Global prevalence of hepatitis B virus serological markers among healthcare workers:A systematic review and meta-analysis

BACKGROUND The hepatitis B virus(HBV)infection is a global public health concern that affects about 2 billion people and causes 1 million people deaths yearly.HBV is a bloodborne disease and healthcare workers(HCWs)are a high-risk group because of occupational hazard to patients’blood.Different regions of the world show a highly variable proportion of HCWs infected and/or immunized against HBV.Global data on serologic markers of HBV infection and immunization in HCWs are very important to improve strategies for HBV control.AIM To determine the worldwide prevalence of HBV serological markers among HCWs.METHODS In this systematic review and meta–analyses,we searched PubMed and Excerpta Medica Database(Embase)to identify studies published between 1970 and 2019 on the prevalence of HBV serological markers in HCWs worldwide.We also manually searched for references of relevant articles.Four independent investigators selected studies and included those on the prevalence of each of the HBV serological markers including hepatitis B surface antigen(HBsAg),hepatitis e antigen(HBeAg),immunoglobulin M anti-HBc,and anti-HBs.Methodological quality of eligible studies was assessed and random-effect model meta-analysis resulted in the pooled prevalence of HBV serological markers HBV infection in HCWs.Heterogeneity(I²)was assessed using theχ²test on Cochran’s Q statistic and H parameters.Heterogeneity’sources were explored through subgroup and metaregression analyses.This study is registered with PROSPERO,number CRD42019137144.RESULTS We reviewed 14059 references,out of which 227 studies corresponding to 448 prevalence data among HCWs(224936 HCWs recruited from 1964 to 2019 in 71 countries)were included in this meta-analysis.The pooled seroprevalences of current HBsAg,current HBeAg,and acute HBV infection among HCWs were 2.3%[95% confidence interval(CI):1.9-2.7],0.2%(95%CI:0.0-1.7),and 5.3%(95%CI:1.4-11.2),respectively.The pooled seroprevalences of total immunity against HBV and immunity acquired by natural HBV infection in HCWs were 56.6%(95%CI:48.7-63.4)and 9.2%(95%CI:6.8-11.8),respectively.HBV infection was more prevalent in HCWs in low-income countries,particularly in Africa.The highest immunization rates against HBV in HCWs were recorded in urban areas and in high-income countries including Europe,the Eastern Mediterranean and the Western Pacific.CONCLUSION New strategies are needed to improve awareness,training,screening,vaccination,post-exposure management and treatment of HBV infection in HCWs,and particularly in low-income regions.

Development of Fok-I based nested polymerase chain reaction-restriction fragment length polymorphism analysis for detection of hepatitis B virus X region V5M mutation

AIM: To develop a Fok-I nested polymerase chain reaction(PCR)-restriction fragment length polymorphism analysis(PRA) method for the detection of hepatitis B virus X region(HBx) V5 M mutation.METHODS: Nested PCR was applied into DNAs from 198 chronic patients at 2 different stages [121 patients with hepatocellular carcinoma(HCC) and 77 carrier patients]. To identify V5 M mutants, digestion of nested PCR amplicons by the restriction enzyme Fok-I(GGA TGN9↓) was done. For size comparison, the enzymetreated products were analyzed by electrophoresis on 2.5% agarose gels, stained with ethidium bromide, and visualized on a UV transilluminator.RESULTS: The assay enabled the identification of 69 patients(sensitivity of 34.8%; 46 HCC patients and 23 carrier patients). Our data also showed that V5 M prevalence in HCC patients was significantly higher than in carrier patients(47.8%, 22/46 patients vs 0%, 0/23 patients, P < 0.001), suggesting that HBx Ag V5 M mutation may play a pivotal role in HCC generation in chronic patients with genotype C infections.CONCLUSION: The Fok-I nested PRA developed in this study is a reliable and cost-effective method to detect HBx Ag V5 M mutation in chronic patients with genotype C2 infection.

Transformation of hepatitis B serologic markers in babies born to hepatitis B surface antigen positive mothers

