拉米夫定联合中药治疗慢性乙型肝炎临床研究
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摘要
目的:评价拉米夫定联合双虎清肝颗粒和乙肝益气解郁冲剂治疗慢性乙型肝炎的临床疗效,对中医药慢性乙型肝炎疗效进行评价。
方法:采用多中心、随机、双盲、对照方法,共纳入病例278例,随机分配到治疗组和对照组,治疗组140例,对照组138例。治疗组联合服用拉米夫定和双虎清肝颗粒以及乙肝益气解郁冲剂;对照组服用拉米夫定和双虎清肝颗粒模拟剂以及乙肝益气解郁冲剂模拟剂。给药方法:拉米夫定100mg,口服,1/d;双虎清肝颗粒1袋(12g)/次,3/d;乙肝益气解郁冲剂1袋(10g)/次,3/d。观察周期48周,每12周复查1次。观察指标包括:病毒血清学指标、病毒核酸指标、生化指标、免疫学指标、中医症状及证候、世界卫生组织生存质量简表、慢性肝病量表。
结果:(1)病毒血清学应答:治疗24周时,治疗组HBeAg阴转率为28.3%,对照组为27.1%(P>0.05)。治疗组HBeAg/HBeAb转换率为20.8%,对照组为20.3%,无显著性差异(P=0.925)。治疗48周时,治疗组HBeAg阴转率为27.1%,对照组为16.7%,两组比较有显著性差异(P=0.034)(PP)。经意向性分析(ITT),两组无显著性差异(P=0.089)。治疗组HBeAg/HBeAb转换率为28.0%,对照组为17.7%,治疗组高于对照组(P=0.087)(PP)。
(2)病毒核酸应答:治疗24周时,治疗组DNA完全应答率为75.5%,部分应答率为11.2%,无应答率为13.3%;对照组完全应答率为68.8%,部分应答率为13.5%,无应答率为17.7%,两组无显著性差异(P=0.288)。治疗48周时,治疗组DNA完全应答率为57.1%,部分应答率为18.6%,无应答率为24.3%;对照组完全应答率为55.8%,部分应答率为18.2%,无应答率为26.0%,两组亦无显著性差异(P=0.842)。在病毒核酸阴转率方面,治疗组在24周时DNA阴转率高于对照组75.5% vs 68.8%。48周时为57.1% vs55.8%。
(3)生化应答:治疗组3、6、9和12月时ALT复常率分别地为53.8%、73.0%、80.7%、69.1%;对照组分别为54.2%、66.7%、64.8%、67.9%,治疗组在6个月、9个月时ALT复常率显著高于对照组。其中9个月时两组有显著性差异(P=0.017)。
(4)联合应答:治疗24周时,治疗组完全应答12.8%,部分应答80.8%,无应答6.4%;对照组完全应答12.8%,部分应答78.2%,无应答9.0%,两组无显著性差异(P>0.05)。48周时,治疗组完全应答6.0%,部分应答86.5%,无应答7.5%;对照组完全应答5.2%,部分应答84.4%,无应答10.4%,两组无显著性差异(P>0.05)。
(5)免疫学指标:治疗前、治疗24周、48周,两组CD3+、CD4+、CD8+正常/异常人数,经χ2检验,无显著性差异(P>0.05)。治疗前、治疗24周、治疗48周两组CD3+、CD4+、CD8+、CD4+/CD8+值比较,经t检验,无显著性差异(P>0.05)。两组自身治疗前后CD3+、CD4+、CD8+值比较,经单因素重复测量方差分析,两组CD4+下降较疗前有显著性差异(P=0.002),但组间比较无显著性(P=0.721)。
(6)中医症状:治疗48周后,两组患者症状记分比较,在烦躁易怒和舌有齿痕症状方面两组有显著性差异(P=0.027和P=0.043),治疗组烦躁易怒和舌有齿痕消失人数较对照组高,症状消失率分别为81% vs 68%和61% vs 47%。其余各症状均无统计学意义(P>0.05)。治疗组在口苦、食欲不振、大便稀溏、烦躁易怒、失眠的症状消失率方面优于对照组。对照组在胃脘满闷、恶心的消失率方面优于治疗组。表明治疗组在肝胆湿热、肝郁脾虚症状尤其是肝郁脾虚症状的改善方面,优于拉米夫定组。
(7)中医证候:治疗12周、24周、36周、48周时两组进行中医疗效比较,经秩和检验,均无显著性差异(P>0.05)。自身治疗前后比较结果显示:治疗组自身治疗前、24周、48周中医证候积分分别为29.10±10.37、13.76±8.49、11.04±7.58;对照组分别为28.82±29.85、14.15±9.27、11.76±8.53。经重复测量方差分析,两组治疗前后组内均有显著性差异(P<0.001),组间比较无显著性差异(P=0.745)。
(8)生存质量(QOL):两组治疗前、24周、36周、48周在总的生存质量、总的健康状况、生理领域、心理领域、社会关系、环境领域得分情况,经t检验,均无显著性差异,P值均大于0.05。自身治疗前后比较结果显示:治疗组除心理领域和社会关系领域无显著性差异外,其余总的生存质量、总的健康状况、生理领域、环境领域得分较疗前均有显著提高,经自身配对t检验,P值分别为0.001,0,0.002和0.028。对照组除社会关系领域无显著性差异外,其余总的生存质量、总的健康状况、生理领域、心理领域、环境领域得分较疗前均有显著提高,经自身配对t检验,P值分别为0,0,0.001,0.048和0.004。
