艾滋病中医辨证特点与临床研究
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摘要
研究目的
艾滋病于1981年在美国同性恋者中首先发现。1982年9月24日,美国疾病控制中心(CDC)正式提出了获得性免疫缺陷综合征的概念,指出艾滋病是不明原因的细胞免疫缺陷所导致的卡波,肉瘤、卡氏肺囊虫肺炎和其它严重的机会性感染。1986年,国际微生物学会和病毒学分会将LAV/HTLV-Ⅲ/ARV统一命名为人类免疫缺陷病毒(human immunodeficiency virus,简称HIV),又称艾滋病病毒。这种病毒侵入人体后破坏人体免疫功能,使人体发生多种不可治愈的感染和肿瘤从而最后导致被感染者死亡。该病潜伏期长,传播速度快,病情复杂,目前仍无法完全治愈,至今尚无特效药。目前,用药虽可抑制病毒在体内复制,但停药后病毒仍然繁殖,因此,目前药物治疗难以治愈。成为当今世界疑难病症之一。西方所推崇的高效抗逆转录抗病毒疗法(HAART)虽然大大降低AIDS的发病率和死亡率,但是药物联合使用受到许多限制,有高达60%的患者由于持续性、毒性、药物抵抗等原因。导致抗病毒治疗的失败。主要问题包括：①不能根除体内的HIV；②需要长期以至终身服药；③目前仅有5个国产抗HIV药物,昂贵的药费以及药物的毒副作用,使得长期服药依从性差；④HIV-1的高变异率和逐渐升高的耐药性,使抗病毒治疗面临着越来越多的问题。在全世界都在致力于攻克艾滋病的同时,我国中医药也在不断探索治疗艾滋病的方法。由于传统医学在治疗疑难病症方面具有其整体辨证论治及扶正祛邪的独特优势,研究及开发防治艾滋病的中药,对于我国乃至全世界都具有重大而深远的意义。
中医药被越来越多的运用于艾滋病治疗,且日益受到国际医学界的重视。当前,如何从中医药学的视角认识艾滋病,形成理论并指导临床,已成为广大中医药工作者的重要课题,本课题将从中医治疗理论及临床与实验等方面,进行相关研究,提出以益气解毒法作为治疗艾滋病的基本治法。以期能够总结出具有普遍适用性的中医药治疗艾滋病的治疗原则及方法。
本项目作为湖北省重大课题,是在湖北省政府和卫生厅的大力支持下,精选组方成“扶正抗艾方”,并将该方制成颗粒作为院内制剂,在前期大量的药学研究(包括药物提取、成型工艺、中试放大试验及质量标准研究)和毒理研究(急性毒性试验)基础之上,进行的临床观察试验。其研究目的是通过本临床观察试验,研究中药扶正抗艾方治疗艾滋病的远期临床疗效并探讨其对免疫功能的影响。本次研究还尝试性的使用心理干预疗法观察了对正在进行HAART治疗的艾滋病病人免疫功能的影响。
临床研究
一扶正抗艾方对艾滋病患者中医症状的疗效性评价及免疫功能的影响
目的：观察扶正抗艾方对艾滋病患者中医症状以及免疫功能的影响
研究方法
1研究对象
本课题36例临床观察病例来源于蕲春、南漳县中医院和疾控中心的病例。男22例,女14例；平均年龄为45.1±10.63岁；平均体重为57.0±7.15千克；感染途径为：不明原因3例,输血感染13例,性接触6例,有偿供血14例；所有病例均否认有家族遗传性疾病；均无西药和草药用药史。
2诊断标准
2.1西医诊断标准：参照2001年《中华人民共和国国家标准HIV/AIDS诊断标准及处理原则》。
2.2中医诊断标准：参照2004年国家中医药管理局组织的专家论证小组制定的《中医药治疗艾滋病临床技术方案(试行)》。
3病例纳入标准
3.1符合西医HIV/AIDS诊断标准,中医辨证标准；
3.2 CD4+范围为200-500/mm3；
3.3受试者年龄在18-65岁；
3.4自愿受试,并签署知情同意书者；
3.5未参与其他临床试验者；
3.6凡符合本病诊断及辨证标准,并排除以下“排除病例标准”中各项者,均可纳入试验病例。
4病例排除标准
4.1患有严重的心血管、呼吸、内分泌、肾、血液或精神系统疾病；
4.2年龄在18岁以下或65岁以上者,妊娠或哺乳期妇女；
4.3过敏体质,或对本药过敏者；
4.4有严重机会性感染者。
5病例脱落的处理
5.1当患者脱落后,研究者应尽可能与患者联系,完成所能完成的评估项目,尽可能记录最后一次服药时间。
5.2对因不良反应而脱落者,经随访后判断与试验药物有关者,记录脱落时的疗效并记录于不良反应报告表中；因疗效差而脱落者,按无效处理；非疗效和不良事件而脱落的：用药不足1/2疗程者,不记疗效；超过(或含)1/2疗程者,记录最后一次服药时的疗效。
5.3对于任何脱落病例,研究者必须在CRF表中填写以上其中的一个脱落原因。
5.4凡是入选并已经使用编号药物的病人,无论是否脱落,均应记录和保留CRF表,既作留档,也是进行意向性分析(ITT analysis)所需。脱落病人无需另补。
6剔除标准
6.1纳入后发现不符合纳入标准的病例；
6.2纳入后总用药量不足方案规定药量的20%或超过方案规定药量的120%的病例。
7中止试验标准
7.1临床试验中CD4+<200/mm3应中止试验。
7.2出现严重并发症或病情迅速恶化者应中止试验。
7.3患者在临床试验过程中不愿意继续进行临床试验,向主管医生提出退出临床试验的要求,可退出该病例临床试验。
8症状体征分级量化标准
参照国家中医药管理局专家组制定的相关标准及《中药新药临床研究指导原则》的有关标准,制定临床症状、体征记分标准。
9治疗方法
9.1药品来源
试验药物：扶正抗艾颗粒,药物组成：黄芪、党参、甘草、姜黄、紫草等。湖北省中医院提供。
9.2药品包装
药品包装含：编号、药物名称(临床研究专用药)、药物组成、功能主治、用法用量、规格、贮藏、使用期限。
9.3服药方法
给药方案：扶正抗艾颗粒1袋/次,每天服3次,饭后服用。
9.4疗程
疗程为12个月。自2009年1月底——2010年1月底。
9.5合并用药
在研究过程中,对合并症及用药应统一掌握。
9.5.1所有病例在试验期间不得合并使用能影响本药疗效的中西药物。
9.5.2观察期间必须加服其它内服药或作其它治疗的,必须在观察表中作记录(包括药名、剂量、用法)。合并机会性感染者常规处理。合并肿瘤者终止治疗。
9.6药品管理
9.6.1试验前管理：试验前由研制者准备试验药品。
9.6.2试验期管理：建立试验药品试验期管理制度。每个研究单位指定一名专门的试验用药品管理员。药品专柜上锁、室温保存。建立专用的《扶正抗艾颗粒临床试验用药品使用记录表》,记录试验用药发放日期、药物编号、受试者姓名、给药数量及回收药品数量,药品管理员签字。
9.6.3试验后管理：由药品管理员负责将剩余药品集中返还湖北省中医院或按程序销毁。
9.7观测指标及检测方法
9.7.1临床症状和体征：通过记分量化后比较；
9.7.2免疫功能指标(CD4计数、CD4/CD8比值)：流式细胞检测技术；
9.7.3IL-2、IFN-γ含量检测：双抗夹心ELISA法检测血清IL-2、IFN-Y含量。
9.7.4病毒载量：荧光定量RT-PCR；
9.8临床质量控制
9.8.1研究者应按病例报告表要求,如实、详细、认真记录表中各项内容,以确保病例报告表内容真实、可靠,病例报告表不得涂改,如确有笔误,只能在填错的项目上划一横线,在其上填写正确内容,并在旁边签字,注明日期。
9.8.2临床试验中所有观察结果和发现均应加以核实,以确保数据的可靠性,确保临床试验中各项结论均来源于原始数据。在临床试验和数据处理阶段应有相应的管理措施。
10疗效评定标准：参照国家中医药管理局专家组制定的相关标准及《中药新药临床研究指导原则》的有关标准。
11统计学处理：采用卡方检验和T检验。
结果
1中医症状、体征的变化
1.1治疗后患者主要症状、次要症状和主要体征总积分变化与治疗前相比均有统计学意义(*P<0.05),可看出总积分较前显著减少。
1.2总积分：治疗后患者主要、次要症状和主要体征总积分、以及总症状(主要、次要症状)积分和总积分(主要、次要症状及主要体征)较疗前均明显减少,有统计学意义(*P<0.05,)。
1.3卡洛夫斯基积分：较疗前明显增加,有统计学意义(*P<0.05)。
