Fu, Michael

Harvala, Heli

Simmonds, Peter

English

Oxford University Research Archive

ED I T OR I A LA need for confirmatory testing of isolated HBcAb-positiveresults in screening programsINTRODUCTIONGlobally, an estimated 246 million individuals arechronically infected with HBV.[1] HBV infection is theprimary etiological agent of HCC and cirrhosis, both ofwhich are associated with substantial morbidity andmortality.[2] Screening and vaccination are cost-effec-tive strategies for reducing the burden of HBVinfection.[3] However, HBV infection, even whenasymptomatic, carries a wide range of adversepsychosocial burdens on affected individuals,impacting their mental health-related quality of life,personal relationships, education, employment, andaccess to health care.[2]Chronic HBV infection is defined by the presence ofHBsAg for a minimum of 6 months.[4] The appearanceof antibodies against HBsAg (anti-HBs) after a declinein HBsAg levels indicates recovery from infection, whileimmunocompetent individuals who have never beeninfected with HBV typically have positive anti-HBs titers(≥ 10 mIU/mL) after successful vaccination.[3] It isestimated that at least one-third of the global populationhas been infected or previously exposed to HBV,demonstrated by antibodies to the HBV core antigen(anti-HBc).[4] However, most individuals with past HBVinfection remain unaware that they were ever exposed,especially those originating from an HBV-endemiccountry.[5]Anti-HBc positivity in individuals without HBsAgprimarily indicates recovery from HBV infection.However, isolated anti-HBc positivity (immunoglobinM) could also indicate acute HBV infection.Unfortunately, anti-HBc assay positivity, mainly inindividuals testing negative for HBsAg and negativefor anti-HBs, can also result from biological falsereactivity (also termed false positivity or nonspecificreactivity) in assays used for anti-HBc screening,especially among individuals from low-prevalenceregions who lack risk factors for HBV infection.Consequently, interpreting isolated anti-HBc reactiveresults can be challenging. The issue is complicatedby the global increase in vaccination uptake, wherefalse positivity should also be considered in individualswithout prior HBV infection but who test positive forboth anti-HBs and anti-HBc antibodies. It is imperativefor guidelines to discuss optimal testing strategies foranti-HBc so that the diagnosis of a positive anti-HBcresult is made with certainty, given the implications forthe affected individuals and stakeholders.CURRENT GUIDELINES FOR ANTI-HBc TESTINGIn line with the World Health Organization’s (WHO)targets for viral hepatitis elimination, the US Centers forDisease Control and Prevention (CDC) has recentlyrecommended a one-time universal screening of alladults for HBV infection with 3 laboratory tests: HBsAg,anti-HBs, and anti-HBc.[3] This recommendation con-trasts with the American Association for the Study ofLiver Diseases (AASLD) guidelines, which do notrecommend general anti-HBc testing due to issues withfalse positivity.[6] Indeed, a 6.2% median anti-HBcpositivity rate from HBsAg-negative individuals in theUnited States[3] means many individuals would beidentified as anti-HBc–positive from population-widescreening.Elsewhere, the European Association for the Studyof the Liver (EASL),[7] the Asian Pacific Association forthe Study of the Liver (APASL),[4] and the AASLD[6]recommend testing for HBsAg and anti-HBc in allpatients scheduled to receive immunosuppressivetherapy or cytotoxic chemotherapy. Due to thesignificant morbidity and mortality associated withHBV reactivation in HBsAg-negative and anti-HBc–positive individuals, guidelines advocate that thesepatients undergoing high-potency immunosuppressionAbbreviations: AASLD, American Association for the Study of Liver Diseases; anti-HBc, hepatitis B virus core antibody; anti-HBsAb, hepatitis B virus surfaceantibody; APASL, Asian Pacific Association for the Study of the Liver; CDC, Centers for Disease Control and Prevention; EASL, European Association for the Study ofthe Liver; FDA, Food and Drug Administration; PPV, positive predictive value; WHO, World Health Organization.- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproductionin any medium, provided the original work is properly cited.Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.Received: 14 August 2024 | Accepted: 30 August 2024DOI: 10.1097/HC9.0000000000000554Hepatology Communications. 2024;8:e0554. www.hepcommjournal.com | 1Downloaded from http://journals.lww.com/hepcomm by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8K2+Ya6H515kE= on 10/04/2024should be initiated with antiviral prophylaxis andcontinued 12–18 months after cessation.International guidelines also recommend universalanti-HBc screening for blood donors in low-endemiccountries to defer potentially infectious donors whotest anti-HBc–positive and prevent the transfusionof their blood components.[8] This is because anti-HBc–positive blood donors who test HBsAg-negativewith undetectable HBV DNA (termed “occult” HBVinfection) have been associated with HBV transfusiontransmission to immunocompromised recipients, caus-ing significant mortality.