(9)慢性肝病量表(CLDQ):两组治疗前、24周、36周、48周进行疲劳度、精力、情感、腹部症状、系统症状、焦虑度六大类症状记分比较,经t检验,均无显著性差异(P>0.05)。自身治疗前后比较结果显示:两组六大类症状记分均有非常显著性差异(P<0.001)。治疗后各症状记分均增长,症状改善明显。
结论:拉米夫定联合双虎清肝颗粒和乙肝益气解郁冲剂治疗慢性乙型肝炎,在增强抗病毒疗效、抗炎保肝降酶、改善部分临床症状方面优于单用拉米夫定。
Objective：To Study the efficacy of Lamivudine combined with Double TigersClearing away Liver-fire Granule and YiGanYiQiJieYu Powder in treating chronic hepatitis B.and to make the clinic effectiveness assessment of Tradiional Chinese Medidne.
Methods：This was a multi-center, randomized (1:1), double-blinded and controlledclinic trial. 278 patients of chronic hepatitis B. whose serum HBV-DNA and HBeAg arepositive were dividing into two groups randomly. The treated group included 140 cases whilethe controlled group had 138 cases. The therapeutic group were treated with Lamivudineorally 100mg once daily combined with YiGanYiQiJieYu Powder orally 10mg tid. andDouble Tigers Clearing away Liver-fire Granule 10mg tid. once daily, while the control groupwere treated with Lamivudine orally 100mg once daily only. 48 weeks regarded as onetreatment course，The Liver function，Marking thing of hepatitis B，HBV-DNA. Theimmunology index. The traditional Chinese medicine symptoms and syndromemanifestations. The quality of life(QOL) and the chronic liver disease questionnaire weremeasured respectively at baseline, 12 weeks, 24 weeks, 36 weeks and 48 weeks.
Results：1. Serological response: After 24 weeks，the turning negative rate of HBeAgin the therapeutic group was 28.3%, not higher than that in control group which was27.1%(P>0.05).The turning rate of HBeAg/anti-HBe in the therapeutic group was 20.8%, nothigher than that in control group which was 20.3%(P>0.05). After 48 weeks，the turningnegative rate of HBeAg in the therapeutic group was 27.1%, obviously higher than that incontrol group which was 16.7%(P=0.034)(PP). The turning rate of HBeAg/anti-HBe in thetherapeutic group was 28.0%, higher than that in control group which was17.7%(P=0.087)(PP).
