| BackgroundHeaptitis B virus infection is the most common cause of acute and chronic liver disease worldwide,and it is a major global health problem.HBV serologic markers are used to identify different phases of HBV infection.Although the serogic findings that allow both the diagnosis of HBV infection as well as assessing of its clinical course are already well established,the dynamics of viral proteins expression and of the antibodies production may vary during the infection natural course.This cause the HBV infection to be occasionally associated with the presence of uncommon serological profiles,which could lead to doubts in the interpretation of results or suspicion of a serological results being incorrect.Coexistence of HBsAg and anti-HBs comprise a peculiar serological finding,since it contemplates components that indicate immunity and,at the same time,developing infection.However,despite the presence of neutralizing antibodies,this serological profile correlates with active viral replication and may be observed in acute or chronic hepatitis B infection.The mechanism that could lead to this serological pattern had not been well delineated and understanded.Its existence has been justified mainly be the emergence of HBV mutants and the presence of non-productive anti-HBs antibodies,as was discussed.Considering that results from individual epidemiological studies can be strongly affected by available sample sizes,a better way to clarify this phenomenon is to summarize all available evidence from relevant observational studies.Quantitative evaluation of the immune response to anti-HBs is commonly described in international units(IU/L),and it is generally accepted that anti-HBs levels over 10 IU/L are productive.However,to assess this response thoroughly,it would be helpful to determine both the concentration and affinity of anti-HBs.Although various investigators have reported the coexistence of HBsAg and anti-HBs from cross-sectional studies,there has been no documentation on the natural course of this phenomenon.ObjectiveIn the current study,we aimed to conducte a comprehensive Meta analysis to evaluate this phenomenon.Affinity of anti-HBs was determined in carriers with coexistenc of HBsAg.We analyzed the changes in anti-HBs level in a cohort of HBV carries who were followed prospectively.Based on the depth sequencing technique,the changes of the virus quasispecies during the natural history of the coexistence of HBs Ag and anti-HBs were analyzed.Methods1.A systematic search was performed of Pubmed,Web of Science,Medline,Embase and Cochrance.The publications related to the coexistence of HBsAg and anti-HBs were retrieved and supplemented by manual retrieval of relevant references.The assessed outcomes included: age,sex,HBe Ag,HBV DNA levels,ALT levels and the mutants of “a” determitant.The continuous variables are presented as mean difference(MD)with 95% confidence interval(CI).Dichotomous variables were presented as risk ratio(RR)with 95% CI.Statistical heterogeneity was examined using I2 tests.2.We selected 122 patients with coexistence of HBs Ag and anti-HBs and 122 patients with HBsAg positive but anti-HBs negative.HBsAg level were analyzed.HBsAg “a” determinant variants and wild type sequence were selected.Based on the the Jameson-Wolf algorithm for calculating antigentic index.12 patients with coexistence of HBsAg and anti-HBs and 12 healthy subjects vaccinated with HB were selected,and anti-HBs levels were analyzed.Anti-HBs affinity was determine by ELISA.3.A total of 4169 inviduals with chronic hepatitis B virus infection were enrolled between 2009 and 2010 in community based study of Wuwei City.Serum samples collected at baseline and follow up examination were tested for HBsAg,anti-HBs every 1 year.A multivariate regreesion analysis was used to assess the factors contributing to the positive of serum anti-HBs.The factors examined include age,gender,HBV DNA level,HBe Ag,ALT level.HBV S gene were amplified and sequenced.Serial