Clinical Characteristics Of Immune Control Phase And Immune Escape Phase In Patients With Chronic HBV Infection

Objective:To compare the clinical characteristics of immune control phase and immune escape phase in patients with chronic HBV infection,and to analyze the diagnostic value of clinical parameters by ROC curve,statistically analyze the 95%reference range of each index,and compare the difference in the clinical features between the confirmed group and the clinical misjudgment group.Providing a scientific basis for clinical standardized management and precise diagnosis and treatment for patients with chronic HBV infection.Materials and Methods:A total of 328 patients with chronic HBV infection who were admitted to the hospital of Yan'an University from January 2016 to January 2019,and who under went liver biopsy after informed consent were enrolled.These cases were followed up every3-6 months.When patients develop to the cirrhosis or liver cancer or start antiviral therapy,follow-up will be stopped.The follow-up include general information?name,gender,age,height,weight,history of drinking,family history,onset time,medical history,contact information?,biochemistry?ALT,AST?,virology?hsHBVDNA?,hepatitis B series quantification,hepatitis B virus genotyping,imaging?Upper abdominal B-ultr-asound,LSM?,liver histopathology data?inflammation activity,liver fiber staging?.According to the"Guidelines for the Prevention and Treatment of Chronic Hepatitis B?2015 Edition?".The liver pathological results A<2 and F<2 were determined as the immune control group,A?2 and/or F?2 were determined as the immune escape group.For the immune control phase,when ALT<80U/L,A<2 and F<2,the case will be defined as the confirmed group,and when ALT<80U/L,but A?2 and/or F?2,the case will be defined as the clinical misjudgment group.For immune escape phase,when ALT?80U/L,A?2 and/or F?2,the case will be defined as the confirmed group,when ALT?80U/L,but A<2 and F<2,the case will be defined as the clinical misjudgment group.The collected data were statistically analyzed by SPSS22.0 software.The logarithmic transformation of hsHBVDNA and HBsAg was performed before statistical analysis.The normal distribution data was expressed by mean±standard deviation,and the skewed distribution data is expressed by the median?M?and the interquartile range?P25 to P75?.Normal distribution two sample mean comparisons use two independent sample t tests,nonconforming normal distribution samples use Mann-Whitney U test.With a=0.05 as the test standard,P<0.05 indicates that the difference is statistically significant.The upper and lower limits of the 95%reference value range of the normal distribution data are expressed by the mean±1.64s,and the upper and lower limits of the 95%reference value range of non-normal distribution data are expressed by the percentile method?P₅,P95?.The diagnostic value of clinical parameters of immune control phase and immune escape phase was evaluated by ROC curve,sensitivity and specificity.Results:1.Among the 328 patients,157?47.9%?were males and 171?52.1%?were females.The median age?interquartile range?is 42.00?33.00-48.00?,the maximum and minimum ages are 14.00 and 66.00 respectively.Among them,146 cases?44.5%?had no history of chronic hepatitis B,106 cases?32.3%?had chronic hepatitis B family history,but no LC and HCC family aggregation phenomenon,76 cases?23.2%?had chronic hepatitis B family history,and There are LC and HCC family aggregation phenomena.2.Among the 328 patients collected,103 patients were tested for hepatitis B virus genotype,of which 6?5.8%?were B genotype,90?87.4%?were C genotype,and 7?6.8%?were D genotype.3.The tiime of followed up was 1 to 30 years,and the median follow-up time was10 years.By the end of follow-up,25 patients?7.6%?had progressed to LC.14?4.3%?of them were developed from the immune escape phase,11?3.4%?were developed from the immune control phase,7 of them were misdiagnosed during the immunological control phase,and no patient progressed to HCC during follow-up.4.Comparison of immune control group and immune escape group in chronic HBV infection4.1.Comparison of general data between immune control group and immune escape group in chronic HBV infectionThere was no significant difference in gender distribution between the immune control group and the immune escape group??