2. Virological response: After 24 weeks，the complete response rate of the therapeuticgroup was 75.5%, partial response rate was 11.2%, non-response rate was 13.3%, the controlgroup was respectively 68.8%,13.5% and 17.7%, there had no different between twogroups(P=0.288). After 48 weeks，the complete response rate of the therapeutic group was57.1%, partial response rate was 18.6%, non-response rate was 24.3%, the control group wasrespectively 55.8%,18.2% and 26.0%. there had no different between two groups(P=0.842).The turning negative rate of HBV-DNA of the therapeutic group was higher than the controlgroup that was 75.5% vs 68.8% (P=0.288) at week 24 and .57.1% vs 55.8% (P=0.842) atweek 48.
3. Biochemical response:The ALT normalization rate of the therapeutic group wasrespectively53.8%,73.0%,80.7% and 69.1% at 12wk,24wk,36wk and 48wk, while the controlgroup was 54.2%,66.7%,64.8% and 67.9%, The normalization rate of the therapeutic group in6 and 9 month is significantly high than the control group, especially at 36wk, there had significant difference between two groups(p=0.017).
4. Combined response: After 24 weeks，the complete response rate of the therapeuticgroup was 12.8%, partial response rate was 80.0%, non-response rate was 6.4%, the controlgroup was respectively 12.8%,78.2% and 9.0%, there had no different between twogroups(P>0.05). After 48 weeks，the complete response rate of the therapeutic group was6.0%, partial response rate was 86.5%, non-response rate was 7.5%, the control group wasrespectively 5.2%,84.4% and 10.4%. there had no different between two groups (P>0.05).
5. Immunologic indexes: before treatment, after 24 and 48 weeks,the normal/abnormalmembers of CD3+、CD4+、CD8+ had no signature different(p>0.05).The proportion of CD3+、CD4+、CD8+、CD4+/CD8+ between two groups had no significant difference (p>0.05). TheCD4+ level of the two groups had significantly lower than itself before treatment,but therehad no significant differency between two groups (P=0.721).
6. TCM symptoms: After 48 weeks，there had a significant difference on integration ofrestless tantrum and indentation tongue (P=0.027和P=0.043)，the disappeared numbers ofthis two symptoms in the therapeutic group was more than the control group,Thedisappearance rate is 81% vs 68%和61% vs 47%。The rest symptoms had not statisticallysignificant (P>0.05).The therapeutic group had a higherly disappearance rate on thesymptoms such as bitter taste of mouth , poor appetite ,stool loose, restless tantrum andwakeful than the control group,while the control group is higher in gastric cavity full andinactive, sick than the treatment group.The consequence showed that the therapeutic groupsurpassed the lamivudine group in improving the hepatochlic hygropyrexia and stagnation ofliver-QI with deficiency of the spleen symptoms.
7. TCM syndrome manifestations: There had no significant difference on the syndromeintegration between two groups at 12wks、24wks、36wks and 48wks. The syndromeintegration of two groups were more lower on the syndrome integration than itself beforetreatment.
8. WHOQOL-BREF：There had no different between two groups in total quality of lifeand total healthy level,and in physical, psychology, social, environmental domain at 0week,24week, 36week,48 week (p>0.05).Excerpt the psychology and social domain had nosignificant difference ,the other domains are all higher than itself at 0 week (p<0.05 or p<0.01)in the therapeutic group. The control group in all domains are higher than itself at 0 week(p<0.05 or p<0.01) excerpt the social domain.
9. CLDQ: There had no different between two groups on tiredness degree, energy,affection, abdominal symptom, system symptom and anxiety degree (p>0.05) at 0week,24weeks, 36weeks and 48weeks. The integration of two groups were more lower on thesyndrome indentation than itself before treatment.
Conclusion：The combination treatment with Lamivudine combined with DoubleTigers Clearing away Liver-fire Granule and YiGanYiQiJieYu Powder on chronic hepatitis B is superiorior to using Lamivudine only on the aspect of strengthening antivirus, antiinflammatory ,protecting liver ,lowering enzyme and improving part clinic symptoms.
