| Objective: In order to improve the efficacy of antiviral therapy,a new antiviral therapy scheme,entecavir combined with granulocyte macrophage colony stimulating factor,was explored for the efficacy and safety in the treatment of HBe Ag positive chronic hepatitis B and compared with that of the curative effect treated by entecavir,and the virological response and improvement of liver function were also observed and compared.At the same time,the changes of chemokines CXCL10,CXCL12 and CXCL16 were observed in order to study the effect of immune factors on the treatment of hepatitis B with antiviral therapy.Methods: Selecting cases of chronic hepatitis B patients who were recruited and followed up in our hospital from December 2016 to December 2019.Enrolled patients were randomly divided into two groups and treated with ETV or ETV combined with GM-CSF for 48 weeks.After 48 weeks,the patients who had not turned negative in HBs Ag continuing ETV treating and followed up to 72 weeks.To analyze the clinical data of patients in each visit point,and to compare the negative changes of HBs Ag,HBV DNA and HBe Ag between the two groups,and to observe the recovery of liver function.In addition,the plasma samples of some patients who have completed 48 weeks of treatment were selected.The levels of CXCL10,CXCL12 and CXCL16 in the two groups of patients and healthy controls were measured by ELISA.At 48 weeks,the negative rate of HBs Ag in single drug group and combined drug group was 1.20% and 2.27%,respectively.At 72 weeks,the clearance rate of HBs Ag in the two groups was the same as before.The clearance rate of HBs Ag in combined drug group was higher than that in single drug group,but the difference was not statistically significant(P > 0.05).In terms of virological response,the negative rate of HBV DNA in single drug group and combined drug group was 51.8% and 54.5% respectively at 48 weeks,and the cumulative negative rate of HBV DNA at 72 weeks was 61.4% and 63.6% respectively.During the treatment and follow-up,the negative rate of HBV DNA in the combination group was higher than that in the single drug group,but the difference was not statistically significant(P > 0.05).In response to HBe Ag,the cumulative negative rate of HBe Ag was 13.3% and 20.5% in the single drug group and the combined drug group at 48 weeks,and 14.5% and 23.9% at 72 weeks,respectively.The negative rate of HBe Ag in the combination group was higher than that in the single drug group,but the difference was not statistically significant(P > 0.05).At 48 weeks,the seroconversion rate of HBe Ag in single drug group and combined drug group was 0 and 10.2% respectively;at 72 weeks,the seroconversion rate of HBe Ag was 0 and 11.40% respectively;at 48 weeks and 72 weeks,the seroconversion rate of HBe Ag in combined drug group was significantly higher than that in single drug group(P < 0.001).In terms of biochemical response,the recovery rate of ALT in the combination group was significantly higher than that in the single drug group(P < 0.05).The early recovery rate of AST in the combined group was significantly higher than that in the single group(P < 0.05).During 48 weeks of treatment,there were no serious adverse events and abnormal laboratory indexes higher than level 3 in both groups.The level of CXCL10 in ETV group at 0,12,24,36 and 48 weeks was 2.32(0.09～29.68)ng/ml,26.07(2.84～36.91)ng/ml,22.44(4.19～53.61)ng/ml,5.02(0.00～36.30)ng/ml,12.13(3.37～24.03)ng/ml,respectively.The level of CXCL10 in ETV + GM-CSF group at 0,12,24,36 and 48 weeks was2.18(0.05～22.11)ng/ml,24.05(0.44～58.61)ng/ml,24.08(1.90～46.23)ng/ml,12.98(3.30～22.48)ng/ml,24.27(7.29～26.34)ng/ml,respectively.The level of CXCL12 in ETV group at 0,12,24,36 and 48 weeks was0.53(0.01～1.22)ng/ml,0.37(0.14～1.12)ng/ml,0.58(0.34～1.27)ng/ml,0.53(0.29～0.90)ng/ml,0.55(0.21～1.07)ng/ml,respectively.The level of CXCL12 in ETV+GM-CSF group at 0,12,24,36 and 48 weeks was 0.16(0.07～0.78)ng/ml,0.48(0.10～1.67)ng/ml,0.91(0.12～1.38)ng/ml,0.13(0.01～0.33)ng/ml,0.24(0.14～0.38)ng/ml,respectively.The levels of CXCL16 in ETV group at 0,12,24,36 and 48 weeks was227.91(168.86～964.04)pg/ml,697.29(208.35～1489.59)pg/ml,845.36(380.48～1068.56)pg/ml,621.59(423.97～1055.20)pg/ml,625.99(352.79～1156.38)pg/ml,respectively.The levels of CXCL16 in ETV+GM-CSF group at 0,12,24,36 and 48 weeks was 405.97(212.78～802.86)pg/ml,716.24(490.68～1255.71)pg/ml,664.84(272.04～907.10)pg/ml,659.50(467.55～872.67)pg/ml,847.00(461.49～1999.73)pg/ml,respectively.The levels of CXCL10,CXCL12 and CXCL16 in health control,respectively,were 645.14(312.47～1494.45)pg/ml,14.85(7.41～28.73)ng/ml,10997.62(6178.53～19123.03)pg/ml.Which was significantly higher than that of patients in both groups(P < 0.001).The level of CXCL10 began to decrease at 36 weeks in the ETV group and 12 weeks in the ETV+GM-CSF group.During the therapeutic period,there was no obvious trend of increase or decrease of CXCL12 in the ETV group;while in the ETV+GM-CSF group,CXCL12 increased at 12 weeks,and decreased gradually from 24 weeks to 48 weeks.The kinetic trends of CXCL16 in ETV group and ETV+GM-CSF group were similar,which increased at 12 weeks,decreased at 24 weeks,and continued to increase from 36 weeks to 48 weeks later.However,the kinetic rang of CXCL16 in the ETV+GM-CSF group was even greater than that in the ETV group.Conclusion: compared with ETV alone regimen,ETV+GM-CSF regimen could improve the negative-conversing rate of HBs Ag,HBV DNA and HBe Ag,but the difference is not statistically significant.Compared with the ETV regimen,the ETV+GM-CSF regimen significantly improved the HBe Ag seroconversion rate and the early renormalization rate of ALT and AST.In immunology test,the levels of CXCL10,CXCL12 and CXCL16 in HBe Ag positive chronic hepatitis B patients were significantly lower than those in healthy people.The rise of CXCL10,CXCL12 and CXCL16 in 12 weeks is beneficial to the inhibition of HBV.Both ETV combined with GM-CSF regimen and ETV alone regimen in the treatment of HBe Ag-positive chronic hepatitis B showed good efficacy in inhibiting virus replication and improving liver function.Compared with the ETV monotherapy,the combination of ETV and GM-CSF significantly improved the serological conversion rate of HBe Ag and significantly reduced the recovery time of patients’ liver function.The HBs Ag negativeconversion rate of patients in the ETV combined GM-CSF treatment group was higher than that in the ETV alone treatment group,but the difference was not statistically significant.The chemokine experiment found that the level of CXCL10,CXCL12,CXCL16 in peripheral blood of patients with HBe Ag-positive chronic hepatitis B was significantly lower than that of the healthy control,indicated HBV infection had an obvious inhibitory effect on the immune system of patients.ETV combined with GM-CSF regimen in the treatment of HBeag-positive chronic hepatitis B patients was beneficial to the increase of CXCL12 and the recovery of host immune system. |
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