²=0.123,P=0.726?.There was no significant difference in age between the two groups?Z=-1.124,P=0.261?.There was no significant difference in the polyhistory??²=0.166,P=0.920?.4.2.Comparison of clinical data between immune control group and immune escape group in chronic HBV infection.There was no significant difference in the course of disease between the two groups?Z=-0.860 P=0.390?,and there were differences in hsHBVDNA and HBsAg levels?Z=-7.644 P=0.000??Z=-10.346 P=0.000?,There were no differences in HBeAg,HBsAb,HBeAb,HBcAb levels?Z=-0.653 P=0.514??Z=-0.710 P=0.478??Z=-1.698P=0.089??t=0.735 P=0.463?.ALT,AST,LSM levels were different?Z=-7.261P=0.000??Z=-6.447 P=0.000??Z=-9.447 P=0.000?.5.Analysis of the confirmed group and the clinical misjudgment group in the immune control phase of chronic HBV infection.5.1.Analysis of general data of the confirmed group and the clinical misjudgment group in the immune control phase of chronic HBV infectionThere were no differences in gender,age,and hepatitis B family history between the confirmed group and the clinical misjudgment group??²=0.112 P=0.738???²=-0.068P=0.946???²=0.166 P=0.920?.5.2.There were differences in hsHBVDNA and HBsAg between the two groups?Z=-3.055 P=0.002??Z=-6.096 P=0.000?,and there were no differences in HBeAb and HBcAb between the two groups?Z=-1.768 P=0.077??t=-0.446 P=0.656?,ALT,AST,and LSM levels are obviously different between the two groups?Z=-2.361 P=0.018??Z=-2.569 P=0.010??Z=-4.304 P=0.000?.6.Comparison of the confirmed group and the clinical misjudgment group in the immune escape phase of chronic HBV infection6.1.Comparison of general data between the confirmed group and the clinical misjudgment group in the immune escape phaseThere were no differences in gender,age,and history of hepatitis B between the confirmed group and the clinical misjudged group??²=0.199 P=0.656??Z=-1.310P=0.190???²=1.099 P=0.577?.6.2.Comparison of clinical data between the confirmed group and the clinical misjudged group in the immune escape phaseThere were significant differences in hsHBVDNA and HBsAg between the two groups?Z=-3.315 P=0.001??Z=-6.076 P=0.000?,and there were no differences in HBeAb and HBcAb between the two groups?Z=-0.333 P=0.739??t=0.779 P=0.437?.There were differences in ALT,AST,and LSM?Z=-2.855 P=0.004??Z=-2.871 P=0.004??Z=-7.138P=0.000?.7.Comparison of different family history group of immune control phase and immune escape phase in chronic HBV infection7.1.Comparison of different family history groups during the immune control phaseThere was no difference in gender and age between the group with hepatitis B family history but no LC and HCC family aggregation phenomenon?group A?and the group with hepatitis B family and LC and HCC family aggregation phenomenon?group B???2=1.585 P=0.208??Z=-1.212 P=0.226?.There were no differences in hsHBVDNA,HBsAg,HBeAb,HBcAb between the two groups?Z=-1.339 P=0.180??Z=-1.056 P=0.219??Z=-1.891 P=0.059?,?t=-0.623P=0.535?,there were no significant differences in ALT,AST,LSM between the two groups?Z=-0.477 P=0.634??Z=-0.187 P=0.852??Z=-0.142 P=0.887?.7.2.Comparison of different family history groups in immune escape phaseThere were no differences in gender and age between the group with hepatitis B family history but no LC and HCC family aggregation phenomenon?group C?and the group with hepatitis B family and LC and HCC family aggregation phenomenon?group D???