Hepatitis B surface antigen-negative but hepatitis B envelope antigen-positive false occult hepatitis B virus infection:A case report

BACKGROUND Occult hepatitis B infection(OBI)is characterized by the detection of hepatitis B virus(HBV)DNA in serum(usually HBV DNA<200 IU/mL)or the liver but negativity for hepatitis B surface antigen(HBsAg).The diagnosis of OBI relies on the sensitivity of assays used in the detection of HBV DNA and HBsAg.HBsAg assays with inadequate sensitivity or inability to detect HBV S variants may lead to misdiagnosis of OBI in people with overt HBV infection.CASE SUMMARY We report a HBsAg-negative but hepatitis B envelope antigen-positive patient who had a significant HBV DNA level.The patient was initially diagnosed as having OBI.However,sequence analysis revealed a unique insertion of amino acid residues at positions 120-124 in the S protein,which affects the formation of a disulfide bond that is associated with the formation of a loop.It is well known that there is an overlap between the S protein and Pol protein.We found that this new insertion site occurred in polymerase/reverse transcriptase domain,indi-cating that this insertion might be involved in HBV pathogenicity.The patient was finally diagnosed with a false OBI.CONCLUSION An insertion of amino acid residues at positions 120-124 of the S protein affects the formation of immunodominant epitopes and results in negative HBsAg levels.

Genetic diversity and occult hepatitis B infection in Africa: A comprehensive review

BACKGROUND Occult hepatitis B infection(OBI)is a globally prevalent infection,with its frequency being influenced by the prevalence of hepatitis B virus(HBV)infection in a particular geographic region,including Africa.OBI can be transmitted th-rough blood transfusions and organ transplants and has been linked to the development of hepatocellular carcinoma(HCC).The associated HBV genotype influences the infection.AIM To highlight the genetic diversity and prevalence of OBI in Africa.METHODS This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and involved a comprehensive search on PubMed,Google Scholar,Science Direct,and African Journals Online for published studies on the prevalence and genetic diversity of OBI in Africa.RESULTS The synthesis included 83 articles,revealing that the prevalence of OBI varied between countries and population groups,with the highest prevalence being 90.9%in patients with hepatitis C virus infection and 38%in blood donors,indicating an increased risk of HBV transmission through blood transfusions.Cases of OBI reactivation have been reported following chemotherapy.Genotype D is the predominant,followed by genotypes A and E.CONCLUSION This review highlights the prevalence of OBI in Africa,which varies across countries and population groups.The study also demonstrates that genotype D is the most prevalent.

Chronic hepatitis B and occult infection in chemotherapy patients-evaluation in oncology and hemato-oncology settings:The CHOICE study

BACKGROUND Reactivation of hepatitis B virus(HBV)infection is a well-known risk that can occur spontaneously or following immunosuppressive therapies,including cancer chemotherapy.HBV reactivation can cause significant morbidity and even mortality,which are preventable if at-risk individuals are identified through screening and started on antiviral prophylaxis.AIM To determine the prevalence of chronic HBV(CHB)and occult HBV infection(OBI)among oncology and hematology-oncology patients undergoing chemo-therapy.METHODS In this observational study,the prevalence of CHB and OBI was assessed among patients receiving chemotherapy.Serological markers of HBV infection[hepatitis B surface antigen(HBsAg)/anti-hepatitis B core antigen(HBc)]were evaluated for all patients.HBV DNA levels were assessed in those who tested negative for HBsAg but positive for total anti-HBc.RESULTS The prevalence of CHB in the study cohort was determined to be 2.3%[95%confidence interval(95%CI):1.0-4.2].Additionally,the prevalence of OBI among the study participants was found to be 0.8%(95%CI:0.2-2.3).CONCLUSION The findings of this study highlight the importance of screening for hepatitis B infection in oncology and hematology-oncology patients undergoing chemotherapy.Identifying individuals with CHB and OBI is crucial for implementing appropriate antiviral prophylaxis to prevent the reactivation of HBV infection,which can lead to increased morbidity and mortality.

