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        核苷和核苷酸類藥物治療慢性乙型肝炎的長期性

        2014-04-28 06:00:10參加慢性乙型肝炎長期治療討論會專家
        傳染病信息 2014年6期
        關(guān)鍵詞:抗病毒乙型肝炎纖維化

        參加慢性乙型肝炎長期治療討論會專家

        ·特別報道·

        核苷和核苷酸類藥物治療慢性乙型肝炎的長期性

        參加慢性乙型肝炎長期治療討論會專家

        核苷和核苷酸類藥物(NAs)已成功用于慢性乙型肝炎(CHB)治療。目前一致認(rèn)為,乙型肝炎病毒(HBV)復(fù)制是肝損傷和疾病進(jìn)展的關(guān)鍵因素,因此CHB治療的主要目的是最大限度地持續(xù)抑制HBV復(fù)制。現(xiàn)已證明,應(yīng)用NAs長期治療CHB可明顯改善肝臟組織學(xué)、逆轉(zhuǎn)肝纖維化或肝硬化,以及減少肝細(xì)胞癌的發(fā)生。本文對CHB長期治療的必要性、臨床獲益及管理進(jìn)行了綜述。

        肝炎,乙型,慢性;核苷和核苷酸類藥物;長期治療;管理

        近20年來,臨床和流行病學(xué)研究表明,持續(xù)、活躍的乙型肝炎病毒(HBV)復(fù)制是慢性乙型肝炎(CHB)疾病進(jìn)展的最重要因素,只有長期抑制HBV復(fù)制,才有可能防止疾病進(jìn)展。但HBV在復(fù)制過程中,在肝細(xì)胞核內(nèi)形成共價閉合環(huán)狀DNA(cccDNA)并可持續(xù)存在[1];核苷和核苷酸類藥物(NAs)主要抑制HBV復(fù)制的逆轉(zhuǎn)錄環(huán)節(jié),對cccDNA無直接抑制或清除作用;CHB患者存在特異性免疫功能障礙[2-5],而NAs無直接的免疫調(diào)節(jié)作用[5]。因此,現(xiàn)有NAs抗病毒治療很難徹底清除HBV,僅部分HBV e抗原(HBeAg)陽性并伴有明顯丙氨酸氨基轉(zhuǎn)移酶(ALT)升高的患者可實(shí)現(xiàn)HBeAg血清學(xué)轉(zhuǎn)換,甚至HBV表面抗原(HBsAg)消失或HBsAg血清學(xué)轉(zhuǎn)換,而大部分CHB患者,尤其是HBeAg陰性CHB和肝硬化患者,需要長期抗病毒治療[6]。因此,目前國內(nèi)外CHB管理指南或共識均將治療目標(biāo)確定為:最大限度地長期抑制HBV復(fù)制,減輕肝細(xì)胞炎癥壞死和纖維化,延緩和減少肝臟失代償、肝硬化、肝細(xì)胞癌(HCC)及其并發(fā)癥的發(fā)生,從而改善生活質(zhì)量和延長存活時間[7-10]。為幫助臨床醫(yī)生正確認(rèn)識NAs治療的長期性,合理選擇抗病毒藥物、系統(tǒng)監(jiān)測其療效和不良事件并長期隨訪其臨床轉(zhuǎn)歸,國內(nèi)部分肝臟病學(xué)和感染病學(xué)專家根據(jù)國內(nèi)外最新研究證據(jù),經(jīng)過認(rèn)真討論和反復(fù)修改,最終形成本文。

