干扰素联合拉咪呋啶治疗慢性乙型肝炎的抗HBV的疗效的临床研究
|
摘要
目的：探讨干扰素联合拉咪呋啶治疗慢性乙型肝炎的抗HBV的治疗效果。方法：将142例血清HBeAg、HBV-DNA阳性慢性乙型肝炎患者随机分成四组：干扰素治疗组(A组)35例，拉咪呋啶治疗组(B组)38例，干扰素联合拉咪呋啶治疗组(C组)29例，一般疗法组(D组)40例。检测治疗1年后血清HBeAg及HBV-DNA阴转率及动态变化、肝功能ALT好转率及动态变化、外周血CD_4~+，CD_4~+／CD_8~+变化、观察肝组织学变化、不良反应等，探讨干扰素联合拉咪呋啶治疗慢性乙型肝炎的抗HBV的治疗效果。结果：干扰素组、拉咪呋啶组、干扰素联合拉咪呋啶组及一般疗法组的HBeAg阴转率分别为20.00％、15.79％、34.48％和2.50％；血清HBV-DNA阴转率分别为37.14％、55.26％、65.52％和0.00％；肝功能ALT。复常率分别为40.00％、60.53％、72.41％和10.00％。在HBeAg阴转率方面，干扰素组、干扰素联合拉咪呋啶组的疗效明显优于一般疗法组(P＜0.05)。在血清HBV-DNA阴转率方面，干扰素组、拉咪呋啶组、干扰素联合拉咪呋啶组的疗效明显优于一般疗法组(P＜0.05)，拉咪呋啶组干扰素联合拉咪呋啶组的疗效明显优于干扰素组(P＜0.05)。在肝功能ALT.复常率方面，干扰素组、拉咪呋啶组、干扰素联合拉眯呋啶组的疗效明显优于一般疗法组(P＜0.05)，干扰素联合拉咪呋啶组的疗效明显优于干扰素组(P＜0.05)。 干扰素联合拉咪呋啶组治疗后外周血CD_4~+／CD_8~+比值较治疗前明显提高(P＜0.05)。当血清HBV-DNA＜100Pg／ml时，分析血清HBV-DNA阴转率，干扰素联合拉咪呋啶组疗效优于单用干扰素组(P＜0.05)；分析血清HBeAg阴转率，干扰素联合拉咪呋啶组疗效优于单用拉咪呋啶组(P＜0.05)。干扰素联
干扰素联合拉眯吠陡治疗慢性乙型肝炎的抗HBV的疗效的临床研究 提要
合拉咪吱碗治疗慢性乙型肝炎未见明显增加不良反应的发生率。结
论：干扰素联合拉眯吱咤对慢性乙型肝炎的抗病毒治疗是有效的、安
全的，尤其适合于血清HBVlNA＜100Pg／ml的患者。
[Objective]To evaluate the therapeutic efficacy of interferon combinated lamivudine and interferon or lamivudine monotherapy in patients with chronic hepatitis B [Methods] 142 patients with chronic hepatitis B wliose HbeAg HBV-DNA were positive were chosen according to the standard criterion and randomly divided into 4 groups:35 patients were treated with interferon for 4 months (A group) ,38 patients were treated with lamivudine at least 1 year(B group), 29 patients were treated with interferon combinated lamivudine in the same ways(C group),40 patients were treated with Ganlixin and ChuiPengChao as control(D group). We tested the response rates of serum HBV-DNA and HBeAg. the ALT normalization rate the growth of CD4+/ CD? in peripheral blood of every group after 1 year. We observed the histological improvement of the liver before and after therapy and the adverse events. [Results] The response rate of serum HBeAg of A group B group C group and D group were 20.00% 15.79% 34.48%and2.50% respectively,it was
significantly greater of A group and C group than of D group respectively.The response rate of serum HBV-DNA of those four groups were 37.14% 55.26% 65.52 %andO.OO% respectively,it was significantly greater of A group B group and C group than of D group respectively,and was significantly greater of B group and C group than of A group respectively.The ALT normalization rate of those four groups were 40.00 % 60.53 % 72.41% and 10.00%
respectively, it was significantly greater of A group> B group and C group than of D group respectively, and was significantly greater of C group than of A group. The response rate of HBV-DNA was significantly greater to interferon combined lamivedine than to interferon monotherapy and the response rate of HBeAg is significantly greater to interferon combined lamivedine than to lamivudine monotherapy among patients with low level viremia (HBV-DNA<100pg/ml). The growth of CD4+/ CD8+ is significantly greater to interferon combinated lamivudine than to interferon or lamivudine monotherapy . Meanwhile,liver boipy was done in 1 patient before and after the treatment with interferon combinated lamivudine, which showed obvious histological improvement. Combination therapy has not increased the rate of adverse events [Conclution] The therapeutic effective rate to interferon combined lamivudine is greater than interferon or lamivudine
monotherapy ,especially when whose serum HBV-DNA level was lower than 100pg/ml.
