艾滋病与幽门螺杆菌感染关系的研究进展
Research Progress on the Relationship between HIV/AIDS and Helicobacter pylori Infection
DOI: 10.12677/acm.2024.1451544, PDF, HTML, XML, 下载: 40  浏览: 65 
作者: 谢玉娟:广州医科大学研究生院,广东 广州;詹远京*:广州医科大学附属市八医院消化内科,广东 广州
关键词: 幽门螺杆菌艾滋病CD4 T细胞免疫功能根除治疗Helicobacter pylori HIV/AIDS CD4 Tlymphocyte Immunity Eradication Therapy
摘要: 幽门螺杆菌和艾滋病都是全球性公共卫生问题,多年以来一直有研究关注两者相互感染的关系。多项研究的数据显示出幽门螺杆菌的发病率与艾滋病毒之间存在负相关,特别是在CD4 T淋巴细胞计数低于200 cells/μl阈值的患者,部分研究发现这类特殊人群的幽门螺杆菌根除效果似乎要比普通人群差。该综述主要从艾滋病毒合并幽门螺杆菌感染的流行情况、危险因素、治疗等方面进行描述。
Abstract: HIV/AIDS and Helicobacter pylori infections remain major global public health problems, many studies focus their attention on the relationship between HIV/AIDS and Helicobacter pylori. Several studies have detected a lower prevalence of H. pylori in patients with HIV infection, especially in patients with CD4 Tlymphocyte count below 200 cells/μl. Moreover, some studies have found that the eradication effect of Helicobacter pylori in this special population seems to be worse than that in the general population. This review describes the prevalence, risk factors and treatment of HIV complicated with Helicobacter pylori infection.
文章引用:谢玉娟, 詹远京. 艾滋病与幽门螺杆菌感染关系的研究进展[J]. 临床医学进展, 2024, 14(5): 1223-1229. https://doi.org/10.12677/acm.2024.1451544

1. 引言

幽门螺杆菌是一种定植于胃粘膜的革兰氏阴性、微嗜氧、有鞭毛的杆状细菌,主要以螺旋形式出现,主要以粪–口途径传播。高达95%的幽门螺杆菌感染者会发生以胃窦为基础的急性胃炎,随后演变为慢性活动性胃炎,多达50%的胃溃疡和80%的十二指肠溃疡与这种感染性胃炎有关 [1] 。不仅如此,幽门螺杆菌还是一种I类致癌物质 [2] ,与弥漫型和肠型胃癌的风险增加有关,可以通过胃炎→萎缩→肠化生→异型增生→癌的顺序发生发展;而且75%以上的MALT淋巴瘤患者可以检出幽门螺杆菌 [3] 。艾滋病毒感染人体后主要攻击人体的免疫系统,随着病程进展,免疫细胞进行性减少 [4] [5] ,免疫功能失去平衡,从而引起多种机会性感染 [6] ,但幽门螺杆菌感染不属于艾滋病毒机会性感染的范畴;两者合并感染的影响因素、相互作用机制等仍在持续探索中。