1.4中医证候疗效：根据证候疗效判定标准,从病例数分析中医证候疗效：有效24例,占66.7%；稳定5例,占13.8%；无效7例,占19.5%。总有效率80.5%。
2免疫功能：
CD4计数、CD4/CD8比值：疗后患者CD4计数无明显升高,无统计学意义(*P>0.05),CD4计数变化构成比有效7例,占19.4%；稳定25例,占69.4%；无效4例,占11.2%。总有效率88.8%。
3对白介素-2(Interleukin-2, IL-2)γ干扰素(Interferon-γ, IFN-Y)的影响：疗后两种细胞因子的表达均较疗前明显增高,均有统计学意义(*P<0.05)。
4病毒载量：治疗后病毒载量较疗前略有减少,但无统计学意义(*P>0.05)。根据病毒载量判定标准统计其变化的构成比,有效20例,占55.6%；稳定9例,占25%；无效7例,占19.4%。总有效率80.6%。
结论
1临床症状、体征
本研究结果充分显示,患者治疗后的乏力、纳呆、脱发、头痛、肌肉痛等症状的单独积分较治疗前明显减少,提示本方能使患者的以上症状明显减轻。治疗后主要、次要症状和主要体征总积分、以及总症状(主要、次要症状)积分和总积分(主要、次要症状及主要体征)较疗前均明显减少；卡洛夫斯基积分较疗前明显增加。而且根据证候疗效判定标准,从构成比分析中医证候疗效,总有效率80.5%。提示了“扶正抗艾方”能明显改善患者症状体征,提高患者生活质量,从而也体现了中医药治疗艾滋病的优势所在。
2免疫功能疗后患者CD4+计数较疗前无明显升高,且CD4+/CD8+比值较疗前略有下降。但根据免疫功能(CD4+绝对计数)疗效判定标准分析CD4+变化的构成比,总有效率88.8%。
3对白介素2 (Interleukin-2, IL-2)、γ干扰素(Interferon-γ, IFN-Y)的影响：治疗后两种细胞因子的表达均较治疗前明显增高,均有统计学意义(P<0.05)。
4病毒载量
治疗后患者病毒载量较疗前略有减少,但无统计学意义(*P>0.05)。但根据病毒载量判定标准统计其变化的构成比,总有效率80.6%。提示本方对病毒的复制也有一定的抑制和稳定作用。
二心理干预对艾滋病病人HAART治疗效果的影响
目的：探讨心理干预对艾滋病病人高效抗逆转录病毒治疗(HARRT)期间CD4+细胞计数及免疫指标(IL-2及IFN-γ)的影响。
方法：对照组16例单纯进行HARRT治疗：奈韦拉平(NVP)+司他夫丁(D4T)+去羟肌酐散(DDI)。心理干预组16例,在HAART治疗基础上进行心理干预,分别检测CD4+细胞计数及免疫指标(IL-2及IFN-γ)。
结果：1、治疗前两组CD4+细胞计数差异无统计学意义(P>0.05),治疗后两组的CD4+细胞计数均有统计学意义(P<0.05),但心理干预组CD4+细胞计数明显增高,与对照组比较有统计学意义；2、心理干预组治疗前后免疫指标细胞因子IL-2、IFN-γ差异有统计学意义(P<0.05),对照组治疗前后免疫指标细胞因子IL-2、IFN-γ的变化无统计学意义(P>0.05)。
结论：在HAART治疗基础上配合心理干预,可以有效改善慢性艾滋病病人的CD4+细胞计数及免疫指标(IL-2及IFN-γ)。
Research purposes
AIDS in 1981, first discovered in the U.S. homosexuals. September 24,1982, the U.S. Centers for Disease Control (CDC) formally proposed the acquired immunodeficiency syndrome concept that AIDS is unexplained cellular immune deficiency caused by Kaposi, sarcoma, Pneumocystis carinii pneumonia and other serious opportunistic infections. In 1986, the International Society for Microbiology and viruses credits will LAV/HTLV-Ⅲ/ARV Naming the human immunodeficiency virus (human immunodeficiency virus, called HIV), also known as HIV. The virus invades the human body immune function, so that occurrence of a variety of human infections and tumors incurable infection which eventually lead to death. The incubation period is long, speed of dissemination, disease complex, is still not fully healed, so far no specific drugs. At present, although drugs can inhibit virus replication in the body, but after stopping the virus is still breeding, therefore, difficult to cure the current drug treatment. Become one of the world difficult cases. The high esteem the West antiretroviral antiviral therapy (HAART) is significantly reduced AIDS morbidity and mortality, but the drug combination by many constraints, there are up to 60% of patients with sustained, toxicity, drug resistance and other factors. Led to the failure of antiviral therapy. Main issues include:①the body can not eradicate HIV;②need long-term and even lifelong medication;③Currently, only five made anti-HIV drugs, expensive drugs and drug side effects, makes long-term poor drug compliance;④HIV-1 high mutation rate and gradually increased resistance to antiviral therapy is facing a growing number of questions [4]. In the world are working to overcome AIDS, while also continue to explore the Chinese medical treatment for AIDS. Because traditional medicine in the treatment of difficult cases has the overall syndrome differentiation and uphold the unique advantages of research and development of Chinese medicine against AIDS, both for China and the world of great and far-reaching significance.
