晚期AIDS病人HAART后免疫重建的研究进展

高效抗反转录病毒治疗(HAART)的应用,极大地降低了艾滋病病毒(HIV)感染者/艾滋病(AIDS)病人(简称HIV/AIDS病人)并发症的发病率和病死率。然而,部分晚期AIDS病人的病毒抑制与免疫重建并不同步,发生免疫重建炎症综合征(IRIS)或免疫重建失败(INR),极大地影响了临床预后。文章针对HAART后免疫重建的特点、影响因素及治疗手段相关的研究进展进行综述。     

重视艾滋病患者的免疫重建炎症综合征

艾滋病即获得性免疫缺陷综合征(AIDS)的病原体为人类免疫缺陷病毒(HIV)。HIV导致机体细胞免疫功能部分或完全丧失,继而发生机会性感染、肿瘤等致死性疾病。上世纪90年代开始应用的高效联合抗逆转录病毒治疗(highly active antiret-roviral therapy,HAART)能够使患者免疫功能得到重建,使艾滋病患者的病死率下降5倍多[1],是目前治疗HIV/AIDS患者唯一有效的方法。艾滋病患者免疫功能的重建是指经抗病毒治疗后,HIV所引起的免疫异常能恢复至正常或接近正常水平,即:①CD4 T淋巴细胞增加;②CD4 T淋巴细胞恢复对记忆抗原刺激的正常反应…     

HIV/AIDS患者HAART后免疫重建不良影响因素的Meta分析

目的 系统评价HIV/AIDS患者HAART后发生免疫重建不良的影响因素。方法 计算机检索PubMed、Web of Science、EMbase、the Cochrane Library、CNKI、维普、万方及中国生物医学文献数据库,检索HIV/AIDS患者HAART免疫重建不良影响因素的相关研究。检索时限为建库至2023年2月。经2位研究者独立筛选文献、提取资料并评价文献质量后,采用Review Manager 5.3以及Stata 16.0对数据进行Meta分析。结果 共纳入17个研究,包括21 443例患者。Meta分析结果显示,基线CD4细胞计数（OR=1.19,95%CI:1.14～1.24,P<0.000）、年龄（OR=1.91,95%CI:1.41～2.60,P<0.000）、性别（男性）（OR=1.62,95%CI:1.47～1.78,P<0.000）是HIV/AIDS患者HAART后发生免疫重建不良的危险因素。结论 基线CD4细胞计数、性别（男性）和年龄是HIV/AIDS患者HAART后发生免疫重建不良的危险因素。     

艾滋病的免疫功能重建研究进展

人类免疫缺陷病毒(HIV)感染人体后主要引起CL4~+ T细胞进行性减少,细胞免疫功能缺陷,最后导致严重的机会性感染或肿瘤。1996年以前,人们一直认为艾滋病(AIDS)的免疫破坏是不可逆转的。高效联合抗逆转录病毒治疗(HAART)出现后,人们普遍接受了免疫能重建的观点,越来越多的研究表明HAART治疗后HIV/AIDS患者的免疫力可以恢复,并能够对抗机会性感染。随着对AIDS发病机制和免疫病理的深入研究,一些新的治疗策略和手段纷纷涌现,其目标在于更快和更进一步的恢复机体免疫力,以预防机会性感染和增加HIV特异性免疫力。本文对近年艾滋病免疫重建研究的一些新治疗策略进行如下简述。 1 CD4~+细胞减少的机制和免疫重建艾滋病的最主要免疫病理是CD4~+ T细胞数量的减少。感染HIV后体内CD4~+ T细胞数量不断减少,这种减少一般分4期。第1期以CD4~+ T细胞数量短期内一过性迅速减少     

HIV/AIDS病人治疗过程中免疫重建综合征的初步观察

目的 探讨艾滋病病毒(HIV)感染者/艾滋病(AIDS)病人经高效抗逆转录病毒治疗(HAART)后,最初3个月的免疫重建综合征问题. 方法 对收治的HIV/AIDS病人,在抗病毒治疗的前3个月内的临床症状、CD 4 T淋巴细胞计数及病毒载量进行描述. 结果 27例接受HAART的HIV/AIDS病人中,治疗的前3个月CD 4 T淋巴细胞均上升,病毒载量下降有的甚至检测不到,出现免疫重建综合征12例;并发肺炎6例(细菌性4例、霉菌性2例),卡氏肺囊虫肺炎(PCP)3例,巨细胞病毒(CMV)感染1例,结核6例(颈部淋巴结结核3例,肠结核1例,结核性胸膜炎1例,血行播散型结核并脑膜炎1例),带状疱疹1例. 结论 HAART可使免疫重建,包括CD 4 T淋巴细胞功能上升、病毒载量下降和其他的治疗益处,同时也会激活一些接受抗病毒治疗HIV/AIDS病人的炎症反应.     