²=2.987 P=0.084??Z=-1.813 P=0.070?.There were no differences in hsHBVDNA,HBsAg,HBeAb,HBcAb between the two groups?Z=-0.627 P=0.531??Z=-1.243 P=0.214??Z=-1.497 P=0.113?,?t=1.215P=0.228?,there were no significant differences in ALT,AST,LSM between the two groups?Z=-1.690 P=0.091??Z=-0.813 P=0.416??Z=-0.080 P=0.936?.7.3.Statistics on clinical outcomes of different family history groups in immune control phase and immune escape phaseTwo groups of patients were followed up to 10 years,there was 1 case developed to LC in group A of the immune control phase.There were 3 cases developed to LC in group B of the immune control phase.There were 2 cases developed to LC in group C of the immune escape phase.There were 4 cases progressed to LC in group D of the immune escape phase.8.Diagnostic value and evaluation of HBV M,hsHBVDNA,ALT,AST,LSM and various joint indicators in the diagnosis of immune control phase and immune escape phase8.1.Diagnostic value and evaluation of HBV M,hsHBVDNA,ALT,AST,LSM and various combined indicators in the diagnosis of immune escape phaseThe area under the ROC curve of hsHBVDNA was 0.660,the 95%confidence interval was 0.576 to 0.744,the standard error was 0.043,the P value was 0.001,the sensitivity was 44.4%,the specificity was 88.2%,the Yoden index was 0.333,and the diagnostic cut off value was 4.070lgIU/ml,The area under the ROC curve of HBSAg was0.793,the 95%confidence interval was 0.724 to 0.863,the standard error was 0.035,the P value was 0.000,the sensitivity was 65.7%,the specificity was 88.9%,and the Yoden index was 0.509,and the diagnostic cut off value was 3.824 lgIU/ml.The area under the ROC curve of ALT was 0.638,the 95%confidence interval was 0.548 to 0.728,the standard error was 0.046,the P value was 0.000,the sensitivity was 34.3%,the specificity was 87.0%,and the Yoden index was 0.213,and the diagnostic cut off value was 103.5U/L.The area under the ROC curve of AST was 0.639,the 95%confidence interval was 0.552 to 0.725,the standard error was 0.044,the P value was 0.004,the sensitivity was 31.5%,the specificity was 87.2%,and the Yoden index was 0.278.The cutoff value was 91.5U/L.The area under the ROC curve of LSM was 0.844,the 95%confidence interval was 0.782 to 0.906,the standard error was 0.032,the P value was0.000,the sensitivity was 78.7%,the specificity was 79.6%,and the Yoden index was0.583.The cutoff value was 5.25Kpa.The area under the ROC curve of hsHBVDNA combined with the ALT was 0.700,the 95%confidence interval was 0.620 to 0.781,the standard error was 0.041,the P value was 0.000.The area under the ROC curve of hsHBVDNA combined with HBsAg was 0.846,the 95%confidence interval was 0.785to 0.906,the standard error was 0.031,the P value was 0.000.The area under the ROC curve of hsHBVDNA combination with the ALT and HBsAg was 0.861,the 95%confidence interval was 0.803 to 0.918,the standard error was 0.029,and the P value was0.000.The area under the ROC curve of hsHBVDNA combined with HBsAg,ALT,and LSM ROC curves was 0.917,and the 95%confidence interval was 0.874 to 0.960.The standard error is 0.022 and the P value is 0.000.8.2.Diagnostic value and evaluation of HBV M,hsHBVDNA,ALT,AST,LSM and various combined indicators in the diagnosis of immune control phaseThe area under the ROC curve of hsHBVDNA was 0.648,the 95%confidence interval was 0.559 to 0.737,the standard error was 0.046,the P value was 0.002,the sensitivity was 36.8%,the specificity was 86.5%,the Yoden index was 0.233,and the diagnostic cutoff value was 2.784lgIU/ml.The area under the ROC curve of HBSAg was0.795,the 95%confidence interval was 0.720 to 0.871,the standard error was 0.038,the P value was 0.000,the sensitivity was 73.7%,the specificity was 86.8%,and the Yoden index was 0.545.The diagnostic cutoff value was 3.607 lgIU/ml.The area under the ROC curve of ALT was 0.614,the 95%confidence interval was 0.524 to 