Reactivation of hepatitis B virus infection – an important aspect of multifaceted problem

In this editorial we comment on the article published in the recent issue of the W orld Journal of Gastroenterology.We focus specifically on the problem of occult hepatitis B virus(HBV)infection,that is a result of previous hepatitis B(PHB)and a source for reactivation of HBV.The prevalence of PHB is underestimated due to the lack of population testing programs.However,this condition not only com-plicate anticancer treatment,but may be responsible for the development of other diseases,like cancer or autoimmune disorders.Here we unveil possible mecha-nisms responsible for realization of these processes and suggest practical approa-ches for diagnosis and treatment.

合肥地区献血者血液筛查非重复反应性标本与OBI标本间HBV血清学特征分析

目的 了解血液筛查非重复反应性标本与隐匿性乙型肝炎病毒感染(OBI)标本间HBV血清学特征的相关性。方法 收集本科室2021年1月—2023年1月血液筛查ELISA结果均为阴性,仅NAT反应性的标本共144份,其中TMA法联检反应性标本92份,PCR法单人份检测HBV DNA反应性标本52份。联检反应性标本补充TMA法鉴别检测和PCR法单人份检测,2种方法检测均无反应性的标本纳入NRR标本组,任1种方法检出HBV DNA反应性的标本纳入OBI标本组。对2组标本完成HBsAg、抗-HBs、HBeAg、抗-HBe、抗-HBc检测,分析NRR标本与OBI标本在血清学模式和阳性率上是否存在差异。结果 联检反应性标本补充检测均阴性标本53份,纳入NRR标本组。91份标本在任1种方法中检测出HBV DNA反应性,纳入OBI标本组。2组标本血清学检测均未检出HBsAg和HBeAg,抗-HBs检出率NRR标本组为64.15%,OBI标本组为47.25%;抗-HBc检出率NRR标本组为86.79%,OBI标本组为94.51%;抗-HBe检出率NRR标本组为35.85%,OBI标本组为52.75%。2组标本血清学模式:NRR标本组表现最多的模式为抗-HBs+、抗-HBc+(32.08%),OBI标本组表现最多的模式为抗-HBe+、抗-HBc+(37.36%)。结论 NRR标本与OBI标本在HBV血清学检测中的部分检测结果间存在差异,但NRR标本中较高的抗-HBc阳性率提示仍有较高的可能存在HBV感染风险。

An overview of occult hepatitis B virus infection

Occult hepatitis B virus (HBV) infection (OBI), alternatively defined as occult hepatitis B (OHB), is a challenging clinical entity. It is recognized by two main characteristics: absence of HBsAg, and low viral replication. The previous two decades have witnessed a remarkable progress in our understanding of OBI and its clinical implications. Appropriate diagnostic techniques must be adopted. Sensitive HBV DNA amplification assay is the gold standard assay for detection of OBI. Viral as well as host factors are implicated in the pathogenesis of OBI. However, published data reporting the infectivity of OBI by transfusion are limited. Several aspects including OBI transmission, infectivity and its relation to the development of chronic liver diseases and hepatocellular carcinoma have to be resolved. The aim of the present review is to highlight recent data on OBI with a focus on its virological diagnosis and clinical outcome.

Occult infection related hepatitis B surface antigen variants showing lowered secretion capacity

AIM:To elucidate the molecular mechanisms underlying hepatitis B virus(HBV)occult infection of genotype C.METHODS:A total of 10 types of hepatitis B surface antigen(HBs Ag)variants from a Korean occult cohort were used.After a complete HBV genome plasmid mutated such that it does not express HBs Ag and plasmid encoding,each HBs Ag variant was transiently co-transfected into Hu H-7 cells.The secretion capacity and intracellular expression of the HBV virions and HBs Ags in their respective variants were analyzed using real-time quantitative polymerase chain reaction assays and commercial HBs Ag enzyme-linked immunosorbent assays,respectively.RESULTS:All variants exhibited lower levels of HBs Ag secretion into the medium compared with the wild type.In particular,in eight of the ten variants,very low levels of HBs Ag secretion that were similar to the negative control were detected.In contrast,most variants(9/10)exhibited normal virion secretion capacities comparable with,or even higher than,the wild type.This provided new insight into the intrinsic nature of occult HBV infection,which leads to HBs Ag sero-negativeness but has horizontal infectivity.Furthermore,most variants generated higher reactive oxidative species production than the wild type.This finding provides potential links between occult HBV infection and liver disease progression.CONCLUSION:The presently obtained data indicate that deficiency in the secretion capacity of HBs Ag variants may have a pivotal function in the occult infections of HBV genotype C.