干扰素联合拉眯吠陡治疗慢性乙型肝炎的抗HBV的疗效的临床研究 提要
合拉咪吱碗治疗慢性乙型肝炎未见明显增加不良反应的发生率。结
论：干扰素联合拉眯吱咤对慢性乙型肝炎的抗病毒治疗是有效的、安
全的，尤其适合于血清HBVlNA＜100Pg／ml的患者。
[Objective]To evaluate the therapeutic efficacy of interferon combinated lamivudine and interferon or lamivudine monotherapy in patients with chronic hepatitis B [Methods] 142 patients with chronic hepatitis B wliose HbeAg HBV-DNA were positive were chosen according to the standard criterion and randomly divided into 4 groups:35 patients were treated with interferon for 4 months (A group) ,38 patients were treated with lamivudine at least 1 year(B group), 29 patients were treated with interferon combinated lamivudine in the same ways(C group),40 patients were treated with Ganlixin and ChuiPengChao as control(D group). We tested the response rates of serum HBV-DNA and HBeAg. the ALT normalization rate the growth of CD4+/ CD? in peripheral blood of every group after 1 year. We observed the histological improvement of the liver before and after therapy and the adverse events. [Results] The response rate of serum HBeAg of A group B group C group and D group were 20.00% 15.79% 34.48%and2.50% respectively,it was
significantly greater of A group and C group than of D group respectively.The response rate of serum HBV-DNA of those four groups were 37.14% 55.26% 65.52 %andO.OO% respectively,it was significantly greater of A group B group and C group than of D group respectively,and was significantly greater of B group and C group than of A group respectively.The ALT normalization rate of those four groups were 40.00 % 60.53 % 72.41% and 10.00%
respectively, it was significantly greater of A group> B group and C group than of D group respectively, and was significantly greater of C group than of A group. The response rate of HBV-DNA was significantly greater to interferon combined lamivedine than to interferon monotherapy and the response rate of HBeAg is significantly greater to interferon combined lamivedine than to lamivudine monotherapy among patients with low level viremia (HBV-DNA<100pg/ml). The growth of CD4+/ CD8+ is significantly greater to interferon combinated lamivudine than to interferon or lamivudine monotherapy . Meanwhile,liver boipy was done in 1 patient before and after the treatment with interferon combinated lamivudine, which showed obvious histological improvement. Combination therapy has not increased the rate of adverse events [Conclution] The therapeutic effective rate to interferon combined lamivudine is greater than interferon or lamivudine
monotherapy ,especially when whose serum HBV-DNA level was lower than 100pg/ml.
