中医辨证论治治疗慢性乙型肝炎与拉米呋定对照的疗效评价研究
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摘要
中医治疗肝脏疾病,辨证论治是其优势也是特色。本文拟运用循证医学中临床决策分析的基本思路,对中医辨证论治治疗CHB的疗效评价方法学进行初步的研究。并在基于目前中医药治疗CHB现有的文献资料及临床试验观察数据的基础上,模拟在不同的临床干预下CHB的疾病进程及其生存质量的变化,从临床医生角度进行CHB的临床决策分析。全文共分疗效评价和远期结局的疗效评价两个部分。
第一部分中医辨证论治治疗CHB的疗效评价
1基于文献研究的中医辨证论治治疗CHB的疗效评价
目的:基于文献,评价中医辨证论治治疗CHB与西药核苷类抗病毒药物比较的疗效优势,为中医辨证论治治疗CHB远期结局的疗效评价提供源数据。
方法:采取Cochrane系统评价方法,检索肝胆病组临床试验数据库(2006年3月),CENTRAL(2006年第1期),PubMed(1966～2007),EMbase(1966～2007),OVID(1965～2006),CBM disc(1978～2007),CNKI(1979～2007)电子数据库,检索不受语种限制。纳入以CHB患者为研究对象,比较中药(中药+核苷类药物)与核苷类抗病毒药物疗效的所有对照试验及系统评价。评价纳入研究的质量,按测量指标、干预措施、治疗疗程进行亚组分析,并用RevMan4.2软件进行Meta分析。
结果:共纳入44篇文献,包括3974例CHB患者,纳入文献中均为中药与LAM比较的对照研究。Meta分析显示差异有统计学意义的结局为:中药组在治疗12个月结束后6个月随访时HBeAg复发率较LAM绝对减少了37%;治疗6个月停药后、治疗12个月结束后6个月随访时的DNA复发率分别较LAM组绝对降低了23%、44%;治疗3个月、6个月、24个月时,中药组HA降低量优于LAM组;治疗24个月时中药组LN降低量优于LAM组;治疗3个月、24个月时中药组PCⅢ降低量优于LAM组;治疗3个月时中药组Ⅳ-C降低量优于LAM组;治疗6个月、治疗6个月结束后6个月随访时中药组的ALT复常率分别较LAM组绝对增加了29%、49%;中药组对CHB主要症状、体征缓解率较LAM组绝对增加了22%;但在治疗3个月、6个月时中药组DNA阴转率较LAM组绝对降低了14%、21%。纳入文献中无LAM组优于中药联合组的证据支持。
结论:基于现有文献证据,中医辨证论治治疗CHB对ALT复常/降低、血清肝纤维化指标降低、DNA阴转、HBsAg阴转、HBeAg阴转、防止DNA复发、防止HBeAg阳转、症状体征恢复均有效;目前无LAM优于中药联合组的证据;但本系统评价因纳入文献用药时间不同未进行总体效应合并分析,对中医辨证论治治疗CHB的整体疗效还需要更为大量的文献支持。
2基于临床试验的中医辨证论治治疗CHB的疗效评价
目的:观察中医辨证论治治疗CHB的疗效;为中医辨证论治治疗CHB远期结局的疗效评价提供源数据。
方法:采用两中心前瞻性队列研究。暴露组于广安门医院肝病门诊进行中医辨证论治治疗,对照组于佑安医院进行LAM治疗,两组疗程均为6个月,随访3个月。并观察两组患者治疗前后生化学指标、病毒学指标、乙肝病毒标记物指标、证候积分的变化及不良事件发生情况。
结果:共纳入124例CHB患者,LAM非暴露组40例,中医辨证论治暴露组84例。
基线分析:中药暴露组与LAM非暴露组在性别、ALT水平基线上具有可比性;中药暴露组在年龄、HBeAg阴性患者数、病程、证候积分上高于LAM非暴露组;中药组HBV DNA水平低于LAM组。
混杂因素分析:log10 DNA水平是ALT复常与否的混杂因素。在其它变量保持不变时,治疗6个月后,log10 DNA每增加1个copy/ml,ALT复常的OR值平均减少0.782倍。在治疗结束后随访时log10 DNA每增加一个1个copy/ml,ALT复常的OR值平均减少0.592倍;log10 DNA水平是DNA阴转与否的混杂因素。在其它变量固定时,当log10 DNA每增加1个copy/ml,治疗3个月时DNA阴转的OR值平均减少0.418倍,治疗6个月时的DNA阴转OR值平均减少0.421倍,治疗结束后3个月随访时的DNA阴转OR值平均减少0.488倍。HBeAg阳性是治疗6个月时DNA阴转与否的混杂因素,当其它变量固定时,HBeAg阳性患者的DNA阴转可能性是HBeAg阴转患者的DNA阴转可能性的0.153倍;log10 DNA水平是HBeAg阴转与否的混杂因素,当其它自变量固定时,log10 DNA每增加1个copy/ml,HBeAg阴转的OR值平均增加1.396倍。
ALT复常率:在治疗3个月、6个月、治疗结束后3个月随访时,基线DNA水平=1.00e+04copies/ml的患者,中药暴露组的ALT复常率分别为48.8%、58.1%、88.4%,与LAM非暴露组(42.5%、65%、87.5%)比较,差异无统计学意义(P＞0.05);DNA水平＜1.00e+04copies/ml的患者,中药暴露组的ALT复常率分别为61.5%、79.5%、97.4%。
DNA阴转率:在治疗6个月、治疗结束后3个月随访时,对HBeAg阳性且HBV DNA=1.00e+04copies/ml的患者,中药暴露组的DNA阴转率分别为33.3%、66.7%,LAM非暴露组分别为32.1%、51.5%,两组比较差异无统计学意义(P＞0.05);对HBV DNA＜1.00e+04copies/ml的患者,中药暴露组DNA阴转率均为57.1%,LAM非暴露组分别为71.4%、42.9%,两组比较差异无统计学意义(P＞0.05)。对于HBeAg阴性且HBV DNA=1.00e+04copies/ml的患者,在治疗6个月时,中药暴露组的DNA阴转率为75.0%,LAM组为40.0%,两组DNA阴转率无统计学差异(P＞0.05);治疗结束后3个月随访时,中药暴露组的DNA阴转率为81.3%,LAM非暴露组为20.0%,中药组的DNA阴转率优于LAM组(P=0.025),RR为4.06,95%CI为0.69～23.82,AR为61.3%,中药暴露组的患者在治疗结束后3个月随访时DNA阴转率比非暴露组增加了3.06倍,中药辨证论治治疗与DNA阴转具有一定的因果联系,暴露于中药组的DNA阴转率较LAM组增加了61.3%。