Chinese medicine is more and more used in AIDS treatment, and increasing attention by the international medical community., How to understand from the perspective of AIDS medicine to form a theoretical and clinical guidance, has become the important subject of Chinese medicine practitioners, Chinese medicine treatment of this subject from theory and other aspects of clinical and experimental, conducting related research, presented by Qi Toxin treatment of AIDS as a basic treatment method. In order to be able to sumup the universal applicability of Chinese Medicine principles and methods of treatment.
The project as a major issue in Hubei Province, is the Health Department of Hubei Provincial Government and the strong support of the selected group of parties as "anti-Ai Fang Fu Zheng", and the party made of particles as hospital preparations, a large number of pharmaceutical research in the early (including drug extraction, molding process, the pilot plant and the quality standard) and Toxicology (acute toxicity test) the basis for the clinical observation trial. The aim is to observe the passage of the clinical trial to study the anti-Ai Fuzheng Treatment of AIDS long-term clinical efficacy and to investigate its effects on immune function. The study also tested the use of psychological intervention therapy observed HAART treatment of AIDS patients being immune function.
Clinical Research
1 Fuzheng Anti-AIDS Preseription effects symptoms of AIDS medicine evaluation and immune function
Objective:To observe Fuzheng Anti-AIDS Preseription on AIDS clinical symptoms and immune function
Resesrch Method
1 Research objects
36 cases of this topic from qichun case, Nanzhang Chinese medicine hospitals and CDC control cases.22 males and 14 females; mean age of 45.1±10.63 years; average weight of 57.0±7.15 kg; transmission route was:unknown causes in 3cases,13 cases of infected blood transfusion, sexual contact with 6 cases, paid blood in 14 cases; all cases both deny any family history of disease; no history of Western medicine and herbal medicine.
2 diagnostic criteria
2.1 Western diagnostic criteria:the light in 2001, "The People's Republic of China national standard of HIV/AIDS diagnostic criteria and principles. "
2.2 TCM diagnostic criteria:Refer to the State Administration of TCM in 2004 organized an expert group set argument "of Chinese Medicine Clinical Skills Program (Trial)."
3 Case inclusion criteria
3.1 comply with Western HIV/AIDS diagnostic criteria, TCM standards;
3.2 CD4+ range of 200-500/mm3;
3.3 The subjects were 18-65 years of age;
3.4 The voluntary subjects, and signed the informed consent given;
3.5 were not involved in other clinical trials;
3.6 Diagnosis of the disease and who meet the Diagnostic Criteria, and the exclusion of the following "rule out cases of standards" in the person, can be incorporated into test cases.
4 cases of exclusion criteria
4.1 with severe cardiovascular, respiratory, endocrine, kidney, blood or psychiatric disorders;
4.2 the age of 18 years of age or over 65 years of age, pregnant or lactating women;
4.3 allergies, or allergic to this drug;
4.4 of serious opportunistic infections.
5 cases of Shedding
5.1 When the patient off, the researchers contact with patients as far as possible to complete the assessment of the project can be completed, as Records of the last medication time.
5.2 off due to adverse events were, after follow-up tests after the judge and drug-related were recorded off the effect and the time recorded in the adverse reaction reporting form; due to poor efficacy off who, according to an invalid address; non-effects and adverse events off:the drug is less than 1/2 course of treatment were not recorded efficacy; more than (or including) 1/2 course of treatment were recorded when the last time the efficacy of medication.
5.3 cases for any loss, researchers must fill in the CRF tables for more than one off the reasons.
5.4 Those who have been selected and the number of drugs patients use, whether or off, shall be recorded and retained CRF tables, both for leaving files intention is to conduct analysis (ITT analysis) required. No other up off the patient.
6 Excluding the standard
6.1 included found no cases met the inclusion criteria;
After the total dosage of 6.2 included in the program provided less than 20% of the drug or drug content under the program exceeded 120% of cases.
7 standard suspension test
7.1 Clinical Trials in CD4+<200/mm3 should stop testing.
7.2 serious complications or rapid deterioration should stop testing.
7.3 patients during clinical trials, clinical trials do not want to continue to the competent doctors argue that clinical trials out of the requirements of clinical trials may withdraw from the case.
8 quantitative criteria classification of symptoms and signs
State Administration of Traditional reference standards developed by expert groups and the "guiding principles of Chinese medicine clinical research new drugs, " the relevant standards, the development of clinical symptoms and signs score standards.
9 treatment
9.1 Drug Source
Test drugs:Fuzheng Anti-AIDS Prescription, drugs:Astragalus, Codonopsis, licorice, turmeric, shikonin, etc.. Chinese medicine hospital in Hubei Province to provide.
9.2 Pharmaceutical Packaging
Pharmaceutical Packaging with:number, drug name (Clinical research-specific drug), drug composition, functions, usage quantity, specifications, storage, use period.
9.3 Methods of Taking
Administration of the program:Fuzheng Ai particles 1 bag/ times,3 times a day, after meals.
9.4 Treatment
Treatment for 12 months. Since the end of January 2009-the end of January 2010.