AIM:To better understand the clinical significance of hepatitis B seroiogic markers in babies born to hepatitis B surface antigen (HBsAg) positive mothers, the incidence of maternal seroiogic markers of hepatitis B via placenta and its transformation in these babies were investigated. METHODS: Mothers with positive HBsAg were selected in the third trimester of pregnancy. Their babies received immunoprophylaxis with hepatitis B immunoglobulin and hepatitis B vaccine after birth, and were consecutively followed up for hepatitis B seroiogic markers and HBV DNA at birth, mo 1, 4, 7, 12, and 24. RESULTS: Forty-two babies entered the study, including 16 born to hepatitis B e antigen (HBeAg)-positive HBsAg carrier mothers and 26 to HBeAg-negative HBsAg carrier mothers. Apart from four babies born to HBeAg-positive carrier mothers and demonstrated persistent positive HBeAg eventually became HBV carriers, all other babies developed anti-HBs before 12 mo of age. Among the other 12 babies born to HBeAg-positive carrier mothers, HBeAg was detected in 7 at birth, in 4 at mo 1, and in none of them thereafter. No antibody response to the transplacental HBeAg was detected. Among the babies born to HBeAg-negative carrier mothers, anti-HBe was detected 100% at birth and mo 1, in 88.5% at mo 4, in 46.2% at mo 7, in 4.2% at mo 12 and none in mo 24. Among all the immunoprophylaxis-protected babies born to either HBeAg-positive or HBeAg-negative carrier mothers, anti-HBc was detected in 100% at birth, mo 1 and mo 4, in 78.9% at mo 7, in 36.1% at mo 12 and in none at mo 24. CONCLUSION: HBeAg can pass through human placenta from mother to fetus and become undetectable before 4 mo of age, but no antibodies response to the transplacental HBeAg can be detected till mo 24 in the immunoprophylaxis-protected babies. The sole existence of anti-HBe before 1 year of age or anti-HBc before 2 years of age in babies born to HBsAg carrier mothers may simply represent the transplacental maternal antibodies, instead of indicators of HBV infection status.

Models for predicting hepatitis B e antigen seroconversion in response to interferon-α in chronic hepatitis B patients

AIM:To develop models to predict hepatitis B e antigen(HBe Ag)seroconversion in response to interferon(IFN)-αtreatment in chronic hepatitis B patients.METHODS:We enrolled 147 treatment-nave HBe Agpositive chronic hepatitis B patients in China and analyzed variables after initiating IFN-α1b treatment.Patients were tested for serum alanine aminotransferase(ALT),hepatitis B virus-DNA,hepatitis B surface antigen(HBs Ag),antibody to hepatitis B surface antigen,HBe Ag,antibody to hepatitis B e antigen(anti-HBe),and antibody to hepatitis B core antigen(anti-HBc)at baseline and 12 wk,24 wk,and 52 wk after initiating treatment.We performed univariate analysis to identify response predictors among the variables.Multivariate models to predict treatment response were constructed at baseline,12 wk,and 24 wk.RESULTS:At baseline,the 3 factors correlating most with HBe Ag seroconversion were serum ALT level>4×the upper limit of normal(ULN),HBe Ag≤500 S/CO,and anti-HBc>11.4 S/CO.At 12 wk,the 3 factors most associated with HBe Ag seroconversion were HBe Ag level≤250 S/CO,decline in HBe Ag>1 log10 S/CO,and anti-HBc>11.8 S/CO.At 24 wk,the 3 factors most associated with HBe Ag seroconversion were HBe Ag level≤5 S/CO,anti-HBc>11.4 S/CO,and decline in HBe Ag>2 log10 S/CO.Each variable was assigned a score of1,a score of 0 was given if patients did not have any of the 3 variables.The 3 factors most strongly correlating with HBe Ag seroconversion at each time point were used to build models to predict the outcome after IFN-αtreatment.When the score was 3,the response rates at the 3 time points were 57.7%,83.3%,and 84.0%,respectively.When the score was 0,the response rates were 2.9%,0.0%,and 2.1%,respectively.CONCLUSION:Models with good negative and positive predictive values were developed to calculate the probability of response to IFN-αtherapy.

Clinical utility of hepatitis B surface antigen kinetics in treatment-na?ve chronic hepatitis B patients during longterm entecavir therapy

AIM To investigate the utility of hepatitis B surface antigen(HBsAg) kinetics in chronic hepatitis B patients during long-term entecavir treatment.METHODS This retrospective study included treatment-na?ve chronic hepatitis B patients who received at least 2 years of consecutive entecavir treatment. Patients were followed up at three to six month intervals with liver biochemistry, hepatitis B virus DNA, and abdominal sonography. In hepatitis B e antigen(HBeAg)-positive patients, HBeAg levels were assessed every three to six month until results became negative. Serum HBsAg levels were determined at the baseline, oneyear and five-year time points. Liver cirrhosis was diagnosed through liver biopsy, imaging examinations, or clinical findings of portal hypertension. Hepatocellular carcinoma was diagnosed by histological examination or dynamic image studies.RESULTS A total of 211 patients were enrolled. The median treatment time was 5.24(2.00-9.62) years. Multivariate analysis showed that lower baseline HBsAg levels were associated with an earlier virological response, earlier hepatitis B e antigen(HBeAg) seroconversion, and earlier biochemical response in HBeAg-positive patients(cut-off value: 4 log IU/mL) and an earlier virological response in HBeAg-negative non-cirrhotic patients(cut-off value: 2.4 log IU/mL). Although HBsAg levels decreased slowly during long-term entecavir treatment, higher HBsAg decrease rates were found in the first year for HBeAg-positive non-cirrhotic patients, and patients with higher baseline HBsAg levels. More favorable clinical outcomes were not observed by a rapid HBsAg decline per se, but depended on lower baseline HBsAg levels.CONCLUSION Baseline HBsAg can be used to predict treatment responses. HBsAg levels and decrease rates should be considered together according to disease status while interpreting HBsAg changes.