Persistent occult hepatitis B virus infection:Experimental findings and clinical implications

Hepatitis B virus (HBV) is a highly pathogenic virus that causes chronic liver diseases in millions of people globally. In addition to a symptomatic, serologically evident infection, occult persistent HBV carriage has been identified since nucleic acid amplification assays of enhanced sensitivity became introduced for detection of hepadnaviral genomes and their replicative intermediates. Current evidence indicates that occult HBV infection is a common and long-term consequence of resolution of acute hepatitis B. This form of residual infection is termed as secondary occult infection (SOI). The data from the woodchuck model of HBV infection indicate that exposure to small amounts of hepadnavirus can also cause primary occult infection (POI) where virus genome, but no serological makers of exposure to virus, are detectable, and the liver may not be involved. However, virus replicates at low levels in the lymphatic system in both these forms. We briefly summarize the current understanding of the nature and characteristics of occult hepadnaviral persistence as well as of its documented and expected pathological consequences.

Occult hepatitis B virus infection and blood transfusion

Transfusion-transmitted infections including hepatitis B virus(HBV) have been a major concern in transfusion medicine. Implementation of HBV nucleic acid testing(NAT) has revealed occult HBV infection(OBI) in blood donors. In the mid-1980 s, hepatitis B core antibody(HBc) testing was introduced to screen blood donors in HBV non-endemic countries to prevent transmission of non-A and non-B hepatitis. That test remains in use for preventing of potential transmission of HBV from hepatitis B surface antigen(HBs Ag)-negative blood donors, even though anti-hepatitis C virus testshave been introduced. Studies of anti-HBc-positive donors have revealed an HBV DNA positivity rate of 0%-15%. As of 2012, 30 countries have implemented HBV NAT. The prevalence of OBI in blood donors was estimated to be 8.55 per 1 million donations, according to a 2008 international survey. OBI is transmissible by blood transfusion. The clinical outcome of occult HBV transmission primarily depends on recipient immune status and the number of HBV DNA copies present in the blood products. The presence of donor anti-HBs reduces the risk of HBV infection by approximately five-fold. The risk of HBV transmission may be lower in endemic areas than in non-endemic areas, because most recipients have already been exposed to HBV. Blood safety for HBV, including OBI, has substantially improved, but the possibility for OBI transmission remains.

Pathogenesis of occult chronic hepatitis B virus infection

Occult hepatitis B infection(OBI) is characterized by hepatitis B virus(HBV) DNA in serum in the absence of hepatitis B surface antigen(HBsAg) presenting HBsAg-negative and anti-HBc positive serological patterns.Occult HBV status is associated in some cases with mutant viruses undetectable by HBsAg assays;but more frequently it is due to a strong suppression of viral replication and gene expression.OBI is an entity with world-wide diffusion.The failure to detect HBsAg,despite the persistence of the viral DNA,is due in most cases to the strong suppression of viral replication and gene expression that characterizes this"occult"HBV infection;although the mechanisms responsible for suppression of HBV are not well understood.The majority of OBI cases are secondary to overt HBV infection and represent a residual low viremia level suppressed by a strong immune response together with histological derangements which occurred during acute or chronic HBV infection.Much evidence suggests that it can favour the progression of liver fibrosis and the development of hepatocellular carcinoma.

Role of occult hepatitis B virus infection in chronic hepatitis C

The development of sensitive assays to detect small amounts of hepatitis B virus(HBV) DNA has favored the identification of occult hepatitis B infection(OBI), a virological condition characterized by a low level of HBV replication with detectable levels of HBV DNA in liver tissue but an absence of detectable surface antigen of HBV(HBs Ag) in serum. The gold standard to diagnose OBI is the detection of HBV DNA in the hepatocytes by highly sensitive and specific techniques, a diagnostic procedure requiring liver tissue to be tested and the use of non-standardized non-commercially available techniques. Consequently, in everyday clinical practice, the detection of anti-hepatitis B core antibody(antiHBc) in serum of HBs Ag-negative subjects is used as a surrogate marker to identify patients with OBI. In patients with chronic hepatitis C(CHC), OBI has been identified in nearly one-third of these cases. Considerable data suggest that OBI favors the increase of liver damage and the development of hepatocellular carcinoma(HCC) in patients with CHC. The data from other studies, however, indicate no influence of OBI on the natural history of CHC, particularly regarding the risk of developing HCC.

