获得性免疫缺陷综合征(acquired immune deficiency syndrome，AIDS)，是由人类免疫缺陷病毒(human immunodeficiency virus，HIV)感染引起的一种严重危害人类健康的慢性传染病。自1981年首次确认AIDS以来，全球累计有6500万人感染HIV。如今，AIDS已经导致2500万人死亡，另有3300万人受感染。中国目前活着的HIV/AIDS病例已经超过70万，年发病率上升幅度达到45.04%，AIDS死亡人数已经连续2年超过乙肝。所有数据都显示：我国正处于HIV感染者发病的高峰期，AIDS发病已进入快速增长期，HIV感染已从高危人群向普通人群蔓延，临床救治的压力将越来越大。1996年开始的高效抗逆转录病毒治疗(highly active antiretroviral therapy，HAART)是艾滋病治疗史上的里程碑，不仅能够有效地控制病毒复制、延缓病情进展、延长AIDS患者的生存期，而且能重建AIDS患者的免疫功能，极大地降低了由于感染了HIV所导致的发病和死亡。 近年来，国外有不少关于HAART疗效、毒副反应以及耐药基因突变的研究文献；国内也有一些关于HAART疗效及安全性的文章和报道，却缺乏针对中国HIV/AIDS人群机会性感染及抗病毒治疗效果的长期系统的研究和观察数据。对于临床医师和HIV感染者来说，不管HAART治疗的进展如何，治疗失败是一个不可避免的严重问题，因此，了解本地HIV/AIDS患者机会性感染状况，评估HAART治疗的临床效果，并采取针对性的措施以避免治疗失败就显得尤为重要。另外，虽然HAART治疗能够控制病毒复制、延缓病情进展、延长AIDS患者的生存期，却无法治愈AIDS。因此，探讨AIDS发病机制，找到更为有效的治疗方法，仍然是我们面临的重要课题。本文就我院多年来来收治的388例HIV/AIDS患者进行了系统的研究，从其临床特点，机会性感染发病谱，HAART治疗效果及毒副反应，免疫重建反应，治疗失败原因以及基因耐药模式进行了分析。同时，对于高迁移率族蛋白1(high mobility group box 1 protein，HMGB1)作为一种作用广泛的晚期促炎因子，是否在HIV/AIDS病情进展中发挥了作用，也进行了初步的探讨。 第一篇 高效抗逆转录病毒治疗临床研究 目的 了解本地HIV/AIDS患者的临床特点，机会性感染发病谱，评估其HAART治疗效果及毒副反应，分析免疫重建反应及治疗失败原因，获得其耐药基因模式。 方法 从2003年4月到2009年8月底共收治388例HIV/AIDS患者，从2005年2月到2009年6月为226例成人HIY/AIDS患者提供免费的HAART治疗并随访至2009年9月底。对所有对象都进行了系统的前瞻性研究，并对接受HAART治疗的患者定期随访，了解其临床特点，机会性感染发病谱，评估HAART治疗效果及毒副反应，分析免疫重建反应，治疗失败原因以及耐药基因模式。 结果 ①388例HIV/AIDS患者主要传播途径为性传播；有40.98%的患者胸片检查异常，绝大多数的患者CD4+T淋巴细胞<200/μl；最常见的临床症状为发热，体重减轻，咳嗽及皮肤病变；机会性感染以鹅口疮最为常见，其次为肺部感染，皮肤疱疹，深部真菌感染，合并感染结核者占36.08%。②226例HIV/AIDS患者入组治疗时基线CD4+T淋巴细胞均值为109.46个/ul，死亡8例，病死率3.54%；服用抗病毒药物后出现最多的副反应是：皮瘆，疲倦，食欲改变，恶心呕吐，头痛睡眠困难等，还有3例乳酸酸中毒；有22例患者发生了免疫重建炎性综合征(immune reconstitution inflammatory syndrome，IRIS)，发生率 9.73%； 212例治疗效果良好的患者在治疗24周(6个月)时有70.30%的病例其血浆病毒载量达到检测不到的水平，且CD4+T细胞持续上升；6例治疗失败的病人CD4+T细胞上升不明显，甚至下降至低于治疗前的水平，且没有1例患者的HIY-RNA曾达到50copies/ml以下。③6例治疗失败的病人，除1例外，均有服药依从性不好或中断服药的病史，耐药基因检测显示对核苷类和非核苷类抗病毒药物的广泛耐药。 结论 ①本地HIV/AIDS的人群以农民、无业人员为主，传播途径主要是性传播；机会性感染表现为多系统、多种致病微生物并存，细菌、真菌、病毒均为常见病原，呼吸、消化系统以及皮肤软组织为常见感染部位。②在没有特殊禁忌的情况下，应该尽早启动抗病毒治疗。有效的HAART治疗，能够持久地抑制HIV在患者体内的复制，降低其血浆病毒载量，改善和恢复受损的免疫功能，延长患者的生存期并提高其生活质量，降低HIV相关的发病率和死亡率。本研究显示我们目前使用的国家免费抗病毒治疗一线药物能够获得与西欧国家相近似的病毒抑制效果。③HAART治疗的失败，与患者服药依从性不佳，对抗病毒药物产生耐药基因突变有关。本组一线治疗失败的病例对核苷类逆转录酶抑制剂和非核苷类逆转录酶抑制剂二类抗病毒药物产生了广泛耐药，更换以蛋白酶抑制剂为基础的二线治疗药物后仍然能够获得满意的疗效。 第二篇 高迁移率族蛋白1在HIV感染者/AIDS病人中的表达 目的 通过检测HIV感染者/AIDS患者外周血PBMCs中HMGB1 mRNA的表达水平及HMGB1血浆含量，研究其在HIV感染/AIDS中的临床意义。 方法 应用RT-PCR对74例处于不同病期的HIV/AIDS患者和10例健康对照者PBMCs中HMGB1 mRNA的表达进行检测，同时应用ELISA法检测外周血浆HMGB1、TNF-α和IL-2水平，比较各组血浆HMGB1含量及HMGB1 mRNA表达水平的差异及其与TNF-α、IL-2、及CD4+T淋巴细胞的关系。 结果 PBMCs中HMGB1 mRNA的表达水平及血浆HMGB1含量在AIDS病人组明显高于感染者组(5.16±8.38vs3.60±3.54；24.86±13.51vs11.62±5.41， P<0.05)和正常对照组(5.16±8.38vs2.34±1.98；24.86±13.51 vs10.12±4.34， P<0.05)；AIDS患者经HAART治疗后疗效差组PBMCs中HMGB1 mRNA的表达水平及血浆HMGB1 含量也明显高于疗效好组(4.95±2.71vs 2.14±2.13；34.17±21.49vs 9.14±4.88，P<0.05)；而经HAART治疗后效果好且免疫功能恢复的患者PBMCs中HMGB1 mRNA的表达水平及血浆HMGB1含量均较治疗前明显下降(2.14±2.13 vs 5.16±8.38，P<0.05；9.14±4.88 vs 24.86±13.51，P<0.05)；CD4+T细胞数较低的患者PBMCs中HMGB1 mRNA的表达水平及血浆HMGB1含量则较高，当CD4+T细胞数低于200个/ul时，血浆HMGB1含量以及PBMCs中HMGB1mRNA表达水平与CD4+T细胞数呈负相关(r=-0.639，-0.675)。 结论 HMGB1在HIV/AIDS发病及病情进展过程中可能起重要作用，HMGB1血浆含量及PBMCs中HMGB1 mRNA的表达水平高低与HIV/AIDS患者病情轻重密切相关。 总之，本地HIV/AIDS的人群以农民、无业人员为主，性传播是主要传播途径，机会性感染主要表现为鹅口疮、肺部感染以及结核。在没有特殊禁忌的情况下，应该尽早启动抗病毒治疗，本研究显示我们目前使用的国家免费抗病毒治疗一线药物能够获得与西欧发达国家相近似的病毒抑制效果。HMRT治疗的失败，与患者服药依从性不佳，对抗病毒药物产生耐药基因突变有关。HIV感染者/AIDS病人血浆中HMGB1含量及PBMCs中HMGB1 mRNA的表达水平在AIDS病人组明显高于感染者组和正常对照组，当CD4≤200个/ul时，患者HMGB1血浆含量及其PBMCs中的表达水平明显升高，表明HMGB1水平与CD4+T细胞计数呈负相关，HMGB1的水平高低与病情轻重相关，显示HMGB1在HIV/AIDS发病及病情进展过程中可能起重要作用 关键词 HIV/AIDS，高效抗逆转录病毒治疗，机会性感染，CD4+T细胞，病毒载量，耐药突变，高迁移率族蛋白1