方法:采用多中心、随机、双盲、对照方法,共纳入病例278例,随机分配到治疗组和对照组,治疗组140例,对照组138例。治疗组联合服用拉米夫定和双虎清肝颗粒以及乙肝益气解郁冲剂;对照组服用拉米夫定和双虎清肝颗粒模拟剂以及乙肝益气解郁冲剂模拟剂。给药方法:拉米夫定100mg,口服,1/d;双虎清肝颗粒1袋(12g)/次,3/d;乙肝益气解郁冲剂1袋(10g)/次,3/d。观察周期48周,每12周复查1次。观察指标包括:病毒血清学指标、病毒核酸指标、生化指标、免疫学指标、中医症状及证候、世界卫生组织生存质量简表、慢性肝病量表。
结果:(1)病毒血清学应答:治疗24周时,治疗组HBeAg阴转率为28.3%,对照组为27.1%(P>0.05)。治疗组HBeAg/HBeAb转换率为20.8%,对照组为20.3%,无显著性差异(P=0.925)。治疗48周时,治疗组HBeAg阴转率为27.1%,对照组为16.7%,两组比较有显著性差异(P=0.034)(PP)。经意向性分析(ITT),两组无显著性差异(P=0.089)。治疗组HBeAg/HBeAb转换率为28.0%,对照组为17.7%,治疗组高于对照组(P=0.087)(PP)。
(2)病毒核酸应答:治疗24周时,治疗组DNA完全应答率为75.5%,部分应答率为11.2%,无应答率为13.3%;对照组完全应答率为68.8%,部分应答率为13.5%,无应答率为17.7%,两组无显著性差异(P=0.288)。治疗48周时,治疗组DNA完全应答率为57.1%,部分应答率为18.6%,无应答率为24.3%;对照组完全应答率为55.8%,部分应答率为18.2%,无应答率为26.0%,两组亦无显著性差异(P=0.842)。在病毒核酸阴转率方面,治疗组在24周时DNA阴转率高于对照组75.5% vs 68.8%。48周时为57.1% vs55.8%。
(3)生化应答:治疗组3、6、9和12月时ALT复常率分别地为53.8%、73.0%、80.7%、69.1%;对照组分别为54.2%、66.7%、64.8%、67.9%,治疗组在6个月、9个月时ALT复常率显著高于对照组。其中9个月时两组有显著性差异(P=0.017)。
(4)联合应答:治疗24周时,治疗组完全应答12.8%,部分应答80.8%,无应答6.4%;对照组完全应答12.8%,部分应答78.2%,无应答9.0%,两组无显著性差异(P>0.05)。48周时,治疗组完全应答6.0%,部分应答86.5%,无应答7.5%;对照组完全应答5.2%,部分应答84.4%,无应答10.4%,两组无显著性差异(P>0.05)。
(5)免疫学指标:治疗前、治疗24周、48周,两组CD3+、CD4+、CD8+正常/异常人数,经χ2检验,无显著性差异(P>0.05)。治疗前、治疗24周、治疗48周两组CD3+、CD4+、CD8+、CD4+/CD8+值比较,经t检验,无显著性差异(P>0.05)。两组自身治疗前后CD3+、CD4+、CD8+值比较,经单因素重复测量方差分析,两组CD4+下降较疗前有显著性差异(P=0.002),但组间比较无显著性(P=0.721)。
(6)中医症状:治疗48周后,两组患者症状记分比较,在烦躁易怒和舌有齿痕症状方面两组有显著性差异(P=0.027和P=0.043),治疗组烦躁易怒和舌有齿痕消失人数较对照组高,症状消失率分别为81% vs 68%和61% vs 47%。其余各症状均无统计学意义(P>0.05)。治疗组在口苦、食欲不振、大便稀溏、烦躁易怒、失眠的症状消失率方面优于对照组。对照组在胃脘满闷、恶心的消失率方面优于治疗组。表明治疗组在肝胆湿热、肝郁脾虚症状尤其是肝郁脾虚症状的改善方面,优于拉米夫定组。
(7)中医证候:治疗12周、24周、36周、48周时两组进行中医疗效比较,经秩和检验,均无显著性差异(P>0.05)。自身治疗前后比较结果显示:治疗组自身治疗前、24周、48周中医证候积分分别为29.10±10.37、13.76±8.49、11.04±7.58;对照组分别为28.82±29.85、14.15±9.27、11.76±8.53。经重复测量方差分析,两组治疗前后组内均有显著性差异(P<0.001),组间比较无显著性差异(P=0.745)。
(8)生存质量(QOL):两组治疗前、24周、36周、48周在总的生存质量、总的健康状况、生理领域、心理领域、社会关系、环境领域得分情况,经t检验,均无显著性差异,P值均大于0.05。自身治疗前后比较结果显示:治疗组除心理领域和社会关系领域无显著性差异外,其余总的生存质量、总的健康状况、生理领域、环境领域得分较疗前均有显著提高,经自身配对t检验,P值分别为0.001,0,0.002和0.028。对照组除社会关系领域无显著性差异外,其余总的生存质量、总的健康状况、生理领域、心理领域、环境领域得分较疗前均有显著提高,经自身配对t检验,P值分别为0,0,0.001,0.048和0.004。