Prevalence of occult hepatitis B virus infection in haemodialysis patients from central Greece

AIM:To assess the hepatitis B virus(HBV)-DNA and the prevalence of occult HBV infection in end-stage renal failure(ESRF)patients from Central Greece. METHODS:Sera from 366 ESRF patients attending five out of six dialysis units from Central Greece were investigated for HBV-DNA by real-time polymerase chain reaction.Only serum samples with repeatedly detectable HBV-DNA were considered positive.IgG antibodies to hepatitis C virus(anti-HCV)were tested by a third generation enzyme linked immunosorbent assay(ELISA),while IgG antibodies to hepatitis E virus (anti-HEV)were tested by two commercially available ELISAs.RESULTS:HBV-DNA was detected in 15/366 patient (4.1%)and HBsAg in 20/366(5.5%).The prevalenc of occult HBV infection was 0.9%(3/346 HBsAg negative patients).Occult HBV was not associate with a specific marker of HBV infection or anti-HCV o anti-HEV reactivity.There was no significant differenc in HBV-DNA titres,demographic and biochemica features,between patients with occult HBV infectio and those with HBsAg-positive chronic HBV infection. CONCLUSION:In central Greece,4%of ESRF patient had detectable HBV-DNA,though in this setting,th prevalence of occult HBV seems to be very low(0.9%).

Update on occult hepatitis B virus infection

The event of mutations in the surface antigen gene of hepatitis B virus(HBV) results in undetectable hepatitis B surface antigen with positive/negative anti-hepatitis B core(anti-HBc) antibody status in serum and this phenomenon is named occult hepatitis B infection(OBI). The presence of anti-HBc antibody in serum is an important key for OBI tracking, although about 20% of OBI cases are negative for anti-HBc antibody. The diagnosis of OBI is mainly based on polymerase chain reaction(PCR) and real-time PCR assays. However, real-time PCR is a more reliable method than PCR. OBI is a great issue for the public health problem and a challenge for the clinical entity worldwide. The persistence of OBI may lead to the development of cirrhosis and hepatocellular carcinoma. With regard to OBI complications, the screening of HBV DNA by the highly sensitive molecular means should be implemented for:(1) patients with a previous history of chronic or acute HBV infection;(2) patients co-infected with hepatitis C virus/human immunodeficiency virus;(3) patients undergoing chemotherapy or anti-CD20 therapy;(4) recipients of organ transplant;(5) blood donors;(6) organ transplant donors;(7) thalassemia and hemophilia patients;(8) health care workers;(9) patients with liver related disease(cryptogenic);(10) hemodialysis patients;(11) patients undergoing lamivudine or interferon therapy; and(12) children in time of HBV vaccination especially in highly endemic areas of HBV. Active HBV vaccination should be implemented for the close relatives of patients who are negative for OBI markers. Thus, the goal of this review is to evaluate the rate of OBI with a focus on status of high risk groups in different regions of the world.

Diagnostic strategy for occult hepatitis B virus infection

In 2008,the European Association for the study of the liver(EASL) defined occult hepatitis B virus infection (OBI) as the"presence of hepatitis B virus(HBV) DNA in the liver(with detectable or undetectable HBV DNA in the serum) of individuals testing hepatitis B surface antigen(HBsAg) negative by currently available assays".Several aspects of occult HBV infection are still poorly understood,including the definition itself and a standardized approach for laboratory-based detection,which is the purpose of this review.The clinical significance of OBI has not yet been established;however,in terms of public health,the clinical importance arises from the risk of HBV transmission.Consequently,it is important to detect high-risk groups for occult HBV infection to prevent transmission.The main issue is,perhaps,to identify the target population for screening OBI.Viremia is very low or undetectable in occult HBV infection,even when the most sensitive methods are used,and the detection of the viral DNA reservoir in hepatocytes would provide the best evaluation of occult HBV prevalence in a defined set of patients.However,this diagnostic approach is obviously unsuitable:blood detection of occult hepatitis B requires assays of the highest sensitivity and specificity with a lower limit of detection<10 IU/mL for HBV DNA and<0.1 ng/mL for HBsAg.