2. 艾滋病与幽门螺杆菌关系

2.1. 艾滋病毒合并幽门螺杆菌感染的流行情况

一项研究评估了幽门螺杆菌–艾滋病毒合并感染在全球、区域和次区域的流行情况,估计其全球患病率为1.7‰,且全世界各区域之间存在显著差异,这可能与感染动力学及诊断方法等因素相关 [7] 。多项研究的数据显示HIV阳性受试者幽门螺杆菌感染率较低 [8] [9] [10] 。Nevin等人的系统性综述中,剔除个案报道、综述、狭义文章和重复报道后纳入的29篇文章,除了一个例外,其余研究都报告了HIV阴性受试者的幽门螺杆菌感染率较高 [11] 。Eberhardt等人发现了更大的差异,在HIV阴性和HIV阳性中幽门螺杆菌的流行率分别为87.3%和56.2% [12] 。更有甚者,Fialho、Panos等人研究发现,与HIV阴性患者相比,HIV感染患者的幽门螺杆菌感染率几乎要低更多 [13] [14] 。儿童方面,在一项以医院为基础的调查中,感染HIV、未接受过HAART治疗的乌干达儿童的幽门螺杆菌感染率较低 [15] 。在伊朗,一项研究通过与匹配的对照组相比,发现HIV阳性患者幽门螺杆菌IgG抗体血清阳性率较高,而IgA抗体血清阳性率较低 [16] 。幽门螺杆菌感染后,血清学抗体需要半年左右的时间才会出现,故早期血清学检测有极大的可能出现假阴性,伊朗的这一研究结果与其他相反可能与此相关。

国内,许柯 [17] 等研究发现艾滋病(AIDS)患者中13C-尿素呼气试验检测阳性率低于非HIV感染人群(P < 0.05),提示艾滋病(AIDS)患者的幽门螺杆菌现症感染率低于非HIV感染人群。刘放 [18] 等人则选择14C-尿素呼气试验进行检测,结果显示HIV感染者的幽门螺杆菌感染率低于一般人群。程计林和白雪 [19] [20] 却发现尽管艾滋病组患者幽门螺杆菌感染率小于普通慢性胃病组,但差异无统计学意义(P > 0.05)。

Aleksandra [21] 等人则提出“随着抗逆转录病毒治疗(ART)从HAART前(1993~1997)到HAART早期(1999~2003)和现代HAART (2011~2015)的演变,艾滋病毒合并幽门螺杆菌感染的流行率是否随之改变”这一疑问。于是他们将212名艾滋病毒携带者(PLHIV)与1617名HIV阴性对照组进行了回顾性病例对照研究,通过比较三个确定的HAART期间内窥镜检查结果,发现HAART早期(30.2%)和现代HAART (34.4%) PLHIV合并幽门螺杆菌感染率显著高于HAART前合并感染率(18.2%);而现代HAART患者的较高比率与HIV阴性对照组相似(38.5%)。以上说明了随着抗逆转录病毒治疗(ART)的发展,HIV/幽门螺杆菌合并感染的患病率不断上升。类似的,有研究者根据抗逆转录病毒治疗三个不同时期分组,对706名接受胃肠道内镜检查的HIV感染患者进行了回顾性分析,得出以下结论:抗病毒治疗对艾滋病患者免疫功能的改善与消化系统疾病发生率的降低有一定的相关性;但在HAART时代,幽门螺杆菌感染、反流症状和胃食管反流病的也有所增加 [22] 。这可能是HAART期间患者的酸性分泌增加,也可能是机体免疫改善从而为幽门螺杆菌生长提供有利的条件。此外,在HAART时代,与大环内酯类化合物等抗幽门螺杆菌药物一起进行化学预防的使用显著减少,这也可能是幽门螺杆菌感染患病率增加的原因之一。

2.2. 幽门螺杆菌感染与CD4+T细胞及机体免疫功能的关系

HIV感染患者胃幽门螺杆菌检出率低于普通人群可能与CD4+T细胞计数低下引起的免疫功能低下有关 [23] 。Nevin的综述提出,有五项研究根据受试者的CD4+T细胞计数进行了分层,得出了相同的结论,即CD4+T细胞计数越低,幽门螺杆菌感染的发生率就越低 [24] [25] 。儿童也有类似特点,CD4+T细胞百分比低且HIV处于晚期临床阶段的儿童感染幽门螺杆菌的风险更低 [15] 。喀麦隆的一项研究也得出类似结论,在CD4+T细胞计数低于200 cells/μl的HIV患者中,幽门螺杆菌的流行率也较低 [26] 。加纳一所大学医院就诊的HIV患者中,幽门螺杆菌流行率与CD4+T细胞计数同时下降 [12] 。