(9)慢性肝病量表(CLDQ):两组治疗前、24周、36周、48周进行疲劳度、精力、情感、腹部症状、系统症状、焦虑度六大类症状记分比较,经t检验,均无显著性差异(P>0.05)。自身治疗前后比较结果显示:两组六大类症状记分均有非常显著性差异(P<0.001)。治疗后各症状记分均增长,症状改善明显。
结论:拉米夫定联合双虎清肝颗粒和乙肝益气解郁冲剂治疗慢性乙型肝炎,在增强抗病毒疗效、抗炎保肝降酶、改善部分临床症状方面优于单用拉米夫定。
Objective：To Study the efficacy of Lamivudine combined with Double TigersClearing away Liver-fire Granule and YiGanYiQiJieYu Powder in treating chronic hepatitis B.and to make the clinic effectiveness assessment of Tradiional Chinese Medidne.
Methods：This was a multi-center, randomized (1:1), double-blinded and controlledclinic trial. 278 patients of chronic hepatitis B. whose serum HBV-DNA and HBeAg arepositive were dividing into two groups randomly. The treated group included 140 cases whilethe controlled group had 138 cases. The therapeutic group were treated with Lamivudineorally 100mg once daily combined with YiGanYiQiJieYu Powder orally 10mg tid. andDouble Tigers Clearing away Liver-fire Granule 10mg tid. once daily, while the control groupwere treated with Lamivudine orally 100mg once daily only. 48 weeks regarded as onetreatment course，The Liver function，Marking thing of hepatitis B，HBV-DNA. Theimmunology index. The traditional Chinese medicine symptoms and syndromemanifestations. The quality of life(QOL) and the chronic liver disease questionnaire weremeasured respectively at baseline, 12 weeks, 24 weeks, 36 weeks and 48 weeks.
Results：1. Serological response: After 24 weeks，the turning negative rate of HBeAgin the therapeutic group was 28.3%, not higher than that in control group which was27.1%(P>0.05).The turning rate of HBeAg/anti-HBe in the therapeutic group was 20.8%, nothigher than that in control group which was 20.3%(P>0.05). After 48 weeks，the turningnegative rate of HBeAg in the therapeutic group was 27.1%, obviously higher than that incontrol group which was 16.7%(P=0.034)(PP). The turning rate of HBeAg/anti-HBe in thetherapeutic group was 28.0%, higher than that in control group which was17.7%(P=0.087)(PP).