9.5 combination therapy
In the study, on the complications and medication should be unified control.
9.5.1 All patients in the trial period can not be combined impact of the drug efficacy of traditional Chinese medicines.
9.5.2 Other services added during the observation period for internal medicine or other treatment, must be recorded in the observation table (including drug name, dosage). Combined conventional treatment for opportunistic infections. Combined treatment of tumors that have terminated.
9.6 Drug Administration
9.6.1 Before the test management:the developer of preparation before the test by the test drugs.
9.6.2 Test of management:the establishment of pilot drug trials of management system. Each of the pilot units to appoint a special administrator to use drugs. Counter medicines locked room temperature. The establishment of a dedicated "Fuzheng Ai drug use clinical trials particle log" to record the date of trial drug release, drug number, the subjects name, quantity and delivery quantity recovered drugs, drug administrator signature.
9.6.3 After the test administration:the administrator responsible for the pharmaceutical drugs focus on the return of the remaining hospital of Chinese medicine or procedures to be destroyed in Hubei Province.
9.7 Observation indicators and detection methods
9.7.1 Clinical signs and symptoms:score quantified by comparison;
9.7.2 immune function (CD4 count, CD4/CD8 ratio):flow cytometry;
9.7.3IL-2, IFN-γlevels detected:double-antibody sandwich ELISA, serum IL-2, IFN-γlevels.
9.7.4 viral load:quantitative RT-PCR;
9.8 Clinical Quality Control
9.8.1 Researchers should be required case report form, truthful, detailed, carefully record the table of the elements, to ensure that the case report form is true, reliable, case report forms may not be altered, if indeed there is clerical error, only in the trading department horizontal line on the uniform project, fill out the right in its content, and next to signature, date.
9.8.2 Clinical trial results and found that all the observations should be verified to ensure data reliability, to ensure that the conclusions of clinical trials are derived from raw data. In clinical trials, and data processing phases of the appropriate management measures.
10 evaluation standard:State Administration of Traditional reference standards developed by expert groups and the "guiding principles of Chinese medicine clinical research new drugs," the relevant standards.
11 Statistical analysis:The chi-square test and T test.
Results
1 TCM symptoms and signs of change
1.1 points separate symptoms:patients with post-treatment fatigue, poor appetite, hair loss, headache, muscle pain and other symptoms of the individual scores increased significantly after treatment decreased significantly (* P<0.05).
1.2 Total Points:After treatment in patients with major, minor and major signs symptoms total score, and total symptoms (main, secondary symptoms) and total points score (major, minor and major signs of symptoms) before treatment were significantly less than that statistically significant (* P<0.05).
1.3 Kalovsky points:before treatment significantly increased compared with statistical significance (* P<0.05).
1.4 TCM syndromes:According to the syndromes the diagnostic standard, from the number of cases of TCM syndromes:Effective 24 cases,66.7%; stable in 5 cases,13.8%; ineffective in 7 cases, 19.5%. The total effective rate 80.5%.
2 immune function:
2.1CD4 count, CD4/CD8 ratio:patients with CD4 counts after treatment no significant increase, not significant (P> 0.05) CD4 counts constitute effective than the 7 cases,19.4%; stable in 25 cases,69.4%; invalid 4 cases, accounting for 11.1%. The total effective rate 88.9%.
2.2 interleukin-2、γ-interferon of:after treatment the expression of two cytokines were significantly higher than that before treatment, were statistically significant (P<0.05).
3, viral load:After treatment, viral load decreased slightly compared with before treatment, but no statistical significance (P> 0.05). Viral load determined according to standard statistical changes in the composition of its ratio, effective in 20 cases, 55.6%; stable in 9 cases,25%; ineffective in 7 cases,19.4%. The total effective rate 80.6%.
Conclusions
1 Clinical symptoms and signs
The results fully show that after treatment of fatigue, poor appetite, hair loss, headache, muscle pain and other symptoms of the individual scores increased, decreased, suggesting that this side can alleviate symptoms in patients with the above. After treatment, major, minor and major signs symptoms total score, and total symptoms (main, secondary symptoms) and total points score (major, minor and major signs, symptoms) were significantly lower than before treatment; Kalovsky points significantly increased compared with before treatment. And determine the criteria according to syndromes, from the form of Chinese medicine syndromes than the total effective rate was 80.5%. Suggests "Fuzheng Ai side" can significantly improve the clinical symptoms, improve quality of life, which also reflects the advantages of Chinese medicine to treat AIDS.
2 immune function
Patients with CD4+ counts after treatment than before treatment and no significant increase, and CD4+ /CD8+ratio decreased slightly compared with before treatment. However, according to immune function (CD4+ counts) effect changes in determining the standard of the composition of CD4+ ratio, the total effective rate 88.8%.
3Interleukin-2, Interferon-γ:After treatment, the expression of two cytokines were significantly higher than before treatment, were statistically significant (P<0.05).
4viral load
After treatment, the viral load decreased slightly compared with before treatment, but no statistical significance (P>0.05). However, according to viral load changes in determining the composition of standard statistical ratio of its total effective rate 80.6%. Tip of the parties on virus replication also has a certain role of inhibition and stability.
2 Of psychological intervention on the treatment of AIDS patients HARRT effect
Objective:To explore the psychological intervention for AIDS patients with highly active antiretroviral therapy (HARRT) during the CD4 + cell counts and immune indicators (IL-2 and IFN-γ) effects.
Methods:The control group,16 cases by merely HARRT therapy: nevirapine (NVP)+stavudine (D4T)+didanosine creatinine powder (DDI). Psychological intervention group,16 patients treated in the HARRT on the basis of psychological intervention, were used to detect CD4+ cell counts and immune indicators (IL-2 and IFN-γ).
Results:1, pre-treatment CD4+ cell count differences between the two groups was not statistically significant (P>0.05), the two groups after treatment CD4+ cell counts were statistically significant (P<0.05), but the psychological intervention group was significantly higher CD4+ cell count, compared with the control group was statistically significant; 2, psychological immune parameters before and after treatment intervention group cytokines IL-2, IFN-γsignificantly (P<0.05), control group, immune parameters before and after treatment of cytokines IL-2, IFN-γwas no significant change (P> 0.05).
Conclusion:HAART treatment of psychological intervention on the basis of cooperation can be effective in improving chronic AIDS patients CD4+ cell counts and immune indicators (IL-2 and IFN-γ).