血清学应答率:治疗6个月后,中药暴露组患者HBeAg阴转率/血清学转换率均为6.81%,与LAM非暴露组(8.57%)比较,差异无统计学意义(P＞0.05)。中药暴露组患者出现4例HBsAg阴转(其中1例出现血清学转换),而LAM非暴露组无HBsAg阴转的病例出现。
证候疗效:在治疗3个月时,中药暴露组的证候显效率、有效率、总有效率分别较LAM绝对增加了27.3%、20.6%、47.9%;在治疗6个月时显效率、总有效率分别较LAM绝对增加了70.9%、21.6%;在治疗结束后3个月随访时治愈率、显效率、总有效率分别较LAM绝对增加了25.6%、50.8%和20.1%。
中药暴露组、LAM非暴露组患者均未出现严重的不良事件。
结论:中药在促使血清学转换、恢复肝功能、促进HBV DNA阴转上均有效,且本试验中药促进HBsAg血清学转换优于LAM,对HBeAg阴性患者治疗结束后随访时的DNA阴转率优于LAM,但因样本量较少,仍需加大样本量继续观察。
第二部分运用Markov模型进行中医辨证论治治疗CHB远期结局的疗效评价
目的:模拟在中医辨证论治、LAM干预下CHB的疾病动态变化及转归;预测中医辨证论治、LAM对CHB终点结局的影响,从临床医生角度筛选优化干预措施;验证Markov模型用于中医辨证论治治疗CHB远期结局的疗效评价的可行性和科学性。
方法:分别建立接受中医辨证论治、LAM干预的HBeAg阳性、HBeAg阴性患者的Markov模型,以质量调整生命年(QALYs)为结局指标,运用队列分析的方法估计CHB患者在中医辨证论治、LAM干预下40年间的疾病转归及获得的QALYs,评价中医辨证论治、LAM干预对CHB患者终点结局的影响,一维、二维敏感性分析验证结果的稳健性;并采用10000次Monte Carlo微量模拟的方法预测40年间接受中医辨证论治、LAM干预的CHB患者人均累积获得的QALYs的概率分布,进而通过比较中医辨证论治、LAM为优化干预方案的概率从临床医生角度进行临床决策分析。
结果:在观察的1～40年间,HBeAg阳性患者在接受中药治疗后,约有18.48%～62.49%的患者出现血清学转换,1.4%～36.60%的患者发生肝硬化,仍为CHB的患者约为16.48%～80.12%;HBeAg阳性患者在接受LAM干预后,约有2.90%～23.89%的患者出现血清学转换,约有3.06%～82.33%的患者发生肝硬化,仍为CHB的患者约为14.76%～81.60%;HBeAg阴性患者在接受中药治疗后,约有22.98%～46.74%的患者出现联合应答,约有2.92%～57.07%的患者发生肝硬化,仍为CHB的患者约为19.95%～68.00%;HBeAg阴性患者在接受LAM干预后,约有5.83%～29.43%的患者出现联合应答,约有2.35%～80.21%的患者发生肝硬化,仍为CHB的患者约为17.17%～33.06%。HBeAg阳性接受中药干预的患者,在40年间人均累积QALYs约为28.18,接受LAM治疗的患者人均累积QALYs约为16.07,中药组较LAM组人均累积增加了12.11个QALYs;HBeAg阴性接受中药治疗的患者,人均累积QALYs约为23.36,接受LAM干预的患者人均累积QALYs约为16.84,中药组较LAM组在治疗的40年间人均累积增加了6.52个QALYs。
经10000次Monte Carlo微量模拟,HBeAg阳性接受中药治疗的患者今后40年内人均累积可以获得的QALYs最小值为1,最大值为37,可以获得的QALYs中位数为35;接受LAM治疗的患者今后40年内人均累积获得的QALYs最小值为1,最大值为35,累积获得的QALYs中位数为14。中药干预为最优干预方案的概率为0.636,LAM干预为最优干预方案的概率为0.230,两组之间的差值为0.134。HBeAg阴性接受中药治疗的患者今后40年内人均累积可以获得的QALYs最小值为1,最大值为36,可以获得的QALYs中位数为30;接受LAM治疗的患者今后40年内人均累积获得的QALYs最小为1,最大为35,累积获得的QALYs中位数为15。中药干预为最优干预方案的概率为0.739,LAM干预为最优干预方案的概率为0.258,两组之间的差值为0.003。
结论:基于现有证据,以QALYs为结局指标,以0.05为两组间临床决策有意义的容许差值,中医辨证论治治疗CHB是HBeAg阳性患者的优化干预方案,对HBeAg阴性患者而言,目前尚不能得出中医辨证论治治疗CHB为优化干预方案的概率与LAM有差异的结论;Markov模型可模拟在中医辨证论治、LAM干预下CHB患者的远期结局及QALYs的变化,反映CHB疾病转归的动态变化,并体现中医辨证论治的特色和优势;Markov模型用于中医治疗慢性疾病的远期结局的疗效评价,方法科学、可行,但仍需在今后的研究工作中进一步完善。
The advantages and characteristic for traditional Chinese medicine(TCM) to treat chronic hepatitis B(CHB) is the use of pathogenesis obtained through differentiation of symptoms and signs.The thesis researched on the evaluation methodology of the effectiveness on CHB by TCM in the view of clinical decision analysis in evidence-based medicine.And the simulation of the disease progress and changes in the quality of the life was made with the different interventions,and the clinical decision analysis was made from the point of view of the doctors based on the data of literatures and clinical trials.There were two parts in the thesis;one was the effectiveness evaluation in the short-time,and the other was the one in the long-term.
