New and Old Biomarkers for Diagnosis and Management of Chronic Hepatitis B Virus Infection
2018; Elsevier BV; Volume: 156; Issue: 2 Linguagem: Inglês
10.1053/j.gastro.2018.11.037
ISSN1528-0012
AutoresCarla S. Coffin, Kali Zhou, Norah A. Terrault,
Tópico(s)Liver Disease Diagnosis and Treatment
ResumoTests to detect the presence and activity of hepatitis B virus (HBV) are the cornerstones of diagnosis and management. Assays that detect or measure serum levels of HB surface antigen, HB surface antibody, and HB core antibody are used to identify patients with exposure to HBV, whereas other tests provide information on the level of virus replication, presence of specific variants, and presence of virus reservoirs. Newer diagnostic tests, used only in research settings so far, aim to quantify levels of intrahepatic HBV replication. Other tests have been developed to detect HBV infection in resource-limited settings. We review point-of-care tests (essential in global screening efforts), standard diagnostic tests used in routine clinical management, and newer tests that might be used in clinical trials of agents designed to cure HBV infection. Tests to detect the presence and activity of hepatitis B virus (HBV) are the cornerstones of diagnosis and management. Assays that detect or measure serum levels of HB surface antigen, HB surface antibody, and HB core antibody are used to identify patients with exposure to HBV, whereas other tests provide information on the level of virus replication, presence of specific variants, and presence of virus reservoirs. Newer diagnostic tests, used only in research settings so far, aim to quantify levels of intrahepatic HBV replication. Other tests have been developed to detect HBV infection in resource-limited settings. We review point-of-care tests (essential in global screening efforts), standard diagnostic tests used in routine clinical management, and newer tests that might be used in clinical trials of agents designed to cure HBV infection. Kali ZhouView Large Image Figure ViewerDownload Hi-res image Download (PPT)Norah A. TerraultView Large Image Figure ViewerDownload Hi-res image Download (PPT) Assays that detect or measure serum levels of hepatitis B surface antigen (HBsAg), HB surface antibody (anti-HBs), and HB core antibody (anti-HBc) are used to identify patients who have been exposed to hepatitis B virus (HBV), whereas other tests provide information on the level of virus replication, presence of specific variants, and presence of virus reservoirs. Tests are being developed to quantify levels of intrahepatic HBV replication. These biomarkers are used to identify patients with HBV infection, follow disease progression and response to therapy, and determine efficacy of new agents in clinical trials. The goal of HBV treatment is sterilizing cure, defined as a sustained loss of HBsAg from serum, loss of HBV DNA from serum and liver, loss of covalently closed circular DNA (cccDNA) and HBV DNA integrated into the genome. This may or may not be achievable. A more immediately feasible goal is functional cure, defined as loss of HBsAg, with or without presence of anti-HBs. Access to HBV tests varies worldwide; resource-constrained areas are less likely to have access to tests that measure virus replication or detect variants and have greater reliance on serologic tests. In difficult-to-access populations, point-of-care (POC) tests are important and significant advances have been made in the past few years. An estimated 292 million persons have chronic HBV infection worldwide, but only 10% have been diagnosed.1Polaris Observatory CollaboratorsGlobal prevalence, treatment, and prevention of hepatitis B virus infection in 2016: a modelling study.Lancet Gastroenterol Hepatol. 