Efficacy of a Chinese herbal formula on hepatitis B e antigenpositive chronic hepatitis B patients

BACKGROUND No guideline recommends antiviral therapy for hepatitis B e antigen(HBeAg)-positive chronic hepatitis B patients with persistently normal alanine aminotransferase levels and a high hepatitis B virus(HBV)DNA viral load.AIM To evaluate the feasibility and safety of a Chinese herbal formula as a therapeutic option for chronic HBV infection.METHODS In total,395 patients(30–65 years old)with confirmed HBeAg-positive chronic hepatitis B infection and persistently normal alanine aminotransferase were randomized to receive either Chinese herbal formula or placebo for 96 wk.Endpoints to evaluate therapeutic efficacy included:(1)HBV DNA levels decreased to less than 4 log10 IU/mL at weeks 48 and 96;and(2)HBeAg clearance and seroconversion rates at weeks 48 and 96.RESULTS HBV DNA levels≤4 log10 IU/mL were 10.05%at week 48 and 18.59%at week 96 in the treatment group.The HBeAg clearance and conversion rates were 8.54%and 8.04%at week 48 and 16.08%and 14.57%at week 96,respectively.However,HBV DNA levels≤4 log10 IU/mL were 2.55%and 2.55%at weeks 48 and 96,respectively,and the HBeAg clearance rates were 3.06%and 5.61%at weeks 48 and 96,respectively,in the control group.The quantitative hepatitis B surface antigen and HBeAg levels at baseline and changes during the treatment period as well as the alanine aminotransferase elevation at weeks 12 and 24 were strong predictors of HBeAg clearance.CONCLUSION High rates of HBV DNA reduction,HBeAg clearance and seroconversion could be achieved with Chinese herbal formula treatments,and the treatments were relatively safe for HBeAg-positive chronic hepatitis B-infected patients with persistently normal alanine aminotransferase.The ability of the compound to modulate host immune function probably contributed to this effect.

High-dose hepatitis B immunoglobulin therapy in hepatocellular carcinoma with hepatitis B virus-DNA/hepatitis B e antigen-positive patients after living donor liver transplantation

AIM: To investigate the impact of high-dose hepatitis B immunoglobulin(HBIG) on hepatocellular carcinoma(HCC) and hepatitis B virus(HBV) recurrence and overall survival after living donor liver transplantation(LDLT).METHODS: We investigated 168 patients who underwent LDLT due to HCC, and who were HBV-DNA/hepatitis B e antigen(HBe Ag)-positive, from January 2008 to December 2013. After assessing whether the patients met the Milan criteria, they were assigned to the low-dose HBIG group and high-dose HBIG group. Using the propensity score 1:1 matching method, 38 and 18 pairs were defined as adhering to and not adhering to the Milan criteria. For each pair, HCC recurrence, HBV recurrence and overall survival were analyzed by the Kaplan-Meier method and the log rank test according to the HBIG dose. RESULTS: Among those who met the Milan criteria, the 6-mo, 1-year, and 3-year HCC recurrence-free survival rates were 88.9%, 83.2%, and 83.2% in the low-dose HBIG group and 97.2%, 97.2%, and 97.2% in the high-dose HBIG group, respectively(P = 0.042).In contrast, among those who did not meet the Milan criteria, HCC recurrence did not differ according to the HBIG dose(P = 0.937). Moreover, HBV recurrence and overall survival did not differ according to the HBIG dose among those who met(P = 0.317 and 0.190, respectively) and did not meet(P = 0.350 and 0.987, respectively) the Milan criteria. CONCLUSION: High-dose HBIG therapy can reduce HCC recurrence in HBV-DNA/HBe Ag-positive patients after LDLT.

Clinical significance of hepatitis B e antigen level measurement during long-term lamivudine therapy in chronic hepatitis B patients with e antigen positive