引文
1. Chu CM,Liaw Y- F. Natural history of chronical hepatitis B virus infection:an immunopathological study. J Gastroenterol hepatol 1997 12(Suppl):218-222
2. Cohen JJ. Apoptosis. Immunol Today, 1993,14:357.
3. Bodmer JG. Nomenclature for factors of the HLA system,European Immunogenetics, 1992,19:327
4．张福奎，贾继东，王宝恩，等。慢性乙型肝炎的治疗。中华肝脏病杂志，2000，8(4)253-255。
5．邬祥惠．干扰素在乙型和丙型肝炎治疗上的合理应用．中华传染病杂志，1998，16(1)：4
6. Nancy W. Extended Lamivudine Treatment in patients with chronic hepatitis B e Antigen seroconversion rates: results after 3 years of therapy. Hepatology,2001,33(6)1527-1532.
7. Richer MF. Interferon--induced MxA proten GTP binding and GTP hydrolysis properties.J Biol Chem,1995,270(22):1352.
8. Malmeinen M,Ilonen J, Julkumenl, et al. Expression of MxA protein in blood lymphocytes discriminates between viral and bacterial infections in febrile children.Peadiatric Research,1997,41(5):647.
9. Lai CL, Ching CK, Tung AK,et al. Lamivudine is effective in supressing hepatitis B virus DNA in chinese hepatitis B surface antigen carriers: a placebo--controlled trial.Hepatology, 1997, 25:241-244.
10．王慧芬。肝脏疾病。北京科学技术出版社。2001，1-32
11．病毒性肝炎防治方案。中华肝脏病杂志，2000，8(6)324-329
12. Liaw YF,leung NY, chang TT, et al.effects of extended Lamivudine therapy in Asian patients with chronic hepatitis B Gastroenterology 2000,119:172-180
13. Perrillo RP, Schiff ER,Davis GL,et sl.A randomized controlled trial of interferon alfa-2b alone and after prednisone withdrawal for the treatment of chronic hepatitis B.The hepatitis international Therapy Group. N Engl J Med 1990 323:295-301
14. Thomas HC,Karayiannis P, Brook G,et al.Treatment of hepatitis B virus infection with interferon.Factors predicting response to interferon.J Hepatol 1991:13(suppl):s4-s7.
15．邱望龙 崔雪莲 皇甫丽等。干扰素a-1b治疗前c区变异株引起的慢性乙型肝炎的疗效。中华传染病杂志1999，17(3)193-194
16. Zeuzen S. Dynamics of hepatitis B virus infeition in vivo.J Hepatology, 1997,27:431-436
17. Sharon R.Analysis of hepatitis B viral loacad clecline under potent therapy:complex decay profiles observed.Hepatology,2001 34(5)1012-1020
18．张定风。从机体清除乙型肝炎病毒的规律探讨抗病毒治疗的新策略。中华肝脏病杂志9(4)196-201。
19．陆坚。不同剂量干扰素治疗慢性乙型肝炎疗效观察中华肝脏病杂志2000，8(5)313
20．王淑惠，刘虹，臧隽等。a-1b干扰素治疗慢性乙型肝炎。中华肝脏病杂志19997(1)10
21. Satheesh Naif and Robert Perrillo. Serum Alanine Aminotransferase flares During Interferon Treatment of Chronic Hepatitis B:Is sustained Clearance of HBV DNA Dependent on levels of pretreatment Viremia? Hepatology,2001,34:1021-1026
22．程钢。荧光定量PCR检测乙型肝炎病毒。中华医学检验杂志。1999，22(3) 135-138
23. Knodell RG,lshak KG,Black W et al. Formulation and application of a numerical scoring systen for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology, 1981,1:431-435
24. Chevalliver M,Guerret S,Chossegros P, et al. A histological Semi-quantitative scoring system for evaluation of hepatic fibrosis in needle liver biopsy specimens: Comparison with morphometric studies. Hepatology, 1994,20:349-355
