李夢苑， 葉傳濤， 張 穎， 賈戰(zhàn)生

(第四軍醫(yī)大學(xué)唐都醫(yī)院 傳染科，西安 710038)

HBV復(fù)制再激活研究進(jìn)展

李夢苑， 葉傳濤， 張 穎， 賈戰(zhàn)生

(第四軍醫(yī)大學(xué)唐都醫(yī)院 傳染科，西安 710038)

在非活動(dòng)性或已治愈的HBV感染者中，當(dāng)機(jī)體免疫穩(wěn)態(tài)被打破時(shí)，可能發(fā)生以肝臟炎癥反應(yīng)和HBV DNA水平增高為表現(xiàn)的HBV再激活(HBVr)現(xiàn)象，進(jìn)而引起不同程度的肝功能異常、肝衰竭甚至死亡。對(duì)于HBVr的篩查、免疫抑制方案的危險(xiǎn)分級(jí)以及患者個(gè)體情況等方面的系統(tǒng)性管理是亟待解決的問題，在免疫抑制治療及化療前篩查HBV血清學(xué)標(biāo)志，評(píng)估患者HBVr的發(fā)生風(fēng)險(xiǎn)，制訂合適的個(gè)體化預(yù)防性抗病毒治療方案尤為關(guān)鍵。徹底清除肝細(xì)胞內(nèi)cccDNA是預(yù)防HBVr發(fā)生的根本。從病因、發(fā)病機(jī)制、診斷、預(yù)防及治療等方面詳細(xì)介紹了HBVr的相關(guān)研究進(jìn)展。

肝炎病毒， 乙型； 病毒激活； 綜述

HBV是導(dǎo)致慢性肝臟疾病的重要因素之一，全球HBV感染者約4億，超過1/3的人曾感染過HBV[1]。HBV復(fù)制水平和炎癥反應(yīng)程度主要取決于宿主的免疫狀態(tài)[2]，當(dāng)機(jī)體因各種原因?qū)е虏《九c機(jī)體的免疫穩(wěn)態(tài)被打破，即可能發(fā)生HBV再激活(HBV reactivation，HBVr)，進(jìn)而引起肝損傷，甚至肝衰竭?，F(xiàn)就HBVr的定義、發(fā)生、診斷、預(yù)防及治療等方面作一綜述。

1 HBVr的定義

HBVr是指HBV DNA在非活動(dòng)性或已治愈的HBV感染者血清中突然再次出現(xiàn)或升高，往往伴隨肝臟炎癥活動(dòng)。HBVr常為偶發(fā)，一般發(fā)生于化療、免疫抑制治療后以及宿主免疫狀態(tài)改變時(shí)[3]。據(jù)報(bào)道[4]在慢性HBV感染者中，經(jīng)過免疫抑制治療后HBVr的發(fā)生率為20%～50%，可導(dǎo)致癥狀明顯的急性肝炎、肝衰竭，甚至死亡。

2 HBVr的誘因

2.1 應(yīng)用化療藥物 化療是治療實(shí)體腫瘤和血液系統(tǒng)腫瘤的主要手段之一，惡性腫瘤化療期間使用的細(xì)胞毒性化療藥物及免疫抑制制劑(皮質(zhì)類固醇、蒽環(huán)類藥物、細(xì)胞靶向生物制劑、抗代謝類藥物、酪氨酸激酶抑制劑等)均可導(dǎo)致HBVr的發(fā)生率明顯增高，報(bào)道病例最多的分別為淋巴瘤、乳腺癌、慢性淋巴細(xì)胞性白血病等。

