我国男男性行为人群中人类免疫缺陷病毒感染疫情特点及防治策略

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中国医科大学附属第一医院检验科，国家卫生和计划生育委员会艾滋病免疫学重点实验室，沈阳 110001

目前我国人类免疫缺陷病毒(human immunodeficiency virus，HIV)感染疫情总体处于低流行水平，全人群HIV感染率为0.058%，但全国报告的HIV/艾滋病(acquired immunodeficiency syndrome，AIDS)病例中经男男性行为(men who have sex with men，MSM)途径感染者所占比例增长迅速，1985～2005年MSM所占比例仅为0.3%，2006年为2.5%，2012年上升至19.1%。影响我国MSM人群中HIV感染疫情上升的因素很多，包括人口流动大、梅毒螺旋体感染率高、HIV检测比例低、传统生育观所致的MSM人群与异性婚育现象严重，以及社会大众对同性性行为的歧视现象等[1]，这些因素直接影响了艾滋病防控策略和措施的实施效果。现就我国MSM人群中HIV感染疫情特点和防治策略作一综述。

1 MSM人群中HIV感染流行病学特征

本团队近年来对上海、南京、沈阳、昆明、重庆等7个大中城市MSM人群开展的横断面系列调查研究发现，2012年HIV感染率为9.6%，显著高于2009年的6.8%，也显著高于2008年全国61个大中城市MSM人群平均4.9%的HIV感染率。2009年至今，对北京、沈阳、昆明等10个大中城市6 132名高危MSM人群的大规模前瞻性队列研究发现，HIV新发感染率为5.5/100人年(person year，PY)，高于同期我国女性性工作者(1.4/100 PY)和注射吸毒者(0.7/100 PY)[1,2]，提示MSM人群已成为我国HIV新发感染的主体人群。

2 MSM人群中HIV分子流行病学传播特征

截至2005年，我国MSM人群中流行的主要HIV毒株为欧美B亚型(占71.1%)，CRF_AE亚型仅占24.4%[3]。近年来随着MSM人群中HIV感染人数快速增长，流行亚型也呈现出新特征。至2012年，CRF_AE亚型已成为我国MSM人群中占主导地位的HIV毒株[4-8]，并明显分为2个独立的传播簇，其中一簇在我国南部、东南沿海及辽宁等地区广泛传播，另一簇则主要在北京及辽宁地区传播[9]。同时，在我国MSM人群中还发现了新型HIV重组株CRF55_01B和CRF59_01B，其中CRF55_01B在华南和中南地区某些城市流行率已达10%，CRF59_01B也散在分布于全国多个省份[10,11]。此外，我国MSM人群中HIV流行株的原发耐药比例亦明显高于其他途径的HIV感染人群[12-15]。新型HIV病毒株的出现和快速上升的原发HIV耐药率等因素加大了在MSM人群中控制HIV传播的难度，人们迫切需要探索适合我国的可有效降低MSM人群HIV新发感染水平的综合防治模式。

3 MSM人群中HIV急性感染者的早期发现

HIV感染早期病毒复制水平高，传染性强。及早发现感染者，对其早期进行干预，可有效降低HIV在急性感染期的二代传播，对HIV防控具有重要意义。以往常用第3代酶联免疫吸附试验(enzyme-linked immunosorbent assay，ELISA)进行HIV抗体检测，用于HIV感染筛查。由于HIV感染人体后有一段窗口期，病毒抗体不能被检出，可导致早期感染者的漏检。在窗口期进行P24抗原或病毒核酸检测，是HIV感染早期辅助诊断和进一步缩短窗口期的一种方法。使用多样品集合方法，对采供血机构和HIV抗体阴性的高危人群样品进行集合核酸检测，可及时发现窗口期感染。本团队研究显示，在以MSM人群为主的HIV高危人群中，通过高密度随访和第3代ELISA+集合核酸检测方法进行急性感染者的筛查，投入与产出比是1∶16.9，可节省医疗资源，有助于艾滋病防治的可持续发展[16]。此外，应用化学发光或第4代ELISA可同时检测HIV抗体及P24抗原，有利于窗口期感染者的发现。

4 MSM人群中HIV急性感染者的疾病进展及相关因素

HIV感染后疾病进展速度不同。70%～80%的个体感染后6～10年进入艾滋病期(典型HIV感染者)，仅10%～15%的HIV感染者3年内CD4+T细胞迅速下降(快速进展者)[17]。本团队通过对辽宁、北京及云南地区HIV新发感染者队列随访，发现约37%的新发感染者1年内CD4+T细胞数降至350个/μ l以下，疾病进展速度快于其他感染途径人群，且CD4+T细胞下降及病毒载量上升速度均高于欧洲等国MSM人群新发感染者[18]。早期发现并评估疾病进展速度，对快速进展者及早干预，对降低MSM人群的HIV感染病死率至关重要。国外研究显示，早期出现CXCR4嗜性毒株，感染多药耐药毒株或多重感染，白细胞介素7受体(interleukin 7 receptor，IL-7R)、蛋白精氨酸甲基转移酶6 (protein arginine methyltransferase 6, PRMT6)、CX3C趋化因子受体1(CX3C chemokine receptor 1，CX3CR1)、Toll样受体(Toll-like receptor，TLR)单核苷酸多态性、HIV特异性T细胞应答和浆细胞样树突细胞(plasmacytoid dendritic cell，pDC)数量下降，以及血浆γ 干扰素诱导蛋白10(interferon-γ -inducible protein 10，IP-10)、人类白细胞抗原G(human leukocyte antigen G，HLA-G)水平较高等，与疾病快速进展相关[19-29]。本团队对我国MSM人群中HIV感染者micro-RNA表达水平进行了研究，首次发现快速进展者microRNA明显低于非快速进展者，可预测疾病进展，功能研究发现其可能通过影响细胞凋亡信号通路发挥作用[30]。这组与疾病快速进展相关micro-RNA的发现，对开发HIV感染早期预测疾病进展的分子标记、实施早期干预具有重要意义。

