我國男男性行為人群中人類免疫缺陷病毒感染疫情特點(diǎn)及防治策略

尚紅

中國醫(yī)科大學(xué)附屬第一醫(yī)院檢驗(yàn)科，國家衛(wèi)生和計(jì)劃生育委員會(huì)艾滋病免疫學(xué)重點(diǎn)實(shí)驗(yàn)室，沈陽 110001

目前我國人類免疫缺陷病毒(human immunodeficiency virus，HIV)感染疫情總體處于低流行水平，全人群HIV感染率為0.058%，但全國報(bào)告的HIV/艾滋病(acquired immunodeficiency syndrome，AIDS)病例中經(jīng)男男性行為(men who have sex with men，MSM)途徑感染者所占比例增長迅速，1985～2005年MSM所占比例僅為0.3%，2006年為2.5%，2012年上升至19.1%。影響我國MSM人群中HIV感染疫情上升的因素很多，包括人口流動(dòng)大、梅毒螺旋體感染率高、HIV檢測比例低、傳統(tǒng)生育觀所致的MSM人群與異性婚育現(xiàn)象嚴(yán)重，以及社會(huì)大眾對同性性行為的歧視現(xiàn)象等[1]，這些因素直接影響了艾滋病防控策略和措施的實(shí)施效果?，F(xiàn)就我國MSM人群中HIV感染疫情特點(diǎn)和防治策略作一綜述。

1 MSM人群中HIV感染流行病學(xué)特征

本團(tuán)隊(duì)近年來對上海、南京、沈陽、昆明、重慶等7個(gè)大中城市MSM人群開展的橫斷面系列調(diào)查研究發(fā)現(xiàn)，2012年HIV感染率為9.6%，顯著高于2009年的6.8%，也顯著高于2008年全國61個(gè)大中城市MSM人群平均4.9%的HIV感染率。2009年至今，對北京、沈陽、昆明等10個(gè)大中城市6 132名高危MSM人群的大規(guī)模前瞻性隊(duì)列研究發(fā)現(xiàn)，HIV新發(fā)感染率為5.5/100人年(person year，PY)，高于同期我國女性性工作者(1.4/100 PY)和注射吸毒者(0.7/100 PY)[1,2]，提示MSM人群已成為我國HIV新發(fā)感染的主體人群。

2 MSM人群中HIV分子流行病學(xué)傳播特征

截至2005年，我國MSM人群中流行的主要HIV毒株為歐美B亞型(占71.1%)，CRF_AE亞型僅占24.4%[3]。近年來隨著MSM人群中HIV感染人數(shù)快速增長，流行亞型也呈現(xiàn)出新特征。至2012年，CRF_AE亞型已成為我國MSM人群中占主導(dǎo)地位的HIV毒株[4-8]，并明顯分為2個(gè)獨(dú)立的傳播簇，其中一簇在我國南部、東南沿海及遼寧等地區(qū)廣泛傳播，另一簇則主要在北京及遼寧地區(qū)傳播[9]。同時(shí)，在我國MSM人群中還發(fā)現(xiàn)了新型HIV重組株CRF55_01B和CRF59_01B，其中CRF55_01B在華南和中南地區(qū)某些城市流行率已達(dá)10%，CRF59_01B也散在分布于全國多個(gè)省份[10,11]。此外，我國MSM人群中HIV流行株的原發(fā)耐藥比例亦明顯高于其他途徑的HIV感染人群[12-15]。新型HIV病毒株的出現(xiàn)和快速上升的原發(fā)HIV耐藥率等因素加大了在MSM人群中控制HIV傳播的難度，人們迫切需要探索適合我國的可有效降低MSM人群HIV新發(fā)感染水平的綜合防治模式。

3 MSM人群中HIV急性感染者的早期發(fā)現(xiàn)

HIV感染早期病毒復(fù)制水平高，傳染性強(qiáng)。及早發(fā)現(xiàn)感染者，對其早期進(jìn)行干預(yù)，可有效降低HIV在急性感染期的二代傳播，對HIV防控具有重要意義。以往常用第3代酶聯(lián)免疫吸附試驗(yàn)(enzyme-linked immunosorbent assay，ELISA)進(jìn)行HIV抗體檢測，用于HIV感染篩查。由于HIV感染人體后有一段窗口期，病毒抗體不能被檢出，可導(dǎo)致早期感染者的漏檢。在窗口期進(jìn)行P24抗原或病毒核酸檢測，是HIV感染早期輔助診斷和進(jìn)一步縮短窗口期的一種方法。使用多樣品集合方法，對采供血機(jī)構(gòu)和HIV抗體陰性的高危人群樣品進(jìn)行集合核酸檢測，可及時(shí)發(fā)現(xiàn)窗口期感染。本團(tuán)隊(duì)研究顯示，在以MSM人群為主的HIV高危人群中，通過高密度隨訪和第3代ELISA+集合核酸檢測方法進(jìn)行急性感染者的篩查，投入與產(chǎn)出比是1∶16.9，可節(jié)省醫(yī)療資源，有助于艾滋病防治的可持續(xù)發(fā)展[16]。此外，應(yīng)用化學(xué)發(fā)光或第4代ELISA可同時(shí)檢測HIV抗體及P24抗原，有利于窗口期感染者的發(fā)現(xiàn)。