抗病毒治疗联合益艾康胶囊对HIV/AIDS患者免疫功能重建的影响

目的 评价中医药干预对HIV/AIDS患者免疫功能重建的影响,并对影响免疫功能重建的多因素进行分析。方法 选择已发生免疫重建不良的HIV/AIDS患者109例,采用随机、双盲、安慰剂对照的方法分成中药干预组和非中药干预组,中药干预组采用ART+中药治疗,非中药干预组采用ART+安慰剂治疗,疗程12个月。采用Logistic回归对免疫功能重建的影响因素进行分析,P<0.05差异有统计学意义。结果 中药干预组患者50例,非中药干预组59例,两组人口学特征及ART相关指标差异均无统计学意义（P均>0.05）。干预治疗12个月后,中药干预组患者免疫重建成功率为34.0%(17/50),非中药干预组为16.9%(10/59)。多因素分析结果,HIV/AIDS患者免疫重建成功率中药干预组是非中药干预组的4.048(1.300～12.606)倍,ART时间大于5年是ART时间小于5年的17.619(3.591～86.457)倍,血液和母婴传播是同性性传播的11.343(1.213～106.04)倍。结论 中药干预治疗、ART时间长短及HIV传播途径是艾滋病免疫功能重建的影响因素,排除其他...     

清法类方药对HIV/AIDS患者免疫功能重建的临床疗效和安全性评价

目的 对清法类方药干预HIV/AIDS患者免疫功能重建的临床疗效和安全性进行系统评价,为中医药治疗HIV/AIDS患者提供进一步循证医学证据支持。方法 文献检索从建库至2022年1月1日中文数据库（中国知识资源总库、万方数据库、中国生物医学文献数据库和中国科技核心期刊数据库）和英文数据库（Cochrane图书馆、PubMed数据库、EMBase数据库）的HIV/AIDS患者免疫功能重建的相关研究报告;预先制定详细而严格的选择流程和纳入标准,进行研究筛选、偏倚评价、数据提取、Meta分析和系统评价工作;采用Review Manager 5.3和Stata 14.0软件进行数据分析。结果 共纳入符合纳排标准的15篇随机对照研究,共涉及2 071例患者,其中13篇（86.67%）研究报告被认定为质量较高,评价属低偏倚风险。清法类方药的治疗方式在对CD4细胞计数水平恢复（SMD=0.73,95%CI:0.29～1.16）、免疫功能重建有效率提升（RR=2.15,95%CI:1.21～3.82）、控制HIV病毒载量（MD=-0.32,95%CI:-0.60～-0.03）、改善临床症状体征积分（S...     

中西医结合治疗对艾滋病免疫重建不全者CD4~+T淋巴细胞影响

目的分析云南省中西医结合治疗对高效抗反转录病毒治疗(HAART)后免疫重建不全患者CD4~+ T淋巴细胞(简称CD4细胞)的影响。方法收集2005年9月至2016年12月在云南省接受国家中医药治疗,并在入组前已接受HAART满2年的艾滋病病毒(HIV)感染者/艾滋病(AIDS)病人(简称HIV/AIDS病人)的CD4细胞数据。结果共有781例病人纳入研究,其中免疫重建不全组135例,对照组646例,接受中西医结合治疗后,两组病人CD4细胞计数上升或稳定。治疗后12个月时,免疫重建不全组有效占74.0%,稳定占22.0%,对照组有效占33.9%、稳定占57.4%;治疗24个月时,免疫重建不全组有效占78.0%、稳定占18.1%,对照组有效占39.1%、稳定占51.6%。结论中西医结合治疗可一定程度提高或稳定HIV/AIDS病人CD4细胞计数水平,且对免疫重建不全病人作用更具有优势。     