2.1.1 皮質(zhì)類固醇 皮質(zhì)類固醇可通過抑制免疫效應(yīng)細(xì)胞，降低細(xì)胞因子活性，促進(jìn)病毒復(fù)制，并與HBV基因組中糖皮質(zhì)激素反應(yīng)元件結(jié)合，使HBV被充分激活，HBV的高度復(fù)制或(和)過度表達(dá)病毒抗原、病毒抗原的分泌障礙均可直接導(dǎo)致肝細(xì)胞損傷[4-5]。Yeo等[6]研究表明在128例接受化療的HBsAg陽性癌癥患者未經(jīng)抗病毒預(yù)防治療的情況下，類固醇激素的應(yīng)用是導(dǎo)致HBVr發(fā)生的獨(dú)立危險(xiǎn)因素，比值比為2.7(95%可信區(qū)間：1.0～7.2)。此外，皮質(zhì)類固醇的高劑量(潑尼松用量>20 mg/d)及長療程應(yīng)用(≥4周)都將使HBVr的發(fā)生率顯著升高[7]。

2.1.2 蒽環(huán)類藥物 蒽環(huán)類藥物屬于細(xì)胞周期非特異性藥物，廣泛應(yīng)用于急性白血病、惡性淋巴瘤、乳腺癌、肝癌和胃癌等腫瘤治療中，也是最早發(fā)現(xiàn)可誘發(fā)HBVr的腫瘤化療藥物之一。一項(xiàng)研究[8]選取接受不同化療方案治療的不同癌癥患者1149例，其中接受含多柔比星化療方案的214例患者中3例化療前HBsAg陰性患者在化療后發(fā)生了HBVr，其他組無HBVr病例，研究表明當(dāng)化療方案包含蒽環(huán)類藥物時(shí)，或?qū)⒃龈逪BVr的發(fā)生率。蒽環(huán)類藥物可于體外以劑量依賴的方式刺激HepG2.2.15細(xì)胞產(chǎn)生HBV DNA，在體外針對(duì)HepG2.2.15細(xì)胞系的研究[9]顯示多柔比星的應(yīng)用可增加HBV DNA的生成，且HBV DNA和HBsAg的分泌量隨多柔比星劑量的增加而增加，其機(jī)制可能在于多柔比星可特異地將細(xì)胞周期阻斷于G2/M期，已有研究[9]表明當(dāng)HepG2.2.15的細(xì)胞周期停止于G1、G2期時(shí)，HBV的復(fù)制水平增加。多柔比星的應(yīng)用也可擾亂HBV復(fù)制過程中的相關(guān)信號(hào)通路，導(dǎo)致HBVr的發(fā)生。

2.1.3 細(xì)胞靶向生物制劑 利妥昔單抗和奧法木單抗等抗CD20單抗可通過靶向B淋巴細(xì)胞表面CD20分子而起到殺傷B淋巴細(xì)胞的作用，是細(xì)胞靶向生物制劑的代表藥物，廣泛應(yīng)用于血液系統(tǒng)腫瘤及自身免疫性疾病。據(jù)報(bào)道[10]，約70%～80%的淋巴系統(tǒng)腫瘤為B淋巴細(xì)胞起源，且超過90%的B淋巴細(xì)胞瘤表面可表達(dá)CD20分子。利妥昔單抗的應(yīng)用在很大程度上可改善CD20陽性的B淋巴細(xì)胞瘤患者的預(yù)后。但當(dāng)其與非霍奇金淋巴瘤傳統(tǒng)CHOP方案(環(huán)磷酰胺+多柔比星+長春新堿+潑尼松)聯(lián)用，且無抗HBV預(yù)防性治療時(shí)，約有70% HBsAg陽性患者及10%～20% HBsAg陰性且抗-HBc陽性患者發(fā)生HBVr[11-12]。奧法木單抗作為利妥昔單抗耐藥后的替代治療藥物，其誘發(fā)HBVr的風(fēng)險(xiǎn)與利妥昔單抗相似。兩者均可與B淋巴細(xì)胞表面的CD20結(jié)合，通過補(bǔ)體依賴的細(xì)胞毒性作用和抗體依賴性細(xì)胞介導(dǎo)的細(xì)胞毒作用導(dǎo)致B淋巴細(xì)胞溶解，并抑制B淋巴細(xì)胞增殖，誘導(dǎo)B淋巴細(xì)胞凋亡，這一系列作用可直接導(dǎo)致由B淋巴細(xì)胞分化而來的漿細(xì)胞數(shù)量減少，繼而減少其抗體的產(chǎn)生，由此為化療后病毒的再激活創(chuàng)造了有利的條件[13]。此外，B淋巴細(xì)胞在HBV感染中除了產(chǎn)生中和抗體，其作為抗原遞呈細(xì)胞可與細(xì)胞毒性T淋巴細(xì)胞產(chǎn)生特異性應(yīng)答。利妥昔單抗可以誘導(dǎo)持久的B淋巴細(xì)胞缺失，使細(xì)胞毒性T淋巴細(xì)胞對(duì)HBV感染肝細(xì)胞的免疫反應(yīng)急劇下降，從而導(dǎo)致HBVr的發(fā)生[14]。