AIM： To determine the changes of quantitative hepatitis B e antigen （HBeAg） that predicts early detection of non-response or breakthrough to long-term lamivudine （LAM） therapy. METHODS： Among HBeAg positive chronic hepatitis B patients who failed to achieve HBeAg seroconversion within 12 too, we retrospectively analyzed 220 patients who had received LAM more than 24 too. RESULTS： The mean duration of LAM therapy was 36 （range, 24-72） mo. HBeAg seroconversion after the first 12 mo of LAM therapy was achieved in 53 （24.1%） patients. Viral breakthrough was observed in 105 （47.7%） patients. To find out whether the changing patterns of HBeAg levels can predict the outcome of LAM therapy, we analyzed the reduction rates of HBeAg levels during LAM therapy. Using the decrease more than 90% of pretreatment HBeAg levels, the sensitivity and specificity of response were 96.2% and 70.1%, respectively. Patients were divided into 3 groups according to the reduction patterns of the decrease of quantitative HBeAg： decrescendo, decrescendo-crescendo, no change or fluctuating groups. The optimal time to predict non-response or breakthrough was the first 9 mo of therapy. At 9 mo of therapy, 49 （92.5%） of 53 patients who had achieved HBeAg seroconversion were included in the decrescendo group. On the contrary, in the no change or fluctuating group, only four （7.5%） had achieved HBeAg seroconversion. Among patients who did not show the continuous decrease of HBeAg levels at 9 too, 95.2% （negative predictive value） failed to achieve HBeAg seroconversion. CONCLUSION： Almost all patients who failed to show a continuous decrease of HBeAg levels at 9 mo of LAM therapy were non-response or breakthrough. Therefore, monitoring changes of HBeAg levels during LAM therapy in HBeAg positive chronic hepatitis B may be valuable for identifying patients who are at high risk of non-response or breakthrough.

Seroprevalence of hepatitis B surface antigen in pregnant women attending antenatal clinic in Honiara Solomon Islands,2015

AIMTo determine the seroprevalence of hepatitis B surface antigen (HBsAg) among pregnant women attending antenatal clinic in Honiara, Solomon Islands. METHODSThis descriptive cross-sectional study was carried out in seven area health centers in Honiara. From March to June 2015, identification of eligible pregnant women in each site was conducted using systematic random sampling technique. A total of 243 pregnant women who gave written informed consent were enrolled. Standardized tool was used to record demographics, obstetric history and serology results. HBsAg and hepatitis B e antigen (HBeAg) were tested using point-of-care rapid diagnostic test. All HBsAg positive samples were verified using enzyme-linked immunosorbent assay. RESULTSThe mean age of participants was 26 &plusmn; 6 years. The overall hepatitis HBsAg prevalence was 13.8% with higher rate (22%) reported in women between 30-34 years of age. Majority of HBsAg positive participants were Melanesians (29 out for 33). None of the pregnant women in the 15-19 years and &ge; 40 years tested positive for HBsAg. There was no statistically significant difference in HBsAg prevalence by age, ethnicity, education and residential location. The overall HBeAg seroprevalence was 36.7%. Women between 20-24 years of age had the highest rate of 54.5%. Low level of knowledge about hepatitis B vaccination was reputed. Overall, 54.6% of participants were not aware of their hepatitis B vaccination status and only 65.2% of mothers reported their child had been vaccinated. CONCLUSIONHepatitis B is a disease of public health importance in Solomon Islands and emphasize the need for integrated preventative interventions for its control.

Practical approach in hepatitis b e antigen-negative individuals to identify treatment candidates

The natural history of chronic hepatitis B is characterized by different phases of infection,and patients may evolve from one phase to another or may revert to a previous phase.The hepatitis B e antigen(HBeAg)-negative form is the predominant infection worldwide,which consists of individuals with a range of viral replication and liver disease severity.Although alanine transaminase(ALT)remains the most accessible test available to clinicians for monitoring the liver disease status,further evaluations are required for some patients to assess if treatment is warranted.Guidance from practice guidelines together with thorough investigations and classifications of patients ensure recognition of who needs which level of care.This article aims to assist physicians in the assessment of HBeAgnegative individuals using liver biopsy or non-invasive tools such as hepatitis B s antigen quantification and transient elastography in addition to ALT and hepatitis B virus DNA,to identify who will remain stable,who will reactivate or at risk of disease progression hence will benefit from timely initiation of anti-viral therapy.

Hepatitis B surface antigen and hepatitis B core-related antigen kinetics after adding pegylated-interferon to nucleos(t)ids analogues in hepatitis B e antigen-negative patients