25．周元平．拉咪呋啶对慢性乙型肝炎疗效的组织病理学分析。中华传染病杂志，2000，18(4)244-246
26．袁静。拉咪呋啶治疗慢性重型乙型肝炎疗效观察。中华传染病杂志，2001，19(6)372-374
27．陆志檬。胸腺肽a1单用及联合干扰素a-1b治疗慢性乙型肝炎疗效观察。中华传染病杂志，1999，17(1)24-26
28. Jean-Pierre Villeneuve,Lynn D.Lamivudine Treatment for Decompensated Cirrhosis resulting from chronic hepatitis B.Hepatology,2000,31:207-210
29．刘克洲．干扰素治疗病毒性肝炎．中华肝脏病杂志2001，9(4)24
30. Maini MK,Bertoletti A. How can the cellular immune response control Hepatitis B virus replication. J Viral Hepat, 2000,7:321-326
31．姜荣龙，骆抗先，富宁。CD_4~+NKT细胞在慢性乙型肝炎病毒感染中的意义。中华肝脏病杂志2001，9(1)57
32．王九平，刘俊杉，阎荣。慢性乙型肝炎患者外周血T淋巴细胞糖皮质激素受体的表达及意义。中华传染病杂志，1994，12(1)47-48
33．郭毅，吴辉，李十月等。慢性乙型肝炎患者外周血T细胞受体基因重组的意义。中华传染病杂志，2000，18(2)88-90
34. Kaklimi k,Guidotti LG,Koezuka Y, et al.Natural killer T cell activation inhibits hepatitis B virus replication In vivo. J Exp Med,2000,192: 921-930
35. Sing GK, Ladhams A,Arnoid S, et al.A longitudinal analysis of cytotoxic T lymphfocyte precursor frequencies to the hepatitis B virus in chronically infected patients. J Viral Hepat,2001,8:19-29
35．张定风。从机体清除乙型肝炎病毒的规律探讨抗病毒治疗的新策略。中华肝脏病杂志，2001，9(4)196-202
36. Di Bisceglie. Combination therapy for hepatitis B.Gut 2002;50:443-445
2. Cohen JJ. Apoptosis. Immunol Today, 1993,14:357.
3. Bodmer JG. Nomenclature for factors of the HLA system,European Immunogenetics, 1992,19:327
4．张福奎，贾继东，王宝恩，等。慢性乙型肝炎的治疗。中华肝脏病杂志，2000，8(4)253-255。
5．邬祥惠．干扰素在乙型和丙型肝炎治疗上的合理应用．中华传染病杂志，1998，16(1)：4
6. Nancy W. Extended Lamivudine Treatment in patients with chronic hepatitis B e Antigen seroconversion rates: results after 3 years of therapy. Hepatology,2001,33(6)1527-1532.
7. Richer MF. Interferon--induced MxA proten GTP binding and GTP hydrolysis properties.J Biol Chem,1995,270(22):1352.
8. Malmeinen M,Ilonen J, Julkumenl, et al. Expression of MxA protein in blood lymphocytes discriminates between viral and bacterial infections in febrile children.Peadiatric Research,1997,41(5):647.
9. Lai CL, Ching CK, Tung AK,et al. Lamivudine is effective in supressing hepatitis B virus DNA in chinese hepatitis B surface antigen carriers: a placebo--controlled trial.Hepatology, 1997, 25:241-244.
10．王慧芬。肝脏疾病。北京科学技术出版社。2001，1-32
11．病毒性肝炎防治方案。中华肝脏病杂志，2000，8(6)324-329
12. Liaw YF,leung NY, chang TT, et al.effects of extended Lamivudine therapy in Asian patients with chronic hepatitis B Gastroenterology 2000,119:172-180
13. Perrillo RP, Schiff ER,Davis GL,et sl.A randomized controlled trial of interferon alfa-2b alone and after prednisone withdrawal for the treatment of chronic hepatitis B.The hepatitis international Therapy Group. N Engl J Med 1990 323:295-301
14. Thomas HC,Karayiannis P, Brook G,et al.Treatment of hepatitis B virus infection with interferon.Factors predicting response to interferon.J Hepatol 1991:13(suppl):s4-s7.