Prevalence of occult hepatitis B virus infection

Occult hepatitis B virus(HBV) infection(OBI) is characterized by the persistence of HBV DNA in the liver tissue in individuals negative for the HBV surface antigen.The prevalence of OBI is quite variable depending on the level of endemic disease in different parts of the world,the different assays utilized in the studies,and the different populations studied.Many studies have been carried out on OBI prevalence in different areas of the world and categories of individuals.The studies show that OBI prevalence seems to be higher among subjects at high risk for HBV infection and with liver disease than among individuals at low risk of infection and without liver disease.

Occult hepatitis B virus infection among Egyptian blood donors

AIM:To identify blood donors with occult hepatitis B virus(HBV) infection(OBI) to promote safe blood donation.METHODS:Descriptive cross sectional study was conducted on 3167 blood donors negative for hepatitis B surface antigen(HBsAg),hepatitis C antibody(HCV Ab) and human immunodeficiency virus Ab.They were subjected to the detection of alanine aminotransferase(ALT) and aspartate transaminase(AST) and screening for anti-HBV core antibodies(total) by two different techniques;[Monoliza antibodies to hepatitis B core(Anti-HBc) Plus-Bio-Rad] and(ARC-HBc total-ABBOT).Positive samples were subjected to quantitative detection of antibodies to hepatitis B surface(anti-HBs)(ETI-AB-AUK-3,Dia Sorin-Italy).Serum anti-HBs titers > 10 IU/L was considered positive.Quantitative HBV DNA by real time polymerase chain reaction(PCR)(QIAGEN-Germany) with 3.8 IU/mL detection limit was estimated for blood units with negative serum anti-HBs and also for 32 whose anti-HBs serum titers were > 1000 IU/L.Also,265 recipients were included,34 of whom were followed up for 3-6 mo.Recipients were investigated for ALT and AST,HBV serological markers:HBsAg(ETI-MAK-4,Dia Sorin-Italy),anti-HBc,quantitative detection of anti-HBs and HBV-DNA.RESULTS:525/3167(16.6%) of blood units were positive for total anti-HBc,64% of those were antiHBs positive.Confirmation by ARCHITECT anti-HBc assay were carried out for 498/525 anti-HBc positive samples,where 451(90.6%) confirmed positive.Reactivity for anti-HBc was considered confirmed only if two positive results were obtained for each sample,giving an overall prevalence of 451/3167(14.2%) for total anti-HBc.HBV DNA was quantified by real time PCR in 52/303(17.2%) of anti-HBc positive blood donors(viral load range:5 to 3.5 x 105 IU/mL) with a median of 200 IU/mL(mean:1.8 x 104 ± 5.1 x 104 IU/mL).AntiHBc was the only marker in 68.6% of donors.Univariate and multivariate logistic analysis for identifying risk factors associated with anti-HBc and HBV-DNA positivity among blood donors showed that age above thirty and marriage were the most significant risk factors for prediction of anti-HBc positivity with AOR 1.8(1.4-2.4) and 1.4(1.0-1.9) respectively.Other risk factors as gender,history of blood transfusion,diabetes mellitus,frequent injections,tattooing,previous surgery,hospitalization,Bilharziasis or positive family history of HBV or HCV infections were not found to be associated with positive anti-HBc antibodies.Among anti-HBc positive blood donors,age below thirty was the most significant risk factor for prediction of HBV-DNA positivity with AOR 3.8(1.8-7.9).According to HBV-DNA concentration,positive samples were divided in two groups;group one with HBV-DNA ≥ 200 IU/mL(n = 27) and group two with HBV-DNA < 200 IU/mL(n = 26).No significant difference was detected between both groups as regards mean age,gender,liver enzymes or HBV markers.Serological profiles of all followed up blood recipients showed that,all were negative for the studied HBV markers.Also,HBV DNA was not detected among studied recipients,none developed post-transfusion hepatitis(PTH) and the clinical outcome was good.CONCLUSION:OBI is prevalent among blood donors.Nucleic acid amplification/HBV anti core screening should be considered for high risk recipients to eliminate risk of unsafe blood donation.