Part one:The evaluation of the short-time effectiveness of TCM for CHB.
1.The evaluation of the effectiveness of TCM on CHB based on the data from literature
Objective:To evaluate the effectiveness of TCM compared with nucleoside antivirus drugs for CHB and offer source data for the effectiveness evaluation of TCM in the long-term based on the literature,.
Methods:Via the method of Cochrane systematic review,the authors searched the databases of the Cochrane Hepato-Biliary Group Controlled Trials Register(March, 2006),the Cochrane Central Register of Controlled Trials(CENTRAL)(Issue 1, 2006),Pubmed(from year 1966 to year 2007),EMBASE(from year1966 to year 2007),OVID(from year 1965 to year 2006),the Chinese Biomedical Database(CBM) (from year 1978 to year 2007) and CNKI(from year 1979 to year 2007).And there was no limitation to the language.All the comparison trials and systematic reviews were included that compared the effectiveness between TCM(Or TCM plus nucleoside antivirus drugs) and nucleoside antivirus drugs applied to the CHB patients. The qualities of the included researches in the literature were assessed and the subgroup analysis was performed according to the measurement objectives, interventions and the courses of treatment.Meta-analyses were performed for homogeneous studies by the software of RevMan4.2.
Results:A total of 44 studies involving 3974 patients met the inclusion criteria. And there was no study on TCM compared with other nucleoside antivirus drugs except Lamivudine.The Meta-analysis results with the statistical significance were as follows.(1) Compared with Lamivudine,the HBeAg recurrence rate of TCM group decreased absolutely 37%in the follow-up 6-month visit after the treatment of 12 months.(2) After 6 months' treatment,and in the follow-up 6-month visit after the treatment of 12 months,the DNA recurrence rate of TCM group absolutely decreased 23%and 44%respectively.(3) By the end of treatment of 3 months,6 months and 24 months,decreases in HA levels of TCM group were all more than those of Lamivudine group.(4) By the end of 24 months' treatment the reduction in LN of TCM was greater than that of Lamivudine.(5)The changes in PCⅢfrom baseline level to 3 months and to 24 months were both better in TCM group than thosc in Lamivudine group.(6) Decreases inⅣ-C of TCM group were more than that of Lamivudine group after 3-month treatment.(7) The risk difference of ALT response rate in TCM group were absolutely larger by 29%and 49%at the end of 6-month treatment and in the 6-month follow-up visit after 6-month treatment respectively than those in Lamivudine group.(8) Remission rate on cardinal symptoms and objective signs in TCM group was larger by 22%than that in Lamivudine group.(9) But for DNA suppression rate,it was less by 14%and 21%after 3-month and 6-month TCM treatment than that in Lamivudine group.(10) There was no evidence in the literature that the effectiveness by Lamivudine treatment was better than that by TCM plus Lamivudine.
Conclusions:At first,TCM was effective in normalizing ALT levels/decreasing ALT levels,improving hepatic fibrosis,clearing HBV DNA,achieving virus loss and seroconversion(HBsAg and HBeAg),preventing DNA relapse,preventing HBeAg reconversion,and recovering symptoms and objective signs.Second,TCM plus Lamivudine were more effective than Lamivudine monotherapy.Finally,the overall effectiveness,however,didn't be pooled for analysis in the systematic review due to the different terms of treatment.More evidence was needed to support the overall effectiveness of TCM treatment.
2.The evaluation of the effectiveness of TCM on CHB based on the data from clinical trial
Objective:To evaluate the effectiveness of TCM compared with Lamivudine on CHB and to offer source data for the effectiveness evaluation of TCM in the long-term based on the clinical trials.
Methods:The two-center prospective cohort approach was used.The 84 patients with CHB at the clinic of Guang-an-men hospital were assigned to receive TCM treatment as the exposure group based on the pathogenesis obtained through differentiation of symptoms and signs,one dose once daily,while the other 40 patients at the You-an hospital were received 100mg of Lamivudine once daily as the comparison group.Patients were treated for 6 months and followed for an additional 3 months.
Results:
ALT normalization rate:In the patients whose DNA levels were more than(or equal) 1.00e+04copies/ml at baseline,48.8%,58.1%and 88.4%of the patients received TCM treatment had normalized ALT levels at the end of treatment of 3 months,6 months and at the 3-month follow-up respectively,compared with 42.5%, 65%and 87.5%of the patients with Lamivudine treatment,respectively.It was not significantly different at 5%significance level.In the patients whose DNA levels were less than 1.00e+04copies/ml at baseline,61.5%,79.5%and 97.4%of patients received TCM treatment had normalized ALT levels respectively.