艾滋病于1981年在美国同性恋者中首先发现。1982年9月24日,美国疾病控制中心(CDC)正式提出了获得性免疫缺陷综合征的概念,指出艾滋病是不明原因的细胞免疫缺陷所导致的卡波,肉瘤、卡氏肺囊虫肺炎和其它严重的机会性感染。1986年,国际微生物学会和病毒学分会将LAV/HTLV-Ⅲ/ARV统一命名为人类免疫缺陷病毒(human immunodeficiency virus,简称HIV),又称艾滋病病毒。这种病毒侵入人体后破坏人体免疫功能,使人体发生多种不可治愈的感染和肿瘤从而最后导致被感染者死亡。该病潜伏期长,传播速度快,病情复杂,目前仍无法完全治愈,至今尚无特效药。目前,用药虽可抑制病毒在体内复制,但停药后病毒仍然繁殖,因此,目前药物治疗难以治愈。成为当今世界疑难病症之一。西方所推崇的高效抗逆转录抗病毒疗法(HAART)虽然大大降低AIDS的发病率和死亡率,但是药物联合使用受到许多限制,有高达60%的患者由于持续性、毒性、药物抵抗等原因。导致抗病毒治疗的失败。主要问题包括：①不能根除体内的HIV；②需要长期以至终身服药；③目前仅有5个国产抗HIV药物,昂贵的药费以及药物的毒副作用,使得长期服药依从性差；④HIV-1的高变异率和逐渐升高的耐药性,使抗病毒治疗面临着越来越多的问题。在全世界都在致力于攻克艾滋病的同时,我国中医药也在不断探索治疗艾滋病的方法。由于传统医学在治疗疑难病症方面具有其整体辨证论治及扶正祛邪的独特优势,研究及开发防治艾滋病的中药,对于我国乃至全世界都具有重大而深远的意义。
中医药被越来越多的运用于艾滋病治疗,且日益受到国际医学界的重视。当前,如何从中医药学的视角认识艾滋病,形成理论并指导临床,已成为广大中医药工作者的重要课题,本课题将从中医治疗理论及临床与实验等方面,进行相关研究,提出以益气解毒法作为治疗艾滋病的基本治法。以期能够总结出具有普遍适用性的中医药治疗艾滋病的治疗原则及方法。
本项目作为湖北省重大课题,是在湖北省政府和卫生厅的大力支持下,精选组方成“扶正抗艾方”,并将该方制成颗粒作为院内制剂,在前期大量的药学研究(包括药物提取、成型工艺、中试放大试验及质量标准研究)和毒理研究(急性毒性试验)基础之上,进行的临床观察试验。其研究目的是通过本临床观察试验,研究中药扶正抗艾方治疗艾滋病的远期临床疗效并探讨其对免疫功能的影响。本次研究还尝试性的使用心理干预疗法观察了对正在进行HAART治疗的艾滋病病人免疫功能的影响。
临床研究
一扶正抗艾方对艾滋病患者中医症状的疗效性评价及免疫功能的影响
目的：观察扶正抗艾方对艾滋病患者中医症状以及免疫功能的影响
研究方法
1研究对象
本课题36例临床观察病例来源于蕲春、南漳县中医院和疾控中心的病例。男22例,女14例；平均年龄为45.1±10.63岁；平均体重为57.0±7.15千克；感染途径为：不明原因3例,输血感染13例,性接触6例,有偿供血14例；所有病例均否认有家族遗传性疾病；均无西药和草药用药史。
2诊断标准
2.1西医诊断标准：参照2001年《中华人民共和国国家标准HIV/AIDS诊断标准及处理原则》。
2.2中医诊断标准：参照2004年国家中医药管理局组织的专家论证小组制定的《中医药治疗艾滋病临床技术方案(试行)》。
3病例纳入标准
3.1符合西医HIV/AIDS诊断标准,中医辨证标准；
3.2 CD4+范围为200-500/mm3；
3.3受试者年龄在18-65岁；
3.4自愿受试,并签署知情同意书者；
3.5未参与其他临床试验者；
3.6凡符合本病诊断及辨证标准,并排除以下“排除病例标准”中各项者,均可纳入试验病例。
4病例排除标准
4.1患有严重的心血管、呼吸、内分泌、肾、血液或精神系统疾病；
4.2年龄在18岁以下或65岁以上者,妊娠或哺乳期妇女；
4.3过敏体质,或对本药过敏者；
4.4有严重机会性感染者。
5病例脱落的处理
5.1当患者脱落后,研究者应尽可能与患者联系,完成所能完成的评估项目,尽可能记录最后一次服药时间。
5.2对因不良反应而脱落者,经随访后判断与试验药物有关者,记录脱落时的疗效并记录于不良反应报告表中；因疗效差而脱落者,按无效处理；非疗效和不良事件而脱落的：用药不足1/2疗程者,不记疗效；超过(或含)1/2疗程者,记录最后一次服药时的疗效。
5.3对于任何脱落病例,研究者必须在CRF表中填写以上其中的一个脱落原因。
5.4凡是入选并已经使用编号药物的病人,无论是否脱落,均应记录和保留CRF表,既作留档,也是进行意向性分析(ITT analysis)所需。脱落病人无需另补。
6剔除标准
6.1纳入后发现不符合纳入标准的病例；
6.2纳入后总用药量不足方案规定药量的20%或超过方案规定药量的120%的病例。
7中止试验标准
7.1临床试验中CD4+<200/mm3应中止试验。
7.2出现严重并发症或病情迅速恶化者应中止试验。
7.3患者在临床试验过程中不愿意继续进行临床试验,向主管医生提出退出临床试验的要求,可退出该病例临床试验。
8症状体征分级量化标准
参照国家中医药管理局专家组制定的相关标准及《中药新药临床研究指导原则》的有关标准,制定临床症状、体征记分标准。
9治疗方法
9.1药品来源
试验药物：扶正抗艾颗粒,药物组成：黄芪、党参、甘草、姜黄、紫草等。湖北省中医院提供。
9.2药品包装
药品包装含：编号、药物名称(临床研究专用药)、药物组成、功能主治、用法用量、规格、贮藏、使用期限。
9.3服药方法
给药方案：扶正抗艾颗粒1袋/次,每天服3次,饭后服用。
9.4疗程
疗程为12个月。自2009年1月底——2010年1月底。
9.5合并用药
在研究过程中,对合并症及用药应统一掌握。
9.5.1所有病例在试验期间不得合并使用能影响本药疗效的中西药物。
9.5.2观察期间必须加服其它内服药或作其它治疗的,必须在观察表中作记录(包括药名、剂量、用法)。合并机会性感染者常规处理。合并肿瘤者终止治疗。
9.6药品管理
9.6.1试验前管理：试验前由研制者准备试验药品。
9.6.2试验期管理：建立试验药品试验期管理制度。每个研究单位指定一名专门的试验用药品管理员。药品专柜上锁、室温保存。建立专用的《扶正抗艾颗粒临床试验用药品使用记录表》,记录试验用药发放日期、药物编号、受试者姓名、给药数量及回收药品数量,药品管理员签字。
9.6.3试验后管理：由药品管理员负责将剩余药品集中返还湖北省中医院或按程序销毁。
9.7观测指标及检测方法
9.7.1临床症状和体征：通过记分量化后比较；
9.7.2免疫功能指标(CD4计数、CD4/CD8比值)：流式细胞检测技术；
9.7.3IL-2、IFN-γ含量检测：双抗夹心ELISA法检测血清IL-2、IFN-Y含量。
9.7.4病毒载量：荧光定量RT-PCR；
9.8临床质量控制
9.8.1研究者应按病例报告表要求,如实、详细、认真记录表中各项内容,以确保病例报告表内容真实、可靠,病例报告表不得涂改,如确有笔误,只能在填错的项目上划一横线,在其上填写正确内容,并在旁边签字,注明日期。
9.8.2临床试验中所有观察结果和发现均应加以核实,以确保数据的可靠性,确保临床试验中各项结论均来源于原始数据。在临床试验和数据处理阶段应有相应的管理措施。
10疗效评定标准：参照国家中医药管理局专家组制定的相关标准及《中药新药临床研究指导原则》的有关标准。
11统计学处理：采用卡方检验和T检验。
结果
1中医症状、体征的变化
1.1治疗后患者主要症状、次要症状和主要体征总积分变化与治疗前相比均有统计学意义(*P<0.05),可看出总积分较前显著减少。
1.2总积分：治疗后患者主要、次要症状和主要体征总积分、以及总症状(主要、次要症状)积分和总积分(主要、次要症状及主要体征)较疗前均明显减少,有统计学意义(*P<0.05,)。
1.3卡洛夫斯基积分：较疗前明显增加,有统计学意义(*P<0.05)。
1.4中医证候疗效：根据证候疗效判定标准,从病例数分析中医证候疗效：有效24例,占66.7%；稳定5例,占13.8%；无效7例,占19.5%。总有效率80.5%。