0.705,the standard error was 0.046,the P value was 0.018,the sensitivity was 32.5%,and the specificity was 80.5%,the Yoden index was 0.190,the diagnostic cutoff value was 32.5U/L.The area under the ROC curve of AST was 0.612,the 95%confidence interval was0.517 to 0.706,the standard error was 0.048,the P value was 0.021,the sensitivity was80.7%,the specificity was 30.8%,the Yoden index was 0.220,the diagnostic cutoff value was 48.5U/L.The area under the ROC curve of LSM was 0.708,the 95%confidence interval was 0.624 to 0.793,the standard error was 0.043,the P value was 0.000,the sensitivity was 81.6%,the specificity was 50.0%,the Yoden index was 0.316,the diagnostic cutoff value was 5.15Kpa.The area under the ROC curve of hsHBVDNA combined with ALT was 0.665,the 95%confidence interval was 0.582 to 0.749,the standard error was 0.043,the P value was 0.001.The area under the ROC curve of hsHBVDNA combined with the HBsAg was 0.822,the 95%confidence interval was0.751 to 0.893,and the standard error was 0.036,the P value was 0.000.The area under the ROC curve of hsHBVDNA combined with ALT,HBsAg was 0.830,the 95%confidence interval was 0.761 to 0.898,the standard error was 0.035,the P value was0.000.The area under the ROC curve of hsHBVDNA combined with HBsAg,ALT,and LSM was 0.876,the 95%confidence interval was 0.815 to 0.937,the standard error was0.031,and the P value was 0.000.9.ALT,AST,hsHBVDNA,HBsAg and LSM reference range in immune control phase and immune escape phase of chronic HBV infection9.1.Reference range for each indicator of the immune control phaseThe 95%reference range of hsHBVDNA was less than 3.22 lgIU/ml,the 95%reference range of HBsAg was less than 3.47lgIU/ml,and the 95%reference range of ALT was less than 61.50 U/L,the 95%reference range of AST was less than 54.00U/L,and the 95%reference range of LSM was less than 5.10Kpa.9.2.Reference range for each indicator of the immune escape phaseThe 95%reference range of hsHBDNA was more than 3.57lgIU/ml,the 95%reference range of HBsAg was more than 3.62lgIU/ml,and the 95%reference range of ALT was more than 82.45U/L,the 95%reference range of AST was more than 58.45U/L,and the 95%reference range of LSM wasmore than 5.90Kpa.Conclusion:1.The genotype of C in the immune control phase and immune escape phase of chronic HBV infection in this region accounted for 87.4%,and there was a certain difference between the genotype ratio?96.0%?of immune tolerance phase.2.Patients with Chronic HBV infection in the immune control phase and immune escape phase had chronic hepatitis B family history.There were no significant differences in the clinical indicators between those with LC and HCC aggregation and those without LC and HCC.Therefore,the mechanism of patients with LC and HCC family aggregation problems that are easy to progress to LC and HCC needs further study.3.The hsHBVDNA,HBsAg,ALT,AST and LSM in the immune escape group were significantly higher than those in the immune control group.In the immune control phase,the laboratory indexes of hsHBVDNA,HBsAg,ALT,AST and LSM in the confirmed group were lower than those in the clinical misjudged group.In the immune escape phase,the hsHBVDNA,HBsAg,ALT,AST and LSM in the confirmed group were significantly higher than those in the clinical misjudged group.The immune control phase and immune escape phase of chronic HBV infection are prone to misjudgment,liver tissue pathological biopsy should be actively performed to confirm the diagnosis.4.For the laboratory diagnosis of immune escape phase and immune control phase,the combination of two or more indicators of the above indicators maybe have a higher diagnostic value.5.This study has given a range of reference values for hsHBVDNA,HBsAg,ALT,AST,and LSM in the immune control phase and immune escape phase of chronic HBV infection.It can be referenced in clinical work and further verified.