HBV DNA clearance rate:In the patients whose DNA levels were more than(or equal) 1.00e+04copies/ml at baseline with HBeAg-positive CHB,33.3%and 66.7% of TCM treated patients had undetectable DNA levels at the end of treatment of 6 months and at the follow-up visit respectively in comparison with 32.1%and 51.5% of Lamivudine treated patients(p＞0.05).In the patients whose DNA levels were less than 1.00e+04copies/ml at baseline with HBeAg-positive CHB,57.1%patients who received TCM treatment had undetectable DNA levels both after 6-month treatment and at the 3-month follow-up visit,while 71.4%and 42.9%of the patients who received Lamivudine had undetectable DNA levels respectively(p＞0.05).For the patients with HBeAg-negative CHB and DNA levels more than(or equal) 1.00e+04copies/ml at baseline,at month 6,75.0%of patients who received TCM had undetectable DNA levels compared with 40.0%of patients who received Lamivudine (p=0.280).At the end of follow-up visit,the proportion of patients treated with TCM with undetectable DNA levels was 81.3%compared with 20.0%for Lamivudine treated patients,the difference between the TCM group and the Lamivudine group was statistically significant(p=0.025).
Rate of HBeAg loss and seroconversion:By the end of treatment of 6 month,the rates of HBeAg loss and seroconversion of the TCM patients were both 6.81% compared with both 8.57%of the Lamivudine group(p＞0.05).Four patients in the TCM patients lost HBsAg and one had HBsAg seroconversion,but no patients in the Lamivudine group did so.
Effectiveness of syndromes:After 3-month TCM treatment,the remarkably effective rate,the effective rate and the total effective rate of syndromes were absolutely higher by 27.3%,20.6%and 47.9%than those of the patients in the Lamivudine group respectively.Besides,after 6-month TCM treatment,the remarkably effective rate and the total effective rate of syndromes were absolutely higher by 70.9%and 21.6%%than those of the patients in the Lamivudine group respectively.At the 3-month follow-up visit,the cure rate,remarkably effective rate and the total effective rate in the patients treated with TCM were absolutely higher by 25.6%,50.8%and 20.1%than those of the patients treated with Lamivudine,respectively.
Conclusions:At first,it is effective in TCM group in achieving virus loss and seroconversion,normalizing ALT levels and clearing HBV DNA.Second,TCM offered superior efficacy over lamivudine on the basis of HBsAg loss and seroconversion.Third,TCM offered better HBV DNA clearance result at the follow-up visit in the HBeAg-negative patients.However,more evidence is needed to support the above conclusions due to limited sample amount.
Part two:The evaluation of the long-term effectiveness of TCM on CHB by Markov model
Objective:To estimate the effectiveness of TCM and Lamivudine for adult patients with CHB.
Design:Two 5-health state Markov models were developed for HBeAg-positive and HBeAg-negative CHB patients respectively.The models followed cohorts of HBeAg-positive and HBeAg-negative CHB patients respectively over a period of 40 years,during which the majority of the cohorts would have died if left untreated. Annual transition probabilities of disease progression and the magnitude of treatment effects were obtained from the literature,with a focus on data obtained from Asian patients and meeting the criteria of therapy as described in internationally recognized management guidelines.The potential effect of uncertainty in the model assumptions was tested by using sensitivity analyses.Monte Carlo micro-simulation was used to perform clinical decision analysis on the basis of quality-adjusted life expectancy.
Results:Among the patients with HBeAg-positive CHB received TCM treatment, 18.48%to 62.49%of the patients occurred HBeAg seroconversion,and 1.4%to 36.6%of the patients progressed to compensated cirrhosis in the course of 40 years treatments,and average per patient had gained 28.18 accumulated QALYs in the end of 40 years treatments,compared with 2.90%to 23.89%,3.06%to 82.33%and 16.17 QALYs respectively for the patients treated with Lamivudine.The patients who received TCM had gained more than 12.11 accumulated QALYs per patient than the ones who received Lamivudine.Among the patients with HBeAg-negative CHB treated with TCM,there were 22.98%to 46.74%of patients who had combined response,and 2.92%to 57.06%of patients who progressed to compensated cirrhosis in the course of 40 years,and average per patient had gained 23.36 accumulated QALYs in the end of 40 years treatments,in comparison with 5.83%to 29.43%, 2.35%to 80.21%and 16.84 QALYs of the patients treated with Lamivudine respectively.There were 6.52 accumulated QALYs per patient average gained in the TCM group more than those of the Lamivudine group.
By monte carlo microsimulation for 10000 times,among the HBeAg-positive CHB patients that received TCM,the P0 of QALYs that they would gain average per patient in the end of 40 years treatments was 1,P100 was 37,and P50 was 35, compared with 1,35 and 14 QALYs respectively for the patients who received Lamivudine.The difference of the optimal clinical intervention between TCM and Lamivudine was 0.134.Among the HBeAg-negative CHB patients treated with TCM, the P0 of QALYs that they would gain average per patient in the end of 40 years treatments was 1,P100 was 36,and P50 was 30,compared with 1,35 and 15 QALYs respectively for the patients who received Lamivudine.And the difference of the optimal clinical intervention between TCM and Lamivudine was 0.003.