BACKGROUND Hepatitis B e antigen-negative chronic hepatitis B patients under nucleos(t)ids analogues(NAs)rarely achieve hepatitis B surface antigen(HBsAg)loss.AIM To evaluate if the addition of pegylated interferon(Peg-IFN)could decrease HBsAg and hepatitis B core-related antigen(HBcrAg)levels and increase HBsAg loss rate in patients under NAs therapy.METHODS Prospective,non-randomized,open-label trial evaluating the combination of Peg-IFN 180μg/week plus NAs during forty-eight weeks vs NAs in monotherapy.Hepatitis B e antigen-negative non-cirrhotic chronic hepatitis B patients of a tertiary hospital,under NAs therapy for at least 2 years and with undetectable viral load,were eligible.Patients with hepatitis C virus,hepatitis D virus or human immunodeficiency virus co-infection and liver transplanted patients were excluded.HBsAg and HBcrAg levels(log10 U/mL)were measured at baseline and during ninety-six weeks.HBsAg loss rate was evaluated in both groups.Adverse events were recorded in both groups.The kinetic of HBsAg for each treatment group was evaluated from baseline to weeks 24 and 48 by the slope of the HBsAg decline(log10 IU/mL/week)using a linear regression model.RESULTS Sixty-five patients were enrolled,61%receiving tenofovir and 33%entecavir.Thirty-six(55%)were included in Peg-IFN-NA group and 29(44%)in NA group.After matching by age and treatment duration,baseline HBsAg levels were comparable between groups(3.1 vs 3.2)(P=0.25).HBsAg levels at weeks 24,48 and 96 declined in Peg-IFN-NA group(-0.26,-0.40 and-0.44)and remained stable in NA group(-0.10,-0.10 and-0.10)(P<0.05).The slope of HBsAg decline in Peg-IFN-NA group(-0.02)was higher than in NA group(-0.00)(P=0.015).HBcrAg levels did not change.Eight(22%)patients discontinued Peg-IFN due to adverse events.The HBsAg loss was achieved in 3(8.3%)patients of the Peg-IFN-NA group and 0(0%)of the NA group.CONCLUSION The addition of Peg-IFN to NAs caused a greater and faster decrease of HBsAg levels compared to NA therapy.Side effects of Peg-IFN can limit its use in clinical practice.

e-antigen-negative chronic hepatitis B in Bangladesh

BACKGROUND:Bangladesh is a densely populated country where about 10 million people are chronically infected with hepatitis B virus(HBV).The aim of the present study was to evaluate the biochemical,virological and histological characteristics of HBeAg-negative chronic hepatitis B(CHB). METHODS:Patients were included in this study if they were chronically infected with HBV with detectable DNA.The patients who were co-infected with human immunodeficiency virus,hepatitis delta virus or hepatitis C virus,and previously subjected to antiviral treatment,and those with hepatocellular carcinoma were excluded.The study was conducted during the period of January 2001 to December 2007.During this period 2617 patients with CHB were studied.HBeAg-positive cases were included to compare the characteristics.Among them,237 cases underwent liver biopsy. RESULTS:2296 patients(87.7%)were male,with a mean age of 28.9±13.7 years.2375 patients(90.8%)had CHB,and 242(9.2%)were cirrhotic.HBV DNA levels were 7.6±1.5 copies/ml,ALT was 111.3±212.5 U/L,and AST was 91.5± 148.9 U/L.The number of HBeAg-negative CHB cases was 1039(39.7%).HBeAg-negative patients with a lower DNA load were older,and they had more fibrotic changes in the liver than HBeAg-positive patients.The two groups did not differ in necroinflammatory activity,but the former had lower ALT and AST values.Cirrhosis was more common in e-antigen-negative patients.CONCLUSIONS:e-antigen-negative CHB patients are older and have more hepatic fibrosis patients than HBeAg-positive patients,although they have similar necroinflammatory activity.

On-treatment quantitative hepatitis B e antigen predicted response to nucleos(t)ide analogues in chronic hepatitis B

AIMTo investigate potential predictors for treatment response to nucleos(t)ide analogues (NAs) in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) patients. METHODSSeventy-six HBeAg-positive CHB patients received 96-wk NAs optimized therapy (lamivudine and adefovir dipivoxil) were studied retrospectively. Serum hepatitis B surface antigen, HBeAg, hepatitis B core antibody, hepatitis B virus (HBV) DNA and alanine aminotransferase levels were quantitatively measured before and during the treatment at 12 and 24 wk. Stepwise logistic regression analyses were performed to identify predictors for treatment response, and areas under the receiver operating characteristic curves (AUROC) of the independent predictors were calculated. RESULTSForty-three CHB patients (56.6%) achieved virological response (VR: HBV DNA &le; 300 copies/mL) and 15 patients (19.7%) developed HBeAg seroconversion (SC) after the 96-wk NAs treatment. The HBeAg level (OR = 0.45, P = 0.003) as well as its declined value (OR = 2.03, P = 0.024) at 24-wk independently predicted VR, with the AUROC of 0.788 and 0.736, respectively. The combination of HBeAg titer 1.6 lg PEIU/mL at 24-wk predicted VR with a sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) of 85%, 100%, 100% and 83%, respectively, and the AUROC increased to 0.923. The HBeAg level (OR = 0.37, P = 0.013) as well as its declined value (OR = 2.02, P = 0.012) at 24-wk also independently predicted HBeAg SC, with the AUROC of 0.828 and 0.814, respectively. The HBeAg titer 2.2 lg PEIU/mL at 24-wk predicted HBeAg SC with a sensitivity, specificity, PPV, NPV of 88%, 98%, 88% and 98%, respectively, and the AUROC reached 0.928. CONCLUSIONThe combination of HBeAg level and its declined value at 24-wk may be used as a reference parameter to optimize NAs therapy.

