Relationship Between Hbv-related Chronic Liver Disease With SIBO And The Effect Of Combined Therapeutic Intervention On SIBO And Antiviral Response

Objective（s）:In this research,we investigated the status of Small Intestinal Bacterial Overgrowth（SIBO）in patients with HBV-related chronic liver disease and analysed its influencing factors.To observe the effect of rifaximin in combination with Nucleostide analogues（NAs）for antiviral response to Chronic Hepatitis B（CHB）patients with SIBO positive hepatitis,and to explore the factors affecting SIBO negative hepatitis.Methods:A total of 322 HBV-related chronic liver disease patients who were admitted to the Department of Geriatric Gastroenterology in the First Affiliated Hospital of Kunming Medical University from January 2021 to January 2022 were included.There were 145 cases of CHB,115 cases of HBV-related Liver Cirrhosis（LC）,34 cases of HBV-related Hepatocellular Carcinoma（HCC）,and 28 cases of HBV related Acute-on-chronic Liver Failure（ACLF）.62 healthy subjects were selected as a healthy control during the same period.The Lactulose Hydrogen Breath Test（LHBT）was used to detect the presence of SIBO,to compare the incidence of SIBO in different stages of HBV infection,and to analyse the influencing factors SIBO in patients with HBV-related chronic liver disease.CHB patients with SIBO were treated orally with rifaximin（Alfa Weissman,Italy）,200mg,4 times a day in combination with Nucleostide analogues（NAs）.LHBT was repeated after 3 months later,to compare the changes in LHBT results before and after treatment.Results:1.The positive rate of SIBO in LHBT subjects with HBV-related chronic liver disease was higher than that in normal controls（56.2%vs.11.3%,χ²=41.98,P<0.001）.Among HBV-related chronic liver disease patients,the positive rate of SIBO was 40.7%（59/145）in CHB patients,61.7%（71/115）in LC patients,70.6%（24/34）in HCC patients,and 96.4%（27/28）in ACLF patients.The difference of SIBO positive rate between the groups was statistically significant（P<0.05）.The percentage of CD4⁺T cells and the ratio of CD4⁺/CD8⁺T cells in peripheral blood of HBV-associated chronic liver disease patients were lower than those in normal control group.In patients with HBV-related chronic liver disease,the percentage of CD4⁺T cells and the ratio of CD4⁺/CD8⁺T cells in peripheral blood of CHB,LC,HCC and ACLF group showed a decreasing trend,and the difference was statistically significant（P<0.05）.In patients with CHB,the positive rate of SIBO in patients with moderate to severe liver damage（70.0%）was higher than that in patients with mild liver damage（29.5%）,and the positive rate of SIBO increased with the severity of liver function damage（χ²=18.02,P<0.001）.Among HBV-related LC patients,the positive rate of SIBO in patients with decompensated stage was higher than that in patients with compensated stage（76.1%vs.52.2%,χ²=6.68,P=0.010）.The positive rate of SIBO increased with the increase of Child-Turcotte-Pugh（CTP A 52.2%,B72.7%and C 84.6%,P=0.027）.2.In patients with HBV-related chronic liver disease,the incidence of SIBO in patients with smoking,drinking,cirrhosis,and ascites history is higher than that in patients without related history（P<0.05）.The mean values of TBIL and GGT in SIBO positive group were higher than those in SIBO negative group（P<0.05）.The percentage of CD4⁺T lymphocytes and the ratio of CD4⁺/CD8⁺were lower in SIBO positive group than in the SIBO negative group and lower in the SIBO negative group than in the healthy control group（P<0.05）.The incidence of SIBO was significantly higher in HBe Ag-positive patients than in HBe Ag-negative patients（77.8%vs.45.3%,χ2=30.71,P<0.001）.The positive rate of SIBO increased with the increase of HBV-DNA replication level（P<0.05）.The SIBO positivite rate of HBV-DNA<10³IU/m L group was 44.5%,HBV-DNA 10³-10⁵IU/m L group was 64.0%,HBV-DNA≥10⁵IU/m L group was 88.9%.In a multivariate analysis,alcohol consumption（OR=5.22,95%CI 2.66-0.23,P<0.001）,liver cirrhosis（OR=3.24,95%CI 1.71-6.15,P<0.001）,ascites（OR=5.14,95%CI 1.85-14.27,P=0.002）,high TBIL（OR=1.02,95%CI 1.01-1.03,P=0.018）,HBe Ag positivite（OR=2.10,95%CI1.05-4.19,P=0.035）and high HBV-DNA replication levels（OR=1.86,95%CI 1.20-2.88,P=0.006）were risk factors for the development of SIBO.TBIL and HBV-DNA were used as test variables to predict the presence of SIBO,and ROC curves were drawn,with areas under curves of 0.604 and 0.701,sensitivity of 50.0%and 52.8%,and specificity of 69.7%and 81.8%,respectively.The clinical cut-off points for SIBO for TBIL and HBV-DNA were 17.50mg/d L and 15,500 IU/m L,respectively.3.In patients with CHB and SIBO treated with rifaximin and NAs,the negative conversion rate of SIBO was 52.27%（23/44）,and the improvement rate of gastrointestinal symptoms was 77.27%（34/44）in CHB patients with SIBO.HBs Ag quantification levels in the SIBO negative group were statistically different before and after the combined treatment intervention（P<0.05）.HBV-DNA quantification decreased after rifaximin combined with NAs in both non-negative and negative SIBO groups compared to that before treatment（P<0.05）.The difference of HBV-DNA between the two groups before and after the intervention of combination therapy was statistically significant（difference=2.78 log10 IU/m L,95%CI 0.15-5.41,P=0.0.39）.The expiratory hydrogen abundance in SIBO non-negative conversion group was higher than that in SIBO negative conversion group before and after treatment（P<0.05）.Patients with low pre-treatment Body Mass Index（BMI）levels had a relatively low rate of negative SIBO after NAs in combination with rifaximin（P<0.05）.HBe Ag positive and exhalation hydrogen（H₂）set before treatment are risk factors for negative SIBO in patients with CHB treated with rifaximine combined with NAs.Compared with HBe Ag-negative patients,HBe Ag-positive patients had a lower negative SIBO rate after combined treatment,and the difference was statistically significant（OR=0.01,95%CI 0.00-0.86,P=0.043）.Patients with a higher H₂set before treatment had a lower negative SIBO rate after combination therapy（OR=0.99,95%CI 0.98-0.99,P=0.033）.Conclusion（s）:1.The incidence of SIBO in patients with HBV-related chronic liver disease was significantly higher than that in normal controls,and the incidence of SIBO increased with the progression of the disease.2.HBV-related chronic liver disease patients with drinking,liver cirrhosis,ascites history,high TBIL,HBe Ag positive,high HBV-DNA level are more likely to develop SIBO.Elevated levels of TBIL and HBVDNA are predictive of SIBO.3.Rifaximin combined with NAs treatment promoted negative SIBO and reduced HBV-DNA expression in SIBO-positive CHB patients.Patients with high pre-treatment breath H₂set values or HBe Ag positivity had a lower SIBO negative rate after NAs combined with rifaximin treatment.