        1 NAs長期治療的必要性

        1.1 病毒因素HBV復(fù)制過程可分6個環(huán)節(jié):①病毒進(jìn)入肝細(xì)胞漿,其核衣殼被裂解而形成松弛型環(huán)狀DNA(rcDNA),后者進(jìn)入肝細(xì)胞核,并在病毒DNA聚合酶和宿主酶的作用下,修復(fù)rcDNA成為cccDNA;②以cccDNA為模板,在宿主細(xì)胞RNA聚合酶作用下,轉(zhuǎn)錄成4種不同長度的病毒信使RNA(mRNA)和前基因組RNA(pgRNA),翻譯HBV的各種蛋白;③病毒聚合酶和衣殼化信號共同作用于pgRNA,啟動逆轉(zhuǎn)錄和核衣殼組裝;④通過逆轉(zhuǎn)錄,合成病毒負(fù)鏈DNA,同時病毒聚合酶消化病毒RNA模板;⑤病毒負(fù)鏈DNA合成后,剩余的RNA作為引物,啟動正鏈DNA合成;⑥完成正鏈DNA合成,形成rcDNA,同時核衣殼被包被上外膜并作為感染性病毒體分泌至細(xì)胞外;或再回到同一個肝細(xì)胞核內(nèi),擴(kuò)增或維持cccDNA庫[11-14](圖1)。

        現(xiàn)有的NAs只作用于HBV復(fù)制的③、④、⑤環(huán)節(jié),對病毒復(fù)制的其他環(huán)節(jié)無明顯作用。因此,cccDNA可在肝細(xì)胞內(nèi)持續(xù)存在并作為HBV的復(fù)制模板,持續(xù)產(chǎn)生子代HBV,感染其他肝細(xì)胞。

        圖1 乙型肝炎病毒復(fù)制過程及NAs作用靶點(diǎn)Figure 1 Replication course of HBV and action target of NAs

        cccDNA一旦在肝細(xì)胞核內(nèi)形成,即具有高度穩(wěn)定性,可持續(xù)產(chǎn)生子代病毒而不受細(xì)胞分裂的影響。據(jù)數(shù)學(xué)模型推算,應(yīng)用阿德福韋酯(ADV)治療的患者,需要14.5年才能完全清除其肝細(xì)胞核中的cccDNA[1,15]。因此,盡管NAs治療可有效抑制HBV復(fù)制,少數(shù)患者可達(dá)到HBeAg血清學(xué)轉(zhuǎn)換甚至HBsAg消失,但肝細(xì)胞核內(nèi)仍可能殘存cccDNA,停藥后仍有可能復(fù)發(fā)[16-18]。

        1.2 藥物因素NAs在細(xì)胞內(nèi)經(jīng)磷酸化后,生成三磷酸核苷活性產(chǎn)物,通過競爭抑制作用,阻止內(nèi)源性核苷酸參與HBVDNA的復(fù)制,快速有效地減少HBV DNA的合成[19]。有研究表明,ADV、替諾福韋酯(TDF)、恩替卡韋(ETV)和替比夫定(LdT)可抑制逆轉(zhuǎn)錄啟動;拉米夫定(LAM)、ADV、TDF、ETV和LdT可抑制病毒負(fù)鏈DNA合成;ETV和LdT可抑制正鏈DNA合成(圖1)[20],但對HBV復(fù)制的中間產(chǎn)物cccDNA不起作用。因此,NAs不能清除在治療前已存在的,或在治療過程中因未完全抑制HBV復(fù)制而新產(chǎn)生的cccDNA。

        此外,cccDNA、HBeAg和HBsAg的減少或清除主要依賴于宿主免疫系統(tǒng)的作用[1,13]。NAs可暫時改善機(jī)體對HBV的免疫應(yīng)答[21-27],但無直接免疫調(diào)節(jié)作用[5]。盡管NAs可有效降低肝細(xì)胞和血清中HBV DNA水平,但對血清中HBeAg和HBsAg水平無明顯降低作用[16,18-20]。因此,NAs有限療程治療難以達(dá)到停藥后持久的免疫應(yīng)答。