Exploration of nucleos(t)ide analogs cessation in chronic hepatitis B patients with hepatitis B e antigen loss

BACKGROUND Nucleos(t)ide analogs(NAs)cessation in chronic hepatitis B(CHB)patients remains a matter of debate in clinical practice.Current guidelines recommend that patients with hepatitis B e antigen(HBeAg)seroconversion discontinue NAs after relatively long-term consolidation therapy.However,many patients fail to achieve HBeAg seroconversion after the long-term loss of HBeAg,even if hepatitis B surface antigen(HBsAg)loss occurs.It remains unclear whether NAs can be discontinued in this subset of patients.AIM To investigate the outcomes and factors associated with HBeAg-positive CHB patients with HBeAg loss(without hepatitis B e antibody)after cessation of NAs.METHODS We studied patients who discontinued NAs after achieving HBeAg loss.The Cox proportional hazards model was used to identify predictors for virological relapse after cessation of NAs.The cut-off value of the consolidation period was confirmed using receiver operating characteristic curves;we confirmed the cut-off value of HBsAg according to a previous study.The log-rank test was used to compare cumulative relapse rates among groups.We also studied patients with CHB who achieved HBeAg seroconversion and compared their cumulative relapse rates.Propensity score matching analysis(PSM)was used to balance baseline characteristics between the groups.RESULTS We included 83 patients with HBeAg loss.The mean age of these patients was 32.1±9.5 years,and the majority was male(67.5%).Thirty-eight patients relapsed,and the cumulative relapse rate at months 3,6,12,24,36,60,120,and 180 were 22.9%,36.1%,41.0%,43.5%,45.0%,45.0%,45.0%,and 52.8%,respectively.Twentysix(68.4%)patients relapsed in the first 3 mo after NAs cessation,and 35 patients(92.1%)relapsed in the first year after NAs cessation.Consolidation period(≥24 mo vs<24 mo)(HR 0.506,P=0.043)and HBsAg at cessation(≥100 IU/mL vs<100 IU/mL)(HR 14.869,P=0.008)were significant predictors in multivariate Cox regression.In the PSM cohort,which included 144 patients,there were lower cumulative relapse rates in patients with HBeAg seroconversion(P=0.036).CONCLUSION HBeAg-positive CHB patients with HBeAg loss may be able to discontinue NAs therapy after long-term consolidation,especially in patients with HBsAg at cessation<100 IU/mL.Careful monitoring,especially in the early stages after cessation,may ensure a favorable outcome.

Epidemiology of viral hepatitis in Somalia:Systematic review and meta-analysis study

AIM To provide a clear understanding of viral hepatitis epidemiology and their clinical burdens in Somalia.METHODS A systematic review and meta-analysis was conducted as Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A comprehensive literature search of published studies on viral hepatitis was performed from 1977-2016 in Pub Med, Google Scholar, Science Direct, World Health Organization African Index Medicus and the Africa Journals Online databases, as well as on the Ministry of Health website. We also captured unpublished articles that were not available on online systems.RESULTS Twenty-nine studies from Somalia and Somali immigrants(United Kingdom,United States,Italy,Libya)with a combined sample size for each type of viral hepatitis[hepatitis A virus(HAV):1564,hepatitis B virus(HBV):8756,hepatitis C virus(HCV):6257,hepatitis D virus(HDV):375 and hepatitis E virus(HEV):278]were analyzed.The overall pooled prevalence rate of HAV was 90.2%(95%CI:77.8%to 96%).The HAV prevalence among different age groups was as follows:<1 year old,61.54%(95%CI:40.14%to79.24%);1-10 years old,91.91%(95%CI:87.76%to94.73%);11-19 years old,96.31%(95%CI:92.84%to 98.14%);20-39 years old,91.3%(95%CI:83.07%to 95.73%);and>40 years old,86.96%(95%CI:75.68%to 93.47%).The overall pooled prevalence of HBV was 18.9%(95%CI:14%to 29%).The overall pooled prevalence among subgroups of HBV was20.5%(95%CI:5.1%to 55.4%)in pregnant women;5.7%(95%CI:2.7%to 11.5%)in children;39.2%(95%CI:33.4%to 45.4%)in patients with chronic liver disease,including hepatocellular carcinoma(HCC);7.7%(95%CI:4.2%to 13.6%),12.4%(95%CI:6.3%to 23.0%)and 11.8%(95%CI:5.3%to 24.5%)in age groups<20 years old,20-39 years old and>40years old,respectively.The HBV prevalence among risk groups was 20%(95%CI:7.19%to 44.64%)in female prostitutes,21.28%(95%CI:7.15%to48.69%)in hospitalized adults,5.56%(95%CI:0.99%to 25.62%)in hospitalized children,60%(95%CI:31.66%to 82.92%)in patients with acute hepatitis,33.55%(95%CI:14.44%to 60.16%)in patients with ancylostomiasis,12.34%(95%CI:7.24%to 20.26%)in patients with leprosy and 20.19%(95%CI:11.28%to33.49%)in schistosomiasis patients.The overall pooled prevalence of HCV was estimated as 4.84%(95%CI:3.02%to 7.67%).The prevalence rates among blood donors,risk groups,children and patients chronic liver disease(including HCC)was 0.87%(95%CI:0.33%to 2.30%),2.43%(95%CI:1.21%to 4.8%),1.37%(95%CI:0.76%to 2.46%)and 29.82%(95%CI:15.84%to 48.98%),respectively.The prevalence among genotypes of HCV was 21.9%(95%CI:15.36%to 30.23%)in genotype 1,0.87%(95%CI:0.12%to 5.9%)in genotype 2,25.21%(95%CI:18.23%to 33.77%)in genotype 3,46.24%(95%CI:37.48%to 55.25%)in genotype 4,2.52%(95%CI:0.82%to7.53%)in genotype 5,and 1.19%(95%CI:0.07%to16.38%)in genotype 6.The overall pooled prevalence of HDV was 28.99%(95%CI:16.38%to 45.96%).The HDV prevalence rate among patients with chronic liver disease,including HCC,was 43.77%(95%CI:35.09%to 52.84%).The overall pooled prevalence of HEV was46.86%(95%CI:5.31%to 93.28%).CONCLUSION Our study demonstrates a high prevalence of all forms of viral hepatitis in Somalia and it also indicates that chronic HBV was the commonest cause of chronic liver disease.This highlights needs for urgent public health interventions and strategic policy directions to controlling the burden of the disease.