2. Virological response: After 24 weeks，the complete response rate of the therapeuticgroup was 75.5%, partial response rate was 11.2%, non-response rate was 13.3%, the controlgroup was respectively 68.8%,13.5% and 17.7%, there had no different between twogroups(P=0.288). After 48 weeks，the complete response rate of the therapeutic group was57.1%, partial response rate was 18.6%, non-response rate was 24.3%, the control group wasrespectively 55.8%,18.2% and 26.0%. there had no different between two groups(P=0.842).The turning negative rate of HBV-DNA of the therapeutic group was higher than the controlgroup that was 75.5% vs 68.8% (P=0.288) at week 24 and .57.1% vs 55.8% (P=0.842) atweek 48.
3. Biochemical response:The ALT normalization rate of the therapeutic group wasrespectively53.8%,73.0%,80.7% and 69.1% at 12wk,24wk,36wk and 48wk, while the controlgroup was 54.2%,66.7%,64.8% and 67.9%, The normalization rate of the therapeutic group in6 and 9 month is significantly high than the control group, especially at 36wk, there had significant difference between two groups(p=0.017).
4. Combined response: After 24 weeks，the complete response rate of the therapeuticgroup was 12.8%, partial response rate was 80.0%, non-response rate was 6.4%, the controlgroup was respectively 12.8%,78.2% and 9.0%, there had no different between twogroups(P>0.05). After 48 weeks，the complete response rate of the therapeutic group was6.0%, partial response rate was 86.5%, non-response rate was 7.5%, the control group wasrespectively 5.2%,84.4% and 10.4%. there had no different between two groups (P>0.05).
5. Immunologic indexes: before treatment, after 24 and 48 weeks,the normal/abnormalmembers of CD3+、CD4+、CD8+ had no signature different(p>0.05).The proportion of CD3+、CD4+、CD8+、CD4+/CD8+ between two groups had no significant difference (p>0.05). TheCD4+ level of the two groups had significantly lower than itself before treatment,but therehad no significant differency between two groups (P=0.721).
6. TCM symptoms: After 48 weeks，there had a significant difference on integration ofrestless tantrum and indentation tongue (P=0.027和P=0.043)，the disappeared numbers ofthis two symptoms in the therapeutic group was more than the control group,Thedisappearance rate is 81% vs 68%和61% vs 47%。The rest symptoms had not statisticallysignificant (P>0.05).The therapeutic group had a higherly disappearance rate on thesymptoms such as bitter taste of mouth , poor appetite ,stool loose, restless tantrum andwakeful than the control group,while the control group is higher in gastric cavity full andinactive, sick than the treatment group.The consequence showed that the therapeutic groupsurpassed the lamivudine group in improving the hepatochlic hygropyrexia and stagnation ofliver-QI with deficiency of the spleen symptoms.
7. TCM syndrome manifestations: There had no significant difference on the syndromeintegration between two groups at 12wks、24wks、36wks and 48wks. The syndromeintegration of two groups were more lower on the syndrome integration than itself beforetreatment.
8. WHOQOL-BREF：There had no different between two groups in total quality of lifeand total healthy level,and in physical, psychology, social, environmental domain at 0week,24week, 36week,48 week (p>0.05).Excerpt the psychology and social domain had nosignificant difference ,the other domains are all higher than itself at 0 week (p<0.05 or p<0.01)in the therapeutic group. The control group in all domains are higher than itself at 0 week(p<0.05 or p<0.01) excerpt the social domain.
9. CLDQ: There had no different between two groups on tiredness degree, energy,affection, abdominal symptom, system symptom and anxiety degree (p>0.05) at 0week,24weeks, 36weeks and 48weeks. The integration of two groups were more lower on thesyndrome indentation than itself before treatment.
Conclusion：The combination treatment with Lamivudine combined with DoubleTigers Clearing away Liver-fire Granule and YiGanYiQiJieYu Powder on chronic hepatitis B is superiorior to using Lamivudine only on the aspect of strengthening antivirus, antiinflammatory ,protecting liver ,lowering enzyme and improving part clinic symptoms.
引文
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