杀伤细胞免疫球蛋白样受体基因与人类免疫缺陷病毒感染/艾滋病患者抗反转录病毒治疗后发生免疫重建不良的相关性

目的探讨杀伤细胞免疫球蛋白样受体(KIR)基因与人类免疫缺陷病毒感染/艾滋病(HIV/AIDS)患者抗反转录病毒治疗(ART)后发生免疫重建不良的关系。方法纳入2007年5月至2019年12月就诊于广西医科大学附属武鸣医院和马山县人民医院艾滋病门诊的接受ART≥1年的HIV/AIDS患者, 并分为免疫重建不良组和免疫重建良好组。使用序列特异性聚合酶链反应(PCR-SSP)测定KIR基因型, 计算16个KIR基因型的基因型频率(PF), 统计学比较采用χ2检验, 采用多因素logistic回归分析探究KIR基因与免疫重建不良的关系。结果共纳入HIV/AIDS患者102例, 其中免疫重建不良患者44例, 免疫重建良好患者58例。免疫重建不良组中KIR2DL5的PF为59.09%(26/44), 高于免疫重建良好组的36.21%(21/58), 差异有统计学意义(χ2=5.27, P=0.022)。对混杂因素年龄和基线CD4+ T淋巴细胞计数进行校正后的多因素logistic回归分析显示, KIR2DL5与免疫重建不良具有相关性, KIR2DL5表达阳性可能是HIV/AIDS患者接受ART后...     

HIV感染者免疫功能重建新视角:CD4/CD8比值

CD4+T淋巴细胞(简称CD4细胞)计数是衡量艾滋病病毒(HIV)感染者免疫状态的经典指标,但近年来的研究发现,仅用CD4细胞绝对计数难以精确反应艾滋病(AIDS)病人的免疫状态,特别是经过抗病毒治疗后CD4细胞500个/μL以上的患者。CD4/CD8比值在正确评价免疫功能中的价值逐渐受到关注。HIV感染后导致CD4/CD8比值倒置,经抗反转录病毒治疗(ART)后也难以恢复正常。基线状态、治疗方案、合并巨细胞病毒(CMV)感染等因素均影响CD4/CD8比值的恢复。CD4/CD8比值与HIV感染后异常免疫激活相平行,不仅作为艾滋病预后的预测因子,也与非AIDS相关事件的发生以及HIV储存库有关。CD4/CD8比值恢复正常有望作为评估HIV感染者免疫功能重建的新指标。     

HIV/AIDS患者免疫重建炎性综合征的诊治

免疫重建炎性综合征（immune reconstitution inflammatory syndrome,IRIS）是部分HIV／AIDS患者在高效抗反转录病毒治疗后发生的一组疾病。IRIS主要与机体在免疫功能恢复过程中产生了针对残存活性／非活性抗原的过度免疫炎症反应以及免疫调节功能的缺失有关。临床多表现为抗病毒治疗后已有疾病的恶化或出现新发疾病。IRIS相关的感染原多见于分枝杆菌、新型隐球菌、巨细胞病毒等,临床上因特异性感染原的不同而表现各异。早期诊断、及时治疗IRIS,对更好地开展AIDS的抗病毒治疗非常重要。     

Immune reconstitution syndrome associated with leprosy: two cases

Few cases of leprosy as immune reconstitution syndrome have been reported in patients with HIV/AIDS. Two cases of leprosy as immune reconstitution syndrome in AIDS persons are described, and clinical features, diagnostic criteria and pathogenesis are discussed.     

Identifying risk factors of immune reconstitution inflammatory syndrome in AIDS patients receiving highly active anti-retroviral therapy

Immune reconstitution inflammation syndrome typically occurs within days after patients undergo highly active anti-retroviral therapy and is a big hurdle for effective treatment of AIDS patients. In this study, we monitored immune reconstitution inflammation syndrome occurrence in 238 AIDS patients treated with highly active anti-retroviral therapy. Among them, immune reconstitution inflammation syndrome occurred in 47 cases (19.7%). Immune reconstitution inflammation syndrome patients had significantly higher rate of opportunistic infection (p < 0.001) and persistently lower CD4⁺ cell count (p < 0.001) compared to the non-immune reconstitution inflammation syndrome patients. In contrast, no significant differences in HIV RNA loads were observed between the immune reconstitution inflammation syndrome group and non-immune reconstitution inflammation syndrome group. These data suggest that a history of opportunistic infection and CD4⁺ cell counts at baseline may function as risk factors for immune reconstitution inflammation syndrome occurrence in AIDS patients as well as potential prognostic markers. These findings will improve the management of AIDS with highly active anti-retroviral therapy.     