Human leukocyte antigen-DP loci are associated with the persistent infection of hepatitis B virus in Chinese population

A genome-wide association study recently showed that genetic variants in human leukocyte antigen (HLA)-DP loci were strongly associated with a risk of persistent infection of hepatitis B virus (HBV) in Japanese and Thai individuals and variants in interleukin 28B (IL-28B) have been associated with responses to anti-hepatitis C virus (HCV) treatment. The aim of this study was to investigate whether the HLA-DP loci and IL-28B were associated with different outcomes of chronic HBV infection (CHB) in Chinese subjects. The rs9277535 near HLA-DPB1,rs3077 near HLA-DPA1, and rs12979860 near IL-28B were genotyped by direct sequencing in 185 CHB patients and 193 self-limited hepatitis B virus (SLHBV)-infected subjects who recovered from HBV infection. The rs9277535 near HLA-DPB1 was strongly associated with CHB (P=0.000 018 1, OR=1.905). This association was observed independent of HBV e antigen (HBeAg) status and HBV viral loads in HBeAg-positive CHB patients (P=0.000 4, OR=1.956), in HBeAg-negative CHB patients (P=0.000 9, OR=1.857), and in HBeAg-negative CHB individuals without detectable levels of HBV DNA in serum (P=0.001 1, OR=2.05). The rs3077 near HLA-DPA1 was associated with CHB (P=0.020 6, OR=0.686 5) and HBeAg-positive CHB infection status (P=0.014 3, OR=0.604 7). Meanwhile, a genetic variation of insertion-deletion (INDEL) polymorphism (rs361527, -/ATAAATGTTGA) near HLA-DPA1 was found to be associated with CHB (P=0.030 7, OR=0.702 8) and HBeAg-positive CHB infection status (P=0.023 3, OR=0.619). However,the rs12979860 genotype near IL-28B had no correlation with CHB. This study demonstrated that in the Han Chinese populations, HLA-DP loci, but not IL-28B, were associated with persistence of infection in different outcomes of HBV-infected patients; however, the mechanism needs to be further investigated.

Hepatitis B core-related antigen:Are we near a treatment endpoint?

Different serological and virological markers in chronic hepatitis B patients guide staging of viral infection,and initiation and response to therapy.Due to the persistence of intrahepatic covalently closed circular DNA(cccDNA)in the hepatocyte nucleus,hepatitis B is not curable.Even after undetectable hepatitis B virus DNA levels,the persistence of hepatitis B surface antigen and novel markers such as hepatitis B core-related antigen(HBcrAg)indicate the persistence of intrahepatic cccDNA.In this study,HBcrAg levels at baseline and after 24 and 48 wk of antiviral therapy predicted hepatitis B e antigen seroconversion.Due to the poor sensitivity of assays and detectable levels in HBsAg-negative patients,the long-term utility of HBcrAg needs future research.