Conclusions:First,TCM was the optimal intervention compared with Lamivudine for the patients with HBeAg-positive CHB in the long-term at the 0.05 tolerance level, while for the ones with HBeAg-negative,there was no statistical difference between TCM intervention and Lamivudine intervention at the 0.05 tolerance level.Second, Markov model could be used to simulate the progression of CHB and it was feasible for Markov model to assess the long-time outcomes of chronic diseases with the treatment of TCM.However,more researches were needed to make it better in the future work.
第一部分中医辨证论治治疗CHB的疗效评价
1基于文献研究的中医辨证论治治疗CHB的疗效评价
目的:基于文献,评价中医辨证论治治疗CHB与西药核苷类抗病毒药物比较的疗效优势,为中医辨证论治治疗CHB远期结局的疗效评价提供源数据。
方法:采取Cochrane系统评价方法,检索肝胆病组临床试验数据库(2006年3月),CENTRAL(2006年第1期),PubMed(1966～2007),EMbase(1966～2007),OVID(1965～2006),CBM disc(1978～2007),CNKI(1979～2007)电子数据库,检索不受语种限制。纳入以CHB患者为研究对象,比较中药(中药+核苷类药物)与核苷类抗病毒药物疗效的所有对照试验及系统评价。评价纳入研究的质量,按测量指标、干预措施、治疗疗程进行亚组分析,并用RevMan4.2软件进行Meta分析。
结果:共纳入44篇文献,包括3974例CHB患者,纳入文献中均为中药与LAM比较的对照研究。Meta分析显示差异有统计学意义的结局为:中药组在治疗12个月结束后6个月随访时HBeAg复发率较LAM绝对减少了37%;治疗6个月停药后、治疗12个月结束后6个月随访时的DNA复发率分别较LAM组绝对降低了23%、44%;治疗3个月、6个月、24个月时,中药组HA降低量优于LAM组;治疗24个月时中药组LN降低量优于LAM组;治疗3个月、24个月时中药组PCⅢ降低量优于LAM组;治疗3个月时中药组Ⅳ-C降低量优于LAM组;治疗6个月、治疗6个月结束后6个月随访时中药组的ALT复常率分别较LAM组绝对增加了29%、49%;中药组对CHB主要症状、体征缓解率较LAM组绝对增加了22%;但在治疗3个月、6个月时中药组DNA阴转率较LAM组绝对降低了14%、21%。纳入文献中无LAM组优于中药联合组的证据支持。
结论:基于现有文献证据,中医辨证论治治疗CHB对ALT复常/降低、血清肝纤维化指标降低、DNA阴转、HBsAg阴转、HBeAg阴转、防止DNA复发、防止HBeAg阳转、症状体征恢复均有效;目前无LAM优于中药联合组的证据;但本系统评价因纳入文献用药时间不同未进行总体效应合并分析,对中医辨证论治治疗CHB的整体疗效还需要更为大量的文献支持。
2基于临床试验的中医辨证论治治疗CHB的疗效评价
目的:观察中医辨证论治治疗CHB的疗效;为中医辨证论治治疗CHB远期结局的疗效评价提供源数据。
方法:采用两中心前瞻性队列研究。暴露组于广安门医院肝病门诊进行中医辨证论治治疗,对照组于佑安医院进行LAM治疗,两组疗程均为6个月,随访3个月。并观察两组患者治疗前后生化学指标、病毒学指标、乙肝病毒标记物指标、证候积分的变化及不良事件发生情况。
结果:共纳入124例CHB患者,LAM非暴露组40例,中医辨证论治暴露组84例。
基线分析:中药暴露组与LAM非暴露组在性别、ALT水平基线上具有可比性;中药暴露组在年龄、HBeAg阴性患者数、病程、证候积分上高于LAM非暴露组;中药组HBV DNA水平低于LAM组。
混杂因素分析:log10 DNA水平是ALT复常与否的混杂因素。在其它变量保持不变时,治疗6个月后,log10 DNA每增加1个copy/ml,ALT复常的OR值平均减少0.782倍。在治疗结束后随访时log10 DNA每增加一个1个copy/ml,ALT复常的OR值平均减少0.592倍;log10 DNA水平是DNA阴转与否的混杂因素。在其它变量固定时,当log10 DNA每增加1个copy/ml,治疗3个月时DNA阴转的OR值平均减少0.418倍,治疗6个月时的DNA阴转OR值平均减少0.421倍,治疗结束后3个月随访时的DNA阴转OR值平均减少0.488倍。HBeAg阳性是治疗6个月时DNA阴转与否的混杂因素,当其它变量固定时,HBeAg阳性患者的DNA阴转可能性是HBeAg阴转患者的DNA阴转可能性的0.153倍;log10 DNA水平是HBeAg阴转与否的混杂因素,当其它自变量固定时,log10 DNA每增加1个copy/ml,HBeAg阴转的OR值平均增加1.396倍。
ALT复常率:在治疗3个月、6个月、治疗结束后3个月随访时,基线DNA水平=1.00e+04copies/ml的患者,中药暴露组的ALT复常率分别为48.8%、58.1%、88.4%,与LAM非暴露组(42.5%、65%、87.5%)比较,差异无统计学意义(P＞0.05);DNA水平＜1.00e+04copies/ml的患者,中药暴露组的ALT复常率分别为61.5%、79.5%、97.4%。
DNA阴转率:在治疗6个月、治疗结束后3个月随访时,对HBeAg阳性且HBV DNA=1.00e+04copies/ml的患者,中药暴露组的DNA阴转率分别为33.3%、66.7%,LAM非暴露组分别为32.1%、51.5%,两组比较差异无统计学意义(P＞0.05);对HBV DNA＜1.00e+04copies/ml的患者,中药暴露组DNA阴转率均为57.1%,LAM非暴露组分别为71.4%、42.9%,两组比较差异无统计学意义(P＞0.05)。对于HBeAg阴性且HBV DNA=1.00e+04copies/ml的患者,在治疗6个月时,中药暴露组的DNA阴转率为75.0%,LAM组为40.0%,两组DNA阴转率无统计学差异(P＞0.05);治疗结束后3个月随访时,中药暴露组的DNA阴转率为81.3%,LAM非暴露组为20.0%,中药组的DNA阴转率优于LAM组(P=0.025),RR为4.06,95%CI为0.69～23.82,AR为61.3%,中药暴露组的患者在治疗结束后3个月随访时DNA阴转率比非暴露组增加了3.06倍,中药辨证论治治疗与DNA阴转具有一定的因果联系,暴露于中药组的DNA阴转率较LAM组增加了61.3%。