Aleksandra等人通过回顾性分析1993年至2014年间因消化不良症状接受食管胃十二指肠镜检查的303例HIV患者和2642例HIV阴性患者Hp阳性胃炎的组织病理学结果,艾滋病毒与幽门螺杆菌混合感染患者的CD4+T细胞计数显著增加,大多超过200 cells/μl。但是,研究数据还表明CD4+T细胞计数与胃炎形态(P = 0.470)、幽门螺杆菌密度(P = 0.807)、胃炎活动性(P = 0.333)、淋巴滤泡的存在(P = 0.365)和肠化生(P = 0.331)无关 [27] 。Cacciarelli也发现以上特点,还观察到CD4+T细胞计数 < 200 cells/μl的HIV阳性组消化性溃疡要明显少于HIV阴性患者(P = 0.035) [28] 。苏东梅及罗红彬分别在广西、广东地区进行相关研究,得出HIV/AIDS患者幽门螺杆菌感染率低于健康人群的结论,并提出可能与CD4+T细胞计数低下形成胃黏膜免疫功能缺陷相关 [29] [30] 。Th1细胞、Th2细胞是幽门螺杆菌免疫反应的重要组成部分,SatoH在东京采用前瞻性横断面研究,探讨外周血肠归巢CD4+T细胞亚群与慢性幽门螺杆菌胃炎严重程度、胃粘膜幽门螺杆菌数量之间的关系;结果发现组织性胃炎患者外周血肠归巢CD4+T细胞显著高于非慢性胃炎患者,特别是Th1亚群,这表明肠道Th1细胞在HIV感染者慢性胃炎的发生发展中可能起关键作用 [31] 。CD4+T细胞低,机体免疫功能低下,致使胃黏膜局部炎症反应减弱从而不利于Hp的定植,可能降低了Hp的感染率。

2.3. 艾滋病毒合并幽门螺杆菌感染的危险因素

幽门螺杆菌的总体流行率被认为与社会经济条件相关,性别、职业、低社会经济地位、教育水平和饮酒等是幽门螺杆菌感染的已知危险因素 [32] 。Lee JE在2018年10月至2019年2月对韩国釜山国立大学医院门诊就诊的HIV感染者进行社会人口学信息问卷调查,Logistic多变量回归分析中,幽门螺杆菌血清阳性率与饮酒、高CD4+T细胞计数和40~59岁年龄组显著相关,吸烟状况、肥胖、性行为模式和HIV RNA病毒载量却与幽门螺杆菌血清阳性没有显著相关性 [33] 。但在这项研究中,作者没有进一步阐述这些危险因素与艾滋病毒合并幽门螺杆菌感染之间可能的机制等。Marcel Nkuize [34] 等人发现艾滋病毒合并幽门螺杆菌感染人群的以下特点:1) CD4+T细胞计数显著增加(P = 0.008),2) 更有可能是异性恋者(P = 0.047),3) 体重指数更高(P = 0.027),4) 十二指肠溃疡的发生率更高(P = 0.005),5) 病毒载量较低(P < 0.01)等。但是,我们并不能充分证明以上特点与混合感染之间的任何联系,更大的可能只是一种流行病学观察,没有生物决定因素。

幽门螺杆菌经口部分可被胃酸杀灭,剩余部分可通过产生尿素酶分解尿素,其后产生的氨与胃酸中和形成Hp定植及繁殖的微环境 [35] [36] 。马拉维人群中,幽门螺杆菌感染与胃酸过少有关,且与单独感染幽门螺杆菌相比,艾滋病毒和幽门螺杆菌联合感染与胃酸过少的相关性更强 [37] 。这种明显的累加效应的机制尚不明确,但似乎与慢性胃炎、HIV感染者的高胃泌素血症有关。Fabris [38] 对59例HIV阳性患者行胃镜检查及胃窦组织活检,检测血清胃泌素、胃蛋白酶原A、胃蛋白酶原C和壁细胞自身抗体等,发现幽门螺杆菌感染与CD4+计数 > 100 × 106/L的HIV阳性患者胃泌素和胃蛋白酶原C值升高有关。