Interferon-alpha generation and immune reconstitution during antiretroviral therapy for human immunodeficiency virus infection

OBJECTIVES: To quantify the effect of HIV infection and HIV-suppressive therapy on interferon-alpha (IFN-alpha) production by human blood mononuclear cells; to compare, in parallel, effects on CD4+ T-cell numbers; and to ascertain the relationship of these interferon and CD4 parameters to resistance to opportunistic infections. DESIGN: Serial studies of 294 unselected patients with HIV infection during therapy, with outcomes analysis. METHODS: Determination of IFN generation by blood mononuclear cells via bioassay, and T-lymphocyte subset analysis via flow cytometry; serial studies of individual patients; linear regression and chi2 contingency table analysis. RESULTS: HIV burden is inversely related to interferon-alpha generation, much as it is to CD4+ T-cell counts. Both of these recover during HIV-suppressive therapy. Reconstitution of IFN-alpha generation to levels commensurate with protection against opportunistic infection occurs prior to similar restoration of CD4 counts. In the outcomes analyses, such immune reconstitution was associated with protection from recurrent or new opportunistic infection. Conversely, viral suppression without such immunologic recovery was not protective against opportunistic infection. CONCLUSIONS: Rapidly responding IFN-alpha generating cells appear to participate in resistance to opportunistic intracellular infection. Recovery of IFN-alpha generation may be an early marker of immune reconstitution in AIDS.     

Immune reconstitution after potent antiretroviral therapy in AIDS patients with progressive multifocal leukoencephalopathy

Neurological disease is the initial manifestation of acquired immunodeficiency syndrome (AIDS) in 10-20% of patients with HIV infection. Progressive multifocal leukoencephalopathy (PML) predominantly involves the cerebral hemispheres, with a small subset of patients having lesions predominantly or exclusively confined to the cerebellum. The radiological features of PML are typically non-inflammatory. As a result of potent antiretroviral therapy (ART), however, inflammatory lesions are becoming more common in HIV-infected individuals and are due, in part, to immune reconstitution that occurs in recipients of potent ART. In the majority of such cases, the clinical outcome of immune reconstitution PML has been beneficial to the host, although several case reports have described worsening or fatal outcomes in PML patients as a result of potent ART. The following 2 cases of immune reconstitution PML described in this report illustrate the varied radiological manifestations and clinical outcomes that can develop in AIDS patients with PML receiving potent ART. Moreover, these cases highlight the inflammatory changes observed on neuroimaging in AIDS patients with immune reconstitution PML receiving potent ART and to our knowledge are the first reports of immune reconstitution isolated to the cerebellum in such patients.     

FDG-PET/CT findings during immune reconstitution in an HIV-1 patient infected with visceral leishmaniasis

Visceral leishmaniasis can rarely be unmasked by immune reconstitution in human immunodeficiency virus (HIV)-1-infected patients. We report the first case of immune reconstitution associated with leishmaniasis in an HIV patient to be imaged with [¹⁸F]fluorodeoxyglucose positron emission tomography (FDG/PET), at both baseline and after therapy.     

Tegumentary leishmaniasis as a manifestation of immune reconstitution inflammatory syndrome in 2 patients with AIDS

Immune reconstitution inflammatory syndromes (IRISs) have been reported in patients with human immunodeficiency virus/acquired immunodeficiency syndrome (AIDS) since the introduction of highly active antiretroviral therapy (HAART). This syndrome is characterized by clinical manifestations of opportunistic infections when signs of immune reconstitution are observed during therapy. We report on leishmaniasis, suggestive of HAART-induced IRIS, in 2 patients with AIDS. After beginning HAART, 1 patient presented with disseminated, tegumentary lesions, whereas the other patient's preexisting lesions worsened and became more extensive; however, at the same time, their CD4(+) T cell counts were recovering and their virus loads were decreasing significantly. The lesions healed with anti-Leishmania therapy.     

Tuberculosis during early antiretroviral-induced immune reconstitution in HIV-infected children.