2018; 3: 383-403Abstract Full Text Full Text PDF PubMed Scopus (937) Google Scholar Acute or chronic HBV infection is established based on detection of HBsAg in serum using an enzyme immunoassay (EIA) or chemiluminescence immunoassay. However, these laboratory-based immunoassays may not be readily accessible or affordable, particularly in resource-constrained countries. POC tests provide an alternative means of diagnosis (Figure 1). In high-income counties, rapid diagnostic tests offered at POC are needed for populations unable or unwilling to access regular medical care, such as injection drug users or homeless or uninsured individuals. Ideal rapid diagnostic tests are inexpensive, easy to use, and placed within a closed system to avoid cross-contamination. They need a long shelf life for tropical climates and should not require cold chain transportation and storage. Currently available POC tests are small devices that use blood or saliva to detect or measure viral antibodies and/or antigens.2Chevaliez S. Pawlotsky J.M. New virological tools for screening, diagnosis and monitoring of hepatitis B and C in resource-limited settings.J Hepatol. 2018; 69: 916-926Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar The World Health Organization (WHO) has endorsed the use of rapid diagnostic tests for diagnosis of chronic HBV infection,3World Health OrganizationGuidelines on Hepatitis B and C Testing: 2017. World Health Organization, Geneva2017Google Scholar but the American Association for the Study of Liver Diseases (AASLD) and European Association for the Study of the Liver (EASL) guidelines do not. The WHO recommends POC tests to improve access and linkage to care and treatment. Only a few rapid diagnostic tests for HBsAg have met WHO qualification criteria (Vikia HBsAg; Biomérieux, Craponne, France; SD BIOLINE HBsAg; Abbott, Chicago, IL). Recent meta-analyses have shown the performance characteristics of rapid diagnostic tests for HBsAg, using EIA and nucleic acid tests as reference standards. An analysis of 30 studies, in 23,716 individuals from 23 countries, assessed the diagnostic accuracy of 33 brands of rapid diagnostic tests against a reference standard of EIAs. These tests identified patients with chronic HBV infection with a pooled sensitivity of 90.0% and a pooled specificity of 99.5%.4Amini A. Varsaneux O. Kelly H. et al.Diagnostic accuracy of tests to detect hepatitis B surface antigen: a systematic review of the literature and meta-analysis.BMC Infect Dis. 2017; 17: 698Crossref PubMed Scopus (75) Google Scholar The accuracy of these tests did not differ with use of serum, plasma, or venous or capillary whole blood. The POC test accuracy differed between manufacturers. The presence of HIV co-infection significantly reduced sensitivity to 72%, but the high specificity was preserved.4Amini A. Varsaneux O. Kelly H. et al.Diagnostic accuracy of tests to detect hepatitis B surface antigen: a systematic review of the literature and meta-analysis.BMC Infect Dis. 2017; 17: 698Crossref PubMed Scopus (75) Google Scholar False-negative results have been linked with low levels of HBsAg, HBV DNA, mutations in HBsAg, and different HBV genotypes or subtypes.5Scheiblauer H. El-Nageh M. Diaz S. et al.Performance evaluation of 70 hepatitis B virus (HBV) surface antigen (HBsAg) assays from around the world by a geographically diverse panel with an array of HBV genotypes and HBsAg subtypes.Vox Sang. 2010; 98: 403-414Crossref PubMed Scopus (99) Google Scholar However, newer rapid tests have overcome these limitations.6Chevaliez S. Challine D. Naija H. et al.Performance of a new rapid test for the detection of hepatitis B surface antigen in various patient populations.J Clin Virol. 2014; 59: 89-93Crossref PubMed Scopus (18) Google Scholar, 7Gish R.G. Gutierrez J.A. Navarro-Cazarez N. et al.A simple and inexpensive point-of-care test for hepatitis B surface antigen detection: serological and molecular evaluation.J Viral Hepat. 2014; 21: 905-908Crossref PubMed Scopus (27) Google Scholar A study from Gambia compared 3 different POC tests with a serum EIA, and found these POC tests identified patients with chronic HBV infection with 89%–94% sensitivity and 95%–100% specificity; almost all false-negative results were from inactive carriers with low levels of HBsAg.8Njai H.F. Shimakawa Y. Sanneh B. et al.Validation of rapid point-of-care (POC) tests for detection of hepatitis B surface antigen in field and laboratory settings in the Gambia, Western Africa.J Clin Microbiol. 