2.1.4 其他 其他細(xì)胞毒性藥物包括抗代謝類藥物如甲氨蝶呤、硫唑嘌呤、氟尿嘧啶等，植物堿如長春新堿，紫杉烷類如紫杉醇，酪氨酸激酶抑制劑如伊馬替尼，以及大環(huán)內(nèi)酯類免疫抑制劑等均被報(bào)道在化療期間可引發(fā)HBVr，但其具體機(jī)制仍不詳[4,15]。

2.2 應(yīng)用生物制劑 自身免疫性疾病應(yīng)用免疫抑制藥物和細(xì)胞毒性藥物所造成的HBVr已有廣泛報(bào)道。其中，TNFα類藥物如英夫利昔單抗應(yīng)用于類風(fēng)濕性關(guān)節(jié)炎、強(qiáng)直性脊柱炎、炎性腸病及銀屑病等引起HBVr的報(bào)道十分多見。2011年一項(xiàng)系統(tǒng)性綜述[16]表明，在257例HBV血清學(xué)標(biāo)志物陽性的患者中，應(yīng)用抗TNFα類藥物后，HBVr的總體發(fā)生率為39%，其中未進(jìn)行預(yù)防性抗病毒治療組中HBVr的發(fā)生率約是進(jìn)行預(yù)防性抗病毒治療組的2.5倍。英夫利昔單抗的應(yīng)用與肝損傷密切相關(guān)?？筎NFα所引起HBVr的機(jī)制尚未明確。有研究[17-23]表明，肝內(nèi)TNFα的表達(dá)水平與免疫平衡相關(guān)，高水平的TNFα可增強(qiáng)CD8+T淋巴細(xì)胞對(duì)病毒的應(yīng)答。TNFα阻斷劑通過靜脈給藥，可迅速達(dá)到血藥濃度的峰值從而產(chǎn)生最大生物效應(yīng)，但同時(shí)將不可避免的導(dǎo)致TNFα清除，進(jìn)而導(dǎo)致HBVr的發(fā)生。其他藥物如柳氮磺吡啶[24]、阿巴西普[25]等應(yīng)用后也有引起HBVr的報(bào)道，但仍缺乏循證醫(yī)學(xué)證據(jù)。2.3 器官與組織移植 實(shí)體器官移植如肝移植、腎移植、心臟移植、肺移植以及造血干細(xì)胞移植術(shù)后通常需要長期服用免疫抑制劑來抵抗供體與受體之間的排異反應(yīng)。據(jù)報(bào)道[26-27]，若器官供體HBsAg陽性，則在未進(jìn)行抗病毒預(yù)防性治療前，HBVr的發(fā)生率較高，在腎移植中可達(dá)50%～94%。肝移植中，若供體乙型肝炎血清學(xué)標(biāo)志物陽性，則受體發(fā)生HBVr的幾率將大大增加[28]。在異體造血干細(xì)胞移植術(shù)后，總HBVr發(fā)生率約為10%，且長療程使用環(huán)孢素及非低劑量利妥昔單抗是HBVr發(fā)生的獨(dú)立危險(xiǎn)因素[29]。環(huán)孢素引起HBVr的機(jī)制可能是由于抑制了Ca2+依賴的轉(zhuǎn)錄因子，如活化T淋巴細(xì)胞核因子，核因子-κB和IL-2等，上述細(xì)胞因子可較好地評(píng)估抗原特異性的細(xì)胞毒性T淋巴細(xì)胞的增殖和活化，從而使HBV的復(fù)制增加[30]。有研究表明[28]，術(shù)前抗-HBs陽性的受體在移植術(shù)后，抗-HBs滴度將逐漸減低直至消失，繼而出現(xiàn)HBV DNA及HBsAg。因此在肝移植術(shù)后應(yīng)用拉米夫定或肌注乙型肝炎免疫球蛋白保持抗-HBs滴度在前6個(gè)月>300 IU/μl，6個(gè)月后>100 IU/μl，可有效預(yù)防HBVr的發(fā)生[28]。