Clinical significance of occult hepatitis B virus infection

Occult hepatitis B virus(HBV) infection(OBI) is defined as the presence of HBV DNA in the liver(with or without detectable HBV DNA in serum) for individuals testing HBV surface antigen negative.Until recently,the clinical effect of OBI was unclear on the progression of liver disease;on the development of hepatocellular carcinoma;and on the risk for reactivation or transmission of HBV infection.Several studies suggest a high prevalence of OBI among patients with cryptogenic chronic liver disease,but its role in the progression to cirrhosis remains unclear.Although OBI has been well documented in human immunodeficiency virus(HIV) -positive patients,especially among those coinfected with hepatitis C virus,further studies are needed to determine its current clinical impact in HIV setting.

Occult hepatitis B virus infection among Mexican human immunodeficiency virus-1-infected patients

AIM: To determine the frequency of occult hepatitis B infection (OHBI) in a group of human immunodeficiency virus (HIV)-1+/ hepatitis B surface antigen negative (HBsAg)- patients from Mexico.

Occult hepatitis B virus infection:A complex entity with relevant clinical implications

Occult hepatitis B virus(HBV) infection is a world-wide entity,following the geographical distribution of detectable hepatitis B.This entity is defined as the persistence of viral genomes in the liver tissue and in some instances also in the serum,associated to negative HBV surface antigen serology.The molecular basis of the occult infection is related to the life cycle of HBV,which produces a covalently closed circular DNA that persists in the cell nuclei as an episome,and serves as a template for gene transcription.The mechanism responsible for the HBsAg negative status in occult HBV carriers is a strong suppression of viral replication,probably due to the host’s immune response,co-infection with other infectious agents and epigenetic factors.There is emerging evidence of the potential clinical relevance of occult HBV infection,since this could be involved in occult HBV transmission through orthotopic liver transplant and blood transfusion,reactivation of HBV infection during immunosuppression,impairing chronic liver disease outcome and acting as a risk factor for hepatocellular carcinoma.Therefore it is important to bear in mind this entity in cryptogenetic liver diseases,hepatitis C virus/ HIV infected patients and immunosupressed individuals.It is also necessary to increase our knowledge in this fascinating field to define better strategies to diagnose and treat this infection.

Clinical impact of occult hepatitis B virus infection in immunosuppressed patients

Occult hepatitis B infection(OBI), is characterized by low level hepatitis B virus(HBV) DNA in circulating blood and/or liver tissue. In clinical practice the presence of antibody to hepatitis B core antigen in hepatitis B surface antigen(HBsAg)-/anti-HBs-negative subjects is considered indicative of OBI. OBI is mostly observed in the window period of acute HBV infection in blood donors and in recipients of blood and blood products, in hepatitis C virus chronic carriers, in patients under pharmacological immunosuppression, and in those with immunodepression due to HIV infection or cancer. Reactivation of OBI mostly occurs in anti-HIV-positive subjects, in patients treated with immunosuppressive therapy in onco-hematological settings, in patients who undergo hematopoietic stem cell transplantation, in those treated with anti-CD20 or anti-CD52 monoclonal antibody, or anti-tumor necrosis factors antibody for rheumatological diseases, or chemotherapy for solid tumors. Under these conditions the mortality rate for hepatic failure or progression of the underlying disease due to discontinuation of specific treatment can reach 20%. For patients with OBI, prophylaxis with nucleot(s)ide analogues should be based on the HBV serological markers, the underlying diseases and the type of immunosuppressive treatment. Lamivudine prophylaxis is indicated in hemopoietic stem cell transplantation and in onco-hematological diseases when high dose corticosteroids and rituximab are used; monitoring may be indicated when rituximab-sparing schedules are used, but early treatment should be applied as soon as HBsAg becomes detectable. This review article presents an up-to-date evaluation of the current knowledge on OBI.