samples were obtained from 58 patients with coexistence of HBsAg and anti-HBs during follow up.HBsAg level,anti-HBs level,HBeAg,HBV DNA level and ALT level were tested.4.In 6 consecutive patients after anti-HBs become positive in chronic HBV infection,the HBV S gene were amplified and pyrosequencing.Quasispecies heterogeneity characterization was comfucted using bioinformatics analysis.Results1.Of the 6867 studied identified in the search,23 articles involving 1709 cases met the inclusion criterias.The overall results demonstrated that the prevalence of coexistence of HBsAg and anti-HBs in the HBsAg positive population was 4.15%(95% CI: 4.00%-5.00%).The carriers with coexistence of HBsAg and anti-HBs were older than the control group(MD= 1.96;95% CI: 0.07-3.86,P = 0.04).The pooled results of the rate of HBeAg positeve(OR = 1.15,95% CI: 0.93-1.42,P = 0.21)and ALT level(MD =-4.05 IU/L,95% CI:-15.15-7.05,P=0.47)did not show significant difference.But the level of HBV DNA(MD= 0.30 log10 copies/ml;95% CI: 0.05-0.55,P = 0.02)was significant lower in carriers with coexistence of HBsAg and anti-HBs.The rate of mutation in "a" determinant site of 129,130,131,133,134,135,138 and 145 were significantly higher in carriers with coexistence of HBsAg and ant-HBs.2.The HBsAg levle were no significantly difference between carriers with coexistence of HBsAg and anti-HBs and chronic HBV infection(F=2.12,P=0.15).HBsAg “a” determinant mutants presented significant increased antigenic index in MHR(t=3.00,P=0.01)and “a” determinant(t=2.83,P=0.02).There was no significant difference in the anti-HBs affinity constant(t = 0.34,P = 0.74)between patients with coexistence of HBsAg and anti-HBs and healthy subjects vaccinated with HB.3.In a mean follow up of 22 months,the average annual rate of anti-HBs production in CHB was 1.41±0.28%.Cumulative risk for coexistence of HBs Ag and anti-HBs was higher in patients at ages ≥ 50 years(RR: 1.02,95% CI: 1.00-1.04,P=0.03),HBeAg positive(RR: 3.42,95% CI:1.90-6.17,P<0.01),baseline ALT abnormalities(RR: 3.65,95% CI:1.94-6.89,P<0.01)and higher HBV DNA level(RR: 2.25,95% CI: 1.26-3.99,P <0.01).Dynamic observation of the HBV markers showed that the HBsAg level and ALT level were no significant different after anti-HBs become positive,but the HBV DNA level was decreased significantly(t=3.26,P<0.01).36 carriers with coexistence of HBsAg and anti-HBs were continuous observed.The dynamic tendency in HBsAg level(F=0.78,P=0.46),anti-HBs level(F=1.11,P=0.34),HBV DNA level(F=0.42,P=0.66)and ALT level(F=0.39,P=0.68)were no significant difference.4.All 6 patients were detected “a” determinant mutants.4/6 were wild predominant and 2/6 were “a” determinant mutants predominant.Viral population had no significant change after anti-HBs become positive.The quasispecies complexity(at aa levle: P=0.39,at nt levle: P=0.51)and quasispecies diversity(genetic distance at aa levle: P=0.68,genetic distance at nt levle: P=0.86,dS: P=0.86,dN: P=0.71)also had no significant chang.Conclusions1.HBV DNA levels of coexistence of HBsAg and anti-HBs are lower than CHB,suggesting that viral replication was lower in carrers with coexistence of HBsAg and anti-HBs.2.There was no significant difference in the anti-HBs affinity constant.This suggesting that anti-HBs in carrers with coexistence of HBsAg and anti-HBs is protective.The “a” determinant mutation can increase the HBsAg “a” determinant antigenic index.3.HBsAg and anti-HBs coexistence is a natural process of HBV development,HBsAg positive patients can naturally develop to coexistence of HBsAg and anti-HBs.Factors affecting this process are baseline HBV DNA levels,HBe Ag status,and age of infected persons.4.Viral population had no significant change after anti-HBs become positive.The coexistence of HBsAg and anti-HBs is not caused by the decrease in the binding of anti-HBs to mutants of “a” determinant.It is a course of chronic HBV infection. |
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