[9]However, these guidelines do not mention thesignificant issue of high false-positive rates associatedwith anti-HBc assays. The CDC and AASLD guidelinesstate that Food and Drug Administration (FDA)-approved anti-HBc assays have specificities of over96%.[3,6] However, specificity measures a test’s ability toidentify disease-free individuals correctly. In contrast,the much lower positive predictive value (PPV) shouldbe the metric used to delineate false-positive fromtrue-positive results.ANTI-HBc FALSE REACTIVITYThe low PPV among current assays found fromreal-world studies should be noted in internationalguidelines. For example, the Abbott PRISM assay, anFDA-approved assay, was found to have a 14% falsepositivity rate among HBsAg-negative and initially anti-HBc reactive blood donors in Germany.[10] A recentstudy found that the Architect anti-HBc II assay,another FDA-approved assay, had a PPV of only79% when screening HBsAg-negative blood donors inEngland,[11] that is, 21% of the reactive samples wouldbe false positive. This figure contrasts with the assay’shigh specificity (99.93% from 633,948 donationstested by the English blood service). We note thatthese studies were conducted with blood donorsamples, and although blood donors may reflect thegeneral population, the results of these studies maynot be entirely generalizable. Nonetheless, even with ahigh specificity of 99%, no assay is perfect, and thePPV is expected to be low in low-prevalence popula-tions. This does not mean that the assay becomesunreliable, and screening services need to interpretresults in the context of the population setting wherethe assay is used.When large populations with low anti-HBc sero-prevalence are screened, high false positivity ratescould outnumber true diagnoses. Mass screening wouldresult in increasing numbers of individuals wronglyidentified as positive. This issue becomes more urgentas community-based seroprevalence testing may bepursued more globally to achieve HBV eliminationgoals. Screening for anti-HBc antibodies withoutmeasures to exclude false-positive results could affecta large number of otherwise healthy individuals with nohistory of HBV infection. Individuals who lack anunderstanding of resolved HBV infection may experi-ence anxiety and distress due to the negative publicperceptions surrounding HBV positivity. It seemsnecessary for screening programs to introduce mea-sures to identify and reduce notification of false-positiveanti-HBc results.A CALL FOR AN ANTI-HBc TESTINGSTRATEGYAn important purpose of testing strategies is tominimize the likelihood of misdiagnoses by incorpo-rating an optimal number of tests to ensure that thepositive and negative predictive values are as close to100% as possible. Although the CDC affirms thatisolated anti-HBc–positive results may be false-posi-tive in individuals without risk factors, they suggestthat repeat testing with the same anti-HBc assay isnecessary to confirm results.[3] While a very smallproportion of initially reactive results may not be repeatreactive on the same assay, many false-positiveresults would remain unidentified if a single-assaytesting strategy was utilized. In blood donor screeningin England, a low-endemic country, it has been shownthat adding 1 supplemental anti-HBc assay is sufficientto almost eliminate false-positive diagnoses from aninitial anti-HBc assay without affecting negative pre-dictive value.[11] Bayesian modeling demonstrated thatfalse-positive diagnoses would become extremely rarewhen using a 2-assay testing strategy compared to asingle-assay strategy, even at the lowest seropreva-lences and assay sensitivities.[12] We acknowledgethat there is no gold standard anti-HBc assay, andthere is a likelihood that a sample that initially testspositive in one assay but tests negative in the secondassay may mean that the first assay’s result is false-positive or that the second assay’s result is false-negative.In support of a gold standard testing strategy for anti-HBc, we propose that reflex testing should be per-formed on initially isolated anti-HBc–positive specimens(with or without anti-HBs from vaccination) using adifferent supplemental anti-HBc assay of similar sensi-tivity. Negative results in either assay would indicateanti-HBc negativity, while positivity in both assayswould confirm true anti-HBc positivity. This strategywould be similar to the 2-assay testing strategyrecommended by the WHO for HBsAg screening inlow-prevalence settings.[13]Without confirming true-positive results, data gath-ered and used without adjustment would inaccuratelyassess the global epidemiology and burden of HBVinfection to guide WHO elimination targets. Further,2 | HEPATOLOGY COMMUNICATIONSgiven the costs and side effects of HBV treatment, not tomention the worry associated with HBV reactivation, theuse of confirmatory assays for anti-HBc seems justifiedas a means to avoid prophylactic antiviral treatmentfrom being initiated in those with unconfirmed isolatedanti-HBc reactive test results.COMMUNICATION WITH AFFECTEDINDIVIDUALSWith any gold standard testing algorithm, there is aneed for appropriate communication of false-positiveresults to minimize the psychosocial impact of notifi-cation. In 2-assay testing strategies, individuals withfalse-positive results should be reassured that theirhealth is not adversely affected. Individuals could beadvised that test anomalies found in healthy individ-uals