2.4 合并其他感染 合并其他病毒感染可影響HBV感染的自然史，引起HBVr的多數(shù)為與HIV或HCV的共感染。當(dāng)HIV病毒感染后機(jī)體處于免疫缺陷狀態(tài)，CD4+、CD8+T淋巴細(xì)胞數(shù)量減少，機(jī)會(huì)性感染增加，抗原遞呈過程中程序性死亡受體1/細(xì)胞程式死亡-配體1 相互作用所致的T淋巴細(xì)胞耗竭、調(diào)節(jié)性T淋巴細(xì)胞介導(dǎo)的免疫抑制均可能是HBV特異性免疫應(yīng)答低下的原因，從而使HBV呈高水平復(fù)制。在高效抗逆轉(zhuǎn)錄病毒治療后，其直接的藥物肝毒性、免疫重建炎性綜合征、HBV耐藥所導(dǎo)致的HBVr，均可增加患者的肝病相關(guān)死亡風(fēng)險(xiǎn)[31]。 HBx可通過反式轉(zhuǎn)錄激活因子、有絲分裂信號(hào)等增強(qiáng)HIV基因組兩端長末端重復(fù)序列活性，上調(diào)HIV RNA水平及其蛋白表達(dá)，從而使HIV活化，進(jìn)一步使HBV復(fù)制得以增強(qiáng)，且增加了HBV的病毒變異幾率[32-34]。

HBV/HCV擁有相同的傳播途徑，因而二者重疊感染在臨床上也較為常見。HBV/HCV共感染后不斷在動(dòng)態(tài)中發(fā)展持衡，通常表現(xiàn)為血清較高水平的HCV RNA和低水平的HBV DNA[35]。在HBV/HCV重疊感染人群中，臨床檢測HBsAg陰性的隱匿性HBV感染比例約為5%～10%[36]。相關(guān)研究[37-40]報(bào)道在以干擾素及利巴韋林為抗病毒方案的治療后，HCV病毒得以清除，但繼而偶發(fā)HBVr，其機(jī)制可能是在抗病毒治療后HCV獲得持久的病毒學(xué)應(yīng)答，HCV核心蛋白對(duì)HBV復(fù)制的抑制作用解除，從而使HBV再度激活。近期一項(xiàng)來自法國的研究[41]報(bào)道了4例HBV/HCV重疊感染者應(yīng)用直接抗病毒藥物(DAA)后在早期出現(xiàn)了HBVr，并且與HBV感染狀態(tài)無關(guān)，與DAA藥物種類無關(guān)。但也有研究[42]顯示在服用雷迪帕韋/索非布韋的173例患者中，60%為HBV/HCV重疊感染，均并未出現(xiàn)HBVr。因此，應(yīng)用DAA能否引起HBVr仍不明確。