        1.3 宿主因素慢性HBV感染是一個長期的發(fā)展過程[7]。在我國,接受NAs治療的CHB患者中,大部分是在嬰幼兒時期感染HBV,其病程較長,一般肝組織學(xué)均表現(xiàn)有不同程度的壞死炎癥和肝纖維化,甚至肝硬化。但肝臟組織學(xué)改善尤其是纖維化改善需要較長的期限。Chang等[22]隨訪57例經(jīng)ETV治療的HBeAg陽性或陰性患者,發(fā)現(xiàn)治療48周時Ishak纖維化評分下降1者僅為32%(18/57),但治療至中位時間6年(范圍3~7年)時,Ishak纖維化評分下降1者升至88%(50/57)。

        1.4 臨床實(shí)踐臨床實(shí)踐表明,即使按照國內(nèi)外現(xiàn)行CHB管理指南或共識建議的標(biāo)準(zhǔn)停藥,復(fù)發(fā)率仍較高(表1)[28-31]。

        停藥后復(fù)發(fā)率的高低與鞏固治療時間、判斷復(fù)發(fā)的標(biāo)準(zhǔn)和停藥后隨訪時間有關(guān)[38-43]。鞏固治療時間越長,復(fù)發(fā)率越低[35-36]。Jiang等[35]報道,鞏固治療≥18個月者的復(fù)發(fā)率(15.4%)明顯低于鞏固治療<18個月者(47.5%)。

        表1 CHB患者NAs治療停藥后復(fù)發(fā)率Table 1 Recurrence rate after NAs treatment arrested in CHB patients

        關(guān)于判斷復(fù)發(fā)的標(biāo)準(zhǔn),各家報道不一。多數(shù)報道以病毒學(xué)復(fù)發(fā)為標(biāo)準(zhǔn),但其標(biāo)準(zhǔn)也不一致,有的以停藥后血清中又檢測到HBV DNA為復(fù)發(fā);有的以停藥后血清HBV DNA升高≥1000拷貝/ml為復(fù)發(fā);也有以停藥后血清HBV DNA升高≥2000 IU/ml為復(fù)發(fā)。少數(shù)報道以臨床復(fù)發(fā)為標(biāo)準(zhǔn),但其標(biāo)準(zhǔn)也各異,有的以停藥后血清HBV DNA升高≥10 000拷貝/ml及ALT≥2倍正常值上限為臨床復(fù)發(fā);有的以停藥后血清HBV DNA≥2000 IU/ml,ALT升高≥2倍正常值上限為臨床復(fù)發(fā)。在停藥標(biāo)準(zhǔn)、鞏固治療時間和隨訪時間相同的情況下,一般病毒學(xué)復(fù)發(fā)率高于臨床復(fù)發(fā)率。

        停藥后隨訪時間越長,復(fù)發(fā)率越高。Liu等[43]報道,停藥后隨訪至6、12、24、36、48和60個月,累計病毒學(xué)復(fù)發(fā)率(血清HBVDNA≥10 000拷貝/ml)分別為26.2%、43.6%、49.7%、52.1%、56.1%和56.1%,隨隨訪時間延長,復(fù)發(fā)率升高。