 Acquired immune deficiency syndrome(AIDS) is a severe infectious disease caused by human immunodeficiency virus(HIV) infection. The term AIDS applies to the most advanced stages of HIV infection, defined by the occurrence of any of more than 20 opportunistic infections(OIs) or HIV-related cancers. Since 1981, the beginning of the epidemic, 25 million people have died of HIV-related causes. Collectively, these deaths represent an incalculable loss of human potential. Individually, each is associated with enduring trauma in households and communities. According to estimates by WHO and UNAIDS, 33 million people were living with HIV/AIDS at the end of 2008. About 700 thousands people are now living with HIV/AIDS in China and the death toll of AIDS had exceed that of hepatitis B. The incidence of it raised 45.04% last year, and the evidence showed that HIV infection has overspreaded from highrisk population to general population. The application and promotion highly active antiretroviral therapy(HAART), making antiretroviral therapy achieved good clinical results, effectively reduces HIV-associated morbidity and mortality, improved the survival and quality of the infected persons, is an important milestone in the history of treatment and prevention of AIDS. There were many papers and reports in the field of HAART efficacy, side-effection and toxicity , but lack of long-term observation data and systemic study aimed at Chinese people who living with HIV/AIDS. As we know, the time between infect of HIV and the diagnosis of AIDS can be 7-10 years, or even longer. Antiretroviral therapy (ART) can slow the disease progression by decreasing an infected person's viral load. HIV infection is chronic and that exposure to HAART is likely to be life-long, there is a need to evaluate the long-term effect of HAART in this population. In this paper, we first report the outcomes of highly active antiretroviral therapy and the expression of HMGB1 in patients with HIV /AIDS. This study includes two parts as follows: Part Ⅰ The Clinical Study on Highly Active Antiretroviral Therapy Objective To elucidate general characteristics of HIV/AIDS patients seeking care at Changsha Infectious Disease Hospital and evaluate the long-term efficacy of HAART and assess the resistance mutation of nonnucleoside reverse transcriptase inhibitor (NNRTI) -based regimens in routing clinical practice. Methods From April 2003 to August 2009, 388 HIV/AIDS cases were hospitalized, among them 226 cases were given two nucleoside reverse transcriptase inhibitor and one NNRTI antiretroviral therapy(ART). First, clinical characteristics of all the 388 cases were analysed; Then, 226 cases who received HAART were followed up and we assessed there CD4 + T cells and HIV-1 viral load; Last, 6 cases who failed on first regimen were further investigated by using the genotypic resistance tests. Results Among these patients, most of them had been infected by sexual contact. The most common symptoms were fever, weight loss, cough and diarrhea, rashes and glands swollen. 