4 MSM人群中HIV急性感染者的疾病進(jìn)展及相關(guān)因素

HIV感染后疾病進(jìn)展速度不同。70%～80%的個(gè)體感染后6～10年進(jìn)入艾滋病期(典型HIV感染者)，僅10%～15%的HIV感染者3年內(nèi)CD4+T細(xì)胞迅速下降(快速進(jìn)展者)[17]。本團(tuán)隊(duì)通過對遼寧、北京及云南地區(qū)HIV新發(fā)感染者隊(duì)列隨訪，發(fā)現(xiàn)約37%的新發(fā)感染者1年內(nèi)CD4+T細(xì)胞數(shù)降至350個(gè)/μ l以下，疾病進(jìn)展速度快于其他感染途徑人群，且CD4+T細(xì)胞下降及病毒載量上升速度均高于歐洲等國MSM人群新發(fā)感染者[18]。早期發(fā)現(xiàn)并評估疾病進(jìn)展速度，對快速進(jìn)展者及早干預(yù)，對降低MSM人群的HIV感染病死率至關(guān)重要。國外研究顯示，早期出現(xiàn)CXCR4嗜性毒株，感染多藥耐藥毒株或多重感染，白細(xì)胞介素7受體(interleukin 7 receptor，IL-7R)、蛋白精氨酸甲基轉(zhuǎn)移酶6 (protein arginine methyltransferase 6, PRMT6)、CX3C趨化因子受體1(CX3C chemokine receptor 1，CX3CR1)、Toll樣受體(Toll-like receptor，TLR)單核苷酸多態(tài)性、HIV特異性T細(xì)胞應(yīng)答和漿細(xì)胞樣樹突細(xì)胞(plasmacytoid dendritic cell，pDC)數(shù)量下降，以及血漿γ 干擾素誘導(dǎo)蛋白10(interferon-γ -inducible protein 10，IP-10)、人類白細(xì)胞抗原G(human leukocyte antigen G，HLA-G)水平較高等，與疾病快速進(jìn)展相關(guān)[19-29]。本團(tuán)隊(duì)對我國MSM人群中HIV感染者micro-RNA表達(dá)水平進(jìn)行了研究，首次發(fā)現(xiàn)快速進(jìn)展者microRNA明顯低于非快速進(jìn)展者，可預(yù)測疾病進(jìn)展，功能研究發(fā)現(xiàn)其可能通過影響細(xì)胞凋亡信號通路發(fā)揮作用[30]。這組與疾病快速進(jìn)展相關(guān)micro-RNA的發(fā)現(xiàn)，對開發(fā)HIV感染早期預(yù)測疾病進(jìn)展的分子標(biāo)記、實(shí)施早期干預(yù)具有重要意義。

5 MSM人群中HIV急性感染者的治療前景

20世紀(jì)90年代以來，抗反轉(zhuǎn)錄病毒治療(anti-retroviral therapy，ART)在全球廣泛應(yīng)用，明顯降低了艾滋病的發(fā)病率及病死率。但ART不能徹底清除病毒，停藥后病毒即反彈，患者需終身服藥，其毒副作用及耐藥等問題難以避免，成為艾滋病防控的瓶頸[31]。2013年，法國巴斯德研究所及美國霍普金斯大學(xué)研究人員報(bào)道了2個(gè)令人振奮的艾滋病“功能性治愈”信息。美國“密西西比州嬰兒”出生時(shí)攜帶HIV，接受18個(gè)月ART，停藥半年后檢測不到具有復(fù)制能力的HIV[32]。法國14例早期HIV感染者接受平均36.5個(gè)月的ART，停藥后平均隨訪89個(gè)月病毒亦未反彈，提示早期有效的ART可能使小部分HIV感染者實(shí)現(xiàn)功能性治愈(5%～15%)[33]。近期，《新英格蘭雜志》報(bào)道了2項(xiàng)HIV感染早期抗病毒治療隊(duì)列的研究結(jié)果，均提示早期治療有助于CD4+T細(xì)胞恢復(fù)[34,35]。但是，這2項(xiàng)研究并未探索早期治療后臨床癥狀是否得到改善，且均在感染早期病毒達(dá)到峰值后開始治療，HIV可能已經(jīng)導(dǎo)致人體廣泛損傷[36]。因此，早期發(fā)現(xiàn)MSM人群中的HIV急性感染者，實(shí)施抗病毒治療，探索其對病毒儲(chǔ)存庫清除、免疫重建及改善臨床癥狀的效果，同時(shí)降低HIV二代傳播，已成為HIV感染預(yù)防及治療領(lǐng)域急需深入研究的重要課題。