2免疫功能：
CD4计数、CD4/CD8比值：疗后患者CD4计数无明显升高,无统计学意义(*P>0.05),CD4计数变化构成比有效7例,占19.4%；稳定25例,占69.4%；无效4例,占11.2%。总有效率88.8%。
3对白介素-2(Interleukin-2, IL-2)γ干扰素(Interferon-γ, IFN-Y)的影响：疗后两种细胞因子的表达均较疗前明显增高,均有统计学意义(*P<0.05)。
4病毒载量：治疗后病毒载量较疗前略有减少,但无统计学意义(*P>0.05)。根据病毒载量判定标准统计其变化的构成比,有效20例,占55.6%；稳定9例,占25%；无效7例,占19.4%。总有效率80.6%。
结论
1临床症状、体征
本研究结果充分显示,患者治疗后的乏力、纳呆、脱发、头痛、肌肉痛等症状的单独积分较治疗前明显减少,提示本方能使患者的以上症状明显减轻。治疗后主要、次要症状和主要体征总积分、以及总症状(主要、次要症状)积分和总积分(主要、次要症状及主要体征)较疗前均明显减少；卡洛夫斯基积分较疗前明显增加。而且根据证候疗效判定标准,从构成比分析中医证候疗效,总有效率80.5%。提示了“扶正抗艾方”能明显改善患者症状体征,提高患者生活质量,从而也体现了中医药治疗艾滋病的优势所在。
2免疫功能疗后患者CD4+计数较疗前无明显升高,且CD4+/CD8+比值较疗前略有下降。但根据免疫功能(CD4+绝对计数)疗效判定标准分析CD4+变化的构成比,总有效率88.8%。
3对白介素2 (Interleukin-2, IL-2)、γ干扰素(Interferon-γ, IFN-Y)的影响：治疗后两种细胞因子的表达均较治疗前明显增高,均有统计学意义(P<0.05)。
4病毒载量
治疗后患者病毒载量较疗前略有减少,但无统计学意义(*P>0.05)。但根据病毒载量判定标准统计其变化的构成比,总有效率80.6%。提示本方对病毒的复制也有一定的抑制和稳定作用。
二心理干预对艾滋病病人HAART治疗效果的影响
目的：探讨心理干预对艾滋病病人高效抗逆转录病毒治疗(HARRT)期间CD4+细胞计数及免疫指标(IL-2及IFN-γ)的影响。
方法：对照组16例单纯进行HARRT治疗：奈韦拉平(NVP)+司他夫丁(D4T)+去羟肌酐散(DDI)。心理干预组16例,在HAART治疗基础上进行心理干预,分别检测CD4+细胞计数及免疫指标(IL-2及IFN-γ)。
结果：1、治疗前两组CD4+细胞计数差异无统计学意义(P>0.05),治疗后两组的CD4+细胞计数均有统计学意义(P<0.05),但心理干预组CD4+细胞计数明显增高,与对照组比较有统计学意义；2、心理干预组治疗前后免疫指标细胞因子IL-2、IFN-γ差异有统计学意义(P<0.05),对照组治疗前后免疫指标细胞因子IL-2、IFN-γ的变化无统计学意义(P>0.05)。
结论：在HAART治疗基础上配合心理干预,可以有效改善慢性艾滋病病人的CD4+细胞计数及免疫指标(IL-2及IFN-γ)。
Research purposes
AIDS in 1981, first discovered in the U.S. homosexuals. September 24,1982, the U.S. Centers for Disease Control (CDC) formally proposed the acquired immunodeficiency syndrome concept that AIDS is unexplained cellular immune deficiency caused by Kaposi, sarcoma, Pneumocystis carinii pneumonia and other serious opportunistic infections. In 1986, the International Society for Microbiology and viruses credits will LAV/HTLV-Ⅲ/ARV Naming the human immunodeficiency virus (human immunodeficiency virus, called HIV), also known as HIV. The virus invades the human body immune function, so that occurrence of a variety of human infections and tumors incurable infection which eventually lead to death. The incubation period is long, speed of dissemination, disease complex, is still not fully healed, so far no specific drugs. At present, although drugs can inhibit virus replication in the body, but after stopping the virus is still breeding, therefore, difficult to cure the current drug treatment. Become one of the world difficult cases. The high esteem the West antiretroviral antiviral therapy (HAART) is significantly reduced AIDS morbidity and mortality, but the drug combination by many constraints, there are up to 60% of patients with sustained, toxicity, drug resistance and other factors. Led to the failure of antiviral therapy. Main issues include:①the body can not eradicate HIV;②need long-term and even lifelong medication;③Currently, only five made anti-HIV drugs, expensive drugs and drug side effects, makes long-term poor drug compliance;④HIV-1 high mutation rate and gradually increased resistance to antiviral therapy is facing a growing number of questions [4]. In the world are working to overcome AIDS, while also continue to explore the Chinese medical treatment for AIDS. Because traditional medicine in the treatment of difficult cases has the overall syndrome differentiation and uphold the unique advantages of research and development of Chinese medicine against AIDS, both for China and the world of great and far-reaching significance.