SETTING: Referral paediatric hospital, Cape Town, South Africa. OBJECTIVE: To describe the clinical manifestations of Mycobacterium tuberculosis (TB) associated disease in human immunodeficiency virus (HIV) infected children during early antiretroviral-induced immune reconstitution. DESIGN: Case series. RESULTS: Eleven patients with probable or culture confirmed TB were identified. Seven presented after a median 25 (range 8-54) days on highly active antiretroviral therapy (HAART) with pulmonary TB and one also had extra-pulmonary disease. Three of the patients had a prior history of TB and presented with relapse or recurrent disease. Four patients with TB developed a tuberculous paradoxical reaction; one died of suspected tuberculous immune reconstitution pneumonitis. The duration of pre-HAART anti-tuberculosis treatment and antiretroviral treatment ranged from 21 to 59 and 6 to 105 days, respectively, when they presented with a paradoxical reaction. Drug-resistant (isoniazid and rifampicin) TB was cultured from one patient with relapse disease. Chest radiograph features present during immune reconstitution were increasing or new intrathoracic lymphadenopathy, parenchymal infiltrates and pleural effusions. CONCLUSION: This report documents the clinical presentation of TB during the early phase of HAART which may be attributed to HAART-mediated immune reconstitution. More research is needed to improve the accuracy of TB diagnosis in HIV-infected children.     

Characteristics of autoimmune thyroid disease occurring as a late complication of immune reconstitution in patients with advanced human immunodeficiency virus (HIV) disease

Experimental evidence from animal models has provided a framework for our current understanding of autoimmune disease pathogenesis and supports the importance of genetic predisposition, molecular mimicry, and immune dysregulation. However, only recently has evidence emerged to support the role of immune dysregulation in human organ-specific autoimmune disease. In the current study of the "late" manifestation of autoimmune thyroid disease (AITD) in a cohort of human immunodeficiency virus (HIV)-positive patients following highly active antiretroviral therapy (HAART), we discuss how immune dysregulation and factors associated with the immunopathology of HIV infection fit the current understanding of autoimmunity and provide a plausible basis for our clinical observations. De novo diagnoses of thyroid disease were identified between 1996 and 2002 in 7 HIV treatment centers (5/7 centers completed the study). Patients were diagnosed as clinical case entities and not discovered through thyroid function test screening. Paired plasma specimens were used to demonstrate sequential rise in thyroid antibodies.Seventeen patients were diagnosed with AITD (median age, 38 yr; 65% were of black African or black Caribbean ethnicity; and 82% were female). The median duration of immune reconstitution was 17 months. Graves disease (GD) was diagnosed in 15 of 17 patients. One patient developed hashithyrotoxicosis with atypically raised C-reactive protein, and another developed hypothyroidism. One GD patient had associated secondary hypoadrenalism. The estimated combined prevalence of GD for 4 treatment centers for female patients was 7/234 and for males was 2/1289. The denominator numbers were matched controls, from 4 centers able to provide data, who commenced HAART during the same time (January 1996 to July 2002) and who did not develop clinical AITD. The mean baseline pre-HAART CD4 count was 67 cells/mL, and the mean increase from nadir to AITD presentation was 355 cells/mL. AITD patients were more likely than controls (95% confidence interval, chi-square test) to be severely compromised at baseline (as defined by a CD4 count < 200 cells/mL or the presence of an acquired immunodeficiency syndrome [AIDS]-defining diagnosis), and to experience greater CD4 increments following HAART. AITD may be a late manifestation of immune reconstitution in HIV-positive patients taking HAART, and immune dysregulation may be an important factor.     

A fatal case of kaposi sarcoma due to immune reconstitution inflammatory syndrome

The prevalence of AIDS-related Kaposi sarcoma (KS) has markedly declined in the era of highly active antiretroviral therapy (HAART) although it remains one of the most common AIDS-defining malignancies. Although immune reconstitution inflammatory syndrome (IRIS)-related KS (IRIS-KS) represents only a fraction of the IRIS cases, it can be a life-threatening situation. This report describes a fatal case of IRIS-KS. A 32-year-old man with HIV/AIDS was initiated on HAART and experienced rapid immunological and virological response to therapy. He subsequently experienced progressively severe dyspnea and papulonodular skin lesions and was admitted to the hospital with hypoxic respiratory failure. Bronchoscopy revealed numerous friable endobronchial lesions. Histopathology of a skin lesion was consistent with KS. The relatively rapid progression of disease in the setting of improvement in immune function after initiating HAART suggested IRIS-KS. This report reviews previously published cases of IRIS-KS and describes risk factors, immunopathogenesis and treatment options.