2015; 53: 1156-1163Crossref PubMed Scopus (66) Google Scholar Although lower levels of sensitivity may be acceptable in areas in which access to any testing is limited, the application of POC tests requires consideration of benefits (broader access) vs risks (missed cases). One study found increased liver stiffness (>7.2 kPa) in 17% of patients with negative results from POC tests for HBsAg, raising concerns about missed cases with significant liver disease.8Njai H.F. Shimakawa Y. Sanneh B. et al.Validation of rapid point-of-care (POC) tests for detection of hepatitis B surface antigen in field and laboratory settings in the Gambia, Western Africa.J Clin Microbiol. 2015; 53: 1156-1163Crossref PubMed Scopus (66) Google Scholar Certainly, POC or DBS tests are useful for epidemiology studies to define disease burden and effects of vaccination or other interventions. Capillary dried blood spot (DBS) tests are cheap and accessible and, unlike rapid diagnostic tests, can measure levels of HBsAg and HBV DNA (Figure 1). In a meta-analysis of DBS for detection of HBsAg, the DBS identified patients with chronic HBV infection with a weighted sensitivity value of 99% and specificity value of 100% (compared to venous blood tests).9Lange B. Cohn J. Roberts T. et al.Diagnostic accuracy of serological diagnosis of hepatitis C and B using dried blood spot samples (DBS): two systematic reviews and meta-analyses.BMC Infect Dis. 2017; 17: 700Crossref PubMed Scopus (61) Google Scholar When DBS are used to detect HBV DNA, the amount of blood analyzed affects sensitivity. In a meta-analysis of DBS (compared to venous blood tests), DBS detected HBV DNA with a pooled estimated sensitivity value of 95% and specificity of 99%.10Lange B. Roberts T. Cohn J. et al.Diagnostic accuracy of detection and quantification of HBV-DNA and HCV-RNA using dried blood spot (DBS) samples—a systematic review and meta-analysis.BMC Infect Dis. 2017; 17: 693Crossref PubMed Scopus (60) Google Scholar Additionally, DBS might not always detect lower levels of virus—this might not be a major issue, because patients with low-level viremia are typically not candidates for antiviral therapy. No DBS tests have been approved for use by the US Food and Drug Administration. Rapid diagnostic tests for anti-HBs are available but have been less extensively studied than HBsAg tests. These tests detect anti-HBs with 96%–98% specificity, but only 60%–70% sensitivity; false-negative results are largely related to low titers of anti-HBs.11Bottero J. Boyd A. Gozlan J. et al.Performance of rapid tests for detection of HBsAg and anti-HBsAb in a large cohort, France.J Hepatol. 2013; 58: 473-478Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 12Poiteau L. Soulier A. Roudot-Thoraval F. et al.Performance of rapid diagnostic tests for the detection of anti-HBs in various patient populations.J Clin Virol. 2017; 96: 64-66Crossref PubMed Scopus (9) Google Scholar Levels of sensitivity are >90% when levels of anti-HBs are >150 U/L.12Poiteau L. Soulier A. Roudot-Thoraval F. et al.Performance of rapid diagnostic tests for the detection of anti-HBs in various patient populations.J Clin Virol. 2017; 96: 64-66Crossref PubMed Scopus (9) Google Scholar In resource-constrained countries, rapid diagnostic tests for HBsAg, followed by vaccination, could be a better approach than additional tests for anti-HBs by rapid diagnostic tests. It would be helpful to have rapid tests to detect HB e antigen (HBeAg), to select patients for treatment when tests for HBV DNA are not available. This is particularly relevant for identification of pregnant women who may benefit from antiviral therapy in the last trimester as a means of reducing mother-to-child transmission of HBV. Limited data indicate the specificity and sensitivity of POC tests for HBeAg is high. In a study comparing POC tests to EIA, as a reference standard, in 942 patients (303 HBeAg-positive), the serum POC identified patients with HBeAg with 96.4% sensitivity and 99.0% specificity, with comparable or higher performance for whole blood samples.13Clement F. Dewint P. Leroux-Roels G. Evaluation of a new rapid test for the combined detection of hepatitis B virus surface antigen and hepatitis B virus e antigen.J Clin Microbiol. 