        2 NAs長期治療的臨床獲益

        2.1 改善肝臟組織壞死炎癥及逆轉(zhuǎn)纖維化和肝硬化應(yīng)用NAs長期治療可改善CHB患者的肝組織壞死炎癥和纖維化逆轉(zhuǎn)。Dienstag等[44]用LAM治療CHB患者,隨訪至中位治療時間3.5年,56%患者肝組織壞死炎癥改善,33%無改變。Xu等[45]應(yīng)用LAM治療CHB至10年,19例患者有基線和10年時配對的肝活檢標(biāo)本,結(jié)果21%(4/19)肝纖維化/肝硬化完全逆轉(zhuǎn),47%(9/19)Ishak評分改善,32%(6/19)肝纖維化無改善。Hadziyannis等[46]用ADV治療70例HBeAg陰性CHB患者,治療至192周或240周時,分別有86%和83%患者肝組織壞死炎癥改善,73%和75%患者纖維化改善。Marcellin等[47]用ADV治療171例HBeAg陽性CHB患者,其中15例有基線和隨訪5年的配對肝活檢資料,67%患者肝組織壞死炎癥改善,60%患者纖維化改善。Liaw[48]報道,641例接受TDF治療的患者中,489例(76%)完成240周治療,348例(54%)有基線和240周時肝活檢結(jié)果,該348例患者中,304例(87%)肝組織學(xué)改善,176例(51%)240周時發(fā)生肝纖維化逆轉(zhuǎn)(P<0.000 1);96例(28%)基線為肝硬化(Ishak評分為5或6)患者中,71例(74%)患者于240周時肝活檢Ishak評分下降≥1,表示肝硬化逆轉(zhuǎn)。Schiff等[49]報道,10例進(jìn)展性肝纖維化或肝硬化患者(基線Ishak評分4),經(jīng)ETV累計治療6年(范圍267~297周),所有10例患者的肝臟組織學(xué)均改善,Ishak肝纖維化評分和Knodell肝組織壞死炎癥評分較基線分別平均下降2.2和7.6分,4例基線為肝硬化患者的Ishak評分均降至4或以下。

        2.2 逆轉(zhuǎn)或緩解失代償一項(xiàng)隨機(jī)非盲研究[50]報道,195例失代償肝硬化患者應(yīng)用ETV 1 mg/d或 ADV 10mg/d治療,48周時病毒抑制率分別為57%和20%,MELD評分下降為2.6和1.7。一項(xiàng)雙盲研究入組112例CHB失代償患者,隨機(jī)分為TDF組(45例)、TDF和恩曲他濱(Truvada)聯(lián)合治療組(45例)及ETV組(22例),治療48周后,3組應(yīng)答率相同,病毒學(xué)應(yīng)答率(HBV DNA<400拷貝/ml)分別為71%、88%和73%;ALT復(fù)常率分別為57%、76%和55%;3組MELD中位評分和CTP評分下降2分及以上者的比例相同[51]。

        2.3 延緩或阻止肝病進(jìn)展LAM長期治療(中位治療時間89.9個月)142例HBeAg陽性但無肝硬化患者,其累計肝硬化發(fā)生率明顯低于124例未治療的HBeAg陽性對照組[52]。一項(xiàng)雙盲隨機(jī)對照研究[53]表明,用LAM長期治療(中位治療時間32.4個月)436例肝硬化患者,與未治療的215例對照組比較,治療組和對照組的肝病進(jìn)展分別為7.8%(34/436)和17.7%(38/215)(P=0.001)。VIRGIL研究報道[54],ETV中位治療時間20個月(范圍11~32個月)且出現(xiàn)病毒學(xué)應(yīng)答(血清HBV DNA<80 IU/ml)的CHB患者,發(fā)生失代償?shù)母怕氏陆?1%。

        2.4 預(yù)防和減少HCC的發(fā)生多項(xiàng)研究報道,應(yīng)用LAM長期治療CHB患者可明顯降低HCC發(fā)生率[55-58]。Su等[59]報道,666例接受ETV單藥治療肝硬化患者為ETV組,621例未接受治療患者為對照組,在隨訪2.7年中,ETV組的HCC發(fā)生率為2.4%,對照組為5.2%(P=0.009),降低59%。Wu等[60]對中國臺灣健康保險研究數(shù)據(jù)庫(NHIRD)中1997年1月至2010年12月間CHB患者數(shù)據(jù)進(jìn)行回顧性分析,納入21 595例CHB患者,接受NAs治療至少3個月,為抗病毒治療組;另21 595例采用保肝藥物治療的患者作為對照組,結(jié)果抗病毒治療組7年HCC發(fā)生率顯著低于對照組(7.32%vs22.7%,P<0.001)。