constitute a separate entity from true-positiveresults found in patients. In testing strategies thatutilize only 1 anti-HBc assay, clear communicationshould be given to individuals testing isolated anti-HBc–positive (or with anti-HBs positivity resulting fromvaccination). Here, individuals could be advisedthat results were not confirmed, and there is uncer-tainty about whether the individual had past HBVinfection. Regular staff training and laboratory qualityassessments should be enforced to enable robustanti-HBc laboratory testing and reduce the risk offalse-positive results. Optimizing messaging throughcounselor training and appropriately worded standardinformation for individuals and their health providers iscrucial.In summary, high false-positive rates observed inanti-HBc assays in low-risk and low-endemic popula-tions lead to unnecessary notification of apparentlypositive results. Policymakers have a clinical andsocietal duty of care to ensure accurate screening testresults. Implementing a 2-assay anti-HBc testingstrategy as a gold standard would avoid unnecessaryadditional testing, surveillance, treatment, and psycho-logical effects on individuals testing false-positive.Incorrect seroprevalence data from poor diagnosticsalso impacts HBV epidemiology and elimination strat-egies. Effective communication is vital; stakeholdersinvolved in HBV screening must develop notificationstrategies that minimize stress and anxiety for individ-uals who test false-positive.FUNDING INFORMATIONThe researchers are funded by the National Institute forHealth and Care Research, grant number NIHR203338.The funding source was not involved in the writing ofthis manuscript.CONFLICTS OF INTERESTThe authors have no conflicts to report.Michael X. Fu1Peter Simmonds1Heli Harvala2,31Nuffield Department of Medicine, University of Oxford,Oxford, UK2Radcliffe Department of Medicine, University of Oxford,Oxford, UK3Microbiology Services, NHS Blood and Transplant,Colindale, UKCorrespondenceMichael X. Fu,Nuffield Department of Medicine, Peter MedawarBuilding for Pathogen Research, 3 S Parks Road,Oxford OX1 3SY, UK.Email: michael.fu@ndm.ox.ac.ukPeter Simmonds,Nuffield Department of Medicine, Peter MedawarBuilding for Pathogen Research, 3 S Parks Road,Oxford OX1 3SY, UK.Email: peter.simmonds@ndm.ox.ac.ukHeli Harvala,Nuffield Department of Medicine, Peter MedawarBuilding for Pathogen Research, 3 S Parks Road,Oxford OX1 3SY, UK.Email: heli.harvala@ndcls.ox.ac.ukORCIDMichael X. Fu https://orcid.org/0000–0002–3108–7917Heli Harvala https://orcid.org/0000–0001–9154–4190REFERENCES1. World Health Organization. World Health Statistics 2024:Monitoring Health for the SDGs, Sustainable DevelopmentGoals. 2024.2. Hsu YC, Huang DQ, Nguyen MH. Global burden of hepatitis Bvirus: Current status, missed opportunities and a call for action.Nat Rev Gastroenterol Hepatol. 2023;20:524–37.3. Conners EE, Panagiotakopoulos L, Hofmeister MG, SpradlingPR, Hagan LM, Harris AM, et al. Screening and testing forhepatitis B virus infection: CDC recommendations—UnitedStates, 2023. MMWR Recomm Rep. 2023;72:1–25.4. Sarin SK, Kumar M, Lau GK, Abbas Z, Chan HLY, Chen CJ, et al.Asian-Pacific clinical practice guidelines on the management ofhepatitis B: A 2015 update. Hepatol Int. 2016;10:1–98.5. Bixler D, Barker L, Lewis K, Peretz L, Teshale E. Prevalenceand awareness of Hepatitis B virus infection in the United States:January 2017–March 2020. Hepatol Commun. 2023;7:e0118.6. Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP,Jonas MM, et al. Update on prevention, diagnosis, and treatmentof chronic hepatitis B: AASLD 2018 hepatitis B guidance.Hepatology. 2018;67:1560–99.7. Lampertico P, Agarwal K, Berg T, Buti M, Janssen HLA,Papatheodoridis G, et al. EASL 2017 Clinical PracticeEDITORIAL | 3Guidelines on the management of hepatitis B virus infection. JHepatol. 2017;67:370–98.8. FDA Recommendations Concerning Testing of Antibody toHepatitis B Core Antigen (Anti-HBc). 1991. Accessed July 7,2024. http://www.fda.gov/cber/memo.htm9. Fu MX, Simmonds P, Andersson M, Harvala H. Biomarkersof transfusion transmitted occult hepatitis B virus infection:Where are we and what next? Rev Med Virol. 2024;34:e2525.10. Schmidt M, Nübling CM, Scheiblauer H, Chudy M, Walch LA,Seifried E, et al. Anti-HBc screening of blood donors: Acomparison of nine anti-HBc tests. Vox Sang. 2006;91:237–43.11. Fu MX, Ingram J, Roberts C, Nurmi V, Watkins E, Dempsey N,et al. Blood donation screening for hepatitis B virus core antibodies:The importance of confirmatory testing and initial implication for rareblood donor groups. Vox Sang. 2024;119:447–59.12. Parry JV, Easterbrook P, Sands AR. One or two serologicalassay testing strategy for diagnosis of HBV and HCV infection?The use of predictive modelling. BMC Infect Dis. 2017;17(suppl 1):705.13. World Health Organization. WHO Guidelines on Hepatitis Band C Testing. 2017. Accessed July 1, 2024. https://iris.who.int/bitstream/handle/10665/254621/9789241549981-eng.pdf?sequence=14 | HEPATOLOGY COMMUNICATIONS

A need for confirmatory testing of isolated HBcAb-positive results in screening programs

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A need for confirmatory testing of isolated HBcAb-positive results in screening programs

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