血清学应答率:治疗6个月后,中药暴露组患者HBeAg阴转率/血清学转换率均为6.81%,与LAM非暴露组(8.57%)比较,差异无统计学意义(P＞0.05)。中药暴露组患者出现4例HBsAg阴转(其中1例出现血清学转换),而LAM非暴露组无HBsAg阴转的病例出现。
证候疗效:在治疗3个月时,中药暴露组的证候显效率、有效率、总有效率分别较LAM绝对增加了27.3%、20.6%、47.9%;在治疗6个月时显效率、总有效率分别较LAM绝对增加了70.9%、21.6%;在治疗结束后3个月随访时治愈率、显效率、总有效率分别较LAM绝对增加了25.6%、50.8%和20.1%。
中药暴露组、LAM非暴露组患者均未出现严重的不良事件。
结论:中药在促使血清学转换、恢复肝功能、促进HBV DNA阴转上均有效,且本试验中药促进HBsAg血清学转换优于LAM,对HBeAg阴性患者治疗结束后随访时的DNA阴转率优于LAM,但因样本量较少,仍需加大样本量继续观察。
第二部分运用Markov模型进行中医辨证论治治疗CHB远期结局的疗效评价
目的:模拟在中医辨证论治、LAM干预下CHB的疾病动态变化及转归;预测中医辨证论治、LAM对CHB终点结局的影响,从临床医生角度筛选优化干预措施;验证Markov模型用于中医辨证论治治疗CHB远期结局的疗效评价的可行性和科学性。
方法:分别建立接受中医辨证论治、LAM干预的HBeAg阳性、HBeAg阴性患者的Markov模型,以质量调整生命年(QALYs)为结局指标,运用队列分析的方法估计CHB患者在中医辨证论治、LAM干预下40年间的疾病转归及获得的QALYs,评价中医辨证论治、LAM干预对CHB患者终点结局的影响,一维、二维敏感性分析验证结果的稳健性;并采用10000次Monte Carlo微量模拟的方法预测40年间接受中医辨证论治、LAM干预的CHB患者人均累积获得的QALYs的概率分布,进而通过比较中医辨证论治、LAM为优化干预方案的概率从临床医生角度进行临床决策分析。
结果:在观察的1～40年间,HBeAg阳性患者在接受中药治疗后,约有18.48%～62.49%的患者出现血清学转换,1.4%～36.60%的患者发生肝硬化,仍为CHB的患者约为16.48%～80.12%;HBeAg阳性患者在接受LAM干预后,约有2.90%～23.89%的患者出现血清学转换,约有3.06%～82.33%的患者发生肝硬化,仍为CHB的患者约为14.76%～81.60%;HBeAg阴性患者在接受中药治疗后,约有22.98%～46.74%的患者出现联合应答,约有2.92%～57.07%的患者发生肝硬化,仍为CHB的患者约为19.95%～68.00%;HBeAg阴性患者在接受LAM干预后,约有5.83%～29.43%的患者出现联合应答,约有2.35%～80.21%的患者发生肝硬化,仍为CHB的患者约为17.17%～33.06%。HBeAg阳性接受中药干预的患者,在40年间人均累积QALYs约为28.18,接受LAM治疗的患者人均累积QALYs约为16.07,中药组较LAM组人均累积增加了12.11个QALYs;HBeAg阴性接受中药治疗的患者,人均累积QALYs约为23.36,接受LAM干预的患者人均累积QALYs约为16.84,中药组较LAM组在治疗的40年间人均累积增加了6.52个QALYs。
经10000次Monte Carlo微量模拟,HBeAg阳性接受中药治疗的患者今后40年内人均累积可以获得的QALYs最小值为1,最大值为37,可以获得的QALYs中位数为35;接受LAM治疗的患者今后40年内人均累积获得的QALYs最小值为1,最大值为35,累积获得的QALYs中位数为14。中药干预为最优干预方案的概率为0.636,LAM干预为最优干预方案的概率为0.230,两组之间的差值为0.134。HBeAg阴性接受中药治疗的患者今后40年内人均累积可以获得的QALYs最小值为1,最大值为36,可以获得的QALYs中位数为30;接受LAM治疗的患者今后40年内人均累积获得的QALYs最小为1,最大为35,累积获得的QALYs中位数为15。中药干预为最优干预方案的概率为0.739,LAM干预为最优干预方案的概率为0.258,两组之间的差值为0.003。
结论:基于现有证据,以QALYs为结局指标,以0.05为两组间临床决策有意义的容许差值,中医辨证论治治疗CHB是HBeAg阳性患者的优化干预方案,对HBeAg阴性患者而言,目前尚不能得出中医辨证论治治疗CHB为优化干预方案的概率与LAM有差异的结论;Markov模型可模拟在中医辨证论治、LAM干预下CHB患者的远期结局及QALYs的变化,反映CHB疾病转归的动态变化,并体现中医辨证论治的特色和优势;Markov模型用于中医治疗慢性疾病的远期结局的疗效评价,方法科学、可行,但仍需在今后的研究工作中进一步完善。
The advantages and characteristic for traditional Chinese medicine(TCM) to treat chronic hepatitis B(CHB) is the use of pathogenesis obtained through differentiation of symptoms and signs.The thesis researched on the evaluation methodology of the effectiveness on CHB by TCM in the view of clinical decision analysis in evidence-based medicine.And the simulation of the disease progress and changes in the quality of the life was made with the different interventions,and the clinical decision analysis was made from the point of view of the doctors based on the data of literatures and clinical trials.There were two parts in the thesis;one was the effectiveness evaluation in the short-time,and the other was the one in the long-term.