Chinese medicine is more and more used in AIDS treatment, and increasing attention by the international medical community., How to understand from the perspective of AIDS medicine to form a theoretical and clinical guidance, has become the important subject of Chinese medicine practitioners, Chinese medicine treatment of this subject from theory and other aspects of clinical and experimental, conducting related research, presented by Qi Toxin treatment of AIDS as a basic treatment method. In order to be able to sumup the universal applicability of Chinese Medicine principles and methods of treatment.
The project as a major issue in Hubei Province, is the Health Department of Hubei Provincial Government and the strong support of the selected group of parties as "anti-Ai Fang Fu Zheng", and the party made of particles as hospital preparations, a large number of pharmaceutical research in the early (including drug extraction, molding process, the pilot plant and the quality standard) and Toxicology (acute toxicity test) the basis for the clinical observation trial. The aim is to observe the passage of the clinical trial to study the anti-Ai Fuzheng Treatment of AIDS long-term clinical efficacy and to investigate its effects on immune function. The study also tested the use of psychological intervention therapy observed HAART treatment of AIDS patients being immune function.
Clinical Research
1 Fuzheng Anti-AIDS Preseription effects symptoms of AIDS medicine evaluation and immune function
Objective:To observe Fuzheng Anti-AIDS Preseription on AIDS clinical symptoms and immune function
Resesrch Method
1 Research objects
36 cases of this topic from qichun case, Nanzhang Chinese medicine hospitals and CDC control cases.22 males and 14 females; mean age of 45.1±10.63 years; average weight of 57.0±7.15 kg; transmission route was:unknown causes in 3cases,13 cases of infected blood transfusion, sexual contact with 6 cases, paid blood in 14 cases; all cases both deny any family history of disease; no history of Western medicine and herbal medicine.
2 diagnostic criteria
2.1 Western diagnostic criteria:the light in 2001, "The People's Republic of China national standard of HIV/AIDS diagnostic criteria and principles. "
2.2 TCM diagnostic criteria:Refer to the State Administration of TCM in 2004 organized an expert group set argument "of Chinese Medicine Clinical Skills Program (Trial)."
3 Case inclusion criteria
3.1 comply with Western HIV/AIDS diagnostic criteria, TCM standards;
3.2 CD4+ range of 200-500/mm3;
3.3 The subjects were 18-65 years of age;
3.4 The voluntary subjects, and signed the informed consent given;
3.5 were not involved in other clinical trials;
3.6 Diagnosis of the disease and who meet the Diagnostic Criteria, and the exclusion of the following "rule out cases of standards" in the person, can be incorporated into test cases.
4 cases of exclusion criteria
4.1 with severe cardiovascular, respiratory, endocrine, kidney, blood or psychiatric disorders;
4.2 the age of 18 years of age or over 65 years of age, pregnant or lactating women;
4.3 allergies, or allergic to this drug;
4.4 of serious opportunistic infections.
5 cases of Shedding
5.1 When the patient off, the researchers contact with patients as far as possible to complete the assessment of the project can be completed, as Records of the last medication time.
5.2 off due to adverse events were, after follow-up tests after the judge and drug-related were recorded off the effect and the time recorded in the adverse reaction reporting form; due to poor efficacy off who, according to an invalid address; non-effects and adverse events off:the drug is less than 1/2 course of treatment were not recorded efficacy; more than (or including) 1/2 course of treatment were recorded when the last time the efficacy of medication.
5.3 cases for any loss, researchers must fill in the CRF tables for more than one off the reasons.
5.4 Those who have been selected and the number of drugs patients use, whether or off, shall be recorded and retained CRF tables, both for leaving files intention is to conduct analysis (ITT analysis) required. No other up off the patient.
6 Excluding the standard
6.1 included found no cases met the inclusion criteria;
After the total dosage of 6.2 included in the program provided less than 20% of the drug or drug content under the program exceeded 120% of cases.
7 standard suspension test
7.1 Clinical Trials in CD4+<200/mm3 should stop testing.
7.2 serious complications or rapid deterioration should stop testing.
7.3 patients during clinical trials, clinical trials do not want to continue to the competent doctors argue that clinical trials out of the requirements of clinical trials may withdraw from the case.
8 quantitative criteria classification of symptoms and signs
State Administration of Traditional reference standards developed by expert groups and the "guiding principles of Chinese medicine clinical research new drugs, " the relevant standards, the development of clinical symptoms and signs score standards.
9 treatment
9.1 Drug Source
Test drugs:Fuzheng Anti-AIDS Prescription, drugs:Astragalus, Codonopsis, licorice, turmeric, shikonin, etc.. Chinese medicine hospital in Hubei Province to provide.
9.2 Pharmaceutical Packaging
Pharmaceutical Packaging with:number, drug name (Clinical research-specific drug), drug composition, functions, usage quantity, specifications, storage, use period.
9.3 Methods of Taking
Administration of the program:Fuzheng Ai particles 1 bag/ times,3 times a day, after meals.
9.4 Treatment
Treatment for 12 months. Since the end of January 2009-the end of January 2010.
