Immune Response In Patients With Chronic Hepatitis B And The Efficacy Of Lamivudine Therapy On Immune Function

Hepatitis B virus (HBV) damages the health of people seriously. It is reported that there are 350 millions persons suffering from chronic HBV infection all of the world. HBV infection has been a severe public problem of health. Therefore,it is very important to improve the treatment method and search for more effective therapy of chronic hepatitis B (CHB).The pathological changes of hepatitis B is evoked by immunopathogenesis. The difference of clinical turnover is determined by the difference of immune reaction of human body. Now, people show more and more attention to the relation between the feature of immune response and antiviral efficacy. Antiviral therapy displays a key role for treatment of CHB,but the antiviral medicine only can inhibit the replication of HBV nowadays, and it is impossible to clean up HBV completely through forthcoming therapy method. It may be a basic strategy combining antiviral therapy and enhancing specific immunity to control HBV permanently.The response to lamividine (LAM) therapy may be related to immune reaction. Therefore, this research observes the feature of immune response in CHB patients and analysises the relationship between clinical efficacy and immune reaction. It will help us select therapy scheme, also it is beneficial to judge the efficacy and prognostic of antiviral therapy, and further find a new immunotherapy method.Objects: To investigate the effect of Lamivudine (LAM) treatment on IFN-r (Th1 type cytokine) and IL-4 (Th2 type cytokine) in patients with CHB,and observe the changes of T lymphocyte subsets and CD28 functional subsets.Methods:1.Sixty-six patients with CHB were selected in the study. Admitted criteria for our study were: age 35±9.4 years, detectable HBsAg, HBeAg, serum HBV DNA≥105copies/ml, or undetectable HBeAg, HBV DNA≥104Copies/ml, ALT>80U/L,ALB>30g/L,PLT>100×1012/L. All patients were treated with LAM at a dose of 100mg /d for a year. Serum levels of INF-r and IL-4 were measured with enzyme linked immunosorbent assay (ELISA) at baseline and 3, 6, 9 and 12 months during the treatment. Serum indexes including liver function, HBsAg, HBsAb, HBeAg, HBeAb, HBcAb and HBV DNA were also measured. Twenty healthy volunteers were served as normal control.2. Twenty patients with CHB were selected. Simultaneously selected 15 HBV carriers and 13 HBsAg carriers whose liver function are normal. Twenty healthy volunteers were served as normal control. The therapy scheme to CHB patients is the same as above. T lymphocyte subsets and CD28 functional subsets were measured with flow cytometry at baseline and 12 months during the treatment. Other serum indexes were also measureed as above.Results:1.At the end of treatment in sixty-six patients with CHB, in HBeAg positive patients negativity rate and seroconversion rate of HBeAg was 34.6% and 21.2%, normalization rate of ALT was 76.9%, HBV DNA negativity rate was 68.3%. The complete response rate to LAM treatment was 21.1%, the partial response rate was 48.1%, and the non-response rate was 30.8%.2.The changes of serum IFN-r,IL-4 levels: In CHB patients the ratios of IFN-r/IL-4 were lower than control group. In complete response group, the release of IFN-γincreased, and IL-4 were inhibited gradually during LAM therapy. The IFN-r/ IL-4 ratios were approximate to control group, sometimes even higher than them. Whereas the IFN-r/IL-4 ratios in patients with partial response and non-response were lower than those of control group. Before treatment the IFN-r levels in patients with complete response were higher than partial response and non response. And patients with high IFN-r levels showed higher rate of complete response and lower rate of non response than those with low IFN-r levels (P<0.01). Patients with high ALT levels showed higher IFN-r levels and higher IFN-r/IL-4 ratios than those with low ALT levels (p<0.05,p<0.05). In HBeAg negative patients, the ratios of IFN-r to IL-4 increased slowly but cannot reach the levels of control group at last. 3. The changes of T lymphocyte subsets and CD28 functional subsets: Compared with control group the percent of CD4+ T cell decreased, and the cell count of CD4+,CD8+ T cell count were all lower than control group. In HBV carriers the percents of CD4+ and CD8+ T cell were normal, and the cell count decreased (p<0.05). In HBsAg carriers the percent and cell count of CD4+ and CD8+ T cell were all normal. The percent of CD4CD28+ and CD8CD28+ T cell were normal, but the cell count were lower than control group (p<0.01,p<0.05; p<0.01,p<0.05). The cell count of T lymphocyte subsets and CD28 functional subsets all increased during LAM therapy. Patients with HBV DNA negative after therapy showed higher CD4+ T cell count than those patients with non-negative of HBV DNA (p<0.05), whereas the CD8+ T cell count and the ratios of CD4+ /CD8+ has no difference between them .Conclution:1. In patients with CHB the levels of IFN-r decreased and the IL-4 levels increased. It displays that Th2 cells prevailed and Th1/Th2 losed balance. Cellular immune functions are obviously in disorder in patients with hepatitis B, which might be closely associated with the chronicity of HBV infection.2. The patients with high IFN-r levels showed higher rate of complete response and lower rate of non-response than those with low IFN-r levels to LAM treatment. It indicates that the patients with better immune fuction show higher rate of response to LAM treatment. It is very important to detect the immune function before antiviral therapy.3. The patients with high ALT levels showed higher IFN-r levels and IFN-r/IL-4 ratios than those with low ALT levels,and they showed higher rate of complete response and lower rate of non-response to LAM treatment. The increasing of ALT indicats that the body has capability of immune clearance, which is helpful to grasp the opportunity of antiviral therapy.4. Complete response patients after LAM treatment showed Th1 superior response and Th1/Th2 balance recovered. Whereas patients with partial response and non-response remained Th2 superior response. The response to LAM therapy is related to the balance of Th1/Th2. However, the treatment with LAM cannot induce general HBeAg seroconversion, and the recovery of immune function were transient in part patients.Thus combination of LAM and other immunomodulator may be a reasonable therapatic strategy of anti-HBV.5. T lymphocyte subsets and CD28 functional subsets are reduced in CHB patients. It induced the decent of cellular immune function. Our result also indicates that the cell count can reflect the disorder of T lymphocyte subsets more sensitively than percent.6. The immune function of HBV carriers had decreased because of active viral replication, whereas every measured index was still normal in HBsAg carriers. The change of immune fuction not only relates to HBV infection, but also is concerned with the replication of HBV DNA.