        但也有一些研究報道,NAs長期治療對CHB患者的HCC發(fā)生率無影響[61-70],這可能與研究對象不同(如患者的種族、遺傳、年齡、性別、病期、基線HBV DNA和HBsAg水平、HBV基因型、CHB和肝癌家族史等構(gòu)成不同)、樣本量小、隨訪時間短等因素有關(guān)。如TDF治療6年的注冊研究報道,治療組的HCC年發(fā)生率為0.4%,與按REACH-B評分獲得的預(yù)期HCC發(fā)生率比較,最初5年TDF有效治療對HCC發(fā)生率并無影響,但5年后兩組的差異有統(tǒng)計學(xué)意義[71](圖2)。

        3 NAs長期治療應(yīng)注意的問題

        3.1 初治藥物選擇應(yīng)用低耐藥基因屏障的NAs如LAM長期治療,可產(chǎn)生較高的HBV耐藥突變率。發(fā)生耐藥突變的患者,特別是肝硬化患者更易發(fā)生疾病進(jìn)展,甚至死亡[53,55]。因此,亞太、歐洲和美國肝病學(xué)會的CHB管理共識或指南均推薦,NAs初治患者應(yīng)選擇強(qiáng)效、高耐藥基因屏障的藥物,即ETV和TDF作為優(yōu)選或一線單藥治療[8-10]。我國CHB防治指南也建議:“如條件允許,初始治療時宜選用抗病毒作用強(qiáng)和耐藥發(fā)生率低的藥物”[7]。

        圖2 應(yīng)用TDF單藥治療初治的有或無代償期肝硬化患者7年觀察和預(yù)測的累計HCC發(fā)生率Fiture 2 HCC incidence rate by 7-year observed and predicted of patientsw ith or w ithout com pensatory cirrhosis after initial TDF along

        3.2 依從性患者對長期治療的依從性不僅與耐藥發(fā)生有關(guān),還與抗病毒治療的療效有關(guān)。Hilleret等[72]報道,用ADV治療至2年時,依從性差的患者血清HBV DNA檢測不到的患者比例明顯低于依從性好的患者(21%vs42%,P<0.01)。與依從性好的患者比較,依從性差的患者的HBeAg陽性率、血清HBV DNA載量和病毒學(xué)突破率均較高[73-75]。

        據(jù)調(diào)查,歐美一些國家CHB患者對NAs治療的依從性約50%[74-77]。據(jù)對我國110個城市741家醫(yī)院的684名肝病相關(guān)臨床醫(yī)師其診治的LAM經(jīng)治CHB患者調(diào)查結(jié)果表明,自行停藥換藥者為47%~49%,其中治療1年內(nèi)自行停藥換藥者占19%~24%[78]。葉麗華等[79]報道,未遵醫(yī)囑用藥的患者占16.7%。因此,加強(qiáng)對患者抗病毒治療依從性的教育刻不容緩。

        3.3 耐藥監(jiān)測耐藥是NAs長期治療CHB所面臨的主要問題之一。耐藥可引發(fā)病毒學(xué)突破、生化學(xué)突破、病毒學(xué)反彈及肝炎發(fā)作,少數(shù)患者可出現(xiàn)肝臟失代償、急性肝衰竭,甚至死亡[80]。臨床試驗(yàn)數(shù)據(jù)表明,LAM、ADV和ETV治療1年耐藥突變率分別為20.0%、0和0;治療4年耐藥突變率分別為64.7%、25.7%和0.9%[79]。ADV治療HBeAg陽性CHB患者5年累計耐藥突變率為14.6%[81]。LdT單藥治療104周耐藥突變率為25.8%[82]。根據(jù)已發(fā)表的數(shù)據(jù),TDF治療5年尚未發(fā)現(xiàn)對其耐藥的CHB病例。關(guān)于耐藥監(jiān)測,請見參考文獻(xiàn)[83]。