6 MSM高危人群暴露前的預(yù)防策略

傳統(tǒng)行為干預(yù)策略，如禁欲、保持單一性伴、100%使用安全套，以及擴(kuò)大檢測及時(shí)發(fā)現(xiàn)HIV感染者等，曾為降低MSM人群中HIV新發(fā)感染率發(fā)揮一定的積極作用。但該人群難以做到禁欲和保持單一性伴，且“信-知-行”分離現(xiàn)象較為突出，單純開展健康教育和咨詢已不能有效控制其無保護(hù)性肛交的發(fā)生率。因此，除行為干預(yù)措施外，生物醫(yī)學(xué)防控策略已成為探索HIV感染預(yù)防的熱點(diǎn)。一項(xiàng)在美國、泰國、南非等國家開展的國際多中心研究顯示，采用暴露前預(yù)防用藥(pre-exposure prophylaxis，PrEP)，MSM人群的HIV感染率降低44%[37]。針對異性性行為人群的研究結(jié)果顯示，在肯尼亞和烏干達(dá)對HIV單陽配偶家庭實(shí)施PrEP，保護(hù)率達(dá)67%～75%[38]。Gomez等對預(yù)防HIV感染的衛(wèi)生經(jīng)濟(jì)學(xué)分析顯示，在高危人群中開展PrEP預(yù)防是一項(xiàng)具有較好收益的投資，但PrEP的經(jīng)濟(jì)有效性還取決于藥物費(fèi)用、流行狀況、暴露前預(yù)防方案的覆蓋和優(yōu)先級策略，以及個(gè)體依從性和對PrEP效力的評估[39]。大規(guī)模服用PrEP藥物，價(jià)格高昂，發(fā)展中國家難以承擔(dān)，且目前PrEP需每天進(jìn)行，可能存在HIV耐藥的風(fēng)險(xiǎn)；長期常規(guī)采用PrEP者中，約70%出現(xiàn)頭痛、腹瀉、抑郁等不良反應(yīng)[37]，7%出現(xiàn)嚴(yán)重藥物不良反應(yīng)[38]，且部分接受PrEP的高危人群易發(fā)生更多的無保護(hù)性行為，感染HIV的風(fēng)險(xiǎn)反而增加。PrEP對預(yù)防我國MSM人群中HIV新發(fā)感染的預(yù)防作用尚處于研究評估階段。

7 HIV疫苗研究任重道遠(yuǎn)

2007年，被科學(xué)界廣泛寄予厚望的艾滋病候選疫苗——復(fù)制缺陷型Ad5腺病毒載體疫苗Ⅱb期臨床試驗(yàn)宣告失敗，給艾滋病疫苗研究帶來重創(chuàng)[40]。目前唯一顯示有效性的艾滋病疫苗試驗(yàn)為RV144試驗(yàn)，其采用重組金絲雀痘病毒載體疫苗ALVAC初次免疫，重組gp120亞單位疫苗AIDSVAX加強(qiáng)，可將HIV感染率降低31.2%[41]。盡管RV144的有效性有限，但為HIV疫苗研究帶來了曙光，對HIV疫苗研究具有重要意義。近年來，從HIV感染者體內(nèi)分離并鑒定出具有廣泛中和活性的抗體，成為艾滋病研究領(lǐng)域中的主要突破之一[42]。動(dòng)物模型研究顯示，廣譜中和抗體能有效阻止HIV感染或在感染動(dòng)物中抑制病毒復(fù)制[43,44]，但目前為止尚無有效疫苗能在人體中誘導(dǎo)產(chǎn)生這些抗體[45]。CD8+T細(xì)胞應(yīng)答對控制病毒的重要作用使其在疫苗研發(fā)中仍具有重要意義[46]。近期，Picker團(tuán)隊(duì)研究發(fā)現(xiàn)，一種對猴免疫缺陷病毒(simian immunodeficiency virus，SIV)感染具有保護(hù)作用的SIV基因重組巨細(xì)胞病毒載體，可誘導(dǎo)識別由主要組織相容性復(fù)合體(major histocompatibility complex，MHC)Ⅰ及Ⅱ呈遞廣譜多肽的CD8+T細(xì)胞，對基于細(xì)胞免疫的疫苗研制具有重要意義[47]。此外，科學(xué)家也在積極研究探討能否使天然免疫應(yīng)答成為疫苗策略的一部分[48]。2013年4月，處于Ⅱb期的基于DNA/Ad5的HVTN505 HIV疫苗臨床試驗(yàn)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遠(yuǎn)。

綜上所述，MSM人群已成為我國HIV新發(fā)感染的主體，系統(tǒng)研究MSM人群中HIV新發(fā)感染特點(diǎn)、疾病進(jìn)展速度及關(guān)鍵影響因素，有針對性地實(shí)施綜合干預(yù)，探索早期治療療效，對降低我國艾滋病的發(fā)病率及病死率具有重要意義。

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