Part one:The evaluation of the short-time effectiveness of TCM for CHB.
1.The evaluation of the effectiveness of TCM on CHB based on the data from literature
Objective:To evaluate the effectiveness of TCM compared with nucleoside antivirus drugs for CHB and offer source data for the effectiveness evaluation of TCM in the long-term based on the literature,.
Methods:Via the method of Cochrane systematic review,the authors searched the databases of the Cochrane Hepato-Biliary Group Controlled Trials Register(March, 2006),the Cochrane Central Register of Controlled Trials(CENTRAL)(Issue 1, 2006),Pubmed(from year 1966 to year 2007),EMBASE(from year1966 to year 2007),OVID(from year 1965 to year 2006),the Chinese Biomedical Database(CBM) (from year 1978 to year 2007) and CNKI(from year 1979 to year 2007).And there was no limitation to the language.All the comparison trials and systematic reviews were included that compared the effectiveness between TCM(Or TCM plus nucleoside antivirus drugs) and nucleoside antivirus drugs applied to the CHB patients. The qualities of the included researches in the literature were assessed and the subgroup analysis was performed according to the measurement objectives, interventions and the courses of treatment.Meta-analyses were performed for homogeneous studies by the software of RevMan4.2.
Results:A total of 44 studies involving 3974 patients met the inclusion criteria. And there was no study on TCM compared with other nucleoside antivirus drugs except Lamivudine.The Meta-analysis results with the statistical significance were as follows.(1) Compared with Lamivudine,the HBeAg recurrence rate of TCM group decreased absolutely 37%in the follow-up 6-month visit after the treatment of 12 months.(2) After 6 months' treatment,and in the follow-up 6-month visit after the treatment of 12 months,the DNA recurrence rate of TCM group absolutely decreased 23%and 44%respectively.(3) By the end of treatment of 3 months,6 months and 24 months,decreases in HA levels of TCM group were all more than those of Lamivudine group.(4) By the end of 24 months' treatment the reduction in LN of TCM was greater than that of Lamivudine.(5)The changes in PCⅢfrom baseline level to 3 months and to 24 months were both better in TCM group than thosc in Lamivudine group.(6) Decreases inⅣ-C of TCM group were more than that of Lamivudine group after 3-month treatment.(7) The risk difference of ALT response rate in TCM group were absolutely larger by 29%and 49%at the end of 6-month treatment and in the 6-month follow-up visit after 6-month treatment respectively than those in Lamivudine group.(8) Remission rate on cardinal symptoms and objective signs in TCM group was larger by 22%than that in Lamivudine group.(9) But for DNA suppression rate,it was less by 14%and 21%after 3-month and 6-month TCM treatment than that in Lamivudine group.(10) There was no evidence in the literature that the effectiveness by Lamivudine treatment was better than that by TCM plus Lamivudine.
Conclusions:At first,TCM was effective in normalizing ALT levels/decreasing ALT levels,improving hepatic fibrosis,clearing HBV DNA,achieving virus loss and seroconversion(HBsAg and HBeAg),preventing DNA relapse,preventing HBeAg reconversion,and recovering symptoms and objective signs.Second,TCM plus Lamivudine were more effective than Lamivudine monotherapy.Finally,the overall effectiveness,however,didn't be pooled for analysis in the systematic review due to the different terms of treatment.More evidence was needed to support the overall effectiveness of TCM treatment.
2.The evaluation of the effectiveness of TCM on CHB based on the data from clinical trial
Objective:To evaluate the effectiveness of TCM compared with Lamivudine on CHB and to offer source data for the effectiveness evaluation of TCM in the long-term based on the clinical trials.
Methods:The two-center prospective cohort approach was used.The 84 patients with CHB at the clinic of Guang-an-men hospital were assigned to receive TCM treatment as the exposure group based on the pathogenesis obtained through differentiation of symptoms and signs,one dose once daily,while the other 40 patients at the You-an hospital were received 100mg of Lamivudine once daily as the comparison group.Patients were treated for 6 months and followed for an additional 3 months.
Results:
ALT normalization rate:In the patients whose DNA levels were more than(or equal) 1.00e+04copies/ml at baseline,48.8%,58.1%and 88.4%of the patients received TCM treatment had normalized ALT levels at the end of treatment of 3 months,6 months and at the 3-month follow-up respectively,compared with 42.5%, 65%and 87.5%of the patients with Lamivudine treatment,respectively.It was not significantly different at 5%significance level.In the patients whose DNA levels were less than 1.00e+04copies/ml at baseline,61.5%,79.5%and 97.4%of patients received TCM treatment had normalized ALT levels respectively.