15．邱望龙 崔雪莲 皇甫丽等。干扰素a-1b治疗前c区变异株引起的慢性乙型肝炎的疗效。中华传染病杂志1999，17(3)193-194
16. Zeuzen S. Dynamics of hepatitis B virus infeition in vivo.J Hepatology, 1997,27:431-436
17. Sharon R.Analysis of hepatitis B viral loacad clecline under potent therapy:complex decay profiles observed.Hepatology,2001 34(5)1012-1020
18．张定风。从机体清除乙型肝炎病毒的规律探讨抗病毒治疗的新策略。中华肝脏病杂志9(4)196-201。
19．陆坚。不同剂量干扰素治疗慢性乙型肝炎疗效观察中华肝脏病杂志2000，8(5)313
20．王淑惠，刘虹，臧隽等。a-1b干扰素治疗慢性乙型肝炎。中华肝脏病杂志19997(1)10
21. Satheesh Naif and Robert Perrillo. Serum Alanine Aminotransferase flares During Interferon Treatment of Chronic Hepatitis B:Is sustained Clearance of HBV DNA Dependent on levels of pretreatment Viremia? Hepatology,2001,34:1021-1026
22．程钢。荧光定量PCR检测乙型肝炎病毒。中华医学检验杂志。1999，22(3) 135-138
23. Knodell RG,lshak KG,Black W et al. Formulation and application of a numerical scoring systen for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology, 1981,1:431-435
24. Chevalliver M,Guerret S,Chossegros P, et al. A histological Semi-quantitative scoring system for evaluation of hepatic fibrosis in needle liver biopsy specimens: Comparison with morphometric studies. Hepatology, 1994,20:349-355
25．周元平．拉咪呋啶对慢性乙型肝炎疗效的组织病理学分析。中华传染病杂志，2000，18(4)244-246
26．袁静。拉咪呋啶治疗慢性重型乙型肝炎疗效观察。中华传染病杂志，2001，19(6)372-374
27．陆志檬。胸腺肽a1单用及联合干扰素a-1b治疗慢性乙型肝炎疗效观察。中华传染病杂志，1999，17(1)24-26
28. Jean-Pierre Villeneuve,Lynn D.Lamivudine Treatment for Decompensated Cirrhosis resulting from chronic hepatitis B.Hepatology,2000,31:207-210
29．刘克洲．干扰素治疗病毒性肝炎．中华肝脏病杂志2001，9(4)24
30. Maini MK,Bertoletti A. How can the cellular immune response control Hepatitis B virus replication. J Viral Hepat, 2000,7:321-326
31．姜荣龙，骆抗先，富宁。CD_4~+NKT细胞在慢性乙型肝炎病毒感染中的意义。中华肝脏病杂志2001，9(1)57
32．王九平，刘俊杉，阎荣。慢性乙型肝炎患者外周血T淋巴细胞糖皮质激素受体的表达及意义。中华传染病杂志，1994，12(1)47-48
33．郭毅，吴辉，李十月等。慢性乙型肝炎患者外周血T细胞受体基因重组的意义。中华传染病杂志，2000，18(2)88-90
34. Kaklimi k,Guidotti LG,Koezuka Y, et al.Natural killer T cell activation inhibits hepatitis B virus replication In vivo. J Exp Med,2000,192: 921-930
35. Sing GK, Ladhams A,Arnoid S, et al.A longitudinal analysis of cytotoxic T lymphfocyte precursor frequencies to the hepatitis B virus in chronically infected patients. J Viral Hepat,2001,8:19-29
35．张定风。从机体清除乙型肝炎病毒的规律探讨抗病毒治疗的新策略。中华肝脏病杂志，2001，9(4)196-202
36. Di Bisceglie. Combination therapy for hepatitis B.Gut 2002;50:443-445