3 HBVr的發(fā)生機(jī)制

臨床上HBVr通常發(fā)生于HBsAg陽性的慢性HBV感染者，偶可發(fā)生于非活動(dòng)性的HBsAg攜帶者、隱匿性HBV感染者及急性乙型肝炎痊愈后的部分人群[3]。若宿主的免疫狀態(tài)改變，則可能引起HBVr。HBVr的發(fā)生機(jī)制目前仍不十分清楚，但其始動(dòng)因素為針對(duì)HBV復(fù)制的免疫調(diào)控丟失這一觀點(diǎn)已經(jīng)達(dá)成共識(shí)。肝細(xì)胞cccDNA的持續(xù)存在是HBV復(fù)制的模板和再激活的基礎(chǔ)[43]，當(dāng)機(jī)體免疫狀態(tài)低下如應(yīng)用免疫抑制藥物后，淋巴細(xì)胞功能降低，抑制病毒復(fù)制的細(xì)胞因子的分泌也被抑制，均可促進(jìn)HBV的復(fù)制及其蛋白的表達(dá)[44]。當(dāng)免疫抑制作用解除后，淋巴細(xì)胞功能得到恢復(fù)，機(jī)體免疫系統(tǒng)得以重建，此時(shí)細(xì)胞毒性T淋巴細(xì)胞將識(shí)別表達(dá)在肝細(xì)胞表面的HBV蛋白，進(jìn)而殺傷肝細(xì)胞，導(dǎo)致急性的肝細(xì)胞損傷及壞死[45-47]。典型的HBVr可分為3個(gè)階段：(1)HBV復(fù)制增強(qiáng)期；(2)肝損傷期；(3)恢復(fù)期。但并非所有患者均遵循這3個(gè)階段，其病程與病毒載量及宿主免疫狀態(tài)相關(guān)。大部分的患者在經(jīng)歷過HBVr后僅表現(xiàn)為病毒的攜帶狀態(tài)而不出現(xiàn)相關(guān)的臨床癥狀，而部分患者可出現(xiàn)程度不等的肝臟炎癥反應(yīng)[3]。

4 HBVr的診斷

Yeo等[48]早在2004年時(shí)就明確提出，在免疫抑制治療期間或之后患者出現(xiàn)肝炎表現(xiàn)，且HBV DNA水平高于基線水平10倍以上或絕對(duì)值大于40 000 IU/ml，同時(shí)伴有ALT≥3倍正常值上限或增高絕對(duì)值≥100 U/L，在排除其他可能引起肝炎癥狀的病毒感染后，即可診斷為HBVr。除外HBV DNA，在免疫抑制治療期間定期監(jiān)測肝功能及HBV血清學(xué)標(biāo)志物對(duì)早期診斷HBVr也有重要意義。

5 預(yù)防及治療

5.1 HBVr的篩查 為了評(píng)估HBVr發(fā)生的風(fēng)險(xiǎn)并針對(duì)其進(jìn)行預(yù)防性干預(yù)，亞太肝病學(xué)會(huì)及歐洲肝病學(xué)會(huì)等同時(shí)強(qiáng)調(diào)，所有患者在進(jìn)行免疫抑制治療或化療前應(yīng)常規(guī)篩查HBV血清學(xué)標(biāo)志物，監(jiān)測HBsAg、抗-HBc，對(duì)于HBVr的預(yù)防十分重要。2012年歐洲肝病學(xué)會(huì)臨床實(shí)踐指南中強(qiáng)調(diào)，當(dāng)HBsAg陰性但抗-HBc陽性時(shí)，推薦篩查HBV DNA。美國胃腸病學(xué)會(huì)則推薦中危至高危人群應(yīng)普遍篩查HBsAg及抗-HBc，當(dāng)HBsAg陽性或抗-HBc陽性時(shí)，應(yīng)當(dāng)篩查HBV DNA。近期一項(xiàng)針對(duì)接受免疫抑制治療的HBsAg陰性、抗-HBc陽性患者的研究[49]表明，HBV核心相關(guān)抗原作為一種新的HBV病毒學(xué)標(biāo)志物，可作為免疫抑制治療前預(yù)測HBVr發(fā)生的重要指標(biāo)。