9.5 combination therapy
In the study, on the complications and medication should be unified control.
9.5.1 All patients in the trial period can not be combined impact of the drug efficacy of traditional Chinese medicines.
9.5.2 Other services added during the observation period for internal medicine or other treatment, must be recorded in the observation table (including drug name, dosage). Combined conventional treatment for opportunistic infections. Combined treatment of tumors that have terminated.
9.6 Drug Administration
9.6.1 Before the test management:the developer of preparation before the test by the test drugs.
9.6.2 Test of management:the establishment of pilot drug trials of management system. Each of the pilot units to appoint a special administrator to use drugs. Counter medicines locked room temperature. The establishment of a dedicated "Fuzheng Ai drug use clinical trials particle log" to record the date of trial drug release, drug number, the subjects name, quantity and delivery quantity recovered drugs, drug administrator signature.
9.6.3 After the test administration:the administrator responsible for the pharmaceutical drugs focus on the return of the remaining hospital of Chinese medicine or procedures to be destroyed in Hubei Province.
9.7 Observation indicators and detection methods
9.7.1 Clinical signs and symptoms:score quantified by comparison;
9.7.2 immune function (CD4 count, CD4/CD8 ratio):flow cytometry;
9.7.3IL-2, IFN-γlevels detected:double-antibody sandwich ELISA, serum IL-2, IFN-γlevels.
9.7.4 viral load:quantitative RT-PCR;
9.8 Clinical Quality Control
9.8.1 Researchers should be required case report form, truthful, detailed, carefully record the table of the elements, to ensure that the case report form is true, reliable, case report forms may not be altered, if indeed there is clerical error, only in the trading department horizontal line on the uniform project, fill out the right in its content, and next to signature, date.
9.8.2 Clinical trial results and found that all the observations should be verified to ensure data reliability, to ensure that the conclusions of clinical trials are derived from raw data. In clinical trials, and data processing phases of the appropriate management measures.
10 evaluation standard:State Administration of Traditional reference standards developed by expert groups and the "guiding principles of Chinese medicine clinical research new drugs," the relevant standards.
11 Statistical analysis:The chi-square test and T test.
Results
1 TCM symptoms and signs of change
1.1 points separate symptoms:patients with post-treatment fatigue, poor appetite, hair loss, headache, muscle pain and other symptoms of the individual scores increased significantly after treatment decreased significantly (* P<0.05).
1.2 Total Points:After treatment in patients with major, minor and major signs symptoms total score, and total symptoms (main, secondary symptoms) and total points score (major, minor and major signs of symptoms) before treatment were significantly less than that statistically significant (* P<0.05).
1.3 Kalovsky points:before treatment significantly increased compared with statistical significance (* P<0.05).
1.4 TCM syndromes:According to the syndromes the diagnostic standard, from the number of cases of TCM syndromes:Effective 24 cases,66.7%; stable in 5 cases,13.8%; ineffective in 7 cases, 19.5%. The total effective rate 80.5%.
2 immune function:
2.1CD4 count, CD4/CD8 ratio:patients with CD4 counts after treatment no significant increase, not significant (P> 0.05) CD4 counts constitute effective than the 7 cases,19.4%; stable in 25 cases,69.4%; invalid 4 cases, accounting for 11.1%. The total effective rate 88.9%.
2.2 interleukin-2、γ-interferon of:after treatment the expression of two cytokines were significantly higher than that before treatment, were statistically significant (P<0.05).
3, viral load:After treatment, viral load decreased slightly compared with before treatment, but no statistical significance (P> 0.05). Viral load determined according to standard statistical changes in the composition of its ratio, effective in 20 cases, 55.6%; stable in 9 cases,25%; ineffective in 7 cases,19.4%. The total effective rate 80.6%.
Conclusions
1 Clinical symptoms and signs
The results fully show that after treatment of fatigue, poor appetite, hair loss, headache, muscle pain and other symptoms of the individual scores increased, decreased, suggesting that this side can alleviate symptoms in patients with the above. After treatment, major, minor and major signs symptoms total score, and total symptoms (main, secondary symptoms) and total points score (major, minor and major signs, symptoms) were significantly lower than before treatment; Kalovsky points significantly increased compared with before treatment. And determine the criteria according to syndromes, from the form of Chinese medicine syndromes than the total effective rate was 80.5%. Suggests "Fuzheng Ai side" can significantly improve the clinical symptoms, improve quality of life, which also reflects the advantages of Chinese medicine to treat AIDS.
2 immune function
Patients with CD4+ counts after treatment than before treatment and no significant increase, and CD4+ /CD8+ratio decreased slightly compared with before treatment. However, according to immune function (CD4+ counts) effect changes in determining the standard of the composition of CD4+ ratio, the total effective rate 88.8%.
3Interleukin-2, Interferon-γ:After treatment, the expression of two cytokines were significantly higher than before treatment, were statistically significant (P<0.05).
4viral load
After treatment, the viral load decreased slightly compared with before treatment, but no statistical significance (P>0.05). However, according to viral load changes in determining the composition of standard statistical ratio of its total effective rate 80.6%. Tip of the parties on virus replication also has a certain role of inhibition and stability.
2 Of psychological intervention on the treatment of AIDS patients HARRT effect
Objective:To explore the psychological intervention for AIDS patients with highly active antiretroviral therapy (HARRT) during the CD4 + cell counts and immune indicators (IL-2 and IFN-γ) effects.
Methods:The control group,16 cases by merely HARRT therapy: nevirapine (NVP)+stavudine (D4T)+didanosine creatinine powder (DDI). Psychological intervention group,16 patients treated in the HARRT on the basis of psychological intervention, were used to detect CD4+ cell counts and immune indicators (IL-2 and IFN-γ).
Results:1, pre-treatment CD4+ cell count differences between the two groups was not statistically significant (P>0.05), the two groups after treatment CD4+ cell counts were statistically significant (P<0.05), but the psychological intervention group was significantly higher CD4+ cell count, compared with the control group was statistically significant; 2, psychological immune parameters before and after treatment intervention group cytokines IL-2, IFN-γsignificantly (P<0.05), control group, immune parameters before and after treatment of cytokines IL-2, IFN-γwas no significant change (P> 0.05).
Conclusion:HAART treatment of psychological intervention on the basis of cooperation can be effective in improving chronic AIDS patients CD4+ cell counts and immune indicators (IL-2 and IFN-γ).
引文
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