| Background:Hepatitis B virus(HBV)DNA-positive hepatocellular carcinoma(HCC)and serum HBs Ag-negative chronic hepatitis B after radical treatment are the types of hepatitis B that seriously affect the prognosis of patients with chronic HBV infection,but their antiviral treatments need to be further explored.HBV-associated liver cancer usually occurs on the basis of cirrhosis.Even antiviral clinicians are accustomed to treating with well-tolerated and safe oral NAs alone,and often ignore one problem: that they can afford it.The good compensatory function of the liver in patients undergoing radical surgery,so can we actively mobilize the body’s anti-tumor immune response through the active application of pegylated interferon sequential nucleoside analogs,while achieving long-term antiviral therapy and HBV DNA and even better clearance of HBs Ag to prevent recurrence of liver cancer deserves further discussion.Serum HBs Ag-negative chronic hepatitis B is concealed due to the occult onset of CHB.At the time of initial diagnosis,most of the diseases have long-term liver dysfunction,and even progress to the stage of decompensation of liver cirrhosis or even HCC.However,if HBs Ag clearance occurs in this part of the patients before progressing to cirrhosis,the risk of cirrhosis and primary hepatocellular cancer(HCC)is small,and the survival rate is not significantly reduced.Therefore,early detection and treatment of serum HBs Ag-negative chronic hepatitis B has very important clinical significance.However,in our country,neither the experts who developed the guidelines nor the professional clinical doctors have not updated and valued HBs Ag-negative chronic hepatitis B,and even a considerable number of medical staff do not recognize the HBs Ag-negative chronic HBV disease stage..The purpose of this study was to evaluate the antiviral influencing factors of HBV DNA-positive HCC and serum HBs Ag-negative chronic hepatitis B after liver resection / ablation,and to explore more effective antiviral strategies and predictive markers to guide clinical Treatment of such patients improves patient prognosis.Method:In this study,two multicenter studies were performed to include patients with HBV DNA-positive HCC and serum HBs Ag-negative chronic hepatitis B patients undergoing liver resection / ablation.The first multicenter study was a prospective,randomized,controlled,and multicenter study that included patients with HBV-DNA-positive primary liver cancer who underwent liver resection / ablation from January 2007 to January 2009.Patients were divided into 4 groups according to the antiviral protocol: the early combination group(entecavir combined with pegylated interferon alpha-2a for 1 year,and then continued to use nucleoside analogs);the late combination group(nucleoside analog treatment 1 48 weeks later,combined with pegylated interferon α-2a for 48 weeks,and then continued to use nucleoside analogues);pure nucleoside analogue treatment group;non-antiviral control group.Check serum HBV DNA,hepatitis B surface antigen and alpha-fetoprotein levels,liver / renal function tests,and liver imaging every 3 months.The primary endpoints included relapse-free survival(RFS),disease recurrence,and overall survival(OS).Test registration number: CHICTR-PRCH-13003986.Registration date: December 14,2013,http://www.chictr.org/showproj.aspx? Item = 5581The second multi-center study selected five regionally representative digestive / liver disease centers in Jilin and Heilongjiang provinces (China-Japan Union Hospital Affiliated to Jilin University,Jilin People’s Hospital,Jilin Province,Hunchun People’s Hospital,Jilin Province,Harbin Medical The Fourth Affiliated Hospital of the University and the Second Hospital of Daqing,Heilongjiang Province).Between January 2012 and January 2015,61 HBs Ag-negative patients who met the inclusion and exclusion criteria were included in the serum HBs Ag-negative occult HBV infection group,which is referred to as the HBs Ag-negative group below.And select 79 chronic HBV patients who received antiviral treatment in the above centers at the same time as the serum HBs Ag positive control group,hereinafter referred to as HBs Ag positive group.Serum and liver tissue CXCL10 levels,and single nucleotide polymorphisms(SNPs)at G-201 A rs1439490 and C-1513 T rs1440802 of CXCL10 gene were detected.To analyze the relationship between CXCL 10 level and CXCL10 gene rs1439490 and rs1440802 loci SNPs with HBs Ag-negative chronic hepatitis B,and further analyze the relationship between CXCL10 gene SNPs and antiviral treatment of HBs Ag-negative chronic hepatitis B patients.Result:1.A total of 447 HBV DNA-positive HCC patients were included.The incidence of RFS and 8-year OS in the early combined treatment group was significantly higher than that in the other two antiviral groups(P <0.05).2.After 48 weeks of antiviral therapy,the number of patients with HBs Ag reduction in the early combination treatment group was greater than 1500 IU / ml than in the advanced combination treatment group and the monotherapy group.The average HBs Ag level in the early combination treatment group was significantly reduced.