多項(xiàng)研究[50-53]顯示，在腫瘤化療前進(jìn)行HBV常規(guī)篩查的人數(shù)僅為總?cè)藬?shù)的13%～22%。 Stine等[54-55]分別調(diào)查了美國風(fēng)濕免疫科和皮膚科在使用生物制劑時(shí)對(duì)HBVr的篩查情況，分別有69%和53%的臨床醫(yī)師能夠在治療前意識(shí)到HBVr的發(fā)生風(fēng)險(xiǎn)。因此，相關(guān)科室提高對(duì)HBVr的認(rèn)識(shí)對(duì)其預(yù)防和治療尤為重要。

5.2 HBVr的預(yù)防 在進(jìn)行免疫抑制治療前，針對(duì)HBVr的預(yù)防十分關(guān)鍵。2014年美國胃腸病學(xué)會(huì)指南[56]提出，對(duì)除HBVr發(fā)生的低風(fēng)險(xiǎn)人群[包括HBsAg陽性/抗-HBc陽性或HBsAg陰性/抗-HBc陽性患者使用傳統(tǒng)免疫抑制劑、關(guān)節(jié)腔內(nèi)局部使用皮質(zhì)類固醇類藥物、口服皮質(zhì)類固醇類藥物療程<1周，或HBsAg陰性/抗-HBc陽性患者長期使用低劑量(≤10 mg)皮質(zhì)類固醇]，其他人群在接受免疫抑制治療前均推薦常規(guī)使用預(yù)防性抗病毒藥物。盡量改變免疫治療方案，避免使用容易引發(fā)HBVr的高危方案。預(yù)防性的抗病毒治療可顯著降低HBVr的發(fā)生率，其相對(duì)危險(xiǎn)度降低率為87%(95%可信區(qū)間：70%～94%)[56]，且可提高HBsAg陽性患者接受免疫抑制治療時(shí)的生存率[57]。預(yù)防性抗病毒治療通常分為2個(gè)階段：預(yù)防期和鞏固期。預(yù)防期治療開始的時(shí)間點(diǎn)目前尚不統(tǒng)一，但大多推薦抗病毒治療應(yīng)至少先于免疫抑制治療前1周。鞏固期通常需在結(jié)束化療后維持約12個(gè)月，至少達(dá)到化療結(jié)束的6個(gè)月。維持抗病毒治療的療程應(yīng)根據(jù)患者HBV DNA水平的動(dòng)態(tài)變化制訂相應(yīng)的個(gè)體化方案。預(yù)防性抗病毒藥物有拉米夫定、阿德福韋酯、恩替卡韋、替諾福韋和替比夫定。美國肝病研究學(xué)會(huì)和歐洲肝病學(xué)會(huì)均推薦當(dāng)預(yù)期療程少于12個(gè)月時(shí)，可選擇拉米夫定和替比夫定。當(dāng)HBV DNA基線水平較高、預(yù)期療程較長時(shí)，則盡量選用恩替卡韋和替諾福韋。一項(xiàng)針對(duì)彌漫性大B淋巴細(xì)胞瘤患者接受R-CHOP方案(美羅華+環(huán)磷酰胺+阿霉素+長春新堿+強(qiáng)的松)治療中使用恩替卡韋和拉米夫定預(yù)防HBVr的單中心隨機(jī)對(duì)照試驗(yàn)[58-59]表明，恩替卡韋在預(yù)防性抗病毒治療中優(yōu)于拉米夫定，HBVr的發(fā)生率分別為6.6%和30%。而阿德福韋酯因其較弱的抗病毒療效及潛在的腎毒性，并不是一線推薦的HBVr預(yù)防用藥。干擾素也因其骨髓抑制作用，使其應(yīng)用十分有限。