        3.4 安全性由于NAs主要從腎臟排泄,因此,在應(yīng)用NAs前,應(yīng)檢測患者血清肌酐水平、計算肌酐清除率和估算腎小球?yàn)V過率(eGFR),如肌酐清除率或eGFR<50ml/min,則應(yīng)調(diào)整NAs治療劑量。此外,還應(yīng)對失代償期肝病、肝硬化、肌酐清除率<60ml/min、同時合并高血壓、蛋白尿、糖尿病、活動性腎小球腎炎、實(shí)體器官移植等患者進(jìn)行腎臟損害的風(fēng)險評估。

        NAs有可能導(dǎo)致腎功能下降[84]。ADV連續(xù)使用4~5年,3%的患者出現(xiàn)腎毒性[10]。有研究報道,ADV和TDF治療可導(dǎo)致Fanconi綜合征、腎功能不全、低磷性骨病和骨密度下降等[85-88]。因此,對用ADV或TDF治療的患者,應(yīng)定期監(jiān)測血肌酐并計算肌酐清除率、血磷和骨密度等。

        GLOBE研究[89]表明,接受LdT治療2年的患者中,有3或4級肌酸激酶(CK)升高(7倍正常值上限)者的比例為12.9%,并有2例出現(xiàn)有癥狀的肌病,如肌疼、肌無力等。Lai等[90]報道,LdT治療52周時CK升高率為7.5%(51/680),1例于LdT治療11個月后發(fā)生肌病。我國任江波等[91]報道,患者的CK升高率與其LdT治療時間長短有關(guān),治療1年者為61.2%,治療5年者為95.9%;CK升高的嚴(yán)重程度也與治療時間長短有關(guān),治療1年時CK 3~4級升高率為4.1%,5年升至14.3%。因此,對接受LdT治療的患者,應(yīng)監(jiān)測血清CK變化和橫紋肌疾病的發(fā)生。

        4 存在問題與未來研究課題

        4.1 提高抗病毒藥物的可及性由于受藥物價格、報銷政策、認(rèn)知水平及支付能力等因素的制約,我國仍有許多CHB患者未接受抗病毒治療;已接受抗病毒治療的患者,也有許多未采用國內(nèi)外CHB管理共識或指南所推薦的高效低耐藥抗病毒藥物治療。因此,應(yīng)通過政府部門、學(xué)術(shù)界、企業(yè)界和民間團(tuán)體之間的良性互動,建立和完善藥物審批及價格形成機(jī)制,充分發(fā)揮政府帶量采購和報銷政策對降低價格和優(yōu)先選擇藥物的強(qiáng)大杠桿作用,以公共衛(wèi)生策略來推動CHB的臨床治療,盡早實(shí)現(xiàn)政府、企業(yè)、患方和醫(yī)方均受益的多贏結(jié)局。

        4.2 制訂行業(yè)規(guī)范,進(jìn)一步提高我國CHB診治水平我國目前有相當(dāng)一部分患者未按現(xiàn)行CHB管理共識或指南的建議進(jìn)行規(guī)范的抗病毒治療和定期隨訪。因此,應(yīng)該充分發(fā)揮專業(yè)團(tuán)體的學(xué)術(shù)引領(lǐng)作用和有關(guān)政府部門的規(guī)范管理功能,進(jìn)一步加大對CHB管理共識或指南的宣傳推廣力度,并制訂具有可操作性且有一定強(qiáng)制性的行業(yè)規(guī)范,提高我國CHB的診治水平和整體衛(wèi)生經(jīng)濟(jì)效益。

