond J.
        • Wallace J.
        • Le Gautier R.
        A qualitative investigation of barriers, support-seeking and coping among South Sudanese people with chronic hepatitis B in Australia.
        Aust J Prim Health. 2019;
        • Saunders C.L.
        • Steventon A.
        • Janta B.
        • Stafford M.
        • Sinnott C.
        • Allen L.
        • et al.
        Healthcare utilization among migrants to the UK: cross-sectional analysis of two national surveys.
        J Health Serv Res Policy. 2021; 26: 54-61
        • Lai C.L.
        • Chien R.N.
        • Leung N.W.
        • Chang T.T.
        • Guan R.
        • Tai D.I.
        • et al.
        A one-year trial of lamivudine for chronic hepatitis B. Asia Hepatitis Lamivudine Study Group.
        N Engl J Med. 1998; 339: 61-68
        • Hadziyannis S.J.
        • Tassopoulos N.C.
        • Heathcote E.J.
        • Chang T.T.
        • Kitis G.
        • Rizzetto M.
        • et al.
        Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B.
        N Engl J Med. 2003; 348: 800-807
        • Chang T.T.
        • Gish R.G.
        • de Man R.
        • Gadano A.
        • Sollano J.
        • Chao Y.C.
        • et al.
        A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B.
        N Engl J Med. 2006; 354: 1001-1010
        • Marcellin P.
        • Heathcote E.J.
        • Buti M.
        • Gane E.
        • de Man R.A.
        • Krastev Z.
        • et al.
        Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B.
        N Engl J Med. 2008; 359: 2442-2455
        • Buti M.
        • Gane E.
        • Seto W.K.
        • Chan H.L.
        • Chuang W.L.
        • Stepanova T.
        • et al.
        Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of patients with HBeAg-negative chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial.
        Lancet Gastroenterol Hepatol. 2016; 1: 196-206
        • Chan H.L.
        • Fung S.
        • Seto W.K.
        • Chuang W.L.
        • Chen C.Y.
        • Kim H.J.
        • et al.
        Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of HBeAg-positive chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial.
        Lancet Gastroenterol Hepatol. 2016; 1: 185-195
        • Bazinet M.
        • Pantea V.
        • Placinta G.
        • Moscalu I.
        • Cebotarescu V.
        • Cojuhari L.
        • et al.
        Safety and Efficacy of 48 Weeks REP 2139 or REP 2165, Tenofovir Disoproxil, and Pegylated Interferon Alfa-2a in Patients With Chronic HBV Infection Naive to Nucleos(t)ide Therapy.
        Gastroenterology. 2020; 158: 2180-2194