2002; 40: 4603-4606Crossref PubMed Scopus (23) Google Scholar No rapid diagnostic test for HBeAg has been approved by the WHO. Tests to detect antigens, antibodies, and viral nucleic acids are used routinely for diagnosis and monitoring of HBV infection (Table 1). Progression of chronic HBV infection involves interactions between the virus and the immune response. Whether the infection persists for months or a lifetime, the serial evaluation of serologic markers, levels of alanine aminotransferase (ALT), and HBV DNA guides management.Table 1Tests Used in Management of Patients with Hepatitis B Virus InfectionDiagnostic testClinical interpretationTypical scenarios for its useHBsAgMarker of acute and chronic HBV infectionInitial presentationAnnually in patients with inactive chronic infectionConcern for seroreversion (in immune-suppressed patients)Quantification of HBsAgAids in defining phase of infection, identifying patients most likely to respond to interferon, and determining likelihood of HBV reactivationAids in distinguishing patients with HBeAg-negative chronic HBV infection from inactive carriersPrediction of mother-to-child transmissionDetermine frequency of measurement of ALT and elastography tests for patients with inactive infectionsTo identify patients for withdrawal of NA therapyTo identify patients unlikely to respond to continued peginterferon therapyAnti-HBsMarker of immunity (natural or with vaccination)Upon presentation and when HBsAg loss has been documentedAnti-HBcMarker of HBV exposureInitial presentationHBeAgAssociated with high levels of HBV DNA, marker of infectivityInitial presentationEvery 6 mo in HBeAg-positive patients on treatmentHBV flares (changes in levels of ALT and HBV DNA)Anti-HBeAssociated with lower levels of HBV DNAInitial presentationEvery 6 mo in HBeAg-positive patients receiving treatmentHBV flares (changes in levels of ALT and HBV DNA)HBV DNADetects HBV infection, used to define phase of infection and need for HBV therapyInitial presentationEvery 6–12 mo in untreated patientsEvery 3 mo for patients receiving treatment until undetectable, then every 6 moFor patients with ALT flaresAnti-HBc–positive persons at risk for HBV reactivation (such as immune-suppressed patients)HBV genotypeGenotypes A–H, determined by detection of specific sequencesWhen considering peginterferon therapyUseful for epidemiology studies and to broadly define disease progressionPrecore or BCP mutationsDetects presence of mutations in the precore and BCP regions of the HBV genomeNone establishedUseful for epidemiology studies and to broadly define disease progressionHBV resistance testsDetects presence (>10%) of specific HBV amino acid substitutions associated with resistance to NAsIn patients with virologic breakthrough on NAs Open table in a new tab In each HBsAg-positive person, tests are used to define the phase of infection (Figure 2), determine viral coinfections, and liver disease severity. Establishing whether a patient has advanced fibrosis or cirrhosis is important for surveillance procedures (for liver cancer and varices) and strongly influences antiviral treatment recommendations. The EASL and AASLD each recommend antiviral therapy for all patients with cirrhosis, regardless of levels of HBV DNA and/or ALT.14Terrault N.A. Lok A.S.F. McMahon B.J. et al.Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance.Hepatology. 2018; 67: 1560-1599Crossref PubMed Scopus (1811) Google Scholar, 15European Association for the Study of the LiverEASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection.J Hepatol. 2017; 67: 370-398Abstract Full Text Full Text PDF PubMed Scopus (2952) Google Scholar For patients without cirrhosis, AASLD and Asian Pacific Association for the Study of the Liver treatment guidelines recommend treatment for individuals with levels of HBV DNA >2000 IU/mL, if they are HBeAg-negative, and >20,000 IU/mL if they are HBeAg-positive and have levels of ALT twice upper limit of normal.14Terrault N.A. Lok A.S.F. McMahon B.J. et al.Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance.Hepatology. 2018; 67: 1560-1599Crossref PubMed Scopus (1811) Google Scholar, 16Sarin S.K. Kumar M. Lau G.K. et al.Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update.Hepatol Int. 2016; 10: 1-98Crossref PubMed Scopus (1460) Google Scholar EASL treatment guidelines endorse a lower ALT and HBV DNA threshold.15European Association for the Study of the LiverEASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection.J Hepatol. 2017; 67: 370-398Abstract Full Text Full Text PDF PubMed Scopus (2952) Google Scholar Clearly, accurate tools to measure HBV DNA are essential for management. Tests to measure HBeAg and the antibody against HBeAg define phase of infection, determine HBV DNA thresholds for initiation of treatment, and serve as an intermediate treatment end point for some patients. Tests to quantify the level of HBsAg (qHBsAg) have been widely used in Europe, Canada, and Asia, but have been available in the United States only since 2017. These tests have an increasingly important role in management of patients with chronic HBV infection. HBV genotypes and mutations in precore, and basal core promoter (BCP) are analyzed in epidemiology and disease progression studies, but this information is infrequently used in diagnosis or management. Accurate methods to detect and quantify HBV DNA are essential to diagnose acute and chronic infections, guide treatment decisions, assess responses to treatment, and determine risk of HBV-related complications. Historically, hybridization assays were used to estimate HBV DNA levels in blood samples, but their level of sensitivity was suboptimal. Amplification-based assays detect HBV DNA with high specificity (99%) and sensitivity (≥95%), with limits of quantitation ranging from 10–20 IU/mL (approximately 50–100 virus genome copies/mL). The WHO established the first international standard for HBV DNA, IU, for calibration of reference reagents used in HBV nucleic acid amplifications techniques. The establishment of this international standard allowed comparison of HBV DNA among different laboratories and assays. There are 3 US Food and Drug Administration–approved assays for HBV DNA quantification (Supplementary Table 1). The high cost and need for specialized equipment limit accessibility of these assays in resource-limited settings. The sensitivity of transcription-mediated and real-time polymerase chain reaction (PCR)–based quantitative assays for HBV DNA obviates the need for qualitative HBV DNA tests. During acute HBV infection, HBV DNA is the only marker of infection during the window phase of the infection (Supplementary Figure 1). Detection of window-phase infections is most relevant to testing of blood and organ donors; use of sensitive nucleic acid tests reduces time to detection of HBV infection after exposure from an average of approximately 32 days (HBsAg detected) to 15 days (HBV DNA detected).17Biswas R. Tabor E. Hsia C.C. et al.Comparative sensitivity of HBV NATs and HBsAg assays for detection of acute HBV infection.Transfusion. 2003; 43: 788-798Crossref PubMed Scopus (227) Google Scholar, 18Candotti D. Laperche S. Hepatitis B virus blood screening: need for reappraisal of blood safety measures?.Front Med (Lausanne). 2018; 5: 29Crossref PubMed Scopus (42) Google Scholar A second window for testing can occur after HBsAg clearance and before anti-HBs is measurable—in this period, anti-HBc is the marker of HBV infection, but HBV DNA can be measured to determine infectivity. Additionally, HBV DNA tests can confirm viremia in patients with chronic infection but with HBsAg mutations that affect the diagnostic accuracy of standard serological assays (ie, diagnostic escape mutants). The frequency of such HBsAg mutants in the general population is unknown. Next-generation HBsAg tests, which include monoclonal and polyclonal antibodies directed against epitopes within and outside the determinant of HBsAg have increased capacity to detect these HBsAg mutants (such as the Elecsys HBsAg II assay; Roche Diagnostics, Risch-Rotkreuz, Switzerland).19Louisirirotchanakul S. Khupulsup K. Akraekthalin S. et al.Comparison of the technical and clinical performance of the Elecsys HBsAg II assay with the Architect, AxSym, and Advia Centaur HBsAg screening assays.J Med Virol. 2010; 82: 755-762Crossref PubMed Scopus (32) Google Scholar HBV DNA tests are important for management of patients with chronic HBV infection (Supplementary Table 2).14Terrault N.A. Lok A.S.F. McMahon B.J. et al.Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance.Hepatology. 2018; 67: 1560-1599Crossref PubMed Scopus (1811) Google Scholar, 15European Association for the Study of the LiverEASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection.J Hepatol. 2017; 67: 370-398Abstract Full Text Full Text PDF PubMed Scopus (2952) Google Scholar, 16Sarin S.K. Kumar M. Lau G.K. et al.Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update.Hepatol Int. 2016; 10: 1-98Crossref PubMed Scopus (1460) Google Scholar Serial monitoring of levels of HBV DNA and ALT is used to determine the need for and response to anti-HBV therapy. AASLD recommended minimum thresholds of HBV DNA for which initiation of antiviral therapy is recommended in patients with increased levels of ALT are ≥2000 IU/mL for HBeAg-negative patients and ≥20,000 IU/mL for HBeAg-positive patients.14Terrault N.A. Lok A.S.F. McMahon B.J. et al.Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance.Hepatology. 2018; 67: 1560-1599Crossref PubMed Scopus (1811) Google Scholar, 15European Association for the Study of the LiverEASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection.J Hepatol. 2017; 67: 370-398Abstract Full Text Full Text PDF PubMed Scopus (2952) Google Scholar, 16Sarin S.K. Kumar M. Lau G.K. et al.Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update.Hepatol Int. 2016; 10: 1-98Crossref PubMed Scopus (1460) Google Scholar The goal of therapy is to achieve undetectable HBV DNA level with a sensitive PCR assay. Serial monitoring of HBV DNA is used to detect the emergence of viral resistance and medication adherence.20Hongthanakorn C. Chotiyaputta W. Oberhelman K. et al.Virological breakthrough and resistance in patients with chronic hepatitis B receiving nucleos(t)ide analogues in clinical practice.Hepatology. 2011; 53: 1854-1863Crossref PubMed Scopus (106) Google Scholar HBsAg originates from the episomal mini-chromosome (cccDNA) and is translated from pre-S1 and S2 messenger RNAs that are transcribed from the S gene. An additional source of HBsAg comes from randomly integrated locations in the host genome. The contributions of HBsAg from cccDNA and integrated sources can differ among individuals (Figure 3). For example, the correlation between level of HBsAg and serum level of HBV DNA, intrahepatic cccDNA, and total HBV DNA was found to be high in HBeAg-positive patients (r = 0.69, 0.71, 0.76). Among HBeAg-negative individuals, there was low correlation between level of HBsAg with HBV DNA (r = 0.28) and no correlation between level of intrahepatic cccDNA and total HBV DNA, possibly due to increasing integration of HBV with longer duration of infection.21Thompson A.J. Nguyen T. Iser D. et al.Serum hepatitis B surface antigen and hepatitis B e antigen titers: disease phase influences correlation with viral load and intrahepatic hepatitis B virus markers.Hepatology. 2010; 51: 1933-1944Crossref PubMed Scopus (348) Google Scholar HBsAg exists as 3 protein subtypes (small, middle, and large) that are not currently differentiated by commercial assays. Additionally, there are 2 non-infectious subviral particles secreted, in spherical and filamentous forms, with 100-fold to 100,000-fold higher levels than mature virions. The production of HBsAg from these subviral particles and integrated HBV DNA within the host genome have been proposed to contribute to HBV’s capacity to evade immune surveillance.22Wooddell C.I. Yuen M.F. Chan H.L. et al.RNAi-based treatment of chronically infected patients and chimpanzees reveals that integrated hepatitis B virus DNA is a source of HBsAg.Sci Transl Med. 2017; 9Crossref PubMed Scopus (273) Google Scholar Commercially available assays for HBsAg include Architect HBsAg QT (Abbott Diagnostics), Elecsys II (Roche Diagnostics), and Liaison XL Murex HBsAg quant (DiaSorin, Saluggia, Italy)—all have lower limits of detection of 0.05 IU/mL (upper limit >50,000 IU/mL with dilution). There is a high level of agreement between results from the Architect HBsAg QT and Elecsys II assays.23Wursthorn K. Jaroszewicz J. Zacher B.J. et al.Correlation between the Elecsys HBsAg II assay and the Architect assay for the quantification of hepatitis B surface antigen (HBsAg) in the serum.J Clin Virol. 