        4.3 研究更可靠的NAs長期治療CHB的停藥標(biāo)準(zhǔn)和監(jiān)測指標(biāo)國內(nèi)外研究報道,即使按照現(xiàn)行的CHB管理共識或指南建議的標(biāo)準(zhǔn)停藥[7-10],停藥后的復(fù)發(fā)率仍高達(dá)50%~70%[21]。因此,有必要研究NAs長期治療CHB更可靠的停藥標(biāo)準(zhǔn)和判斷停藥后復(fù)發(fā)與否的監(jiān)測指標(biāo),如定量HBsAg水平和特異性免疫學(xué)指標(biāo)等[21,92],將停藥后復(fù)發(fā)率降至更低水平。

        4.4 研究現(xiàn)有NAs更有效的長期治療策略有部分肝硬化患者經(jīng)過長期治療后發(fā)生了逆轉(zhuǎn),他們有可能停藥;但還有相當(dāng)一部分患者雖經(jīng)長期治療有所逆轉(zhuǎn),仍有嚴(yán)重的肝纖維化,可能須要終身治療。對肝硬化患者的治療策略值得進(jìn)一步研究。

        Ning等[93]報道,應(yīng)用ETV治療達(dá)到病毒學(xué)抑制的CHB患者,改用聚乙二醇干擾素-2a(Peg IFN-2a)治療,可明顯提高HBeAg血清學(xué)轉(zhuǎn)換率和HBsAg消失率。但也有不同報道[94]。至今關(guān)于NAs與Peg IFN聯(lián)合或序貫治療的研究還較少,尚須進(jìn)行多中心隨機(jī)對照研究證實(shí)。

        4.5 研究NAs長期治療的安全性目前用于CHB治療的NAs中,LAM已有16年歷史,最后被批準(zhǔn)上市的TDF也有7年臨床應(yīng)用歷史。國內(nèi)外臨床研究表明,NAs是安全的。但更長時期的NAs單藥或2種NAs聯(lián)合治療,以及特殊人群,如肝硬化失代償、長期服用他汀類藥物的患者等應(yīng)用NAs長期治療的安全性問題,有待進(jìn)一步觀察和評價。

        參與討論的專家(按姓氏拼音排序):陳成偉、陳士俊、陳永平、成軍、程明亮、竇曉光、段鐘平、高志良、侯金林、賈繼東、江家驥、李杰、李蘭娟、李彤、魯鳳民、茅益民、繆曉輝、寧琴、??∑妗⑷渭t、孫永濤、譚德明、唐紅、唐小平、萬謨彬、王貴強(qiáng)、王豪、王慧芬、王宇明、魏來、翁心華、謝青、尤紅、張文宏、張欣欣、莊輝

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        Long-term NAs treatment of chronic hepatitis B

        Experts Attending the Discussion on Long-treatment of Chronic Hepatitis B

        .ZHUANG Hui,E-mail:zhuangbmu@126.com;WENG Xin-hua,E-mail:xinhua_weng@fudan.edu.cn

        Nucleos(t)ide analogs(NAs)have been successfully used for treatmentof chronic hepatitis B.Hepatitis B virus(HBV) replication is now recognized as the key driver of liver injury and disease progression,so the primary aim of treatment for chronic HBV infection is to maximize sustained suppression of HBV replication to undetectable levels.The long-term treatment has also been shown to achieve substantial histological improvement and regression of liver fibrosis or cirrhosis,and reduction of hepatocellular carcinoma.This paper has reviewed the necessity,clinical benefits and themanagement of long-term treatment for chronic hepatitis B.

        Hepatitis B,chronic;nucleoside and nucleotide analogs;long-term treatment;management

        R512.62

        A

        1007-8134(2014)06-0321-07

        100191,北京大學(xué)醫(yī)學(xué)部病原生物學(xué)系和感染病中心(莊輝),E-mail:zhuangbmu@126.com;200040上海,復(fù)旦大學(xué)附屬華山醫(yī)院感染科(翁心華),E-mail:xinhua_weng@fudan.edu.cn

        (2014-01-20收稿 2014-05-06修回)

        (責(zé)任編委 李軍 本文編輯 陳玉琪)

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