5 MSM人群中HIV急性感染者的治疗前景

20世纪90年代以来，抗反转录病毒治疗(anti-retroviral therapy，ART)在全球广泛应用，明显降低了艾滋病的发病率及病死率。但ART不能彻底清除病毒，停药后病毒即反弹，患者需终身服药，其毒副作用及耐药等问题难以避免，成为艾滋病防控的瓶颈[31]。2013年，法国巴斯德研究所及美国霍普金斯大学研究人员报道了2个令人振奋的艾滋病“功能性治愈”信息。美国“密西西比州婴儿”出生时携带HIV，接受18个月ART，停药半年后检测不到具有复制能力的HIV[32]。法国14例早期HIV感染者接受平均36.5个月的ART，停药后平均随访89个月病毒亦未反弹，提示早期有效的ART可能使小部分HIV感染者实现功能性治愈(5%～15%)[33]。近期，《新英格兰杂志》报道了2项HIV感染早期抗病毒治疗队列的研究结果，均提示早期治疗有助于CD4+T细胞恢复[34,35]。但是，这2项研究并未探索早期治疗后临床症状是否得到改善，且均在感染早期病毒达到峰值后开始治疗，HIV可能已经导致人体广泛损伤[36]。因此，早期发现MSM人群中的HIV急性感染者，实施抗病毒治疗，探索其对病毒储存库清除、免疫重建及改善临床症状的效果，同时降低HIV二代传播，已成为HIV感染预防及治疗领域急需深入研究的重要课题。

6 MSM高危人群暴露前的预防策略

传统行为干预策略，如禁欲、保持单一性伴、100%使用安全套，以及扩大检测及时发现HIV感染者等，曾为降低MSM人群中HIV新发感染率发挥一定的积极作用。但该人群难以做到禁欲和保持单一性伴，且“信-知-行”分离现象较为突出，单纯开展健康教育和咨询已不能有效控制其无保护性肛交的发生率。因此，除行为干预措施外，生物医学防控策略已成为探索HIV感染预防的热点。一项在美国、泰国、南非等国家开展的国际多中心研究显示，采用暴露前预防用药(pre-exposure prophylaxis，PrEP)，MSM人群的HIV感染率降低44%[37]。针对异性性行为人群的研究结果显示，在肯尼亚和乌干达对HIV单阳配偶家庭实施PrEP，保护率达67%～75%[38]。Gomez等对预防HIV感染的卫生经济学分析显示，在高危人群中开展PrEP预防是一项具有较好收益的投资，但PrEP的经济有效性还取决于药物费用、流行状况、暴露前预防方案的覆盖和优先级策略，以及个体依从性和对PrEP效力的评估[39]。大规模服用PrEP药物，价格高昂，发展中国家难以承担，且目前PrEP需每天进行，可能存在HIV耐药的风险；长期常规采用PrEP者中，约70%出现头痛、腹泻、抑郁等不良反应[37]，7%出现严重药物不良反应[38]，且部分接受PrEP的高危人群易发生更多的无保护性行为，感染HIV的风险反而增加。PrEP对预防我国MSM人群中HIV新发感染的预防作用尚处于研究评估阶段。

7 HIV疫苗研究任重道远

2007年，被科学界广泛寄予厚望的艾滋病候选疫苗——复制缺陷型Ad5腺病毒载体疫苗Ⅱb期临床试验宣告失败，给艾滋病疫苗研究带来重创[40]。目前唯一显示有效性的艾滋病疫苗试验为RV144试验，其采用重组金丝雀痘病毒载体疫苗ALVAC初次免疫，重组gp120亚单位疫苗AIDSVAX加强，可将HIV感染率降低31.2%[41]。尽管RV144的有效性有限，但为HIV疫苗研究带来了曙光，对HIV疫苗研究具有重要意义。近年来，从HIV感染者体内分离并鉴定出具有广泛中和活性的抗体，成为艾滋病研究领域中的主要突破之一[42]。动物模型研究显示，广谱中和抗体能有效阻止HIV感染或在感染动物中抑制病毒复制[43,44]，但目前为止尚无有效疫苗能在人体中诱导产生这些抗体[45]。CD8+T细胞应答对控制病毒的重要作用使其在疫苗研发中仍具有重要意义[46]。近期，Picker团队研究发现，一种对猴免疫缺陷病毒(simian immunodeficiency virus，SIV)感染具有保护作用的SIV基因重组巨细胞病毒载体，可诱导识别由主要组织相容性复合体(major histocompatibility complex，MHC)Ⅰ及Ⅱ呈递广谱多肽的CD8+T细胞，对基于细胞免疫的疫苗研制具有重要意义[47]。此外，科学家也在积极研究探讨能否使天然免疫应答成为疫苗策略的一部分[48]。2013年4月，处于Ⅱb期的基于DNA/Ad5的HVTN505 HIV疫苗临床试验由于其不能降低HIV感染而被叫停，使HIV疫苗研究又遭挫折，HIV疫苗的研究任重而道远。

综上所述，MSM人群已成为我国HIV新发感染的主体，系统研究MSM人群中HIV新发感染特点、疾病进展速度及关键影响因素，有针对性地实施综合干预，探索早期治疗疗效，对降低我国艾滋病的发病率及病死率具有重要意义。

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