40.98% of cases' chest X-ray were abnormal and 83.18% of cases' CD4+ T lymphocyte were less than 200 cells/ul. The most common opportunistic infections (OIs) were thrush, pulmonary infection, fungal infected diarrhea, herpes and tuberculosis. Of 226 patients who received HAART, the mortality rate was 3.54%. The most common side effects were tetter, tiredness, nausea, etc, and 22 cases occurred immune reconstitution inflammatory syndrome(IRIS). More than 70% of subjects had HIV viral load＜50copies/ml at the point of 24 weeks, but 6 cases who failed on first regimen showed extensively resistance mutation on both NRTIs and NNRTIs. Conclusion The majority of cases were general population and had contracted HIV/AIDS sexually. Thrush, pulmonary infection emerged as the most frequent OIs. The most common pathogens of OIs were bacteria, fungus and virus. OIs were muti-organs effected and complicated. Antiretroviral therapy (ART) consists of two NRTIs and one NNRTIs could maximally suppress the HIV virus, increase CD4+T cell counts in a majority of subjects and stop the progression of HIV disease. Only few severe toxicities were observed. Analysis of 6 target gene fragments we found that, none had PI major resistance mutation, but showed extensively resistance mutation on both NRTIs and NNRTIs. This study demonstrated the durable effects of China national free antiretroviral therapy and the causes of treatment failure. Part Ⅱ The Expression of HMGB1 in Patients with HIV /AIDS Objective To investigate the expression and clinical significance of high mobility group box-1 protein (HMGB1) in patients with HIV infection/AIDS. Methods Seventy-four patients with HIV infection/AIDS of different pathogentic stage were recruited, while another ten healthy subjects were taken as controls. Expression of HMGB1 mRNA in PBMCs of all cases was detected by RT-PCR. And the levels of HMGB1, TNF-a and IL-2 in plasma were measured by ELISA. Results The expression of HMGB1 mRNA and levels of plasma HMGB1 in AIDS patients were significantly higher than that in cases with HIV infection or controls respectively (P＜0.05). The levels of HMGB1 mRNA and plasma HMGB1 in AIDS patients with poor efficacy after HAART therapy were significantly higher than that in subjects with good efficacy (P＜0.05). And both expression of HMGB1 mRNA and levels of plasma HMGB1 in those AIDS patients, whose immune function rehabilitated to normal level and got good therapy efficacy after HARRT, decreased evidently. Subjects with lower counts of CD4+T cells had higher expression of HMGB1, and there was negative correlation between CD4+ T cell counts and HMGB1 levels when CD4+ T cells decreased to less than 200 cells/ul. Conclusion HMGB1 probably plays an important role in the pathogenesis of HIV infection/AIDS and is closely associated with the disease course. Key words HIV/AIDS, HAART, OIs, CD4+T cells, viral load, resistance mutation, HMGB1