2.4. 艾滋病毒合并幽门螺杆菌感染的治疗

幽门螺杆菌的根除治疗方案多种多样,经验性根除方案为三联根除(两种抗生素 + 一种质子泵抑制剂),而目前我国专家共识推荐尽可能应用含铋剂的四联根除方案(两种抗生素 + 一种质子泵抑制剂 + 一种铋剂),疗程通常为10到14天 [39] 。铋剂可上调幽门螺杆菌生长和代谢相关基因的表达,并阻止质子进入,从而防止细菌细胞质PH的降低,当细胞质PH值保持在中性粒细胞代谢活性增加的范围内时,生长依赖性抗生素的功效就会增强 [40] ;从而一定程度上能克服抗生素耐药性,使幽门螺杆菌根除率效率达到90% [41] [42] 。

Mesfu等在埃塞俄比亚中部进行了一项前瞻性、随机、干预性研究,随机选择HIV阳性/阴性的幽门螺杆菌感染参与者进行标准三联根除疗法;剔除失访者(一名HIV阳性,两名HIV阴性),总根除率为50.0%,其中HIV阴性者为62.5% (15/24),而HIV阳性者为37.5% (9/24),观察到在HIV感染者中有疗效降低的趋势 [43] 。Nkuize等通过病例对照研究发现HIV阳性组幽门螺杆菌根除失败率(24.1%)明显高于对照组(8.8%),其中病例组左氧氟沙星和甲硝唑耐药比例高于对照组(P < 0.05) [44] 。未能根除幽门螺杆菌感染在HIV阳性患者中更为常见可能与抗生素的选择、抗逆转录病毒治疗方案和生活方式等有关。

艾滋病毒合并幽门螺杆菌感染根除失败率较高的原因之一可能是抗生素耐药性 [45] [46] ,因为艾滋病患者经常会因为各种机会性感染而使用多种抗生素 [6] ,艾滋病毒合并幽门螺杆菌感染者则会增加感染抗生素耐药菌种的可能性。一项队列研究发现幽门螺杆菌分离株的主要抗生素(如克拉霉素、左氧氟沙星、甲硝唑)耐药性在HIV阳性个体中的发生率是HIV阴性个体的两倍 [47] ,这些数据提醒我们应该对HIV阳性合并幽门螺杆菌感染个体中的幽门螺杆菌抗菌素敏感性进行持续监测。Nkuize等人发现与HIV阴性患者相比,HIV阳性患者中原发性幽门螺杆菌耐药菌株的流行率更高 [48] 。幽门螺杆菌在胃炎、胃癌、胃黏膜淋巴瘤发生进展过程中发挥重要作用,因此根除治疗有一定的必要性,但艾滋病这类特殊人群幽门螺杆菌根除效果不佳,其疗效受多种因素影响,需要进一步研究来解决。

3. 总结与展望

综上所述,艾滋病毒合并幽门螺杆菌的感染率普遍较低,且与CD4+T细胞计数低下相关,特别是小于200 cells/μl;但随着HAART治疗的进展,幽门螺杆菌感染患病率较以往有所增加。艾滋病人群Hp感染率低可能与机体免疫功能低下、抗生素使用预防治疗机会性感染等相关。此外,也有一部分人尝试探讨艾滋病患者合并幽门螺杆菌感染的危险因素可能有胃酸过少、高胃泌素血症、高胃蛋白酶原、饮酒、肥胖等,但有些也许只是流行性特征,其深层的关系尚有待挖掘。艾滋病毒合并幽门螺杆菌感染根除失败率往往较普通人群高,这与抗生素耐药性、生活方式等有一定的关联。以上这些均需要进一步研究来解释说明。

NOTES

*通讯作者。

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