Correlation of hepatitis B surface antigen expression with clinicopathological and biochemical parameters in liver biopsies: A comprehensive study

BACKGROUND Chronic viral B hepatitis(CHB)is a potentially life-threatening liver disease that may progress to liver failure and cirrhosis.Currently,although combinations of different laboratory methods are used in the follow-up and treatment of CHB,the failure of these procedures in some cases has led to the necessity of developing new approaches.In CHB,the intrahepatic expression pattern of viral antigens,including hepatitis B surface antigen(HBsAg),is related to different phases of inflammation.However,many studies have focused on the intracytoplasmic properties of HBsAg staining,and HBsAg positivity in liver tissue has not been evaluated by objective quantitative methods.AIM To investigate the relationship of image analysis-based quantitative HBsAg expression and its staining patterns with clinicopathological factors and treatment in CHB.METHODS A total of 140 liver biopsies from treatment-naïve cases with CHB infection were included in this study.Following diagnosis,all patients were treated with entecavir(0.5 mg)and followed up at three-month intervals.The percentage of immunohistochemical HBsAg(p-HBsAg)expression in the liver was determined in whole tissue sections of biopsies from each case by image analysis.The immunohistochemical staining pattern was also evaluated separately according to 3 different previously defined classifications.RESULTS A positive correlation between p-HBsAg and serum levels of hepatitis B virus(HBV)DNA and HBsAg was observed(P<0.001).The p-HBsAg value was significantly higher in younger patients than in older patients.When the groups were categorized according to the hepatitis B e antigen(HBeAg)status in HBeAgpositive cases,p-HBsAg was correlated with HBV DNA,hepatitis activity index(HAI)and fibrosis scores(P<0.001).In this group,p-HBsAg and HBsAg expression patterns were also correlated with the viral response(VR)and the serological response(SR)(P<0.001).Multivariate analysis revealed that p-HBsAg was an independent predictor of either VR or SR(P<0.001).In HBeAg-negative patients,although HBsAg expression patterns were correlated with both HAI and fibrosis,no relationship was observed among p-HBsAg,clinicopathological factors and VR.CONCLUSION In pretreatment liver biopsies,the immunohistochemical determination of HBsAg expression by quantitative methods,beyond its distribution within the cell,may be a good predictor of the treatment response,especially in HBeAg-positive cases.

Soluble programmed death-1 is predictive of hepatitis B surface antigen loss in chronic hepatitis B patients after antiviral treatment

BACKGROUND Hepatitis B surface antigen(HBsAg)loss,a functional cure in patients with chronic hepatitis B(CHB)undergoing antiviral therapy,might be an ideal endpoint of antiviral treatment in clinical practice.The factors that contribute to the functional cure remain unclear,and the predictors of functional cure are worth exploring.The concentration and kinetics of soluble programmed death-1(sPD-1)in patients with CHB may play an important role in elucidating the immune response associated with functional cure after nucleos(t)ide analogs therapy.AIM To investigate the factors associated with HBsAg loss and explore the influence of sPD-1 Levels.METHODS This study analyzed the data and samples from patients with CHB who underwent antiviral treatment in a non-interventional observational study conducted at Peking University First Hospital in Beijing(between 2007 and 2019).All patients were followed up:Serum samples were collected every 3 mo during the first year of antiviral treatment and every 6 mo thereafter.Patients with positive hepatitis B e antigen levels at baseline and with available sequential samples who achieved HBsAg loss during antiviral treatment served as the case group.This case group(n=11)was further matched to 44 positive hepatitis B e anti patients without HBsAg loss as controls.The Spearman’s rank correlation test and receiver operating characteristic curves analysis were performed.RESULTS The sPD-1 Levels were higher in patients with HBsAg loss than in those without HBsAg loss from baseline to month 96,and the differences were significant between the groups at baseline(P=0.0136),months 6(P=0.0003),12(P<0.0001),24(P=0.0007),48(P<0.0001),and 96(P=0.0142).After 6 mo of antiviral treatment,the sPD-1 levels were positively correlated with alanine transaminase(ALT)levels(r=0.5103,P=0.0017),and the sPD-1 levels showed apparent correlation with ALT(r=0.6883,P=0.0192)and HBV DNA(r=0.5601,P=0.0703)levels in patients with HBsAg loss.After 12 mo of antiviral treatment,the sPD-1 levels also showed apparent correlation with ALT(r=0.8134,P=0.0042)and HBV DNA(r=0.6832,P=0.0205)levels in patients with HBsAg loss.The sPD-1 levels were negatively correlated with HBsAg levels in all patients after 12 mo of antiviral treatment,especially at 24(r=-0.356,P=0.0497)and 48(r=-0.4783,P=0.0037)mo.After 6 mo of antiviral treatment,the AUC of sPD-1 for HBsAg loss was 0.898(P=0.000),whereas that of HBsAg was 0.617(P=0.419).The cut-off value of sPD-1 was set at 2.34 log pg/mL;the sensitivity and specificity were 100%and 66.7%,respectively.CONCLUSION The sPD-1 levels at 6 mo can predict HBsAg loss after 144 mo of antiviral treatment.