2011; 50: 292-296Crossref PubMed Scopus (75) Google Scholar Additionally, a linearized HBsAg assay is being tested, with increased sensitivity at lower limits of detection (0.005 IU/mL).24Seto W.K. Wong D.K. Fung J. et al.Linearized hepatitis B surface antigen and hepatitis B core-related antigen in the natural history of chronic hepatitis B.Clin Microbiol Infect. 2014; 20: 1173-1180Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar New monoclonal antibody tests to quantify HBsAg protein composition have identified different patterns of proteins with phase of disease—lower proportions of large and middle protein subtypes are detected in inactive carriers compared to patients with acute or chronic HBV infections.25Pfefferkorn M. Bohm S. Schott T. et al.Quantification of large and middle proteins of hepatitis B virus surface antigen (HBsAg) as a novel tool for the identification of inactive HBV carriers.Gut. 2018; 67: 2045-2053Crossref PubMed Scopus (57) Google Scholar Levels of HBsAg differ with phase of infection as well as genotype. The highest levels (>4 log10 IU/mL) are seen in the immune-tolerant (non-inflammatory, high replication) phase and lowest in inactive carriers (approximately 2 log10 IU/mL). Within the same phase, levels of HBsAg are higher in patients with HBV genotype A infection than other genotypes, and lower if pre-S escape mutants are dominant.26Cornberg M. Wong V.W. Locarnini S. et al.The role of quantitative hepatitis B surface antigen revisited.J Hepatol. 2017; 66: 398-411Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar Although level of HBsAg is not associated with likelihood of HBeAg seroconversion, its greatest utility may lie in its ability to differentiate patients with HBeAg-negative, immune-active hepatitis from inactive carriers among indeterminate or gray zone patients—a frequently encountered group in clinical practice.27Di Bisceglie A.M. Lombardero M. Teckman J. et al.Determination of hepatitis B phenotype using biochemical and serological markers.J Viral Hepat. 2017; 24: 320-329Crossref PubMed Scopus (34) Google Scholar Baseline level of HBsAg <1000 IU/mL with levels of HBV DNA <2000 IU/mL identifies patients with inactive chronic HBV genotype D infection with a 90% positive predictive value.28Brunetto M.R. Oliveri F. Colombatto P. et al.Hepatitis B surface antigen serum levels help to distinguish active from inactive hepatitis B virus genotype D carriers.Gastroenterology. 2010; 139: 483-490Abstract Full Text Full Text PDF PubMed Scopus (332) Google Scholar When these cutoff values were applied to patients with HBV genotype B or C infection in the HBV-REVEAL community-based cohort, they identified inactive carriers with a positive predictive value of 83%.29Liu J. Yang H.I. Lee M.H. et al.Serum levels of hepatitis B surface antigen and DNA can predict inactive carriers with low risk of disease progression.Hepatology. 2016; 64: 381-389Crossref PubMed Scopus (90) Google Scholar In patients with inactive chronic HBV infection, levels of HBsAg <100 IU/mL have been associated with and incorporated into simple scoring systems to predict spontaneous loss of HBsAg.30Liu J. Lee M.H. Batrla-Utermann R. et al.A predictive scoring system for the seroclearance of HBsAg in HBeAg-seronegative chronic hepatitis B patients with genotype B or C infection.J Hepatol. 2013; 58: 853-860Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar A more prominent decrease in qHBsAg (such as a reduction of 1 log IU/mL or more) in patients with inactive chronic HBV infection heralds spontaneous HBsAg loss.28Brunetto M.R. Oliveri F. Colombatto P. et al.Hepatitis B surface antigen serum levels help to distinguish active from inactive hepatitis B virus genotype D carriers.Gastroenterology. 2010; 139: 483-490Abstract Full Text Full Text PDF PubMed Scopus (332) Google Scholar Therefore, baseline, and possibly longitudinal, measurement of HBsAg, in conjunction with measurement of HBV DNA and ALT, might be used to identify disease pha
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