5.3 HBVr的治療 若在免疫抑制治療或化療前未進(jìn)行預(yù)防性抗病毒治療，一旦發(fā)生HBVr，將可能導(dǎo)致嚴(yán)重的肝衰竭，應(yīng)及時(shí)采取相應(yīng)措施。針對(duì)HBVr發(fā)生后的相關(guān)癥狀的對(duì)癥治療和及時(shí)的核苷和核苷酸類藥物抗病毒治療是治療的關(guān)鍵。免疫抑制治療的終止也有一定效果，但終止后仍可能使機(jī)體免疫系統(tǒng)重建，導(dǎo)致細(xì)胞毒性T淋巴細(xì)胞介導(dǎo)的大量肝細(xì)胞壞死。因此，這一措施的安全性及有效性仍需進(jìn)一步研究。6 展望

HBVr因其較高發(fā)病率和病死率在臨床上日益受到關(guān)注，因此對(duì)于HBVr的篩查、免疫抑制方案的危險(xiǎn)分級(jí)以及患者的個(gè)體情況等方面的系統(tǒng)性管理是亟待解決的問題。預(yù)防優(yōu)于補(bǔ)救，在免疫抑制治療及化療前篩查HBV血清學(xué)標(biāo)志物，評(píng)估患者HBVr的發(fā)生風(fēng)險(xiǎn)，制訂合適的個(gè)體化預(yù)防性抗病毒治療方案尤為關(guān)鍵。徹底清除肝細(xì)胞內(nèi)cccDNA是預(yù)防HBVr發(fā)生的根本，隨著HBV抗病毒治療及相關(guān)臨床研究的進(jìn)展，相信會(huì)為HBVr的解決帶來新的希望。

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引證本文：LI MY, YE CT, ZHANG Y, et al. Research advances in hepatitis B virus reactivation[J]. J Clin Hepatol, 2017, 33(4): 751-756. (in Chinese) 李夢苑， 葉傳濤， 張穎， 等. HBV復(fù)制再激活研究進(jìn)展[J]. 臨床肝膽病雜志, 2017, 33(4): 751-756.

(本文編輯：邢翔宇)

Research advances in hepatitis B virus reactivation

LIMengyuan,YEChuantao,ZHANGYing,etal.

(DepartmentofInfectiousDiseases,TangduHospital,FourthMilitaryMedicalUniversity,Xi′an710038,China)

In non-active or cured patients with hepatitis B virus (HBV) infection, when the body′s immune homeostasis is broken, HBV reactivation may occur, with the manifestations of liver inflammation and increased HBV DNA level, and lead to varying degrees of abnormal liver function, liver failure, and even death. Systematic management from the aspects of the screening of HBV reactivation, risk stratification of immunosuppression regimens, and patient's individual information needs to be solved urgently. It is very important to perform the screening of HBV serological markers before immunosuppressive therapy and chemotherapy, evaluate the risk of HBV reactivation, and develop individualized prophylactic antiviral therapy. Complete removal of covalently closed circular DNA in hepatocytes is essential for preventing HBV reactivation. This article summarizes related research advances in HBV reactivation from the aspects of its etiology, pathogenesis, diagnosis, prevention, and treatment.

hepatitis B virus； virus activation； reviews

10.3969/j.issn.1001-5256.2017.04.036

2016-10-25；

2016-11-28。

李夢苑(1992-)，女，主要從事HBV感染機(jī)制及細(xì)胞治療的研究。

賈戰(zhàn)生，電子信箱：jiazsh@fmmu.edu.cn。

R512.6

A

1001-5256(2017)04-0751-06