(P <0.05).3.Regardless of the early combination group,the late combination group or the NAs control group,the long-term cumulative HCC recurrence rate was significantly higher in patients whose serum HBs Ag decreased> 1500 IU / ml than in patients whose HBs Ag decreased ≤1500 IU / ml.4.Multivariate analysis showed that early combined therapy and a decrease in HBs Ag of >1500 IU / ml after 48 weeks of treatment were associated with a reduction in mortality and disease recurrence after resection / ablation.5.The average age of the HBs Ag-negative group was 52.8 years,the proportion of family history of hepatitis B was 34.4%,the liver fibrosis(Fibroscan)was F2-4 at 53.4%,and the METAVIR fibrosis stage score was 2.0 ± 1.3,which were significantly higher than the HBs Ag-positive group.Group;while the ALT level was 60.6 ± 24.5IU / L,the liver HBV DNA level was 2.3 ± 1.1 log10 IU / ml,and the METAVIR inflammatory activity score was 1.1 ± 0.3,which was significantly lower than the HBSAG-positive group.There was no significant difference in sex and HBV genotype between the two groups.6.The serum CXCL10 level of patients in the HBs Ag negative group was 157.1 ± 68.9ng / ml,the liver tissue CXCL10 immunostaining score was 0.9 ± 0.9,and the liver tissue CXCL10 m RNA expression level was 1.0 ± 0.5,which were significantly lower than those in the HBs Ag positive group(462.5 ± 218.7,2.6 ± 1.2,2.5 ± 0.3),P values were <0.001.7.The proportion of G / G genotypes in the G-201 A locus of the CXCL10 gene promoter region in patients with serum HBs Ag negative group was significantly higher than that in patients with serum HBs Ag positive group(70.9%),while the proportions of G / A and A / A genotypes It was significantly lower than those in the serum HBs Ag positive group,with a P value of <0.05.8.Regardless of the HBs Ag-negative group or the positive group,the liver tissue CXCL10 immunostaining score and liver tissue CXCL10 m RNA expression level of those with G-201 A loci were significantly lower than those of non-G / G genotypes.And the serum CXCL10 level of G-201 A loci in patients with HBs Ag negative group was significantly lower than that in non-G/ G patients.9.In patients with serum HBs Ag-negative or HBs Ag-positive patients,the METAVIR inflammatory activity score of liver tissue in patients with G-201 A at the promoter region of CXCL10 gene was G / G was significantly lower than that of patients without G / G genotype(P The values are 0.002,0.023).10.Age,ALT level,and G-201 A locus genotype of the CXCL10 gene promoter region are independent influencing factors of sero-negative concealment in HBV infected patients.11.Among HBs Ag-negative patients,the serum CXCL10 level at 3 months was 51.3 ± 24.0 ng / ml,which was significantly lower than that of non-GG patients(70.1 ± 16.1 ng / ml),P <0.05.Among HBs Ag-positive patients,serum CXCL10 levels at 5 months and 6 months were 50.1 ± 18.0 ng / ml and 33.8 ± 9.4 ng / ml,which were significantly lower than those of non-GG patients(81.8 ± 21.1 ng / ml).,53.1 ± 21.3 ng / ml),P <0.01.12.In the HBs Ag-negative group(n = 27),the seroconversion rate of serum virus in patients with GG type was 3 months,6 months,and 12 months,respectively.They were 61.9%,71.4% and 76.2%,which were lower than those of non-GG patients during the same period.Conclusion:1.Early combined antiviral therapy may be a more effective treatment strategy for HBV-DNA positive hepatocellular carcinoma after liver resection / ablation.2.After 48 weeks of antiviral treatment,a decrease in HBs Ag of >1500 IU / ml is associated with a reduction in HCC mortality and disease recurrence.3.The G / G genotype of the G-201 A locus in the promoter region of the CXCL10 gene is an independent influencing factor of HBs Ag-negative HBV infection.4.The G-201 A locus polymorphism in the CXCL10 gene promoter region may affect the antiviral efficacy of HBs Ag-negative HBV infected patients. |
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