HBV DNA clearance rate:In the patients whose DNA levels were more than(or equal) 1.00e+04copies/ml at baseline with HBeAg-positive CHB,33.3%and 66.7% of TCM treated patients had undetectable DNA levels at the end of treatment of 6 months and at the follow-up visit respectively in comparison with 32.1%and 51.5% of Lamivudine treated patients(p＞0.05).In the patients whose DNA levels were less than 1.00e+04copies/ml at baseline with HBeAg-positive CHB,57.1%patients who received TCM treatment had undetectable DNA levels both after 6-month treatment and at the 3-month follow-up visit,while 71.4%and 42.9%of the patients who received Lamivudine had undetectable DNA levels respectively(p＞0.05).For the patients with HBeAg-negative CHB and DNA levels more than(or equal) 1.00e+04copies/ml at baseline,at month 6,75.0%of patients who received TCM had undetectable DNA levels compared with 40.0%of patients who received Lamivudine (p=0.280).At the end of follow-up visit,the proportion of patients treated with TCM with undetectable DNA levels was 81.3%compared with 20.0%for Lamivudine treated patients,the difference between the TCM group and the Lamivudine group was statistically significant(p=0.025).
Rate of HBeAg loss and seroconversion:By the end of treatment of 6 month,the rates of HBeAg loss and seroconversion of the TCM patients were both 6.81% compared with both 8.57%of the Lamivudine group(p＞0.05).Four patients in the TCM patients lost HBsAg and one had HBsAg seroconversion,but no patients in the Lamivudine group did so.
Effectiveness of syndromes:After 3-month TCM treatment,the remarkably effective rate,the effective rate and the total effective rate of syndromes were absolutely higher by 27.3%,20.6%and 47.9%than those of the patients in the Lamivudine group respectively.Besides,after 6-month TCM treatment,the remarkably effective rate and the total effective rate of syndromes were absolutely higher by 70.9%and 21.6%%than those of the patients in the Lamivudine group respectively.At the 3-month follow-up visit,the cure rate,remarkably effective rate and the total effective rate in the patients treated with TCM were absolutely higher by 25.6%,50.8%and 20.1%than those of the patients treated with Lamivudine,respectively.
Conclusions:At first,it is effective in TCM group in achieving virus loss and seroconversion,normalizing ALT levels and clearing HBV DNA.Second,TCM offered superior efficacy over lamivudine on the basis of HBsAg loss and seroconversion.Third,TCM offered better HBV DNA clearance result at the follow-up visit in the HBeAg-negative patients.However,more evidence is needed to support the above conclusions due to limited sample amount.
Part two:The evaluation of the long-term effectiveness of TCM on CHB by Markov model
Objective:To estimate the effectiveness of TCM and Lamivudine for adult patients with CHB.
Design:Two 5-health state Markov models were developed for HBeAg-positive and HBeAg-negative CHB patients respectively.The models followed cohorts of HBeAg-positive and HBeAg-negative CHB patients respectively over a period of 40 years,during which the majority of the cohorts would have died if left untreated. Annual transition probabilities of disease progression and the magnitude of treatment effects were obtained from the literature,with a focus on data obtained from Asian patients and meeting the criteria of therapy as described in internationally recognized management guidelines.The potential effect of uncertainty in the model assumptions was tested by using sensitivity analyses.Monte Carlo micro-simulation was used to perform clinical decision analysis on the basis of quality-adjusted life expectancy.
Results:Among the patients with HBeAg-positive CHB received TCM treatment, 18.48%to 62.49%of the patients occurred HBeAg seroconversion,and 1.4%to 36.6%of the patients progressed to compensated cirrhosis in the course of 40 years treatments,and average per patient had gained 28.18 accumulated QALYs in the end of 40 years treatments,compared with 2.90%to 23.89%,3.06%to 82.33%and 16.17 QALYs respectively for the patients treated with Lamivudine.The patients who received TCM had gained more than 12.11 accumulated QALYs per patient than the ones who received Lamivudine.Among the patients with HBeAg-negative CHB treated with TCM,there were 22.98%to 46.74%of patients who had combined response,and 2.92%to 57.06%of patients who progressed to compensated cirrhosis in the course of 40 years,and average per patient had gained 23.36 accumulated QALYs in the end of 40 years treatments,in comparison with 5.83%to 29.43%, 2.35%to 80.21%and 16.84 QALYs of the patients treated with Lamivudine respectively.There were 6.52 accumulated QALYs per patient average gained in the TCM group more than those of the Lamivudine group.
By monte carlo microsimulation for 10000 times,among the HBeAg-positive CHB patients that received TCM,the P0 of QALYs that they would gain average per patient in the end of 40 years treatments was 1,P100 was 37,and P50 was 35, compared with 1,35 and 14 QALYs respectively for the patients who received Lamivudine.The difference of the optimal clinical intervention between TCM and Lamivudine was 0.134.Among the HBeAg-negative CHB patients treated with TCM, the P0 of QALYs that they would gain average per patient in the end of 40 years treatments was 1,P100 was 36,and P50 was 30,compared with 1,35 and 15 QALYs respectively for the patients who received Lamivudine.And the difference of the optimal clinical intervention between TCM and Lamivudine was 0.003.
Conclusions:First,TCM was the optimal intervention compared with Lamivudine for the patients with HBeAg-positive CHB in the long-term at the 0.05 tolerance level, while for the ones with HBeAg-negative,there was no statistical difference between TCM intervention and Lamivudine intervention at the 0.05 tolerance level.Second, Markov model could be used to simulate the progression of CHB and it was feasible for Markov model to assess the long-time outcomes of chronic diseases with the treatment of TCM.However,more researches were needed to make it better in the future work.
引文
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